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.J
Consum
erV
OL
. 1
8 N
O.
1F
EB
RU
AR
Y 1
98
4
Th
e H
ors
es
ho
e C
rab
: A
Tru
e B
lue
blo
od
6Scientists bleed horseshoe crabs for their blue-coloredblood, w
hich is used to detect bacteria in drugs anddevices. The process leaves questions about the crab'ssu
rvival.
Th
e P
ituita
ry:
A K
ern
el
Of
Wo
nd
er
10
When nature m
ade this pea-sized gland, she gave itpum
pkin-sized responsibilities,
including accountability
inthe areas of birth, grow
th, aging and everyday bodyfunctioning.
Th
ere
's R
ejo
icin
g O
ve
r R
e-J
oin
ts 1
4R
eplacement joints for hips, knees, elbow
s, ankles, toes,shoulders
and fingers
are becom
ing com
monplace,
thanksto new
materials, sealants and surgery techniques.
On
Ma
kin
g F
oo
d L
ab
els
Tru
thfu
l 2
2Food products m
ay not always contain w
hat the labelsclaim
because of economic deception. Such cheating keeps
FDA
officials on
guard.
Hu
ng
er
Is M
ore
Th
an
An
Em
pty
Sto
ma
ch
26
The craving for food is not always w
hat makes a person
want
to eat
or determ
ines that
he or
she has
eaten enough.
Other factors m
ay be involved, including some appetite
control centers
in the
brain.
Ad
vic
e O
n V
ag
ina
l P
rod
uc
ts 3
2A panel of outside experts has som
e suggestions aboutusing products to cleanse and care for the vagina.
Updates
Co
ns
um
er
Fo
rum
Investigators' R
eports
2 T
he
No
teb
oo
k 4
3
35
Su
mm
arie
s o
f C
ou
rt A
ctio
ns
44
38
Putting the squeeze on those who practice econom
ic deception in foodlabeling is a responsibility of FD
A, and orange Juice processing is onefield
where
such deception
is difficult
to detect.
How
FD
A keeps
abreastof econom
ic cheating in food labeling is treated in an article. On M
akingFood
Labels Truthful,
starting on
page 22.
Margaret
M.
Heckler
Secretary, U
.S. D
epartment
ofH
ea
lth a
nd
Hu
ma
n S
erv
ice
.s
Roger
W.
Miller/E
ditor
Harold
C.
Hopkins/E
ditorial D
irector
.lesse R
. N
ichols/Art
Director
Cover
Design:
Zeb R
ogerson
FDA Consumer / February 1984 /i.̂
updates
Patient
Leaflets P
roliferate
Providing patients
with
information
about the
drugs they take has become a popular activity, and
the number of leaflets available is increasing by
leaps and bounds.The
Am
erican M
edical A
ssociation announced
last Novem
ber that it had published 20 new Pa
tient Medication Instruction (PM
I) sheets, bringingto
60 the
total in
its series
of inform
ation sheets
on therapeutic drugs. The list now includes over-
the-counter as well as prescription products.The PM
I sheets were developed by AM
A forphysicians to give to patients at the tim
e a drug isprescribed. Am
ong the drugs covered by the newest PM
Is are phenothiazines, tricyclic antidepressants, antihistam
ines, propoxyphene (Darvon),acetam
inophen, aspirin, potassium supplem
ents,a
nd
me
tho
trexa
te.
PMI sheets are bound 50 to a pad and cost $1
per pad.The Am
erican Association of
Retired
Personsand
National
Retired
Teachers Association
(AARP/N
RTA) Pharmacy Service now
has 55leaflets in its drug inform
ation program. The
leaflets cover more than 190 drugs, representing 80
percent of the drugs that the elderly take.C
alled M
edication Inform
ation Leaflets
forSeniors
(MILS),
the AAR
P/NR
TA leaflets
were
the first national voluntary effort to provide writ
ten drug information to consum
ers at the time a
prescription is filled. By the end of 1983som
ething in the neighborhood of 3 million
leaflets had been distributed, according to thePharm
acy Service. A mem
bership survey showedthat 90 percent of those responding found theleaflets useful and 76 percent said they keep themfo
r fu
ture
refe
ren
ce.
A new program
, launched in September 1983 by
the National Association of R
etail Druggists
(NAR
D),
involves Patient
Information
Leaflets(PILs) abstracted from
the United States Phar-
macopeial D
ispensing Information and its U
pdates. The 32 leaflets, to be provided by pharm
acists when prescriptions are filled, cover 200
drug entities, about 80 percent of the drugs
dispensed in
a com
munity
pharmacy.
The PIL sheet can be personalized for the individual patient. Type size is large and easilyreadable
by patients,
particularly the
elderly. And,the association points out in the Septem
ber 1983issue of the N
ARD
Journal, "the word 'phar
macist' appears five tim
es in the text, attesting tothe
pharmacist's
expertise."The leaflets cover single entities, such as
furosemide,
cimetidine,
allopurinol and
nitroglycerin, and families of drugs, including
beta-adrenergic blockers,
cephalosporins,phenothiazines and thyroids. Although the program
is relatively new, some 600,000 PILs had
been distributed to pharmacists by the end of
Novem
ber 1983.
Originally
intended for
NAR
Dm
embers only, the leaflets are now
available toother
pharmacists.
Cough Syrups M
ay Switch
FDA has proposed sw
itching two prescription
cough-suppressant drugs to nonprescription statusand sale. The drugs—
benzonatate andchlophedianol—
have been used safely for more
than 20 years.The change is part of a proposed standard for
over-the-counter (OTC) antitussives—
cough-reliefproducts—
published in the Oct. 19, 1983, Federal
Register. FD
A issued the proposed standard afterreview
ing the recomm
endations of the AdvisoryR
eview Panel on O
TC C
old, Cough, Allergy,
Bronchodilator, and Antiasthmatic D
rug Products.The panel was one of 17 non-governm
*ent advisorygroups assisting the agency in a m
assive review of
the safety and effectiveness of ingredients in allO
TC
drugs.Because the tw
o prescription drug ingredientsw
ere not reviewed by the panel, FD
A will not per
mit their O
TC m
arketing until public comm
ents onthe proposed standard have been evaluated and thesta
nd
ard
ha
s b
eco
me
fina
l.FD
A concurred with the panel that five ingre
dients already in nonprescription cough-cold products
are safe
and effective.
These are
dextrom
ethorphan and
dextromethorphan
2 /
February 1984
/ FD
A C
onsumer
hydrobromide and codeine, codeine phosphate and
codeine sulfate. (In many states codeine is a
prescription drug.)
Codeine-containing
productsshould have directions clearly stating that a doctorshould be consulted before giving the preparationto a child under the age of 6, according to FD
A'sproposed
standard.The agency also said that new
data proved camphor and m
enthol are safe and effective cough-relieving drugs. Previously, the panel said therew
as not enough evidence to show these ingredients
were effective. C
amphor and m
enthol are used inointm
ents rubbed
on the
chest, and
menthol
isalso used in throat lozenges.
FDA m
ade a number of changes in the labeling
for cough-relief products. One of them
is to allowthe product to be called a ''cough suppressant" or"antitussive
(cough suppressant)"
instead of
justan
"antitussive." M
anufacturers m
ay also
includein labeling a statem
ent that indicates an antitussivecan alleviate, decrease or suppress a cough "tohelp you get to sleep."
The original panel report was published in
September 1976 (see "The C
omm
on Cold: R
eliefBut N
o Cure" in the Septem
ber 1976 issue ofFD
A Consum
er), FDA is issuing the proposed
standards based on this report in segments. The
antitussive drug standard is the third to bepublished. Previously issued w
ere proposed standards
for anticholinergic,
expectorant and
bron-chodilator
drug products
(see "D
rug Standards
Of
fered" in the Updates section of FD
A Consum
er,O
ctober 1982, and "Help for W
heezers" in Up
dates, FD
A C
onsumer,
February 1983.
"The C
omm
on
Co
ld:
Re
lief
Bu
t N
o C
ure
" is
still a
vaila
ble
as a reprint. Copies m
ay be obtained by writing to
FDA
, H
FE-88,
5600 Fishers
Lane, R
ockville, M
d.20857).
Starch Blockers
On
Losing Streak
Ruling for FD
A and against the General N
utrition C
orp. and nine other promoters of starch
blockers, a federal judge in New
York concludedthat "starchblocker pills are declared drugs underthe [Food, D
rug, and Cosm
etic] Act. Their seizure
is therefore
permissible."
The other plaintiffs in the case were Am
ericanH
ealth P
roducts C
o. Inc.,
General
Nutrition
Center
Inc., M
elva N
atural P
roducts Inc.,
Nature's
Bounty Inc.,
Nutrition
Headquarters
Inc., P
hoenix Laboratories
Inc., R
-Kane
Products
Inc., and
Sunrise
Chem
ical Inc.
The ruling
by U
.S. D
istrict Judge Abraham
D
.S
ofa
er
of
the
So
uth
ern
District
of
Ne
w
Yo
rk w
as
the third federal court opinion that has held starchblockers to be unapproved new
drugs. The New
York court's
opinion can
be appealed
within
60days.
Starch blocker tablets were the dietary fad of a
year or so ago. Their manufacturers claim
ed thatthey
prevented, or
"blocked," the
absorption of
starch by the body. This, they said, would allow
aperson to eat w
hatever starchy foods are desiredw
ithout w
eight gain.
FDA
maintained
that since
starch blockers
areclaim
ed to alter a normal function of the body
they should be regulated as drugs, not foods. No
investigational new
drug
(IND
) application
or N
ewD
rug Application
(ND
A) has
been filed
with
FDA
for any starch blocker. (An IND
is an applicationto do clinical testing of a new
drug, and an ND
Ais an application for approval of a new
drug.)Three
independent clinical
trials have
concludedth
at
starch
blo
ckers
do
n't
wo
rk.Betw
een September 1982 and m
id-Novem
ber1983,
FDA
seized starch
blockers w
orth m
ore than
$3.5 m
illion retail.
One seizure took place this past sum
mer, w
henthe
Connecticut
Departm
ent of
Consum
er Protec
tion reported starch blockers being sold in variousparts of the state. An FD
A investigator from the
East H
artford resident
post visited
General
Nutri
tion C
orp. stores
in W
aterbury, M
ilford, Trum
bull, Bridgeport,
Stamford
and Farm
ington.A
t th
e six
loca
tion
s o
f th
is n
atio
na
l h
ea
lth fo
od
chain, the
investigator found
a total
of 1,662
bottles (30 tablets each) and 271 bottles (100 tabletseach). H
e also found a small surprise: 115 shakers
of a powdered concentrate labeled "Starch Blocker
Sprinkles," a
new
form
of the
illegal product. The
label on the shakers said that using the sprinkles
FDA
Consum
er /
February 1984
/ 3
on food would *'put a little fun back in your
die
t."The fun aspect of starch blockers w
as lost onthe investigator. H
e returned to the GN
C locations
with a U
.S. marshal, w
ho seized the several stocksof tablets and sprinkles, valued at $25,000, forb
uria
l in
a la
nd
fill.C
anada, Britain, Australia,
Israel and
West
Ger
many also have taken regulatory action against
starch
blo
ckers.
In a separate action, on Oct. 31, a U
.S. PostalService adm
inistrative law judge found that
General
Nutrition
Corp.
of Pittsburgh
was
engaged in conducting ''a schem
e for obtainingm
oney through the mails by m
eans of false representations regarding the product StarchBlock.
..." Specifically,
the product
ads w
erefound
to be
false because
starch blockers
are in
effective for preventing the digestion of starch.G
NC
's attorney has said the ruling will be
appealed.
Drug
Com
binations C
urbedTo curb abuse of over-the-counter drug products
being sold as if they were controlled substances or
''look-alike" drugs,
FDA
has declared
that the
following products w
ill no longer be allowed on
the
ma
rket:
• OTC
products labeled as stimulants that contain
anything other than caffeine as the active ingredient• O
TC products labeled for any purpose w
henthey contain as their only active ingredients combinations of caffeine and ephedrine (or pseudo-ephedrine),
caffeine and
phenylpropanolamine
(PPA), or
phenylpropanolamine
and ephedrine
(orpseudoephedrine).
FDA's decision, in the form
of an advisory opinion, w
as published in the Nov. 18, 1983, Federal
Register. In addition, the agency m
ailed letters tom
ore
tha
n 3
50
firms
ide
ntifie
d a
s m
an
ufa
cturers/distributors
of these
products advising
that,w
ith one exception, all of these products would be
subject to
regulatory action
imm
ediately if
notre
mo
ved
from
th
e m
arke
t.The only exception: products that contain caf
feine and phenylpropanolamine as their sole active
ingredients that are labeled only as appetite suppressants, diet aids, or diet aids/stim
ulants, andare m
anufactured or in the process of manufacture
before the Novem
ber date. These products have asignificant history of use for purposes other than"recreational use" and the agency thus w
ill allowm
anufacturers to use up existing stocks.(For
more
information
on such
look-alike drugs,
see "O
n The Trail O
f C
ounterfeit D
rugs" in
theD
ecember
1981-January 1982
FDA
Consum
er.)
Reprints
Available
Reprints are available of the articles "H
erbs AreO
ften M
ore Toxic
Than M
agical" and
"Using
Drugs
To Lift
That D
ark Veil
Of
Depression,"
both from
the
October
1983 issue
of FD
A C
onsum
er, and
of "W
ater: The
Num
ber O
neN
utrient," from
the
Novem
ber 1983
issue.In
addition, "H
ow
To Talk
To (And
Listen To)
Your Pharm
acist," from
the
April 1980
FDA
Consum
er, has been updated and reissued as areprint. Single copies of these reprints can be obtained
from
the Food
and D
rug Adm
inistration,H
FE-88,
5600 Fishers
Lane, R
ockville, M
d. 20857.
Multiple
copies are
available from
FD
A, H
FW-40,
at the Rockville address. C
opies of reprints area
lso a
vaila
ble
from
F
DA
's co
nsu
me
r a
ffairs
of
ficers, w
ho are
located in
30 cities
around the
co
un
try.
Quaaludes
Discontinued
Lemm
on Co. of Sellersville, Pa., the only legal
manufacturer
of m
ethaqualone (or
Quaalude)
inthe
United
States,
halted m
anufacture of
the drug
and stopped
distribution Jan.
31. W
hile m
aintaining that the sedative-hypnotic is safe and effective,the
company
acknowledged
that it
had becom
ew
idely abused,
particularly by
so-called "stress
clinics."
Le
mm
on
said
it a
ba
nd
on
ed
ma
nu
factu
re o
f th
edrug
after discussions
with
FDA
and the
Drug
En
force
me
nt
Ad
min
istratio
n.
Methaqualone is abused as a "dow
ner" and can
4 /
February 1984
/ FD
A C
onsumer
be fatal
when
mixed
with
alcohol. B
ecause of
this
potential for abuse, in 1973 the drug was placed in
Schedule
II of
the C
ontrolled S
ubstances A
ct, the
most restricted category for drugs w
ith an acceptedm
edical use. FDA has steadily reduced its recom
mendation
to D
EA for
the m
anufacturing quota
of the drug, which is based on its anticipated
legitimate
use. Prescriptions
declined from
m
orethan
4 m
illion in
1973 to
less than
300,000 in
1982, a reduction of more than 90 percent, in
cluding those
written
in ''stress
clinics."FD
A told a congressional subcomm
ittee lastO
ctober that
its recom
mended
manufacturing
quota might w
ell be reduced further in coming
months.
Legislation subsequently
reported by
theH
ouse Com
mittee on Energy and C
omm
ercew
ould have
outlawed
methaqualone.
States Save On D
rugs
Twenty-four
states and
the D
istrict of
Colum
biasaved m
illions of dollars on drugs in 1983 by usingcom
puterized data
from
FDA
about the
trackrecords of prospective drug suppliers.
The information helped the states buy drugs for
their hospitals and clinics at lower prices by identi
fying those low bidders w
ho are reliable suppliersof
quality products.
In this quality assurance program, w
hich beganw
ith a pilot study involving five states in 1981,FD
A provides a monthly list of acceptable sources
for approxim
ately 3,500
drug products.
The infor
mation com
es from inspections of drug m
anufacturers,
laboratory tests,
compliance
records, and
drug m
arketing applications.
Similar
data have
been provided to the Defense D
epartment and
other federal purchasers of drugs since 1965.FD
A also provides state personnel with training
on videotape
about how
to
interpret the
data, sav
ing the
cost of
travel to
FDA
headquarters.State
users say
the program
:• increases com
petition for the large quantities ofdrugs
they purchase
• provides
objective data
for contracting
decisionsinvolving
multiple
bidders• gives reliable inform
ation about a low bidder's
acceptabilityN
ew York state alone reports savings from
theprogram
in excess of 1 million dollars a year.
States participating
in the
program
are Arizona,Arkansas,
California,
Delaw
are, Florida,
Georgia,
Louisiana, M
aryland, M
ichigan, M
innesota,M
ississippi, M
issouri, N
ew
Jersey, N
ew
York,O
regon, Pennsylvania,
Rhode
Island, Tennessee,
Texas, Virginia,
Washington,
West
Virginia,W
isconsin, W
yoming,
and the
District
of C
olumbia.
In addition,
the C
anadian governm
ent'sH
ea
lth P
rote
ction
Bra
nch
rece
ives
the
FD
A d
ata
.Because the quality assurance inform
ation isalready com
puterized and can be printed anddistributed at virtually no cost, there is no chargeto states that receive it. All states are eligible toparticipate
in the
program.
Advice
On
Tampons
Wo
me
n w
ill so
on
rece
ive a
dvice
on
the
ou
tside
of all tampon packages urging them
to use theleast absorbent tam
pon that meets their needs.
Since 1982, FDA has required that this advice
be part of the information on toxic shock syn
drome (TSS) provided to tam
pon users, but itgenerally has been included inside the box as partof a package insert. Although tam
pon use ingeneral has been associated w
ith TSS, one studyhas also suggested that the risk of getting TSS iseven greater w
ith higher absorbency tampons.
Because of
concern that
manufacturers'
promo
tion of
their products
as providing
greater protec
tion and high absorbency could obscure the advicesuggesting use of the least absorbent tam
pon possible, the N
ational Center for D
evices andR
adiological H
ealth w
rote to
all m
anufacturers in
June 1983 recomm
ending that the advisorym
essage be put on the outside of the package.M
an
ufa
cture
rs w
ere
aske
d to
info
rm
the
cen
ter
of any plans to adopt the additional labeling. Bythe end of August all had agreed to adopt the outside labeling, and tw
o stated they had alreadydone
so before
receiving the
center's request.
FDA
Consum
er /
February 1984
/ 5
The Horseshoe Crab:A Thie Blueblood
by David R. Zimmerman
Boys from a nearby summer camp race along thebeach and into the shallow waters of St. Joseph Bay,o n F l o r i d a ' s G u l f C o a s t . U n d e r t h e d i r e c t i o n o f m a r i n e
biologist Anne Rudloe, Ph.D., of Florida State University, they are hunting scientific treasure: 10,000 numerically coded yellow plastic markers.
Each tag is attached to the tough, brown, horny shellof one of the bay's resident horseshoe crabs. Severalm o n t h s e a r l i e r t w o d o z e n a m a t e u r s c i e n t i s t s f r o m t h e
nonprofit Earthwatch organization caught and tagged theanimals, using electric hand drills to make anchor holes.B l o o d w a s e x t r a c t e d f r o m a b o u t h a l f o f t h e a n i m a l s a n dnoted on the appropriate tags. Then all the animals wereturned loose into the water again. The young campersnow are trying to recapture them for a reward of$1 per tag.
The aim of Dr. Rudloe's tag game: to find out if therecent heavy exploitation of these ancient armoredc r e a t u r e s i s a t h r e a t t o t h e i r s u r v i v a l . W h a t c o n c e r n s h e ris the rush of biomedical scientists and drug manufacturers to use the horseshoe crab to make life-savinghuman drug products.
The blood of the horseshoe crab was found, in the1960s, to be highly valuable because it reacts with, andso can be used to detect, bacterial endotoxin, a dangerous poison produced by some infectious bacteria that canbring on fever, pain, inflammation, shock—and somet i m e s d e a t h .
A s u b s ta n c e i n t h i s b l o o d a l s o r e a c t s w i t h t h e r e d a n dwhite cells in human blood, particularly the cancerouswhite cells of some leukemia patients. One day it may beused for diagnosing this illness.
In their forays into the surf, the collectors capturehorseshoe crabs measuring almost a foot across the thickfrontal helmet, through whieh the animal peers out at itsworld with seven eyes, set in four concealed peekholes.M a t u r e c r a b s — s o m e a s o l d a s t h e c o l l e c t o r s — c r a w lashore on summer high tides to deposit their eggs in thesand. They spend most of their lives in the nearbyshallows, going deeper in winter. Oddly, all four horse
shoe crab species inhabit only the eastern edges of thec o n t i n e n t a l l a n d m a s s e s o f N o r t h A m e r i c a a n d A s i a . T h e
single North American species, Limulus polyphemus, isf o u n d f r o m M a i n e t o Y u c a t a n .
The horseshoe crab is not a crab at all, but belongs tothe spider elass, Arachnida. It appears to be most closelyrelated to scorpions—though its tail is stingless—and toancient trilobites, whose form it recapitulates in thelarval stage.
Horseshoe crabs originated some 400 million years ago."It's an animal that's been made to stay around," saysEllas Cohen, Ph.D., an immunologist at the RoswellPark Memorial Inst i tute in Buffalo, N.Y. Cohen hasbeen a leader in biomedieal research involving the animaland in efforts to protect this unusual creature.
The horseshoe crab may fare better than the owlmonkey, the rhesus monkey and the chimpanzee, whichhave become subjects of conflict between the laboratorys c i e n t i s t s w h o u s e t h e m a n d e n v i r o n m e n t a l s c i e n t i s t s w h ostudy them in the wild and try to protect them. Manyhorseshoe crab users, like Cohen, also are interested inconserving the species. Dr. Rudloe's study is funded byFDA, which regulates medical products made with theanimal's blood. She has been encouraged by drugcompanies, who hope to produce horseshoe crab bloodproducts on a continuing basis.
To obtain the blood, commercial collectors place theanimal on a rack, push a hypodermic needle into thehorseshoe crab's heart, attach a tube, then collect theblood that drains slowly out by gravity in a sterile container. The blood has a striking royal blue hue becauseits oxygen-carrying molecule, hemocyanin, containscopper instead of iron (which gives red blood its color).Depending on the animal's size, it will give up one toseven ounces of blood in this way. The collectors andtheir drug company buyers are reluctant to discuss theprices paid for the blood.
"You're dealing with big money," one scientist says."There are people who've made hundreds of thousandso f d o l l a r s w i t h t h e b l o o d o f t h i s a n i m a l . "
F D A C o n s u m e r / F e b r u a r y 1 9 8 4 / 7
But to Dr. Rudloe, the more basic question is; Howharmful to the horseshoe crab is this bloodletting?
"They don't seem to react too badly," she says."When we take them out of the racks, they move aboutfairly vigorously." FDA, she says, requires that bledcrabs be returned to salt water within 72 hours and, asfar as anyone knows, most survive their blood loss. Butno one knows for sure, and Rudloe's study is the firstattempt to assess their recovery—or lack of it—in ascientific way.
She and her Earthwatch assistants bled 5,000, or abouthalf, of the crabs they caught. Some 60 gallons of theblood was donated to Dr. Cohen and other researchers.The other 5,000 crabs were not bled. Now, with the helpof boys from Camp Nautilus, and fishermen, shrimpers,and others on the bay, Rudloe is retrieving all the tagsshe can, to see if she will get fewer back from bledhorseshoe crabs than from the unbled ones.
Over two summers the collectors retrieved 1,582 of the10,062 tags, or roughly one tag in every six. The returnrate was about 10 percent lower for the crabs that hadbeen bled than for the unbled control animals, whichindicates that bleeding does kill some crabs.
The difference is "just barely" significant statistically.Dr. Rudloe says, adding, "not really enough to warrantanything drastic in the way of changing the harvestprocedures." Rudloe says she bases this conclusion oncomparisons with other commercial fisheries, in which ashort-term 10 percent reduction in population due tofishing does not seriously threaten the population'sex i s tence .
The gravity bleeding method thus may cause littleharm. But Rudloe has heard rumors that some collectorsare trying to obtain more blood by bleeding the animalswith vacuum pumps—which could be lethal. Worse, abiomedical researcher in New England suspects thattruckloads of horseshoe crabs are being carried inland forbleeding. He thinks it unlikely that they are returned tothe sea.
"They are being shipped by the thousands to companies that are using them," says blood specialist JackLevin. Levin is a doctor at Johns Hopkins University inBaltimore who studies horseshoe crabs each summer atthe Marine Biological Laboratory in Woods Hole, Mass.He says that the laboratory's collectors once could find500 large animals in a day along one Cape Cod beach.Today they are lucky to find 50. He blames bloodcollectors. But around Florida, Rudloe says, no seriouspopulation declines have been documented, or evenobserved, although there are reports of local declines inMobile Bay, and other places, declines that predate thedrug companies' interest in these animals.
Outside the biomedical realm, horseshoe crabs havefew human uses. Most people shun them as food, although the Thais eat their eggs. American Indians once
8 / F e b r u a r y 1 9 8 4 / F D A C o n s u m e r
used the sharp tails for spearheads; eel fishermen nowcrush them to bait their traps; shell fishermen destroythem as a competitive threat. But Dr. Levin reckons theseare minor depredations when compared to bloodlettingfo r sc ience and med ic ine .
Although information is sparse, Rudloe cites a recentdrug industry estimate that 30,000 horseshoe crabs arebled each year along the Eastern Seaboard. This could bea tiny number, among uncounted millions. But thecollectors certainly reach for the larger animals, whichare the breeders. Since it's possible that horseshoe crabsdon't begin reproducing until they are 5 to 10 yearsold—scientists simply don't know for sure—the loss of arelatively few mature ones could compromise thepopulation as a whole.
Industrially polluted water appears to kill horseshoecrabs. But the very traits that make the animal medicallyvaluable also protect it against most pollutants, and itcontinues to thrive in sewage-laden harbors of both theUnited States and Japan. In fact, the species' internalsystem of defense against invading bacteria is impressive.
The species needs strong antibacterial defenses, Rudloebelieves, because the shallow bay waters it frequentscontain much decaying matter and bacterial scum. Yet,horseshoe crabs lack an immune system, the multi-targeting defense method that allows modern animals toproduce antibodies directed at specific bacterial speciesand many—perhaps millions—of other menacing alienmolecules. By contrast, the horseshoe crab's primitive butextremely potent defense system, like a cannon fixed inconcrete, seeks out a handful of key biochemical molecules that are constituents of most bacteria that mayi n f e c t t h e m .
It is this remarkable self-protective method that has socaptivated biomedical scientists. Here is how the self-protection system works:
The principal protector of the horseshoe crab's internalenvironment is a primitive white blood cell called theamebocyte. Like the free-living amebas for which it isnamed, it appears self-directed as it perambulates the bloodstream in search of endotoxin-producing bacterial invaders, including coliforms and other fecal bacteria. Whenit finds such a bacterium, the amebocyte releases anenzyme and a clotting substance, which reacts to transform the liquid blood around the bacterium into a stickygel. The bacterium is immobilized and dies, like a tiger ina tar pit. Usually only a tiny bit of gel is formed, but ina massive bacterial infection, much of a horseshoe crab'sblood turns to jelly—and the animal may die as a result.
The active ingredients in this response can be extractedfrom the amebocytes; the purified extract is called LAL,for limulus amebocyte lysate. LAL is incredibly sensitive:It will detect as little as a billionth of a gram ofendotoxin in an eyedropper of water.
The present test for endotoxin requires injecting the
drug product into three to eight rabbits, then monitoringthem carefully for several hours to see if they becomefeverish. This is expensive and slow, and takes manyrabbits' lives. Blood specialist Levin decided that thesame information might be obtained more expeditiouslyusing horseshoe crab blood. Dr. Levin and his colleague.Dr. Frederick Bang, demonstrated that the crab's bloodc o u l d d e t e c t e n d o t o x i n .
Producers of LAL test kits freeze-dry the lysate ext r a c t . I t i s t h e n r e c o n s t i t u t e d w i t h s t e r i l e w a t e r a n d a d d e dto a sample of the drug or antibiotic or biologicalproduct to be tested or, in the case of a medical device,t o t h e s a l i n e s o l u t i o n i n w h i c h t h e d e v i c e h a s b e e nwashed. If endotoxin is present in the sample, a firm clotwill form. In this way manufacturers can withhold fromdistribution products contaminated with endotoxin levelst h a t c o u l d c a u s e s e r i o u s r e a c t i o n s .
'The test is now generally accepted as the best in vitro[test tube] assay for endotoxin," hematologist Peter A.Tomasulo, M.D., of the Milwaukee Blood Center, told aW o o d s H o l e c o n f e r e n c e o n h o r s e s h o e c r a b s a n d m e d i c i n eseveral years ago. "The test is simple and easy to learn,and requires no sophisticated equipment."
The test's principal users thus far are drug companies,for whom. Levin says, it provides a far more sensitiveendotoxin assay than the rabbits.
The LAL test also is being used to detect endotoxin inthe body fluid specimens withdrawn from critically illpatients, although FDA has not specifically approved itfor this purpose. It is particularly valuable. Levinreports, in the diagnosis of bacterial meningitis, a dangero u s i n f e c t i o n o f t h e b r a i n ' s m e m b r a n e s .
"Of all the infectious diseases we treat," Levin says,"meningitis is the one in which rapid diagnosis andtreatment are particularly critical. The difference betweentreating now and in six hours may be life and death."
The standard tests are complicated and time-consuming. Using the experimental LAL test and a single dropof spinal fluid from the patient, meningitis due to gram-negative bacteria can be diagnosed in an hour, speedingthe start of appropriate antimicrobial therapy.
Development of LAL testing of blood has been slower.Dr. Levin says, because blood produces chemicals thatmask the endotoxin's presence. Effective means need tobe developed to remove them. The test has a goodpotential for detecting bacteria in urine.
Meanwhile, Dr. Rudloe worries about the horseshoepopulation. "A horseshoe crab," says the marine biologist, "has needed little else than a sandy beach, a sandyand somewhat estuarine tide flat next to it, and sandb o t t o m s o f f s h o r e . O u r c u r r e n t i n t e r e s t i n i t a s a b i omedical resource must not endanger this elegantlyadapted species and bring its long story to an end."
David R. Zimmerman is a freelance writer.
FDA Consumer / February 1984 / 9
The Pituitary:A K e r n e lOf Wonderby Tim Lark in
The pituitary is truly one ofn a t u r e ' s w o n d e r s . C o n s i d e r t h i s
pea-sized object, nestling in a saddle-shaped bed of bone and hanging bya slender stalk from the underside ofthe brain. This object, weighing one-fiftieth of an ounce, is somehowcapable of producing chemical compounds that in complexity and efficiency make the products of modernindustrial plants seem like Stone Agetechnology. This wonder within, thepituitary gland, may well be the mostconcentrated chemical factory inex i s tence .
Once thought to be no more thana source of mucus (in 1543, the greath u m a n a n a t o m i s t A n d r e a s Ve s a l i u s
gave the gland the Latin name pituita,source of our word "spit"), the pituitary is the body's master gland. Assuch, it acts like a control center forthe finely tuned, interconnectedglandular system (the endocrine system) responsible for processes ofbirth, growth, aging and for thesmooth everyday functioning of thebody. Unless the pituitary properlyreceives messages (such as "releasingfactors") from the hypothalamussection of the brain, and unless itthen sends out precisely meteredmedical signals at the proper time,and unless it in turn properly receivessignals fed back to it from otherglands, life swiftly becomes discordant, leading to bizarre disorders orto death. No matter how the brain,heart, liver, kidneys, and all otherorgans might operate, no matter howwell we might be endowed genetically, a faulty pituitary can make lifenasty, brutish and short.
The signals emitted and receivedby this master gland are of a specialkind called "hormones" (from aGreek word meaning to excite or stirup). Hormones are actually moleculessecreted by one cell type that travelthrough biological fluids to convey amessage or regulatory signal toanother cell type.
As the pituitary's hormones arereleased into the bloodstream, theyhave contact with every area of thebody, but only the target organ orfunction is programmed to receiveand react to the message carried by apart icular hormone.
Based on current knowledge, thehuman pituitary manages to achieveall its vital, complex work by secreting each day just one-millionth of agram of eight different hormones-two from the rear, or posterior,section, and six from the front, oranterior, section. Since the output ofthis master gland is so small, res e a r c h o n t h e c h e m i c a l s t r u c t u r e o f
pituitary hormones has been extraordinarily difficult. For example, to getone milligram of pure thyrotropin-releasing factor (TRF), scientists atthe Tulane University School of
The pituitary gland acts as a control center to relay messages from and to the interconnected glandular system thatdetermines how humans reproduce themselves, grow, age,and carry on the other life processes. On opposite page,drawings show likenesses of the pituitary itself (inset), thisgland and its setting in the brain (top left), and the locationin the body of other glands that communicate with the pituitary, using hormones as signals.
10 / February 1984 / FDA Consumer
Medicine had to make extracts fromsome 2 million pig brains and collect,dissect and process 5 million fragments of sheep hypothalamus—involving 500 tons of brain tissue.
The pituitary's posterior section isresponsible for releasing vasopressin,or antidiuretic hormone (ADH in thehormone "alphabet"), and oxytocin,both stored in the pituitary afterbeing created in the hypothalamus,from which the pituitary is suspended. ADH is released when thebody is under stress, and signals thekidneys to absorb water to maintainthe correct concentrations of mineralsin blood and body fluids. Should thepituitary produce insufficient ADH,a condition called diabetes insipidusoccurs (this is not the same as diabetes mellitus, also called "sugardiabetes"). Those suffering from thisdisorder produce large amounts ofdilute urine—as much as four gallonsa day—a loss which creates an unquenchable thirst. A synthetic formof ADH is one of the treatments fordiabetes insipidus. The other posterior hormone, oxytocin, is believed tohelp regulate the force of uterinecontractions during birth and subsequent milk production in response tothe suckling action of the newborni n f a n t .
The pituitary's six anterior hormones include thyroid-stimulatinghormone, TSH; adrenocorticotropichormone, ACTH; human growthhormone, HGH (also known as thesomatotropic hormone); follicle-stimulating hormone, FSH; luteinizing(ovum-releasing) hormone, LH; andprolactin, PRL, which induces milkproduction.
The feedback mechanism central tothe proper functioning of the pituitary and its target glands is clearlyseen in the way TSH works. WhenTSH reaches the thyroid, that glandbegins to produce its own hormones.When the pituitary in turn detects anincreased concentration of these thyroid hormones in the blood, it reduces its output of TSH. Respondingto this lower TSH concentration, thethyroid then also slows down its production of hormones. This decreasedlevel of thyroid hormones is detectedby the pituitary, which then increasesTSH production. Thus, the pituitarya l s o w o r k s l i k e a k i n d o f c h e m i c a lthermostat, maintaining hormonalbalance by receiving signals and re
acting to them.The importance of a pituitary that
clearly perceives and properly reactsto these signals can be seen in whathappens when one of its targetorgans, the thyroid gland, is under-or over-st imulated. Without sufficientTSH, the thyroid gland soon shrivels,with dramatic effect. A diminishedthyroid causes the human engine toslow down. The skin dries out, hairthins, the body puffs out as cellsflood with water, behavior becomeslistless and sluggish, and the minddeteriorates. If, on the other hand,too much TSH reaches the thyroid,the body begins to burn itself up.Food may be wolfed down, but theflesh nonetheless melts away. Thebody seeks in vain to sweat away itsexcessive heat; the heart pounds, thehands tremble, the eyes seem aboutto burst out of the skull.
When the pituitary operatessmoothly—which, fortunately, italmost always does—FSH and LHwork to perpetuate the species bysignaling the glands in the male testicles to produce sperm cells and themale hormone testosterone, and bystimulating the female to produce asingle mature egg each month. WhenFSH reaches the ovaries, it helps thefollicle (or egg sac) to grow in theearly stages of a woman's menstrualcycle. This follicle also releasesestrogen, a female hormone, at mid-cycle, which serves as the feedbacksignal to the pituitary, prompting itto release just enough LH to causethe follicle to rupture and release itsegg. Unless this sequence unfoldsproperly, a woman will become infertile. Later, if the female givesbirth, PRL will tell the breasts tocommence producing milk, and suckling will induce the pituitary toincrease PRL secretion. However, ifPRL is released at an inappropriatetime, it can cause anovulation (failure to ovulate) or amenorrhea (failure to menstruate) or both. It canalso cause inappropriate milkproduction.
While the pituitary gland is indeedwonderful, no one has ever claimedi t t o be endowed w i th a sense o fhumor. Yet it plays the major role ina fundamental practical joke on thehuman male, a joke remarked on atleast since the time of Shakespeare:the relationship between the male sexurge and alcohol. As described by
the porter in Shakespeare's Macbeth,alcohol ".. .provokes and unpro-vokes: it provokes the desire, but ittakes away the performance. Therefore, much drink may be said to bean equivocator with lechery: it makeshim, and it mars him; it sets him on,and it takes him off; it persuadeshim, and disheartens him." We nowknow why. When alcohol reaches themale gonadal tissue in the testicles,biochemical processes that ordinarilywould be devoted to making the malehormone testosterone are divertedinto breaking down alcohol. Thislowers the body's testosterone level.The pituitary detects this decreaseand responds by producing moreLH, thus signaling the testes to stepup production of testosterone. Desirethus increases by the same mechanism that denies performance. Subjectively, not very funny. But objectively,perhaps one of nature's betterpractical jokes.
Perhaps the most spectacular pituitary hormone is HGH, human growthhormone. Unlike the other anteriorpituitary hormones except PRL,growth hormone acts directly on abody function instead of throughanother gland. Given the righta m o u n t o f G r o w t h H o r m o n e R e l e a s
ing Factor (GHRF) sent from the hypothalamus and proper secretion ofHGH from the pituitary, we grow toa stature dictated by our genetic heritage and by the nutritional and otherenvironmental condit ions encounteredduring infancy and childhood. Butregardless of genetic endowment orfavorable environment, a child whosepituitary fails to supply sufficientHGH wil l become a dwarf. The31- inch "Genera l Tom Thumb"(Charles Stratton), who was a majorattraction in P.T. Bamum's circus, isconsidered an extreme example ofHGH deficiency.
On the other hand, when there istoo much HGH, growth fails to stop,and the child turns into a giant. Ifexcess HGH is produced during adultlife, the skeleton, then consisting ofbones fully formed and hardened,can no longer respond. But the extremities—the hands, feet and chin-can grow, and do, swelling out intogrotesque proportions in a conditioncalled acromegaly, Greek for "largee x t r e m i t i e s . "
Those who despair of progress inhuman relations might reflect on a
12 / February 1984 / FDA Consumer
letter to Time magazine by the greatAmerican neurosurgeon HarveyGushing, who carried out pioneerwork on the function of the pituitary. Dr. Gushing took exception toa photograph of a woman captioned"Uglies," pointing out that she hadbeen a pretty, vigorous woman untila malfunctioning pituitary producedacromegaly. He added that Times h o u l d n o t " . . . b e f r i v o l o u s o v e r t h e
tragedies of disease."When Gushing was in London to
receive an honorary degree, he requested permission to examine theskull of Byrne, the storied Irishgiant, whose skeleton was displayedin the museum of the Royal Collegeof Surgeons. When he stuck hisfinger into the base of Byrne's skull.Gushing found, just as he had expected, clear evidence of a tumor orother pituitary disorder.
As with any regulator or thermostat, the pituitary may produce toolittle (hypofunction) or too much(hyperfunction). If a condition calledpanhypopituitarism occurs, theimpact of insufficient production willbe felt on all the glands controlled bythe pituitary. Too little of theh o r m o n e A G T H a n d t h e a d r e n a l
gland can no longer protect againststress and infection; too little FSHa n d L H a n d t h e f e m a l e c a n n o
longer conceive; too little in the maleand there is impotence; too littleHGH and the result is hypoglycemia(insufficient sugar and henceinsufficient energy source in theblood) and a drastic curtailment ofg rowth .
We have already seen what happens when there is too little TSH. Apituitary with excessive hormonaloutput has equally dramatic thoughopposite impact on the body, such asthe gigantism or acromegaly fromtoo much HGH. For example, whenthe pituitary produces too muchAGTH, a condition called Gushing'sdisease ensues. The body retains excess salt and water, the face bloatsout into a characteristic moon shape,the upper body labors under rolls offat, including a characteristic pad—the "buffalo hump"—between theshoulder blades, and loss of musclein legs and arms makes them weakand spindly.
Pituitary hyperfunction may resultfrom such causes as fungus infection,tumors and infarction (blocked or
congested blood supply). Pituitarytumors are now treated by microsurgery or radiation. Hormonal r/q/i-c/'e/2c/e5--hypopituitarism—can nowbe dealt with by supplying an adequate quantity of the missing or ins u f fi c i e n t h o r m o n e . T h i s i s n o t w i t hout its dangers, however, since it isdifficult to determine exactly howmuch hormone is required. Forexample, in cases of infertility, thedrug Glomid (clomiphene citrate) canstimulate the pituitary into secretingm o r e F S H a n d L H . S t a t i s t i c s s h o wt h a t w o m e n w h o t a k e G l o m i d a n dbecome pregnant deliver more thanone child in 7 to 10 percent of thebirths, compared to I percent in thepopulation as a whole. These multiple births result from ovaries over-stimulated by the pituitary hormonesso that more than one egg may beripe and ready for fertilization at themidcycle t ime of ovulation
Gaution about stimulating or enhancing the production of pituitaryhormones is particularly appropriatenow that the technique of geneticengineering has created bacteriacapable of producing the equivalentof the growth hormone HGH. ThisHGH equivalent, not yet approvedby FDA for general marketing, iscurrently being given to over 3,000American children in a carefullycontrolled research program. Sincethis hormone differs from manyothers in being species-specific (onlyHGH from a human source will do),HGH deficiency until recently required use of the minute quantitiessecured from autopsies. The supplywas therefore extremely limited, thecost high. The new source of HGH isviewed as one of the most important
events in endocrinology over the last15 years. It is of potential benefit tothe estimated 10,000 American children suffering from pituitary dwarfism.
However, there is fear that theavailability of HGH may produce arush to inappropriate and unneededtreatment, such as to extend otherwise normal growth. This couldprove dangerous since research already shows that elevated levels ofblood sugar can accompany treatment with genetically engineeredHGH. When measured against thepotential benefit to children sufferingfrom pituitary dwarfism from insufficient HGH, physicians, parentsand the children may feel this is arisk well worth taking.
But for other children, who have anormal supply of HGH and who arebelow normal (or desired) heightbecause of heredity or what is calledpsychosocia l dwarf ism—slowedgrowth due to stress—there is thedanger not only of hyperglycemiabut, at least theoretically, of atherosclerosis (thickening and hardening ofthe walls of arteries) or even acromegaly. That is why Dr. Alfred M.Bongiovanni, professor of pediatricsat the University of Pennsylvania,warns against abusing HGH and emphasizes the importance of very careful and thorough diagnosis to be surethat the treatment is given only tochildren suffering from pituitaryd w a r fi s m .
In the Old Testament psalm attributed to David, he rejoices, saying,"I am fearfully and wonderfullymade."There can be few better proofsthan the pituitary wonder within.
Tim Larkin is a freelance writer.
FDA Consumer / February 1984 / 13
There's Rejoicing Over Re-jointsby Annabel Hecht
4 4 XT either surgeons nor engineers will ever make aniN artificial hip joint which will last thirty years and
at some time in this period enable the patient to playf o o t b a l l . ' '
So wrote Dr. John Charnley, the pioneering British orthopedic surgeon, in 1961. New designs and newmaterials, some of them recently approved by FDA, mayprove the first part of Charnley's prediction wrong. Buteveryone knows patients with artificial hip jointswill never play football, particularly since three out offive a re 65 o r o lde r.
Artificial hips may not create instant athletes, but theyhave brought relief to hundreds of thousands of peopleonce crippled by arthritis and enabled them to live productive, pain-free lives.
Hips are by no means the only joints that can bereplaced. Artificial knee joints are becoming increasinglycommon. Elbow, ankle, shoulder, toe, and finger jointsare also replaced, although not as frequently as the hipand knee. Operations to replace joints—technically calledarthroplasty—are performed primarily to relieve pain andsecondarily to improve function.
The total number of arthroplasties performed is notknown. A frequently cited number for hip replacementsis 75,000 annually, although some place the figure at100,000. According to Dr. William P. Fortune, orthopedic surgeon at George Washington University School ofMedicine in Washington, D.C., the ratio of hip replacements to knee replacements is 2 to 1 and the ratio of hipsto ankles is 30 to 1. Thus, these three types of jointreplacements alone total 115,000 to 153,000 a year.
Artificial joints are regulated by FDA under theMedical Device Amendments of 1976. In 1982 the agencyissued ''generic" classifications for 49 types of jointreplacements, including three for ankles, four for elbows,four for fingers, 12 for hips, 12 for knees, five forshoulders, two for toes, and seven for wrists. About halfwere put in the regulatory category calling for performance standards and half were put in the category requiring premarket approval before the device can go ont h e m a r k e t .
The first joint to be totally replaced was the hip,anatomically the best place to start, since the hip is asimple ball-and-socket joint. One of the most commonly
used hip joint replacements today is just that—a ball-and-socket joint. The head of the femur (thigh bone) isremoved, and a metal device consisting of a stem toppedby a ball is cemented into the shaft of the bone. This iscalled the femoral component. The femur fits into asocket in the pelvis called the acetabulum. The artificialsocket is called the acetabular component.
Variations on this basic design include femoral components that are tapered so that they fit snugly withoutcement. In one type of device the two components arelinked together. In another, the femoral component terminates in a trunnion, or pin, that fits into the ball part,allowing the head to rotate on the stem. Interchangeableh e a d s a r e a v a i l a b l e t o a l l o w f o r d i f f e r e n c e s i n t h e s i z e o f
patients. Since it is not always necessary to replace bothparts of the hip joint, separate femoral and acetabularcomponents^ are available.
The materials from which these components are mademust be extremely durable, since they must withstand aload actually equal to three to five times the patient'sbody weight with each step. Cobalt or titanium-basedalloys or stainless steel is used for the femoral component, while high-molecular-weight polyethylene or, oca-sionally, metal is usually the material from which theacetabular cup is made. Late in 1982 this list wasb r o a d e n e d t o i n c l u d e c e r a m i c s — n o t t h e k i n d d i s h e s a r emade of, but a material compounded of aluminum oxide.FDA approved two hip replacement systems with ceramiccomponents, one to be cemented in place, the other not.Each consists of a cobalt-chrome alloy femoral stem, aceramic head, and a ceramic acetabular cup.
To Dr. John Charnley, quoted above, goes much ofthe credit for the development of the total hip jointreplacement used today. He was not, however, the firstto come up with such an artificial joint. An ivory balland socket had been implanted in a hip by a Germansurgeon in 1890.
At the turn of the century many European andAmerican surgeons repaired damaged hips and otherjoints by padding the surfaces of the joints with a varietyof materials, including fibrous tissue, celluloid, silverplates, rubber sheets, and even pigs' bladders.
With the development of corrosion-resistant material inthe 1930s and biologically acceptable plastics in the 1940s
FDA Consumer / February 1984 / 15
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and 1950s, real progress in artificial joints could bemade. The concept was explored of replacing the femoralhead with a device that could move freely in theacetabulum. Unfortunately, many of these early devicesbecame loose on the thigh bone or migrated within thepelvis.
Charnley's contribution was his discovery of low-friction arthroplasty. By coupling the smallest diameterball possible on the femoral component with a socketmade from a compound with the least potential for friction, he created an artificial joint that was efficient,durable and moved with ease. Chamley also was the firstto use a newly discovered cement made of polymethylmethacrylate, which fixed the femoral component moresecurely to the bone and thus avoided the loosening thathad plagued previous implants.
The new cement is cold-curing or self-curing and is approved by FDA for use in the United States. It is easy toapply, and because its mechanical properties differ fromthose of the bone and of the metallic implant, it serves asa buffer to absorb the stresses to which the joint is subjected. Still, it is the weakest link in the bone-cement-implant structure. Eventually the cement breaks down,causing the femoral implant to loosen.
This may no longer be a problem, however, since FDAhas recently approved a total hip prosthesis that doesn'tneed cement to be fixed in place. Instead, the stem of thefemoral component has a porous coating of tiny metalbeads ranging in diameter from 150 to 400 micrometers.The beads allow the surrounding tissue to grow into theprosthesis, making it a part of the body.
One disadvantage of the new prosthesis, called the'Torocoat Modified Austin-Moore Total Hip Prosthesis," is that it takes longer for the patient to be upand around than with the standard hip joint replacement.Since time is needed to allow the ingrowth to take place,the patient's activity may be limited up to six monthsafter the operation in contrast to the three months usually required for recuperation following an operation usingthe cemented-type prosthesis.
At this point no one knows how well the new prosthesis will hold up over time. Some of the cementeddevices have served well for more than 10 years. FDA istherefore requiring postmarket surveillance for five yearsafter implantation for all patients identified in the firm'spremarket approval appl ication.
Originally, total hip joints were implanted to relievepain in arthritic patients over 65 years of age, and thesepatients receive about 60 percent of the implants annually. Because of the success of the operation, it is nowavailable to younger patients, including teenagers, withhip problems. The most common reasons for total hipreplacements in the elderly are osteoarthritis (60 percent),fracture-dislocations (II percent), rheumatoid arthritis (7percent), and aseptic bone necrosis (7 percent).
According to the Arthritis Foundation, the success ratefor artificial hips is about 95 percent. Early complications
that may develop include infection, which occurs inabout 1 percent of the hip operations, as well as dislocation and abnormal bone formation. Fracture of thefemur or acetabulum may also occur. Blood clots areanother problem encountered.
Failure of the hip replacement at later dates can becaused by loosening of the cement, fractures of the component, and just plain wear.
If the hip replacement fails, a second operation can bedone, but it is generally less successful than the first timearound. About 6 percent of the hip operations each yearare revisions of previous surgery. If failure is due to infection, it may mean that the second implantation willhave to be delayed until the problem is cleared up. If it isnot possible to implant a second artificial joint, the hipmay have to be immobilized.
There is another form of hip arthroplasty in which thejoint is resurfaced rather than replaced. The top of thethigh bone is simply scraped and capped with a metalhead, while the socket of the hip is cleaned and linedwith plastic. Although it is a less radical procedure,resurfacing doesn't seem to have any advantage over theconventional joint replacement. Failures due to looseningof the prosthetic parts and fracture of the femoral neckhave been reported, according to a 1982 consensus conf e r e n c e h e l d a t t h e N a t i o n a l I n s t i t u t e s o f H e a l t h .
Total hip replacement is not for everyone with painfuljoints. Patients with an active infection of the hip orbladder or any condition that destroys bone, such as atumor, would not be candidates for this type of surgery.Complications such as heart disease or respiratory problems and excess weight also make some people poor risksfor surgery.
Like hip joints, knee joints are replaced to relieve thepain of arthritis or osteoarthritis, improve the range ofmotion, and correct deformities. Although they are affected by arthritis more often than hip joints, knee jointsare replaced less often.
Replacing the knee joint is not as easy as replacing ahip. Anatomically, the knee may look like a hinge, but itis considerably more complicated than that. Bending andstraightening the knee involves rolling, rocking, slidingand gliding motions around a variable axis. Stability isprovided by the surrounding ligaments and muscles.
Early attempts at knee arthroplasty in the 1940s usedmetal molds to cover the condyles (ends of the femur).Unfortunately, such devices did not relieve the patient'spain and were subject to loosening. The next decade sawthe development of hinged knee joints, but these, too,had high failure rates. And, of course, the hinge couldnot duplicate the complex motion of the natural knee.
The real breakthrough in knee joint replacement camein 1968 when an associate of Charnley developed a prosthesis embodying the low-friction concept. Called a poly-centric prosthesis, the new device consisted of two arc-shaped metallic runners, cemented into the ends of thefemur, that moved in two polyethylene tracks cemented
76/ February 1984 / FDA Consumer
into the ends of the tibia (lower leg bone). This designallows a nearly normal range of knee movement.
The polycentric device was soon followed by the geometric prosthesis, in which the two ''runners" of thefemoral component are joined, as are the tracking surfaces of the tibial component. With this device only two,rather than four, components need to be inserted.
During the past decade many new variations on thesebasic designs have been made. However, the quest for theperfect knee joint replacement goes on.
The knee joint prostheses currently available vary indesign from non-constrained and semi-constraineddevices, which depend on the surrounding muscles andligaments for stability, to the totally constrained device inwhich the two parts are joined by a hinge.
Examples of less constrained devices—that is, thosethat permit nearly normal knee movement—include thepolycentric design and prostheses that in effect resurfacethe joint with metal and plastic components fastened inplace with the polymethylmethacrylate cement. In somecases the patella, or kneecap, is resurfaced as well as theends of the femur and tibia. The hinge, still used in caseswhere destruction or deformity of the knee is severe, isan example of a constrained device.
Severe, almost incapacitating pain is the primaryreason most patients seek knee joint replacements. Atfirst only patients with rheumatoid arthritis had suchoperations. Now patients with osteoarthritis as well asother types of knee damage are also candidates. Kneejoints are usually replaced in older patients, those in their60s, and in those who won't be putting too great a strainon the device. A person who does heavy manual laborprobably wouldn't be considered for knee arthroplasty.Joints replaced in younger, more active patients, say intheir 30s, often aren't successful.
Other people who are generally ineligible for total kneearthroplasty include those with poor general health,obesity, infection, bone loss, bone thinning, and excessivedeformity.
Infection and blood clots are the most serious complications following knee joint replacement operations,and special precautions are taken both before and afterthe operation to prevent them. Loosening of the prosthesis and dislocation of the joint also may occur. Unfortunately, artificial knee joints can't be replaced as easilyas hip joints that go wrong. If it is necessary to removean artificial knee joint, the natural joint may have to befused, leaving the patient with a stiff leg.
Another joint in the lower extremities that can bereplaced is the ankle. One of the simpler joints in thebody, the ankle is very stable and has a small range ofmotion compared to the larger joints. For all that, anklesare subjected to tremendous compressive forces, at timesequal to five times the body weight.
The ankle joint is not particularly prone to disablingdiseases. Primary degenerative disease (osteoarthritis) israrely seen in this joint; however, rheumatoid arthritis
FDA Consumer / February 1984 / 17
and post-traumatic degenerative disease following anklefractures do occur. A common method of relieving thepain of these conditions has been fusion of the joint. Thefusion procedure has been so successful that ankle arthroplasty is not often performed. In fact, ankle replacement is usually recommended only for patients withrheumatoid arthritis and patients older than 60 sufferingfrom arthritis following an injury.
Ankle joint prostheses generally are polyethylene andstainless steel components that replace the surfaces of thetibia and the talus, the top bone in the ankle. The tibialcomponent fits over the dome-shaped talar componentlike a roller bearing.
Barring complications, such as delayed wound healing,the patient is usually hospitalized 8 to 12 days and canwalk unaided 6 to 12 weeks after surgery.
The big toe is the only joint in the foot consideredsuitable for total replacement. This is usually done torelieve the pain of osteoarthritis, rheumatoid arthritis,and deformity caused by displacement of the big toe. Thetoe joint replacement is made of silicone elastomer (aflexible plastic) or a polyester-reinforced silicone elastomerthat is soft and pliable and is not cemented in place.
At the other end of the anatomy, replacements areavailable for the shoulder, elbow, wrist and finger joints,but are implanted much less frequently than the artificialjoints in the lower extremities. One reason is that needfor replacement isn't as great. The upper extremity jointsaren't subjected to the kind of pressures put upon theweight-bearing joints of the hips, knees and ankles. Painand disability can be treated in other ways, such assplinting, medication, or physiotherapy. Unaffected jointscan often compensate for the loss of function in otherjo in ts .
In addition, the complexities of these joints make itdifficult to devise replacements that are totally effective.The shoulder, for instance, is the most mobile of all thejoints, yet it is unstable. It behaves like a ball-and-socketjoint, but the two components do not fit together like theball and socket of the hip joint. The shoulder socketcomponent, called the glenoid cavity, located at the upper edge of the shoulder blade (scapula), is more flatthan cup-shaped. The head of the humerus (upper armbone) is held against this surface by the rotator cuff, aband of intermingled muscle and tendon fibers. The interaction of this cuff with the deltoid (shoulder) muscle isw h a t m a k e s t h e s h o u l d e r f u n c t i o n .
Although there is not much call for shoulder jointreplacements, there are a few patients severely disabledby rheumatoid arthritis who may benefit. The operationinvolves replacing the head of the humerus with a component made of alloys such as cobalt-chromium-molybdenum and resurfacing the glenoid cavity with asimilar alloy or ultra-high-molecular-weight polyethylene.
Both components are fixed in place withpolymethylmethacrylate cement.
FDA's ''generic" classification of shoulder joint prostheses includes a constrained device, in which the twocomponents are joined, a non-constrained device with nolinkage across the joint, and a semi-constrained device inwhich the humeral head is replaced with a metal alloy.The classification also includes replacements for theglenoid and humeral components separately.
Complications that have been reported with these prostheses include infection, dislocation of the components,fracture of the scapula, and fracture of the humeralc o m p o n e n t .
Replacing the elbow joint presents still another set ofproblems. The elbow is not the simple hinge it appears tobe. It is not even a single joint but is composed of threesections, involving the three arm bones that meet at thatpoint: the humerus in the upper arm, and the radius andulna, the bones of the forearm. Each section of the jointhas a different stress bearing and different rotationalf u n c t i o n .
The earliest elbow joint replacements were constrained,or hinged, devices that required removal of the lower endof the humerus and sometimes a portion of the ulna forimplantation. Although they provided stability, they hadsome serious complications, including loosening of thedevice and bone erosion and resorption, resulting in fracture of the bone around the device and difficulty insalvaging the bone if the device had to be removed.
Better results have been obtained with semi-constrainedelbow joints—i.e., those in which the two componentsare not linked. The "generic" device classified by FDAconsists of a humeral resurfacing component made of acobalt-chromium-molybdenum alloy and a radial resurfacing component of ultra-strong polyethylene, both fixedin place with polymethylmethacrylate cement.
Two single-joint prostheses are included in FDA'sclassification. One is a medical grade silicone elastomerdevice intended to replace the head of the radius. Experience with this type of device has shown that it canrelieve pain and increase the range of motion of theelbow. The other type of elbow joint, an uncementedmetal alloy replacement for the end of the humerus, hasnot been as successful in relieving pain and is more proneto complications, such as dislocation and blockage ofmotion because of new bone growth.
Elbow joint replacement should be reserved for patients with painful limitation of motion caused byrheumatoid arthritis, trauma, or infectious arthritis forwhom regaining motion is more important than gainingstrength and stability.
The wrist is a key joint in the upper extremity. It ismade up of eight bones, called the carpals, arranged approximately in two rows. The proper balance of the wrist
system depends on the shape of the bones and the integrity of the ligaments that hold them all together. Ifanything happens to those ligaments, the system collapses. Rheumatoid arthritis is a frequent cause of wristdeformity.
Wrist problems can sometimes be solved by fusing thejoints, but if the patient has other deformities of the armor shoulder it may be necessary to preserve some motioni n t h e w r i s t i t s e l f .
A common type of implant for damaged wrists is aone-piece device made of silicone elastomer designed toreplace the lunate, scaphoid or trapezium bones in thewrist. Another type of wrist joint replacement consists ofa single across-the-joint linkage made of polyester-reinforced silicone elastomer, used without cement.
Two types of metal wrist joint replacements are theacross-the-joint (or linked), constrained device and thenon-linked, semi-constrained device. The latter may beeither a one-part radial component made of a metal alloywith a polyethylene bearing surface or a two-part radialcomponent consisting of a metal stem mounted by apolyethylene ball matched with a metal metacarpalc o m p o n e n t .
Nowhere else are the ravages of rheumatic diseasesmore visible than in the hands. The metacarpophalangealjoints (those involving the hand and finger bones) areclassically affected by rheumatoid arthritis. The severedeformity often seen in victims of this disease is theresult of a combination of joint destruction and soft-t i s s u e c o n t r a c t i o n .
Fortunately, for many such patients the pain anddeformity may be relieved with artificial finger joints. Acommon finger joint prosthesis is a single flexible, across-the-joint component made from either a siliconeelastomer or a combination of polypropylene andpolyester material. The whole device may be covered witha silicone rubber sleeve. Such artificial joints may be usedto replace either the metacarpophalangeal, or first finger,joints. One problem with such implants is that they canfracture, leading to inflammation of the joint from bitsof plastic.
Constrained, across-the-joint models consisting of twometal components or a metal and a polyethylene component also are available for finger joint replacement. Boneerosion, loosening of the prosthesis, and joint deformityare some of the complications associated with these joints.
While arthroplasty is becoming a commonplace operation and is, for the most part, successful, patients shouldrealize that such surgery is not without some risk. Jointreplacement is not a cure for arthritis. Furthermore, artificial joints are never as strong as the real thing andmust always be treated with respect.
Annabel Hecht is a member of FDA's publications staff.
FDA Consumer / February 1984 / 19
K n e e A c c o u n t
by Freda Corwin
When you're feeling fit and havethe energy to take brisk, five-mile walks nearly every day, thethought that you may be immobilizedby an arthritic knee seems unthinkable. I'm old enough to knowthat few of us can escape the infirmities brought on by the body's normal wear and tear, but it never occ u r r e d t o m e t h a t a c t i v e m e w o u l d b ea candidate for a total knee replacement. Yet, I was operated on in thefall of 1983, and became one of themany thousands of men and womenin the United States each year tohave total knee replacements, thehonors being about evenly dividedbetween the sexes.
I have always resisted going todoctors. I believe most of the thingsthat ail you get better in time if youhave the patience to let nature takei t s c o u r s e . B u t n o t t h i s t i m e . I n c r e a s
ing pain in my right knee made mechange my mind. I looked aroundfor an orthopedist skilled in jointdiseases. My friends were sure theyhad just the right man for me. Iwound up with an impressive list ofdoctors, including the joints specialistfor the Washington Redskins footballteam. Having decided on one, thefirs t o rde r o f bus iness was a se r i es o fX-rays, including an arthrogram, inwhich a dye is injected into the kneejoint. My condition was diagnosed asosteoarthritis, a degenerative jointdisease that in my case resulted inthe erosion of cartilage of the kneejoint. The radiology report said themeniscal cartilage was ruptured, apparently making conventional surgicalrepair impossible.
This had happened in the fall of1979. For the next four years.
various treatments were prescribed-bed rest, anti-inflammatory medications, exercise, hot and cold applications, cortisone injections, aspirin.Only temporary relief resulted.
I had read enough about arthritisto know that no cure has yet beend i s c o v e r e d f o r t h i s d i s e a s e w h i c h a fflicts upward of 20 millionAmericans in so many differentways. Since none of the treatmentsseemed to work, and the pain had intensified to the point that I had greatdifficulty walking two blocks to thesupermarket, I decided to considers u r g e r y .
T h i s l e d m e t o D r . W i l l i a m P. F o rtune, of the George WashingtonUniversity School of Medicine inWashington, D.C., a pioneer in jointsurgery. After further X-rays I wastold that a knee replacement wouldnot only relieve me of pain, but alsohelp correct a bowing in the legcaused by the osteoarthritis.
I was asked to t h i nk i t ove r. I wasaware that at my age (70 plus) majorsurgery could be a problem andwould require a long convalescence. Ialso knew that knee replacements arenot as successful as hip replacementsbecause the knee is a much more
complicated joint. In Dr. Fortune'swords, the knee is not a hinge jointbut a machine that changes itsfulcrum of motion—rolling, rocking,sliding and gliding.
I didn't take long to make up mymind to have the operation. I enteredthe hospital two days before thesurgery for additional tests and toadjust to my new environment forthe nex t th ree weeks .
I found on my night table a copyo f a n i l l u s t r a t e d a r t i c l e f r o m amedical journal describing in explicitanatomical detail just what was to bedone to my knee—what was to beremoved, and what put in and where.Some patients may not want to knowthe details—but the hospital assumed, and I think correctly, thatevery patient has a right to be fullyinformed. After reading the article, Ifelt fully informed but suspected that
somehow I would no longer be ablet o s e e t h e h u m o r i n t h o s e o l d c r a c k sa b o u t h o u s e m a i d ' s k n e e a n d w a t e ro n t h e k n e e .
The operation under generala n e s t h e s i a l a s t e d m o r e t h a n t w ohours. It included resurfacing of abnormal surfaces of the knee joint-namely, the lower thigh bone(femur), the upper shin bone (tibia),and the underside of the kneecap(patella). The resurfacing componentscan be plastic or metal, held in placeby a special cement. Additional hardware, such as some small pegs and ascrew, is used for furtherr e i n f o r c e m e n t .
Afterward, I was returned to myroom on the orthopedic floor. Themajor concerns now were to guardagainst infection (with antibiotics administered intravenously and thenorally), to be on the alert for bloodclots, and to carry out a system ofexerc ises .
To prevent clots, I was given ablood thinner (warfarin), required towear an elastic thigh-length stockingt o c o n t r o l c i r c u l a t i o n i n t h e l o w e rlimb, and to use, several times a day,a breathing exercise incentive deviceto clear the lungs and to increaseb l o o d fl o w .
As a further precaution againstblood clotting, I volunteered to participate in a new research project todetect potentially dangerous clots,even before they start to form. Thetest consisted of injection into myvein of platelets treated with aradioactive tracer substance,Indium-Ill. The platelets had comefrom blood out of the hospital bloodb a n k . T h e c o n s e n t f o r m I w a s r e
quired to sign said there is little riskof developing hepatitis and the radiation exposure is small—the equivalentof dosages received in many nuclearmedicine procedures. After considering the benefits and risks, I decidedto take the test. A day after theplatelet injection I was placed undera c a m e r a l o a d e d w i t h fi l m s e n s i t i v eto Indium-Ill, and pictures weretaken of the radioactive platelets in
20 / February 1984 / FDA Consumer
t h e b l o o d s t r e a m . T h e fi n i s h e d
photos, unlike X-ray negatives, wereprinted on snapshot-size glossypaper. They showed no evidence ofclots, but I had to continue to wearmy white elastic hose and use thebreathing device. The consent formtold me that the records identifyingme would be kept confidential shouldan FDA inspection of the blood banktake place.
Any doubts I had about the importance of exercise for a patient with abrand new knee were promptlydispelled when I saw two prominentsigns taped to the sling exerciser overmy bed. The first sign gave four-stepdirections for knee flexing, bending,heel lifting, etc. The second said:"Please, Mrs. Corwin is to ambulate'at least qid." Translation: I was towalk four times a day. The signsreminded hospital personnel not tooverlook an essential duty.
There was more. Every morning Iwas taken by wheelchair to join otherorthopedic patients in exercises conducted by physical therapists. A drugtaken beforehand helped alleviate thepain connected with this ratherstrenuous workout. One morning Iwas surprised to find in a wheelchairn e x t t o m i n e a w e l l - k n o w n o u t
patient, Jim Brady, the President'spress secretary. I learned he comesfrom his home to the hospital regularly for therapy. We exchangedpleasantries; it made my day.
I write this 10 weeks after mydischarge from the hospital. There isstill a stiffness in the joint due to atightening of the healing tissues, andi n b e d I s t i l l m u s t w e a r a k n e e i m
mobilizer, a padded splint thatresembles the shinguard worn byhockey goalies. But the bow in myleg has disappeared, and I walkwithout a cane and without pain.Will I be able to resume those long,brisk walks? Perhaps, but a little lessbriskly. I'll take it in stride.
Freda Corwin is the wife of EmilCorwin, a member of FDA's presss ta f f .
F D A C o n s u m e r / F e b r u a r y 1 9 8 4 / 2 1
On Making Food Labels Thithflilby Chris Lecos
Consumers do not always get what they think they arebuying. Although the American food industry as arule markets what it promises, there has always been asmall number of entrepreneurs who cut corners illegally—by giving less than the declared weight on the label or bysubstituting cheaper ingredients than those a foodshopper thinks are in the package.
For example, when buying orange juice, or apple juiceor maple syrup, most shoppers take it for granted thatthis is indeed what they are getting. A shopper checkingthe label's ingredient list and finding the ingredientslooked for will buy it with confidence that the label ist r u t h f u l .
Unfortunately, that is not always the case, and economic deception is not only of concern to FDA but alsoto the responsible members of the food industry. Most ofthese believe such deceptive practices damage the industry's reputation and believability and give a competitive edge to the cheat, who can sell cheaper by cuttingquanti ty or qual i ty.
Such deception violates federal law—primarily theFood, Drug, and Cosmetic Act, which FDA enforces. Asa protection to consumers, FDA has established manyfood standards specifying composition, makeup and labeling it requires for a wide variety of food products.
Although FDA's principal responsibility has alwaysbeen to protect consumers from products harmful topublic health, economic deception is covered in a numberof ways. For example, a product violates the law if itsnet weight is below that given on the label. It may beconsidered adulterated or misbranded if certain ingredients are substituted illegally for those claimed, or if thelabeling is false and misleading.
For the 1984 fiscal year, which began last Oct. 1, FDAofficials in Washington, D.C., sent a directive to theagency's field offices advising them that FDA will"continue to emphasize its commitment to pursue legala c t i o n s w h e r e e c o n o m i c f r a u d i s e n c o u n t e r e d . " T h e r e s u l tis that FDA's field investigators are looking for deceptiveeconomic practices at the same time that they are checking food products for safety.
The directive states that since many economic deceptions are intentional, FDA's Bureau of Foods in Washington, D.C., is prepared to move quickly where a clear-c u t c a s e o f e c o n o m i c f r a u d i s d e m o n s t r a t e d .
Although FDA field investigators are to be alert forany form of economic deception regardless of the product, the directive assigns a higher priority during inspections to certain food categories. In the case of product
substitutions, the agency listed the following food areasand indicated the types of adulterations that have beencommon in the past;• Floney, maple syrup and sorghum products, in whichfructose, invert or corn sugars are substituted wholly orin part for those the manufacturer claims for the products. Last year a federal grand jury in Jackson, Miss.,returned a 13-count criminal indictment against two menfor allegedly manufacturing, processing, shipping andselling foods in interstate commerce that were labeledfalsely as maple syrup, honey and sorghum syrup products. FDA said the products contained corn or sugarsyrup and were artificially flavored—in effect, werecheaper substitutes for the products they were claimedto be .• Apple juices that have been adulterated and misbrandedthrough the use of various sweeteners, water, appleflavoring, apple essence, and other ingredients.• Orange juices that are being marketed as 100 percentorange juice but fail to meet FDA food standards because of the use of pulp-wash solids and other color andflavoring ingredients. These practices have arousedresponsible members of the Florida citrus industry, whichproduces 90 percent of the nation's orange juices.• Olive oil and sesame seed oil in which corn, soy andc o t t o n s e e d o i l s a r e s u b s t i t u t e d .• Breaded shrimp that is sold with less than the minimumof 50 percent shrimp material.• Grated cheese that contains whey solids instead of Parmesan, Romano, or other cheese claimed on the label.• Scallops that aren't scallops because they consist ofcheaper fish fillets cut up to resemble scallops.
In searching for products with net weights less thandeclared weights, FDA's directive emphasizes these products: nuts, instant tea, instant coffee, spices, and over-glazed seafood, especially rock lobster tails processed inF l o r i d a .
Glazing preserves frozen seafood by coating it with alayer of ice. Overglazing means the product is coatedwith too much ice and part of the weight of the ice isincluded in the declared net weight of the product.Although only the seafood is supposed to be included inthe declared weight for the product, FDA has found upto 30 percent of the declared net weight to be glaze or iceweight .
Taylor M. Quinn, associate director for compliance inFDA's Bureau of Foods, said the noted food productsare the ones the agency regards as the biggest problem.He said FDA has met with representatives of the apple.
F D A C o n s u m e r / F e b r u a r y 1 9 8 4 / 2 3
citrus and honey industries because of the illicit practicesof some industry members.
The extent of such economic violations is uncertain,although the general belief is that the problem is a selective one, Quinn said. "Violations tend to be cyclic," hecontinued, "and you can, in fact, find evidence of thesekinds of violations all the way back to the turn of thecentury." With FDA's present staff and financial resources, he added: "All we can do is try to hold it down.We're looking into it so far as our resources will permit."
FDA can take three types of actions against economicdeception: The agency can ask the food manufacturer torecall the product; it can seek legal action to seize andremove the product from the marketplace or, if thenecessary evidence is substantial enough and the casewarrants it, criminal action can be sought.
But prosecution is not always easy, for some companies use such sophisticated methods of adulterating theirproducts that violations are difficult to prove. This isespecially true for some adulterated orange juice, applejuice, and honey and maple syrup products.
FDA regulations define orange juice as a product derived from the unfermented juice of mature oranges.Some small seed fragments cannot be removed during theinitial manufacturing process, but the larger seeds and"excess pulp" must be removed. If the label calls it"orange juice," the consumer is entitled to exactly that.
But orange juice comes in many varieties. FDA hasseparate standards for ordinary orange juice, and fororange juice that is pasteurized, canned, from concentrate(reconstituted), frozen concentrated, canned concentrated,for manufacturing purposes only, with preservative, concentrated for manufacturing, and concentrated with preservative (concentrate is juice with most of the waterremoved). Some products can legally contain sugars orother sweeteners if they are identified on the label.
During manufacture, some pulp from the initial juiceextraction process can be added back to a product soldas orange juice or concentrated orange juice. The unused,excess pulp is not thrown away; instead, it is often storedin tanks and sold to firms making other kinds of beverages. It is usually referred to as washed or spent pulpor as pulp-wash solids. The washing process removes anyremaining juice and sugars.
In some cases of adulteration, washed or spent pulpfrom other processors is used, along with other color andflavoring agents, to produce a product that is illegallylabeled and sold as an orange juice product. Turmeric, aspice and powerful coloring agent not permitted inorange juice, is sometimes added to give the adulterated
products the appearance and taste of orange juice. Sugarsand other sweeteners may also be added.
Adulteration of orange juices sometimes is hard toprove because the water, sugars and components addedillegally are hard to distinguish from those naturallypresent in orange juice, according to Melvin R. Johnston,Ph.D., chief of FDA's plant and protein technologybranch. "Analytically they are so similar to each otherthat chemists cannot always differentiate between them,"he explained.
Some of FDA's problems were outlined in 1982 to aSenate subcommittee by former FDA CommissionerArthur Hull Hayes Jr. after FDA was directed in 1981 topursue a vigorous enforcement policy on any violationsof federal food standards for orange juice products. InApril 1981, FDA conducted a survey to determinewhether processors of orange juice made from concentrate and frozen concentrated orange juice were adulterating these products with water, sugars, preservatives andorange pulp-wash solids and then labeling them as "100percent pure orange juice" or as "orange juice concentrate" without any qualifying or ingredient declaration.This constitutes misbranding.
Of 13 firms inspected during the survey, six madeproducts that had "minor deviat ions" f rom FDA foodstandards or labeling deficiencies. Three other firms wereusing illegal color additives and/or pulp-wash solids. Asa result, FDA seized 10 lots of adulterated orange juice.Samples of orange juice from the seizures revealed thepresence of turmeric. Four more firms were later inspected, including one in Mexico, and 12 more lots of orangejuice adulterated with turmeric were found.
Hayes reported to Congress that the value of adulterated orange juice lots involved during these regulatoryactions in the 1981 and 1982 fiscal years was estimated atnearly $3 million.
The basic problem for FDA in cases of suspectedadulteration, the report continued, is developinglaboratory evidence strong enough to stand up in court."The analytical methodology and procedures necessary toconfirm suspected violations due to added orange pulp-wash solids and most sugars are not sufficiently established to be used in court, thus limiting any vigorous enforcement of the orange juice standards in resolvingadulteration of orange juice from use of these substances," Hayes said.
The Florida citrus industry and the federal governmenthave in recent years sought to improve their analyticalmethods for detecting adulteration, Hayes said, and headded: "Throughout this period of time, adulteration of
24 / February 1984 / FDA Consumer
citrus juices has progressed from simple dilution withwater, sugar and acids to sophisticated methods utilizingsubstances to* obscure adulteration. As the analyticalmethods of detection have improved, so have the techniques of disguising adulteration become moresophisticated."
A regulatory device was hatched to thwart the adulterators. In April 1982 FDA approved a petition by Florida's Department of Citrus to permit the addition of thepreservative sodium benzoate to orange pulp-wash solidswithout declaring the addition on a label. The Floridaagency then published a regulation requiring orange pulp-wash solids to contain sodium benzoate. Thus, if thepulp-wash solids were used by some other firm to produce a fraudulent orange juice, the detection of sodiumbenzoate in the product would serve as evidence of adulteration. Sodium benzoate is permitted as a preservative incertain standardized orange juice products but not insingle-strength (pure) orange juice or frozen concentratedorange juice.
In a further effort to catch cheats, FDA's Bureau ofFoods stepped up its research on ways of confirmingorange juice adulterations and proving them in court.Because orange juices vary by the kind of orange, thetime of year and place grown, soil conditions, and otherfactors, identification is di fficult .
FDA is taking samples of various orange juices produced in the United States, along with adulterated varieties that FDA itself is duplicating, and then subjectingthe samples to analytical techniques in an effort todevelop a profile or 'Tmgerprint" or ''pattern recognition" of what real orange juice is. The analytic methodsbeing used include gas chromatography, high performance liquid chromatography, and the plasma emissionspectrometric method. The data obtained are fed intocomputers to develop the profile. In recent years similarcomputerized pattern recognition methods have been usedon wines and Scotch whisky and to identify sources ofcrude oil spills.
The first phase of the orange juice work was completedlast June and involved 25 samples of authentic and adulterated juices. The second phase, now under way, involves125 samples and will be followed by a phase of researchin which a minimum of 500 samples of adulterated andauthentic orange juices will be analyzed. The researchproject is scheduled to be completed in September 1985.Officials say the results so far have been "extremelypromising."
Apple juice adulterations also are hard to detect sometimes, according to FDA officials. The juice usually is
adulterated by a combination of water, sweeteners, synthetic malic acid, apple flavoring, caramel color, andapple essence. Malic acid is a natural constituent of applejuice and contains only one biologically active chemicalcompound. Synthetic malic acid contains chemical compounds that are both biologically active and biologicallyinactive and, as a result, FDA scientists can detect whena synthetic acid is used. It also is possible to detect applejuice adulteration if the sugar ratios are out of line. Cornor cane sugar use is easy to detect, but some sophisticated operators sometimes switch to the harder-to-detectbeet sugar.
FDA also plans to apply computerized pattern recognition analysis to apple juice adulterations and may expandthis type of food analysis research into other food areas.
One of the more effective actions taken in recent yearsagainst apple juice adulterators was a suit brought by anindustry group, the Processed Apple Institute, againstsome New York state operators. The suit resulted in anout-of-court settlement of nearly $500,(X)0, although theaccused firms did not have to acknowledge any guilt.F D A a l s o i n i t i a t e d s e i z u r e a n d r e c a l l a c t i o n s .
T h e s o - c a l l e d " c a r b o n 1 3 - 1 4 " m e t h o d i s u s e d t o d e t e c tthe illegal use of corn and cane sugar in honey andmaple syrup adulterations as well as in orange and applejuice adulterations. In oversimplified terms, laboratoryscientists are able to distinguish the sugars that are addedfrom those that would be naturally present. When someoperators started using invert and high-fructose sugars,scientists encountered greater difficulty in detecting adulterations until the carbon isotope method of detection wasemployed. The method was developed by a retired U.S.Department of Agriculture biochemist, Jonathan W.White Jr., Ph.D., who is regarded as one of the foremostexperts on honey and maple syrups. However, it is noteffective in detecting adulteration when beet sugars areemployed.
The struggle against some food adulterators is never-ending. While FDA and other scientists strive to developimproved methods for detecting violators, they knowfrom experience that companies that want to adulteratetheir products will be refining their own scientific tools.FDA's Melvin Johnston put it this way during a conference last June of food and drug officials on the detectionof juice adulteration: "It's a good example of the scienceof enforcement becoming the science of adulteration."
Chris Lecos is a member of FDA's publications staff
FDA Consumer / February 1984 / 25
Hunger IsMore ThanAn EmptyStomachby Carol L, Ballentine
Walk into any neighborhooddrugstore and you'll probablyfind a shelf—or shelves—of productsoffered to ''control appetite" or"curb hunger." These days, thin isin and appetite seems to be theenemy—an ogre to be suppressed, ifnot eliminated, so that everyone canhave a body that's a 10.
Yet appetite is an essential bodyfunction. Everyone needs to eat, andthe appetite is what cues the body tot a k e f o o d .
But how exactly does the appetitework? Can it be chemically suppressed? And should it be tamperedw i t h ?
Although it may be logical toassume the stomach is the controllingorgan for hunger, it is not. Themaster control of the appetite lies atthe center of the brain in an areacalled the hypothalamus. The hypothalamus integrates the functions ofthe nervous system and endocrineglands (including the thyroid, adrenaland pituitary glands). Besides stimulating "hunger pangs," the hypot h a l a m u s h a s s o m e c o n t r o l o v e r anumber of physiological functions,including growth, sexual activity,lactation, water balance, menstruation, and metabolism of carbohydrates, protein and fat.
Scientists have long known that thehypothalamus is a prime mover inthe urge to eat. This was determinedby classic studies of feeding behaviorin rats. In those studies, certain areasof the hypothalamus in rats wereeither stimulated or destroyed. Des t r u c t i o n o f o n e a r e a — t h e v e n t r o
medial, or midregion, hypothalamus—induced considerable overeatingand obesity; in contrast, stimulationof this area caused the rats to stopeating, even those previously unfed.W h e n r e s e a r c h e r s m a d e s m a l l l e s i o n sin another area—the outer, or lateral, hypothalamus—the rats stoppedeating. Some of the animals starvedto death, even though there was foodin their cages. Stimulation of thissame area, on the other hand, induced not only eating but licking,
chewing, salivating and active searching for food.
From these studies, some scientistshave assumed that the hypothalamuscontains a "satiety" (fullness) centerand a "feeding" or "appetite"center. These centers are acted uponby various body chemicals that signalt h e n e e d t o e a t a n d t h e n s t i m u l a t e
"hunger pangs," or recognition ofthe des i re t o ea t . Sc ien t i s t s s t i l l don ' tunderstand exactly how this processworks but they know what many oft h e c h e m i c a l s a r e .
O n e o f t h e fi r s t c h e m i c a l s i d e n t ified as giving such signals was gluc o s e . S c i e n t i s t s h a v e k n o w n s i n c e1916 that when blood glucose to thebrain gets low, a person gets hungry.When blood glucose rises—whichhappens when a person eats—appetite decreases. But how glucose actsin the brain to turn appetite on andoff is still a subject of speculation.
One theory is that there is sometype of glucose receptor in the brain,possibly in the ventromedial hypothalamus (satiety center). Thus, thetheory goes, eating causes blood glucose levels to rise, stimulating thefiring of neurons in the satietycenter. This suppresses the appetitecenter and inhibits eating.
Another theory is that high bloodglucose levels prompt the release ofinsulin by the body. Appetite iscurbed when insulin in blood plasmareaches a certain level. Regardless ofthe process, it seems to take time forglucose to act in the brain to causesatiety. That's why specialists advisepeople trying to lose weight to eats lowly.
Much current research on the physiological process of hunger involveschemicals called neurotransmitters,which transmit messages from nervest o o t h e r n e r v e s o r t o m u s c l e s . R educed appetite has been found whenthe brain has high levels of severalneurotransmitters, including serotonin, norepinephrine, epinephrineand dopamine. With serotonin, low
(continued on page 28)
26 / February 1984 / FDA Consumer
levels mean appetite increases.
It is the neurotransmitters that seem to be responsible for the loss of appetite caused by anorectic (appetite-suppressing) drugs. The first prescription drugs to be widely prescribed for appetite suppression were the amphetamines, central nervous system stimulants. However, amphetamines cause serious side effects as well as dependence, and they have gradually been replaced by newer and safer amphetamine-type drugs. Generally, these anorectic agents decrease appetite by stimulating the hypothalamus. According to the American Medical Association's reference book AMA Drug Evaluations (5th edition), the majority seem to facilitate the release of norepinephrine and dopamine; one (fenflura-
28 I February 1984 I FDA Consumer
mine) is thought to decrease appetite by facilitating metabolism of serotonin.
Anorectic drugs affect more than just appetite; they can have dangerous side effects, including hypertension. However, there's hope for dieters whose physicians recommend appetite-suppressing drugs: Three federal government neuroscientists recently reported on studies suggesting that drugs free of such side effects may be developed.
The scientists-Steven M. Paul and Bridget Hulihan-Giblin of the National Institute of Mental Health, and Phil Skolnick of the National Institutes of Arthritis, Diabetes, Digestive and Kidney Diseases-have identified specific binding sites for amphetamine derivatives in the brains of rats.
According to Skolnick, the studies suggested very strongly that the binding sites, found predominantly in the hypothalamus, are involved in the appetite-suppressing action of amphetamines. If this is proved, it opens the possibility of developing an anorectic drug that will act only on these sites to reduce appetite without side effects.
Serotonin has been studied by researchers at the Massachusetts Institute of Technology. Based on these studies, Judith Wurtman, Ph.D., a research scientist in the MIT Department of Nutrition and Food Science, has suggested the existence in humans of a specific hunger for carbohydrates.
(continued on page 30)
Drugs And Your Wa'istline
In the world of products promoted as appetite suppressants, a person can get pretty confused trying to decide what works and what risks each involves. Here's a sampling of the more common products one might encounter on the way to seeking slimness: • Prescription anorectic agents decrease appetite by stimulating thehypothalamus. These include amphetamines and newer drugs, whichare chemically related to amphetamines but have fewer side effects.According to the American MedicalAssociation's reference book AMADrug Evaluations (5th edition), amphetamines are ''not advocated forthe treatment of obesity because therisk of dependence is great. The FDABureau of Drugs has concluded thatthe amphetamines have no advantageover other anorectic drugs that haveless risk, and a few states have prohibited their use for weight control. "Prescription anorectic drugs recommended for treatment of obesityinclude mazindol, phentermine, anddiethylpropion. However, they arerecommended in conjunction withother weight-loss regimens such asdiet and exercise.
Side effects of prescription anorectics include nervousness, irritability, insomnia, blurred vision, dizziness, palpitations, hypertension, sweating, nausea, vomiting, and sometimes diarrhea or constipation. • Phenylpropanolamine (PPA) is theactive ingredient in most nonprescription weight-control products, such asDexatrim, Appedrine, Control, Dietac, Prolamine and Adrinex. PPA isrelated chemically and pharmacologically to amphetamines and affectsthe cardiovascular and central nervous systems similarly, but to a lesserdegree. Side effects include nervous-
ness, insomnia, headaches, nausea, tinnitus (ringing in the ears), and elevated blood pressure. People with high blood pressure or heart, thyroid or kidney disease should not take products with this ingredient except under the advice and supervision of a physician.
PPA is available in doses that equal 75 milligrams a day. In 1979, FDA's Advisory Review Panel on Over-the-Counter Miscellaneous Internal Drug Products, in its review of OTC weight-control products, said that PPA is safe and effective for short-term weight control (up to three months), but at dosages of 25 to 50 milligrams three times a daythat is, 75 to 150 milligrams a day.
Studies made available after the panel's report was submitted, however, have shown that doses of PP A
higher than 75 milligrams may cause a serious elevation in blood pressure. Until FDA completes its review of these findings, the agency will not permit PP A to be marketed at a dosage level higher than 75 milligrams per day. • Benzocaine, the active ingredient inA YDS candy and dietetic lozengesand gum, is a topical anesthetic saidto work by anesthetizing the tongue,reducing the ability to taste foods.Benzocaine is one of two nonprescription ingredients found safe andeffective by the FDA advisory panelthat reviewed OTC weight-reducingingredients. Animal and human studies reviewed by the panel indicatedthat use of benzocaine-containingproducts contributes to weight loss.According to AMA Drug Evaluations, however, "there are no conclusive data to support benzocaine'seffectiveness as an anorexiant."• Bulk producers are substances suchas methylcellulose (found in Meta-
mucil) that absorb liquid in the stomach, creating a feeling of fullness. The advisory review panel that reviewed OTC weight-control ingredients said that bulk producers are safe but their value in reducing weight has not been established.
Many bulk-producing products, such as methylcellulose, are used primarily as bulk laxatives (a use for which they were found both safe and effective). Some, however, are promoted primarily for weight loss.
One such product is Glucomannan, a chemically processed extract from konjac tubers (a root used as a food in many Oriental countries). According to some of the promotional literature, "Glucomannan absorbs liquid and forms a high-fiber gel that contributes to bulk in your digestive system. Bulk produces a feeling of fullness to help switch off your hunger center .... ''
FDA is not aware of any bulkproducing product that has been proven to be effective in causing weight loss. • Spiru/ina is a dark green powder orpill that has been promoted as aweight-loss product. Claims havebeen made that phenylalanine, anamino acid found in spirulina (and inmost other protein sources), "acts onthe brain's appetite center to switchoff your hunger pangs .... ''
FDA is not aware of any evidence that phenylalanine is safe and effective as an appetite suppressant. • Food supplements such as beepollen and certain herbal products(e.g., the Herbalife Slim and TrimProgram) are sometimes promoted bymanufacturers as effective in causingweight loss. No food supplement isapproved by FDA as safe and effective for this purpose.
FDA Consumer I February 1984 I 29
In her book, The CarbohydrateGraver's Diet, Wurtman said, ' 'Serotonin. . .is made from tryptophan, anamino acid. (Amino acids are thecomponents of protein.) When carbohydrate foods are eaten, insulin isr e l e a s e d i n t o t h e b l o o d . I n s u l i n i ncreases the amount of tryptophanthat gets into the brain and subsequently, the level and activity ofserotonin. When enough serotonin isproduced in the brain, it turns offthe hunger for carbohydrates."Wurtman claims that the craving forcarbohydrates can be satisfied onlyby carbohydrate foods because theyare the most effective in increasings e r o t o n i n i n t h e b r a i n .
More evidence supporting the linkbetween hunger and serotonin andnorepinephrine concerns a group ofdrugs called tricyclic antidepressants,which are used to treat depression.O n e c o m m o n s i d e e f f e c t o f t h e s e
drugs is increased appetite and overeating, particularly of carbohydratefoods. According to AM A DrugEvaluations these drugs work byaffecting levels of serotonin andnorepinephrine in the brain. Depression—one symptom of which isappetite change and resultant weightgain or loss—is thought to be linkedw i t h i m b a l a n c e o f t h e s e n e u r o t r a n smitters, as well as with a third,dopamine.
Dopamine, as well as epinephrineand norepinephrine, are produced bystress—both emotional and physical.They prepare the body for "fight orflight": They stimulate the heartbeatand respiration, inhibit gastric secretions, and stimulate blood glucose.
This is one reason exerc ise isrecommended in weight-loss programs. Exercise, in addition toburning calories, also helps suppresshunger. One theory is that physicalactivity, which places stress on thebody, leads to the release of dopamine, epinephrine, and norepinephrine. NIH's Dr. Skolnick observesthat, "It 's a pretty common anecd o t a l o b s e r v a t i o n t h a t i f s o m e o n eruns three miles or plays a prettyvigorous game of tennis, they won'treally be in the mood for a big meal
after that, and that feeling persistsf o r a f e w h o u r s . "
But is hunger all in the mind? Ones u b s t a n c e t h a t s e e m s c o r r e l a t e d w i t hf u l l n e s s i s a h o r m o n e c a l l e d c h o l e -
cystokinin, which is produced in theintestines after eating. A recent studysuggests that cholecystokinin may actindependently of the hypothalamusto decrease hunger. The study, donein 1981 by researchers at CornellMedical Center, purported to showthat cholecystokinin administered torats produces satiety by acting on theabdomen, through gastric nerve fibers. Most scientists, however, stillbelieve that cholecystokinin suppresses hunger by acting on thehypothalamus.
Hunger, in fact, does seem to originate predominantly in the mind—which is to say, the brain. Thestomach alone apparently has littleeffect on appetite. Trying to fool thes tomach seems to be i ne f f ec t i ve i n
weight control—despite claims forvarious diet products that bulk in thestomach aids in weight loss.
According to FDA's Advisory Rev i e w P a n e l o n O T C M i s c e l l a n e o u sInternal Drug Products, the value ofbulk-producing products in reducingweight by controlling appetite hasn o t b e e n e s t a b l i s h e d . M o s t o f t h e
products create bulk in the stomachby absorbing up to 50 times theirweight in water to form a soft hy-drated mass. It has been suggestedthat this mass creates a feeling offullness, thus reducing the desire toeat and causing loss of weight.
However, a study reviewed by thepanel found that the bulk producermethylcellulose (the active ingredientin some common laxatives) is almostcompletely gone from the stomach in30 minutes. The feeling of fullness isthus too short-lived to be very eff e c t i v e .
The comparative fullness or emptiness o f the s tomach seems to havelittle effect on whether a person feelshungry. Removing the nerves of thestomach does not in fact suppressappetite. And, say the authors of onephysiology text, "Nor does it seempossible on purely theoretical
grounds that a bulk-detecting systemcould maintain energy balance, sincethe caloric content of food may bearno relationship to its bulk"—that is,something other than bulk in thestomach must lead to satiety in orderto ensure that the proper amount ofnutrients are consumed. For instance,a person could fill his stomach withw a t e r a n d s t i l l s t a r v e .
"Feeding," says Skolnick, "is avery, very complex problem. And thehigher you go up the phylogenetictree [from simple to more complexanimal species], the more complicated feeding behavior becomes Forinstance, if you take away the senseof smell from many animals, orhumans, feeding behaviors may bedramatically affected." Similarly,altering the ability to taste food canaffect the desire to eat. Some studiesindicate that rats whose tongues havebeen anesthetized with tetracaine areless inclined to eat than those whoc a n s t i l l t a s t e t h e i r f o o d .
Generally, people want to curbtheir appetites because they're tryingto lose weight. But the two are notnecessarily correlated because thephysiological processes of hunger arenot the only factors involved in whypeople eat. People eat for many reasons—because they're bored, becauseit's dinner time, because the food isavailable. The chemical process thattakes place in the body is only onestimulus to eat. That's why weight-control specialists frequently advisepeople trying to lose weight to lookat their eating habits instead oftaking drugs to alter the body'sn a t u r a l m e c h a n i s m s .
The appetite, after all, is a marvelous physiological mechanism. It 'slike an internal mother, making sureyou eat enough each day to providethe needed fuel for your body. Although appetite may feel like an inconvenience at times, it's somethingyou can't l ive without.
Carol Ballentine is a member ofFDA's publications staff Also contributing to this article was MichaelL. Herndon, of the publicationss t a f f
30 / February 1984 / FDA Consumer
W h a f s T h i s G l u c o m a n n a n ?
One of the latest products on thef a d d i e t s c e n e i s G l u c o m a n n a n .
According to much of the promotional l iterature for the product,G l u c o m a n n a n i s " t h e a c t i v e f r a c t i o nof the natural konjac tuber," andone ad boasts that "for over 1,500years, the Japanese have used thisrare fiber to stay slim and losew e i g h t . "
There is, in fact, no evidence thatGlucomannan causes weight loss, andit is not approved by FDA for suchuse—or any other use. Neither is it agreat Oriental mystery.
The product called Glucomannanis made from the tubers of the plantAmorphophallus konjac, also calledAmorphophallus rivieri, which hasbeen widely cultivated in Japan,China, Indonesia and other countriesin East Asia. Its corms (or tubers)are commonly used as food in countries where it is grown. In a 1929account of Chinese culture, China—Mother of Gardens, author ErnestWilson says, "As an undercrop tomaize, Amorphophallus konjac iscommonly cultivated, the tubersbeing used as food after their acridproperties have been removed bywashing in water... .The tubers areground up with water and made intoa curd- l ike compound."
According to another source, flourfrom konjac tubers is commonlyused in Japanese dishes after beingm i x e d w i t h w a t e r t o f o r m a n e d i b l e
gel called "Konnyaku." This gel iss e a s o n e d a n d b o i l e d o r f r i e d . I nHawaii, the stalks are eaten afterbeing sliced, washed, dried andground up.
T h e " L a w r e n c e R e v i e w o f N a t u r a l
Products" (produced by Pharmaceutical Informat ion Associates Ltd.)describes konjac mannan as a polysaccharide (a large molecular weightsugar) derived from konjac flour.
The publication goes on to say thatpolysaccharides such as guar gumand methylcellulose are useful aslaxatives because of their ability toa b s o r b w a t e r a n d s w e l l i n t h e s t o mach and that "konjac mannan hasbeen reported to alleviate moderateconstipation in I to 2 days."
This ability to absorb water—andprovide a "feehng of fullness" in thes t o m a c h — h a s a l s o l e d t o t h e c l a i m sthat the product can promote weightloss. However, there is no evidencethat konjac mannan or any otherbulk producer is useful for thisp u r p o s e .
A. konjac is not commonly growni n t h e U n i t e d S t a t e s b u t c a n b efound sometimes in botanical gardensand some nurseries. Growing four ormore feet, it is an impressive sight,w i t h a s t a l k a b o u t t w o i n c h e s i ndiameter of an olive green color,speckled with rose. It flowers in earlyspring, bearing a bloom in variousshades of red that resembles a hugejack-in-the-pulpit. After the flowerdies, the plant produces a wide umb r e l l a - l i k e l e a f .
Those who might be tempted toacquire A. konjac, either for its ediblecorms or unusual appearance, shouldthink twice however. Although theflower is a wondrous sight, its smellis extremely noxious, resembling theodor of decomposing animal carcasses. It is not a surprise that theplant is also called Devil's Tongueand Skunk L i ly.
F D A C o n s u m e r / F e b r u a r y 1 9 8 4 / 3 1
Advice On \^ginal Products
Douching will not prevent preg- safe and effective for removing vag- inal products. Such particulate mater-nancy and the labels on vaginal inal discharge or secretions. The ial is potentially hazardous because itproducts should carry a warning to four, all marketed as douches, are is abrasive and irritating to thethat effect, a panel of non-govern- dioctyl sodium sulfosuccinate, non- tissues, the panel said,ment experts said recently. The panel oxynol 9, octoxynol 9, and sodium The panel's recommendations fora lso recommended a label s tatement laury l sul fate. label ing cal led for inc luding detai ledadvising pregnant women not to Five ingredients for the relief of instructions on mixing and usingdouche, except on the advice and minor irritation were deemed not douches. In addition to warnings oninstruction of a physician, because of safe and effective by the panel. They use of these products during preg-potential harm to the fetus. are hexachlorophene (already banned nancy, the labels should advise
This advice was part of the 58th— from vaginal products), phenol, women not to overfill the vaginaand last—panel report in FDA's 10- phenolate sodium, sodium salicylate, with fluid. Doing so can force theyear-plus review of the safety and and sodium salicylic acid phenolate. fluid into the uterus and cause ineffectiveness of the ingredients in and Such ingredients will have to be flammation.the labeling for all over-the-counter taken off the market within 12 What should not be included in(OTC) drugs. The vaginal drug prod- months after publication of the final vaginal product labels are claimsuct report came from the Advisory standards for vaginal products. such as "effectively cleanses," "rou-Review Panel on OTC Contraceptive There were insufficient data to es- tine feminine hygiene," "containsand Other Vaginal Drug Products, tablish the safety or effectiveness of only the mildest ingredients," orone of 17 panels assisting in the 28 of the ingredients for one or more "vaginal antiseptic."review. The report was published by of the claimed uses. The panel rec- Like the 57 panel reports that pre-FDA on Oct. 13, 1983. ommended further testing for these ceded it, the report of the advisory
The panel evaluated 38 active in- ingredients, including a familiar panel on OTC vaginal products wasgredients marketed for four types of home remedy, acetic acid (vinegar), published in the Federal Register byuse: relieving minor irritation of the and a stabilized form of aloe vera, a FDA to elicit public comments. Aftervagina, altering the vaginal acidity to plant with a centuries-old reputation the agency has reviewed the reportencourage the growth of normal vag- for healing. (All ingredients with itself and the comments on it, ainal bacterial flora, producing an their classifications are listed in the monograph or standard will be pub-astringent effect, and removing vag- accompanying table.) lished setting forth the acceptableinal secret ions. In addit ion to i ts evaluat ion of the ingredients and label ing for this class
Only 7 of the 38 ingredients were active ingredients, the panel noted of drug products,safe and effective for their intended that two inactive ingredients, silicause. Povidone-iodine is safe and and talc, should not be used in vag- —Annabel Hechteffective for the relief of minor vag-inal irritations, according to thepanel. The group also said that calcium and sodium propionate and D realized, in improved products, great-potassium sorbate are safe and effec- 1 ^ J\KUU^IAJ er safety, and reduced medical costs,t i v e f o r t h i s u s e . H o w e v e r , i n t h e i n s t r u c t e d b y F D A , t h e 1 7p r e a m b l e t o t h e r e p o r t , F D A s a i d i n p a n e l s o f n o n - g o v e r n m e n t e x p e r t sc l a s s i f y i n g c a l c i u m p r o p i o n a t e a n d c o n c e n t r a t e d o n a c t i v e i n g r e d i e n t ssodium propionate as safe and effec- The release of the OTC (over-the- that are contained in the 300,000 ortive the panel relied on studies that counter) advisory review panel report so drug products marketed underwere inadequate. Neither ingredient on vaginal drug products late last various names. In all, the panelshas been previously marketed in year was a milestone for FDA. It reviewed more than 700 ingredients,OTC vaginal drug products and, marked the end of a major phase of many of them several times becausetherefore, may not be marketed at the agency's massive review of the of their various uses in differentthis time. The agency also noted that safety and effectiveness of the hun- kinds of products,potassium sorbate has not been mar- dreds of thousands of nonprescrip- The panels found that only aboutketed to a material extent in the tion drugs sold in the United States. one-third of the ingredients are effec-United States and thus is considered The review, which generated 58 panel tive, as well as safe, for their intend-a new drug. It may not be marketed reports, began in 1972. ed uses. The rest require additionaluntil FDA has approved a New Drug Although much work remains to proof if manufacturers are to con-Application for use in vaginal drug be done to convert the panels' rec- tinue to market them, the panelsp r o d u c t s . o m m e n d a t i o n s i n t o r e g u l a t o r y a c t i o n , s a i d . T h i s d o e s n o t m e a n t h a t o n l y
Four ingredients were considered some consumer benefits have been one-third of all OTC drug products
32 / February 1984 / FDA Consumer
contain effective ingredients. Mostpopular products have safe and effective ingredients even if they sometimes contain other ingredients thatare ineffective or have not yet beenshown to be effective. For instance,the majority of products for painand fever contain aspirin or acetaminophen—both safe and effective—whereas questionable ingredients wererepresented in a small number ofproducts.
The panels not only reviewed thelabeling in use but often developednew labeling. For example, one panelrecommended putting a sunscreenprotection factor (SPF) number onsunscreen product labels to provideconsumers information to help prevent sunburn. That suggestion hasbeen widely adopted by the industry.
Based on panel recommendations,F D A h a s " s w i t c h e d " a n u m b e r o f
prescription drugs to OTC status,saving consumers millions of dollarsa year. The new OTC drugs include:• hydrocortisone creams and ointments for topical use• fluoride rinses and gels for fightingtooth decay• eight antihistamine or nasal decongestant ingredients for colds and hayf e v e r• diphenhydramine hydrochloride anddiphenhydramine monocitrate asnighttime sleep-aid ingredients• dyclonine hydrochloride as a painreliever and anesthetic in some rinses,mouthwashes, gargles, sprays andlozenges
(continued next page)
How The Vaginal ProductIngd^edients Rated
(S = safe and effective; N = not safe and effective; F = evidence of safetyand effectiveness insufficient; further testing needed.)
R e l i e f o f R e m o v e s
A c t i v e I n g r e d i e n t s m i n o r A l t e r s A s t r i n g e n t v a g i n a li r r i t a t i o n p H s e c r e t i o n s
A c e t i c a c i d F
A l k y l a r y l s u l f o n a t e F
A l l a n t o i n F
A l o e v e r a , s t a b i l i z e d F
A l u m F
B e n z a l k o n i u m c h l o r i d e F
B e n z e t h o n i u m c h l o r i d e F
B e n z o c a i n e F
B o r i c a c i d F F F F
B o r o g l y c e r i n F F F F
C a l c i u m a n d s o d i u m
p r o p i o n a t e S *
C i t r i c a c i d F
Diocty l sodiums u l f o s u c c i n a t e S
E d e t a t e d i s o d i u m F
E d e t a t e s o d i u m F
F l e x a c h l o r o p h e n e N
L a c t i c a c i d F
*FDA disagrees with panel recommendation
(continued next page)
FDA Consumer / February 1984 / 33
S o m e i t e m s h a v e b e e n r e m o v e dfrom the market as a result of panelrecommendations. In 1980, as aresult of the review, the agencyremoved sweet spirits of nitre fromthe market. The panel concluded thatthis product, used for many years tor e d u c e f e v e r i n c h i l d r e n a n d t o t r e a tcolic in infants, posed a risk toyoung children.
In 1982, FDA removed camphorated oil, a liniment, because it wasfrequently mistaken for castor oil orcod-liver oil, often with toxic results.(See ''What Ever Happened To Camphorated Oil?" in the July-August1983 FDA Consumer,)
Other ingredients no longer on themarke t as a resu l t o f t he rev iewi n c l u d e :• hexachlorophene, once common indeodorant soaps but now availableby prescription only for special antimicrobial purposes, removed afterdata showed it could cause damageto the central nervous system• tribromsalan, an ingredient removed from drugs and cosmeticsa f t e r i t w a s f o u n d t o m a k e s k i nsensitive to light• zirconium, still safe in most formsof antiperspirants but removed fromaerosol products because of concernit could cause lung nodules• bromides and scopolamine, voluntarily removed from sleep-aids bymanufacturers because of safetyc o n c e r n s
• methapyrilene hydrochloride andmethapyrilene fumarate, removedfrom all OTC drug products becausethese drugs have been demonstratedto cause cancer i n an ima ls
FDA also removed from nonprescription sale all daytime sedativeproducts promoted to relieve "simplenervous tension" after the panel reviewing them said people needingtranquilization or sedation during thedaytime should see a doctor and notrely on these antihistamine-containingproducts.
Vaginal Product Rating - Con V.
(S = safe and effective; N = not safe and effective; F = evidence of safetyand effectiveness insufficient; further testing needed.)
R e l i e f o f
A c t i v e I n g r e d i e n t s m i n o ri r r i t a t i o n
N o n o x y n o l 9 F
O c t o x y n o l 9 F
O x y q u i n o l i n e c i t r a t e F
Oxyqu ino l i ne su l f a te F
Papain
P h e n o l N
P h e n o l a t e s o d i u m N
P o t a s s i u m s o r b a t e S *
P o v i d o n e - i o d i n e S
S o d i u m b i c a r b o n a t e
S o d i u m b o r a t e F
S o d i u m c a r b o n a t e
S o d i u m l a c t a t e
Sodium lauryl sulfate
S o d i u m p e r b o r a t e F
S o d i u m s a l i c y l a t e N
Sodium salicylic acidp h e n o l a t e N
Ta r t a r i c a c i d
V i t a m i n A F
R e m o v e sA l t e r s A s t r i n g e n t v a g i n a l
p H s e c r e t i o n s
V i t a m i n D
Z i n c s u l f a t e
^FDA disagrees with panel recommendation
34 / February 1984 / FDA Consumer
C o n s u m e r F o m m
Successful Eye Surgery
The May 1983 edition of the FDA Consumerfeatured an article by Wallace F. Janssen, FDA'shistorian, entitled, "A Beholder Tells of a LensImp lan t . " . . .
The May article detailed Mr. Janssen's experiences with a cataract, an abnormality of theeye, eventual corneal surgery, and successfulrecovery thereafter.... For my family and I, thearticle was most timely. My mother, at 83 years ofage, had a cataract in her right eye. Of moreimportance was that she had reached that point inthe process of the disease where she had to makeo n e o f t h e t h r e e c h o i c e s w h i c h M r. J a n s s e n
pointed out and explained so well in his article.Her ophthalmologist, who also is a specialist incataract and corneal surgery, advised her of theoptions available and the choice was hers to make.
. .. despite being keen and well advised by herdoctor, she needed help in making her decision.She sought help from my sister and I.. .. I readher the article, stopping often to answer herquestions. Shortly thereafter, following someserious thought, she made the decision to have the
implanted lens. There is no doubt that Mr.Janssen's thoughtful and comprehensive articlewas the turning or convincing point in helping herm a k e h e r d e c i s i o n .
Surgery took place, almost exactly as detailed inthe article, on Oct. 5, 1983. On Oct. 17, 1983, anevaluation was made by the ophthalmologist. Thereport was excellent and my mother was so excitedt h a t s h e w a s t e d n o t i m e t o c a l l a n d t e l l m e a l labout it. She said, "Isn't that just great! Why Ican see better than you now. I can get my driver'sl i c e n s e b a c k . "
D a v i d G . F i e l dFDA program analystBoston Region
Sometimes editing a magazine has specialr e w a r d s .
They Like Safety Game
Thank you for offering such a unique game forchildren in regards to learning the safety of otherswith poisonings ("The Poison Safety Game,"
FDA Consumer / February 1984 / 35
March 1983 FDA Consumer.) Girl Scout TroopNo. 398 greatly appreciates this learningexperience.
S u e R a e A d e l m a n
Sheboygan, Wis.
How Many Died Of Flu
Author Timothy Larkin states in "Flu/Cold—Never The Strain Shall Meet," September 1983FDA Consumer, that "it has been estimated thatmore than 30 million people died in the UnitedStates" during the Spanish flu pandemic of 1918.That would be very nearly one person in three, asthe population of the United States in 1918 wasjust a touch over 100 million. The EncyclopediaBritannica (perhaps not the best source forAmericana, but authoritative nonetheless) gives thefigure as 548,000. I'm inclined to accept thatfigure
John T. PigottPebble Beach, Calif.
We goofed. Obviously, the editors weren't asskeptical as several informed readers were of somenew figures that were incorporated into the articleby mistake while it was under review in FDA.Although the Spanish flu pandemic of 1918-19took a terrible toll, the loss of human lives wasnot nearly as great as our figures indicated.Government and other estimates conservativelyplaced the number of deaths in the United Statesfrom flu and pneumonic complications at about550,000 above the normal 125,000 for the nine-month period that began in September 1918, or atotal of 675,000. The worldwide death toll duringthe pandemic's three waves was estimated to beover 21.6 million, nearly 15.8 million of these inAsia, 2.1 million in Europe, 1.3 million in Africa,1 million in North America, and less than amillion each in Australia-Oceania and SouthAmerica. However, one demographer estimatesthat 20 million died in India alone. After 65 years
T h e T r u t h A b o u t C o u m a r i n
1 would like to know the real truth aboutcoumarin. Page 11 of the October FDA Consumerstates, "There has been no indication that coumarin itself produces this blood-thinning effect inhumans," and on page 6 of the same issue is thisstatement, "Coumarins reduce the ability of theblood to clot." Please clarify this for me.
Gloria Tyndall, R.D.Spartanburg General HospitalSpartanburg, S.C. 29303
Although the use of coumarin as food or as afood additive was prohibited by FDA in 1954, thiswas based not on its blood-thinning properties buton demonstrated liver damage to test animals.Medical literature warns against the ingestion ofcoumarin and derivatives such as dicumarol whentaking certain other drugs, such as aspirin, becauseof the strong possibility of a drug interactioncausing internal bleeding.
FDA knows of no testing of coumarin inhumans, and therefore cannot say for sure thatcoumarin in food products will act as an anticoagulant, but the chemical similarity betweencoumarin and its derivatives used as anticoagulantdrugs is close enough for concern about a potential for adverse effects. The case study describingexcessive menstrual bleeding in a young womanwho had been drinking large quantities of herbalteas containing coumarin is obviously relevantenough to suggest caution in using coumarin in anherbal tea, in a flavoring extract, or ingesting inother ways. This makes good sense, even if therewere no proof whether the menstrual bleedingcould have been caused by other substances thewoman may have ingested, or interaction of suchs u b s t a n c e s w i t h t h e c o u m a r i n .
There are several derivatives of coumarin usedas drugs. Warfarin, for example, used as a blood-
36 / February 1984 / FDA Consumer
thinning medication, is a synthetic closely relatedt o c o u m a r i n .
M o r e O n ' M e l e n c o l i a I '
The reproduction of the engraving by AlbrechtDurer that has come to be known as "Melencolia1" for the article "Melancholy and the Muse" inFDA Consumer for October 1983 is appropriate,but the surmise quoted from Panofsky that it wasoccasioned by the artist's sorrow at the death ofhis mother is simply a guess. It misses the point ofthe picture entirely.
The star rising in the east is Sirius, the brighteststar in Canis Major, the constellation of the dog.This is further exemplified by the dog behind thebanner with the name and the dog sleeping in the
foreground. The period of the year must then beJuly, August and early September, since the artistis working in the north temperate latitudes whenCanis rises with the sun. These days have beenknown traditionally as "the dog days," a timewhen dogs are supposed to be subject to madnessand people are supposed to become listless,depressed and melancholic.
D u r e r h a d s t u d i e d m a t h e m a t i c s w i t h P a c i o l i i nVenice in 1494 and 1505. He drew the first printedstar maps in 1515, numbering the stars on thecharts according to Ptolemy's list. He wasattempting to do for the artist what Ptolemy haddone for the astronomer, to make a mathematicalscience of painting. In his engraving he showsUrania, the muse of astronomy, who is identifiedby the compass she holds and the globe at herfeet. The odd-looking solid behind the dog is anacute rhombohedron, one of many such thatDurer had worked with. The ladder against thebuilding, the scattered carpenter's tools, pieces ofwood, and lead being melted indicate thatconstruction is under way, but in abeyance,perhaps because the mood of the muse, and alsothe artist, is more contemplative than constructive.Even great minds can become depressed when theyreflect on the tasks ahead to convey their meaninga n d i n t e n t t o o t h e r s .
Al lan J. Ryan, M.D.E d i t o r - i n - C h i e f
Sportsmedicine Magazine
As noted in the caption accompanying the engraving, FDA Consumer'5 source of informationon the engraving was E. Panofsky's book AlbrechtDurer, Vol . I , pr inted by Pr inceton Universi tyPress in 1943. However, we would have liked tohave had Dr. Ryan's analysis before we printedt h e O c t o b e r i s s u e .
FDA Consumer / February 1984 / 37
Investigators'Reports
Of Pills ThatPack TooMuch Punchby Evelyn Zaraula
Eye of newt, and toe of frogWool of bat, and tongue of dog
—from Shakespeare's Macbeth
How do tiger bone, rhinoceroshorn, turtle shell, male mouse droppings and scorpions sound fortreating your ailments? Or a pill thatcontains about 23 different herbs, apotent prescription drug or two, andperhaps a dash of lead and cadm i u m ?
These are some of the ingredientsthat have turned up in so-calledChinese herbal remedies, peddled toa r t h r i t i s s u f f e r e r s a l l o v e r t h e U n i t e dS ta tes unde r a dozen names . These
pearl-sized, black or brown pillsalmost always promise the buyer longlife and freedom from pain. Sometimes, though, they end up delivering
ser ious i l l ness o r dea th .Herbal remedies from the Orient
are nothing new. They've been coming into the country for over a century from Taiwan, Hong Kong andSingapore. For most of that timeusers o f t he remed ies haven ' t r e
ported any particularly harmful effects to health authorities. However,experience with the pills has taken amore sinister turn in the past 10years or so. Some people have diedfrom the pills; many cases of illnesshave been reported to FDA.
What has changed? In a 1975 article in the Journal of the AmericanMedical Association, two Universityof California physicians speculatet h a t m a n u f a c t u r e r s o f t h e C h i n e s eherbal remedies, hoping to cash in onthe popularity in this country ofhealth foods and "organic medicines," have put a little somethingextra in their pills. Potent antiinflammatory and analgesic drugshave been added, probably to insureimprovement of painful symptomsand to attract repeat customers.
Analytical tests have revealed thatthe manufacturers also randomlyvary both the drug combinationsfrom time to time and the amount of
each drug, depending probably onthe availability of the individual drugcomponents. Or maybe they figure ifthey include a variety of drugs in thepills, they are bound to relieve something.
Sometimes they do, and that'sunfortunate. Some who use them feelbetter, have less pain, less discomfort. The danger is that many patients may already be taking drugsprescribed by a physician, and thedrugs in the herbal remedies may interact with the other medications, orcause serious side effects, often withtragic results.
In 1974 in the San Francisco Bayarea three cases of serious illness andone death were reported from agranulocytosis—a sudden drop in the production of certain white blood cellsthat leaves the body defenselessagainst bacterial invasion. The patients had been taking 8 to 12Chinese herbal pills daily for weeksor months to relieve arthritis or backpain.
Analysis of the pills showed theycontained aminopyrine—a drug nolonger legal for sale in the UnitedStates—and phenylbutazone, apowerful anti-inflammatory agent.
38 / February 1984 / FDA Consumer
The Arthritis Foundation reports thato t h e r h e r b a l r e m e d i e s f r o m t h eOrient analyzed at the same timewere found to contain steroids,minor tranquilizers and commonpainkillers. Nowhere on the packagesor the inserts were these drugsmentioned—only herbal substances.
In 1980 FDA received reports of adeath, in Atlanta, of a rheumatoidarthritis victim who had been taking''Chuifong Toukuwan" pills containing indomethacin, an anti-inflammatory drug. Also reported fromNew York was the serious illness of aman who took pills containinghydrochlorothiazide, a diuretic.
FDA has warned the public andh e a l t h o f fi c i a l s o n a n u m b e r o f o c c as i o n s a b o u t t h e C h i n e s e h e r b a l r e m edies. The agency has asked the U.S.Cus toms and Pos ta l Se rv i ces t o detain the pills if they come into thecountry—but these products are hardto keep out.
They enter the United States in thebaggage of or on the persons oftravelers. They are mailed in smallshipments from the Far East tohealth food stores. Oriental goodsstores, novelty shops, and evendirectly to the consumer. Or theymay be smuggled in from Mexico orC a n a d a .
A typical shipment of this kindcontains 60 pills and is packaged in acellophane bag or glass bottle. It maybe enclosed in a brightly coloredcardboard box. Depictions of menand women suffering from back orleg pains may appear on the package.
Labeling may be in English and suggest that the pills are good for arthrit is, osteoarthrit is, rheumatism, bonepain, neuralgia or similar conditions.Or there may be no labeling at all.The pills sell in the neighborhood of$55 to $60 per hundred. When pillsare detained and shipped back to thedistributor, the customer may losemoney but still benefit by avoidingthe peril of the pills themselves.
One of the larger distributors ofthese pills on the East Coast wasidentified through a chain of eventsplayed out on the West Coast. Aconcerned citizen complained to theOregon State Board of Pharmacythat a little gift shop in Tillamook,Ore., was selling pills for arthritis.The Tillamook police collected someof the pills and submitted them tothe state pharmacy board, whicht u r n e d t h e m o v e r t o F D A ' s S e a t t l edistrict laboratory for analysis. Whenthe lab report revealed that they contained phenylbutazone, the policeseized the remainder of the shop'sstock of pills. The gift shop ownertold officials his supplier was the JenTai Co. in Port land, Ore.
FDA investigators called on thePortland company, a tiny Orientalapothecary shop, a place fragrantthroughout from herbs in jars thatlined the walls of the shop.Customers, Asians and non-Asiansalike, would bring in slips ofpaper—given to them by acupunct u r i s t s o r ' ' h e a l t h c o u n s e l o r s . " T h e
papers contained the names of vario u s h e r b s . T h e s t a f f w o u l d b l e n d a n
herb mixture as directed on the slipsof paper.
But the shop had other things forsale, specifically certain medicationscalled Tai Fung arthritis pills, thesame pills that had turned up inT i l l a m o o k . W h e n F D A w a r n e d t h e
owner, Jen Tai Tsui, both verballyand in writing that the pills wereunapproved new drugs, he agreed tostop distributing them and promisedto destroy all that he had left.
Just to make sure he had done so,a Seattle investigator then ordered asupply by mail. He received the pills,and they were accompanied by an inf o r m a t i o n s h e e t t h a t r e c o m m e n d e d adose starting at 12 pills a day anddecreasing gradually to six to eightpills daily. An analysis by the Seattledistrict lab showed that each pill contained 16 to 17 milligrams ofphenylbutazone. Taken as directed,the pills would have presented ah e a l t h t h r e a t a n d c o u l d h a v e b e e nf a t a l .
F D A a s k e d t h e c o u r t f o r a n i n
junction against the Jen Tai Co. andits owner, charging sale of prescription drugs without a valid prescription, misbranding through illegallabeling, and other violations of theFood, Drug and Cosmetic Act.
Jen Tai Tsui signed a consentdecree of permanent injunction,agreeing to stop selling the drugs. Healso was required to post a notice ina conspicuous place in his shopwarning customers that the pills contained phenylbutazone and could bedangerous, and was required to so
FDA Consumer / February 1984 / 39
a d v i s e h i s m a i l - o r d e r c u s t o m e r s . H ea s k e d a l l h i s c u s t o m e r s t o r e t u r nwhatever pills they had for destruction under FDA supervision.
Tsui told FDA he had bought thepills from an Oregon travel agent,who in turn implicated the NewWorld Trading and Travel Co. inPhi ladelphia.
In May 1983 a U.S. customs agentassigned to the case spotted andrecognized the proprietor of NewWorld Trading and Travel Co. as thesame man who just the month beforeh a d m a d e a f a l s e d e c l a r a t i o n o f
goods from the Orient. What he haddeclared as teas and spices was infact powdered rhinoceros horn, muchprized by certain Asians for restoringsexual vigor. Trading in rhino horn is
prohibited by the Endangered SpeciesAct. The rhino powder was deniedadmission into the country.
After that episode, FDA and theC u s t o m s S e r v i c e f o c u s e d m o r e a t t e ntion on the little travel agency.Customs sent two young womenagents to the shop, and they encountered no trouble buying both rhinohorn powder and a Chinese herbalmedicine (Chuifong Toukuwan).Based on the undercover buys, alongwith the previous fraud, smugglingand violations of Endangered SpeciesAct, Customs obtained a warrant tosearch the premises of the NewWorld Trading and Travel Co.
On Aug. 5, 1983, a U.S. customss e a r c h t e a m a n d t w o F D A i n v e s t i
gators entered the travel agency. The
search revealed the firm to be a largesmuggling, repacking and distributionc e n t e r f o r C h i n e s e h e r b a l m e d i c i n e s .Placed under seizure were 6,055boxes of Chuifong Toukuwan, 905boxes of rhino horn powder, 275b o x e s o f m i s c e l l a n e o u s C h i n e s e m e d i
cines, and 19 boxes of U.S.-manufactured prescription antibiotics thatwere being held for sale withoutprescriptions. The total value was$91,958.
U.S. Customs is continuing its investigation, an investigation that maysave some unsuspecting folks fromwasting money on dangerous and un-proven Chinese witches' brew.
Evelyn Zamula is a member ofFDA's publications staff.
Quacks Used SmugglingTo smuggle means to import or ex
port anything without paying lawfulcustoms charges or duties. And itwas because of a smuggled packaget h a t F D A ' s D a l l a s d i s t r i c t o f fi c e fi r s tlearned about the illegal activities ofA r t h u r a n d L u c i l l e U s n e r .
A year or so ago Mr. Usner wasstopped at the U.S.-Mexican borderby a U.S. customs official who wasinterested in a package Usner didn'tb o t h e r t o d e c l a r e . B e c a u s e i t c o ntained a drug. Customs notifiedFDA. In a fol low-up investigation,D a l l a s d i s t r i c t o f fi c i a l s l e a r n e d t h a t
the Usners were using their home inAlbuquerque, N.M., to run a busin e s s c a l l e d M e t a b o l i c P r o d u c t s .
Later a physician called FDA's at-
t e n t i o n t o a M e t a b o l i c P r o d u c t s a d
offering a variety of unfamiliar drugproducts for sale to cure an unusuall i s t o f h u m a n a i l m e n t s . T h e D a l l a sd i s t r i c t ' s m e d i c a l o f fi c e r m a d e a nundercover buy and received not onlythe drugs he ordered but bookletsdescribing the Usners' products andthe many conditions they claimedc o u l d b e t r e a t e d . T h e U s n e r sspecialized in alternative cancertreatments, all consisting of unapproved new drugs. The booklets weresubsequently used as evidence ofunapproved label ing.
Investigation of the Usners' homeb u s i n e s s r e v e a l e d a s t o r e h o u s e o f i l
legal drugs, most smuggled into theUnited States from Germany disguised as gifts. U.S. customs officialsseized approximately $15,000 worth
40 / February 1984 / FDA Consumer
of the smuggled drugs still in theirshipping packages. At FDA's requestthe New Mexico Board of Pharmacyembargoed the remaining drugs untilan injunction was filed on Aug. 17,1983.
When FDA investigators sorted outthe embargoed stocks, they found anastonishing number and variety ofdrugs, including injectable productsmade from parts of animals to cureailments of the corresponding partsof humans, tablets and injectableforms of Laetrile, KH3 (a version ofthe so-called rejuvenating drugGerovital), and even DMSO. Theembargoed stock, worth approximately $8,000, was destroyed in alandfill under the supervision ofF D A a n d t h e N e w M e x i c o B o a r d o f
Pharmacy.As a result of these actions, the
Usners en te red in to a consen t decreethat permanently enjoins them fromany activity involving any articleregulated by FDA unless such activity is reviewed and approved by theagency. It was estimated that theUsners' business in illegal and/orsmuggled drugs totaled more than$500,000 over a two-year period.
S e c o n d L o o k
People who have a fear of flyingmight be too nervous to eat and thuswouldn't worry about the safety ofthe food served aboard an airliner,b u t m o s t a i r l i n e t r a v e l e r s t a k e i t f o r
granted that whatever is offered willbe sa fe and who lesome.
FDA investigators routinely inspectfood and drink, including drinkingwater, served on airliners and onother conveyances that travel in interstate commerce—ships, buses andt r a i n s .
Because caterers generally preparefood served on airliners, FDA investigators inspect catering facilitiesto make certain the food is preparedproperly. FDA classifies the facilitiesas ''approved," "provisionally approved," or "not approved." Conveyances are not permitted to dealw i th ca te re rs tha t a re c lass ified as"not approved."
Ogden Food Service Corp. is oneof the catering businesses servinga i r l i n e s o u t o f N e w Yo r k ' s J F K I nternational Airport, one of thebusiest in the world. FDA's Brooklyn
district office is responsible for inspecting the caterers serving this airport as well as the smaller, but alsoextremely busy, LaGuardia Airport.An estimated 50,000 meals per dayare produced by the caterers servingthese airports.
In July 1983 district investigatorsmade a routine inspection of Ogden's
facilities at the airport and foundseveral objectionable conditions andpractices, the most serious being improper storage of food and the useof unclean equipment. Based on thisinspection, the firm was classified as'' provisionally approved.''
This meant that all carriers beingcatered by Ogden were required to be
FDA Consumer / February 1984 / 41
notified of FDA's findings, andsignificant improvements had to bemade within 30 days or the classification would be changed to "not approved." The firm improved on itsconditions and practices, and theclassification was changed to "approved" following a reinspection bythe Brooklyn FDA office.
B l o o d Te s t
Investigators from FDA's Bostond i s t r i c t f o u n d d o u b l e t r o u b l e w h e n
they checked a report of inaccuracyof a medical device made by CopleyPharmaceuticals Inc., Boston.
The first problem was with thedevice itself—a copper sulfate solution commonly used to test thehemoglobin content of potentialblood donors. In the test a sample ofthe potential blood donor's blood isdropped into the copper sulfate solut i o n . P r o t e i n i n t h e b l o o d r e a c t s w i t hthe solution to form a sac of copperproteinate, which encases the sample.If the blood has a satisfactory, orhealthy, level of hemoglobin, the sacw i l l s i n k t o t h e b o t t o m o f t h e s o l ut i o n . B u t i f t h e b l o o d i s d e fi c i e n t i n
hemoglobin—if the person hasanemia, for instance—the sac willremain suspended for 15 or moreseconds before sinking or will floatt o t h e s u r f a c e .
The labels on bottles of coppersulfate list the product's specificgravity, which affects the sac'stendency to sink or float. For correcttest results, this labeled figure mustbe accurate. In the case of CopleyPharmaceuticals' products, it wasn o t .
A n u r s e f r o m a C a l i f o r n i a b l o o dbank had reported to FDA that aquality control analysis done by the
blood bank found that the specificgravity of the product was less thani n d i c a t e d o n t h e l a b e l . F D A ' s e n s u
ing inspection determined that thecompany was aware of the problema n d a t t r i b u t e d i t t o i n a c c u r a c i e s i none of its pyknometers, an instrument used to measure specific gravity. Evidently the cap on thepyknometer had been replaced by acap from a different model, alteringthe weight of the device.
The firm said it had repaired thepyknometer and had advised consignees to destroy the defective product. However, when investigatorsm a d e a v e r i fi c a t i o n c h e c k o f c o m
pany files, they found a second prob l e m : T h e r e w e r e s e r i o u s d e fi c i e n c i e sin the company's procedures forrecording complaints and conductingr e c a l l s .
For instance, the company had norecord of the complaint that led tothe FDA inspection. There was nod o c u m e n t a t i o n o f t h e fi r m ' s c l a i m e d
attempts to recall the defective product, such as copies of letters orrecords of phone calls. And althoughcompany officials said 600 cases ofthe copper sulfate solution had beendestroyed, they did not remember thename of the company that did thework and had no proof of paymentfo r such se r v i ces .
The district accordingly requestedthat the firm formally recall all lotsof the product that might be defective, this time with appropriated o c u m e n t a t i o n a n d u n d e r F D Asuperv is ion.
— This small sample of reports fromthe field was compiled and edited byAnnabel Hecht, Carol Bal lent lne,M i c h a e l H e r n d o n a n d R i c h a r d
Thompson.
42 / February 1984 / FDA Consumer
T h e N o t e b o o k
The Notebook: a potpourri of items of interestgathered from FDA news releases, other newssources, and the Federal Register (designated PR,with date of publication). The Federal Register isavailable in many large public libraries.
■ The isotope CaIiforniuin-252 has FDA'sapproval for use as a sealed neutron source for themeasurement of moisture in the inspection of rawand packaged food, and in controlling food processing (FR Oct. 11, 1983).
■ FDA's Office of Orphan Products Developmentis looking for a sponsor to submit a new drug application for a compound including citric acid,gluconic acid and magnesium hydroxycarbonate todissolve urinary tract calculi and to preventencrusting of indwelling urinary tract catheters {FRNov. 10, 1983).
■ The Treasury Department's Bureau of Alcohol,To b a c c o a n d F i r e a r m s h a s i s s u e d a fi n a l r u l e r e
scinding ingredient labeling regulations for alcoholicbeverages. Mandatory label disclosure of FD&CYellow No. 5 is still required to alert those peoplewho are allergic to this dye {FR Oct. 6, 1983).
■ Drugs that are switched from prescription tononprescription status need a new National DrugCode (NDC) number. NDC is FDA's system foridentifying drug products. The agency said themarketing of an OTC drug with the same NDCnumber that it had as a prescription drug slows theprocessing of health insurance reimbursement claims{FR Nov. 30, 1983).
■ Corn containing between 20 and 100 parts perbillion aflatoxin can be shipped interstate if stateofficials assure FDA the corn will be fed only tomature beef cattle, swine and poultry and will notbe used for dairy or immature animals or in cornproducts for human consumption. Drought andhigh humidity in 1983 contributed to the development of aflatoxin, a potentiallyh a r m f u l t o x i n
caused by mold. The policy will remain in effectuntil January 1985 {FR Nov. 25, 1983).
■ The Public Citizen Health Research Group haspetitioned FDA to include a pregnancy-nursingwarning on all over-the-counter (OTC) drugsregardless of how they are used. Labels of OTCdrugs intended for systemic absorption (i.e., takenorally) must include the warning: "As with anydrug, if you are pregnant or nursing a baby seekprofessional advice before using this product."Drugs used topically (on the skin) and mouthwashesregulated as drugs are not covered by this regulation{FR Nov. 30, 1983).
■ FDA is proposing to amend the performancestandard for laser products to, among other things,extend the applicable wavelength range, simplifyand clarify certain definitions, and modify requirements for safety interlocks {FR Nov. 30, 1983).
■ MARKET BASKET: FDA has proposed revoking GMP (good manufacturing practice) regulationsf o r s m o k e d a n d s m o k e - fl a v o r e d fi s h . T h e
regulations have not been enforced since a 1977 ruling by the U.S. Court of Appeals for the SecondCircuit held that the smoked whtiefish regulationwas promulgated in an arbitrary manner and wasinvalid. .. .Also proposed are amendments to FDA'sstandards of identity for canned bean sprouts, limabeans, carrots, green sweet peppers, red sweet peppers, and potatoes to permit the use of calcium saltsas firming, or crisping, agents {FR Oct. 21, 1983).
Interested persons have been asked to review theinternational standards for quick-frozen fillets ofcod and haddock, ocean perch and flat fish and toc o m m e n t o n t h e n e e d f o r s i m i l a r U . S . s t a n d a r d s
{FR Nov. 15, 28 and 30, 1983).July 1, 1985, is the effective date for FDA's new
regulation permitting the use of antimycotics on thesurface of bulk forms of a variety of cheeses, including Asiago, Caciocavallo Siciliano, mozzarella,and provolone {FR Oct. 24, 1983).
Four issues relating to the standard of identity forbaked products have been resolved following aformal evidentiary public hearing: Lecithin wil l bepermitted as an optional ingredient in egg bread aswell as in other bakery products; spices, spice oil,and spice extract may be used even though they impart an egg-like color; artificial coloring as anoptional ingredient in standardized bakery productsis permissible; and the standard of identity for thevarious types of egg breads requires a minimumcontent of the whole egg solids of one medium-sizedegg per pound {FR Nov. 9, 1983).
F D A C o n s u m e r / F e b r u a r y 1 9 8 4 / 4 3
Summaries of I Court Actions
Summaries of Court Actions are given pursuant to section 705 of theFederal Food, Drug, and Cosmetic Act. Summaries of Court Actions report cases involving seizure proceedings, criminal proceedings, and injunction proceedings. Seizure proceedings are civil actions taken againstgoods alleged to be in violation, and criminal and injunction proceedings are against firms or individuals charged to be responsible for violations. The cases generally involve foods, drugs, devices, or cosmeticswhich were alleged to be adulterated or misbranded or otherwise violative of the law when introduced into and while in interstate commerce,or while held for sale after shipment in interstate commerce. Full courtopinions for these cases are published by either the West PublishingCompany or the Commerce Clearing House Inc. Texts can be obtainedfrom Commerce Clearing House at 1301 Pennsylvania Ave., N.W.,Washington, D.C. 20004.
Summaries of Court Actions are prepared by Food and Drug Division,Office of the General Counsel, HHS.
Published by direction of the Secretary of Health and Human Services.
S E I Z U R E A C T I O N S
F o o d s / P o i s o n o u s a n d D e l e t e r i o u s S u b s t a n c e s
PRODUCT: Swordfish, frozen, at Rochester, W. Dist. N.Y.;C i v i l N o . 8 2 - 1 0 2 0 - T.CHARGED 11-3-82: When shipped by Crocker & WinsorSeafoods, Boston, Mass., the article contained the addedpoisonous and deleterious substance mercury, which mightrender it injurious to health—402(a)(1).DISPOSITION: Default—ordered destruction. (F.D.C. No.63875; S. No. 82-252-486; S.J. No. 1)
Foods/Contamination, Spoilage, Insanitary HandlingPRODUCT: Basil, and anise seed, at Brooklyn, E. Dist.N.Y.; Civi l No. 79-C-814.CHARGED 3-28-79: While held by Gel Spice Co., Inc.,Brooklyn, N.Y., the articles contained rodent filth and hadbeen held under insanitary conditions—402(a)(3), 402(a)(4).DISPOSITION: Consent—authorized release to the dealerfor salvaging. After some delay, the dealer changed plans anddestroyed the articles. (F.D.C. No. 62218; S. No. 79-184-894;S.J. No. 2)
PRODUCT: Pinto beans ( two lots) , at Yakima, E. Dist .Wash.; Civi l No. C-82-335-RJM.CHARGED 4-30-82: While held by Northwest Produce Co.Inc., Yakima, Wash., one lot of the pinto beans contained
rodent filth, and both lots had been held under insanitaryconditions—402(a)(3), 402(a)(4).DISPOSITION: Consent—authorized release to the dealerfor salvaging. (F.D.C. No. 63711; S. No. 82-279-447; S.J.No. 3)
PRODUCT: Tomatoes, peeled, canned, at Miami, S. Dist.Fla.; Civi l No. 83-0390-Civ-EBD.CHARGED 2-16-83: While held for sale, the article was contained in swollen, rusty and/or leaking cans—402(a)(3).DISPOSITION: Default—ordered destruction. (F.D.C. No.63966; S. No. 83-268-780; S.J. No. 4)
Drugs/Human UsePRODUCT: Phendimetrazine tartrate tablets and capsules,at Louisville, W. Dist. Ky.; Civil No. C78-0358-L(A).CHARGED 9-6-78: When shipped by various manufacturers, the articles—labeled in part "QC Timely AppeasseTablets. . . Distributed by Queen City Pharmacal Co., Cincinnati, Ohio," "Phendimetrazine Tartrate tablets 70 mgspeckled Barr Laboratories, Inc., Northvale, N.J.," "ObeparTD. . . Capsules Manufactured for Parmed Pharmaceuticals,Inc., Niagara Falls, N.Y.," "Tutag . . . Detroit, Michigan[or 'Broomfield, Colorado'] . . . Granucaps," and"Phenazine Timecaps . . . Anorexiant. . . Mfg. For: M.M.Mast & Company Cleveland, Ohio"—were new drugs withouteffective approved New Drug Applications—505(a).DISPOSITION: Default—ordered destruction. (F.D.C. No.61849; S. No. 78-132-602 et al.; S.J. No. 5)
M e d i c a l D e v i c e s
PRODUCT: Muscle stimulators, electrical, Bio-Tone, at Sandy Springs, N. Dist. Ga.; Civil No. C8I-75A.CHARGED I-13-81: The articles, which had been distributedby Bio-Body Centers of America, Inc., New York, N.Y., wereaccompanied by a brochure (labeled in part "Bio-Trim Slimming Center . . . Lose Inches Lying Down") and charts (labeled in part "Muscle Group . . . Abdominal Muscle . . .Heavy Hips and Legs"), which labeling contained false andmisleading claims for having dramatic inch reduction, contributing to fat loss by general improvement in ' 'the muscletones in your body," creating a feeling of health and well-being, and being particularly good for flab over the "iliacchest"—502(a); the articles' labeling lacked adequate direc-
44 / February 1984 / FDA Consumer
tions for use for their intended purposes (weight reductionand slimming) and were not exempted—502(0(1); and the articles' labeling lacked adequate warnings against unsafeuses—502(0(2).DISPOSITION: The articles were claimed by VernonBrabham Jr., Sandy Springs, Ga., and Medequip InvestmentCorp., Columbus, Ga. A consent decree of condemnation(entered into by the claimants in the interests of resolving thecontroversy and without admitting to knowledge of the alleged violations prior to the date the complaint was filed)authorized release of the articles for bringing into compliance,by relabeling the devices with revised labeling and with theprescription device legend. The decree prohibited theclaimants as follows: from claiming effectiveness for the purposes charged in the complaint; from claiming that such articles might be used without the prescription of a licensedpractitioner; from using the articles outside a valid doctor/patient relationship; and from using the articles in their "Bio-Trim Slimming Center" establishment.
However, the articles were not relabeled. The claimantsmoved for reconsideration of the consent decree of condemnation, and moved for leave to amend their claim and to asserta defense and counterclaim against the government. Thegovernment asserted that the claimants had failed to complywith the terms of the consent decree and moved for a defaultdecree ordering the articles destroyed. The government alsoopposed the claimants' motions. On Dec. 21, 1982, the courtfound for the government. The court found the following: that the claimants were not able to meet the burden ofshowing either newly discovered evidence or a change in circumstances that worked a grievous wrong; that the amendments sought by the claimant would be subject to dismissaland were therefore futile; and that, since the claimants showedno willingness to comply with the terms of the consent decree,the articles should be destroyed. (F.D.C. No. 63169; S. No.80-164-287; S.J. No. 6)
C R I M I N A L A C T I O N S
DEFENDANTS: J.H. Haar & Sons, and George A. Haar,president. North Bergen, Dist. N.J.; Cr. No. 81-6139G-01.CHARGED 9-16-81: Rice (count 1) and pancake flour mix(count 2) were held under insanitary conditions and were contaminated with rodent filth—402(a)(3), 402(a)(4).DISPOSITION: Guilty plea by corporation to both counts;
$10,000 fine on count I, $10,000 fine on count 2 suspended,and probation for three years. Guilty plea by individual; imprisonment for six months suspended, and probation for twoyears, with a special condition of probation being paymentof $1,000 fine. (F.D.C. No. 63188; S. No. 80-209-462; S.J.No. 7)
DEFENDANTS: International Baking Co., Inc., SimonMani, president. Jack Khashon, vice president, and HatemSafar, plant manager, Arlington, N. Dist. Texas; Cr. No.4 - 8 2 - 11 4 .CHARGED 10-19-82: One lot of hulled sesame seeds (count1) and two lots of whole wheat flour (counts 2 and 3) wereheld under insanitary conditions in a building accessible toinsects and were contaminated with insect filth—402(a)(3),402(a)(4); and, when shipped to Shreveport, La., whole wheatbread (count 4), labeled in part "Mr. Pita Whole Wheat Bread. . . International Baking Co., Inc. General Office . . . Vernon, Calif.," had been prepared and packed under insanitaryconditions-402(a)(3), 402(a)(4).DISPOSITION: The corporation pleaded guilty to count 1and was fined $ 1,000. Simon Mani pleaded guilty to counts1, 2 and 3 and was fined $1,500. Jack Khashou pleaded guilty to counts I and 4 and was fined $1,000 and sentenced toimprisonment for one year; the imprisonment was suspended and probation imposed for two years. Hatem Safar pleadedguilty to count 1 and was sentenced to imprisonment for sixmonths; the imprisonment was suspended and probation imposed for one year. (F.D.C. No. 63627; S. No. 81-210-574et al.; S.J. No. 8)
DEFENDANTS: Pittston Warehouse Corp., and Robert F.Chiarello, president, Brooklyn, E. Dist. N.Y.; Cr. No.8 0 - 0 0 - 3 1 5 .CHARGED 7-1-80: Sage leaves, mustard seed, marjoram,poppy seed, chilies, pimento, basil leaves, ginger, and cassiafrom Indonesia, China, Seychelles and Madagascar were heldunder insanitary conditions in a manner accessible to rodentsand insects and were contaminated with rodent and/or insect filth—402(a)(3), 402(a)(4).DISPOSITION: The defendants served a demand for a billof particulars, a notice of motion for discovery and inspection, and a notice of motion to suppress inspectional evidence.Subsequently, a consent decree of permanent injunction wasentered into and the criminal action was dismissed. (F.D.C.
FDA Consumer / February 1984 / 45
No. 62093; S. No. 78-140-783; S.J. No. 9)
I N J U N C T I O N A C T I O N S
DEFENDANTS: Alva Vet Supply Co., Donald E. Peter-mann, partner, and Michael B. Stevens, partner, Alva, W.Dist. Okla.; Civil No. 82-2048-R.CHARGED 11-10-82 in a complaint for injunction: Thatveterinary prescription drugs, including chloramphenicol, dex-amethasone and isoflupredone acetate, were held for sale, offered for sale, and sold to unauthorized persons without aprescription or other order of a licensed veterinarian; that,accordingly, as prescription veterinary drugs, their labelinglacked adequate directions for lay use and were not exemptedfrom such requirement because the drugs were not being soldonly to or on the prescription or order of a licensedveterinarian and were not in the possession of a licensedveterinarian for his professional use; that, despite warnings,the defendants continued to violate the law; that an FDA inspection revealed drug storage and record-keeping deficiencies, including a lack of filed prescriptions and the storageof prescription drugs on retail shelves in easy reach of anylay person entering the store—502(f)(1).DISPOSITION: A consent decree of permanent injunctionenjoined the complained of violation and enjoined the saleof any prescription veterinary drug unless and until: procedures were established so all such prescription drugs werestored in an area accessible only to firm employees; procedures were established so such prescription drugs were soldonly to or on the prescription of a licensed veterinarian;records were established and maintained demonstrating thatevery such sale was properly based; an accurate drug inventory was prepared and maintained; and the defendantsreported to FDA on the measures that they had taken toassure compliance. (Inj. No. 1014; S. No. 82-267-541 et al.;S.J. No. 10)
DEFENDANTS: Fry Krisp Food Products, Inc., Richard G.Neuenfeldt, president and treasurer, and Richard J.Neuenfeldt, vice president and plant manager, Jackson, E.Dist. Mich.; Civil No. 82-60417.CHARGED 12-13-82 in a complaint for injunction: That thedefendants, at their Jackson, Mich., plant manufactured, processed, packed, labeled, held and distributed in interstate commerce dry breading and batter mixes that had been prepared.
packed and held under insanitary conditions; that the defendants, at their Jackson, Mich., plant, had also manufactured,processed, packed and labeled such foods, which were heldfor sale after interstate shipment of their components; thatFDA inspections of the defendants' plant had disclosed anumber of specified insanitary conditions; and that the defendants had been repeatedly warned of the insanitary conditions and practices in their plant—402(a)(4).DISPOSITION: The defendants moved to seal the court file,and to suppress access to the file except to those involved inthe litigation. The government opposed such motion to suppress, arguing that the disclosure of the FDA investigativereports (the basis for the action) was mandated by statute,and that to grant the motion to suppress would be, in effect,enjoining the operation of FDA regulations relating to thepublic disclosure of information. The court ruled in favor ofthe government. Subsequently, the parties entered into a consent decree of permanent injunction.
The consent decree permanently enjoined the complainedof violation, and enjoined interstate operations unless anduntil the plant and its equipment had been cleaned, a sanitation program had been established, a qualified expert had certified to FDA that the plant met specified requirements, andnecessary FDA analyses and inspections were made. In addition, a copy of the firm's sanitation control program was tobe posted where all employees would see it, employees wereinstructed to comply with such program, and the defendantswere authorized to move to vacate the decree two years aftercompliance had been assured. (Inj. No. 1016; S. No.82-282-787 et al.; S.J. No. 11)
DEFENDANTS: Midwest Blologicals, Inc., and Melvin R.Shultz, president and treasurer, Fenton, E. Dist. Mich.; CivilN o . 8 2 - 4 0 1 4 2 .CHARGED 4-16-82 in a complaint for injunction: That thedefendants manufactured, processed, packed, labeled,distributed in interstate commerce, and held for sale aftershipment of interstate components certain microbiologicalculture media and a certain media-component (defibrinatedsheep blood), which media and media-component are in vitrodiagnostic products; that such media and media-componenthad been manufactured, packed and stored under circumstances that failed to conform with current good manufacturing practice—501(h); that the labeling of the culturemedia included expiration dates which were false and
46 / February 1984 / FDA Consumer
misleading, since the articles were not useful for the periodrepresented by those expiration dates—502(f)(1); the labeling of the culture media and the media-component lacked adequate directions for use—502(f)(1); the quality or purity ofthe culture media fell below its purported quality or purity,since the article contained bacterial contaminants, mold contaminants, or both—502(c); that FDA inspections had shownserious substantial deviations from good manufacturing practice; that FDA laboratory tests determined that a 50-platesample contained bacterial and mold contaminants in 40plates and only mold contaminants in 10 plates; and that thedefendants were wel l aware that thei r act iv i t ies were in v io lat i o n o f t h e l a w.DISPOSITION: A consent decree of permanent injunctionenjoined the complained of violations and enjoined continuedoperations involving interstate articles at the defendants' Fen-ton, Mich., plant unless and until: specified methods, facilitiesand controls had been established, operated and administered;adequate controls were implemented to assure the accuracyand completeness of labeling, including the articles' expiration dates; a qualified expert had certified to FDA that thespecified requirements had been met and all of the articleson hand at the defendants' plant had been examined,necessary tests made, and all examined and tested articles weredestroyed or brought into compliance with the law. (Inj. No.998; S. No. 82-186-991 et al.; S.J. No. 12)
DEFENDANTS: Pharmadyne Laboratories, Inc., andBernard A. Bedrick, president, Elmwood Park, Dist. N.J.;C i v i l N o . 8 0 - 1 3 1 2 .CHARGED 5-8-80 in a complaint for injunction: That thedefendants, at their Elmwood Park, N.J., plant, produced,packed, labeled and distributed in interstate commerce variousdrugs (e.g., allopurinol tablets, chlorothiazide with reserpinetablets, chlorpropamide tablets, chlorthalidone tablets,doxylamine succinate with B-6 tablets, furosemide tablets,hydroxyzine hydrochloride tablets, hydroxyzine pamoatecapsules, metronidazole capsules, spironolactone tablets,spironolactone with hydrochlorothiazide tablets, triamterenewith hydrochlorothiazide capsules, and trimethoprim with sulfamethoxazole tablets); that such drugs were held for saleafter interstate shipment of various of their components; thatsuch drugs were new drugs without effective approved NewDrug Applications; that the labeling of such drugs failed tobear adequate directions for use and the drugs were not ex
empted because of their new drug status; and that the defendants were well aware that their activities, in marketing newdrugs without approved New Drug Applications, were inviolation of the law—505(a), 502(f)(1).DISPOSITION: Upon consent of the parties, without the admission of any facts or law, upon the agreement that thegovernment would withdraw its request for a temporaryrestraining order with respect to allopurinol, chlorpropamide,diethylpropion hydrochloride, doxylamine succinate with B-6,hydroxyz ine hydroch lo r ide , hydroxyz ine pamoate ,metronidazole and trimethoprim with sulfamethoxazole, thedefendants agreed not to distribute or ship a number ofspecified drugs during the pendency of the government's application for a preliminary injunction. The government's application for a temporary restraining order was denied withoutprejudice in all other respects; the specified drugs which thecourt restrained the defendants from shipping werechlorothiazide with reserpine, chlorthalidone (25 mg and 50mg only), furosemide, prochlorperazine, spironolactone,spironolactone with hydrochlorothiazide, and triamterenewith hydrochlorothiazide. The government served written interrogatories on the defendants. The defendants served a request for the production of documents on the government.
Ultimately, a consent decree of permanent injunction wasentered into. The consent decree enjoined the interstate shipment, or the production (using interstate components), of anydrug containing any of the following ingredients: allopurinol,chlorothiazide with reserpine, chlorpropamide, chlorthalidone, diethylpropion hydrochloride, doxylamine succinatewith vitamin B-6, furosemide, hydroxyzine hydrochloride,hydroxyzine pamoate, metronidazole, prochlorperazine,spironolactone, spironolactone with hydrochlorothiazide,triamterene with hydrochlorothiazide, or trimethoprim withsulfamethoxazole, unless and until an approved New DrugApplication was effective with respect to such drug or suchdrug was otherwise approved or exempted. Additional provisions in the decree included a requirement of notice by thedefendants to FDA prior to their intended marketing of a drugon the basis that it was not a new drug, a requirement concerning destruction, embargo or bringing into compliance ofspecified drugs which were on hand or under the control ofthe defendants, and a requirement that the defendants signc o n s e n t d e c r e e s o f c o n d e m n a t i o n i n t h e s e i z u r e a c t i o n s o f
specified drugs claimed by the defendants. (Inj. No. 948; S.No. 80-162-284 et al.; S.J. No. 13)
FDA Consumer / February 1984 / 47
^ 1A A
DEFENDANTS: Pittston Warehouse Corp. (a division ofPittston Stevedoring Corp.) and Robert F. Chiarello, president, Brooklyn, E.Dist. N.Y.; Civil No. 80-3108.CHARGED 11-7-80 in a complaint for injunction: Thatdefendants held foods for sale after such foods had beenshipped in interstate commerce; that such foods containedrodent filth and had been held under insanitary conditions;that FDA inspections revealed specified insanitary conditions;and that the defendants were well aware of the insanitary conditions at their Brooklyn, N.Y., warehouse—402(a)(3),402(a)(4).DISPOSITION: A consent decree of permanent injunctionenjoined the complained of violations, enjoined the defendant to select an expert to certify that the warehouse wasoperated so as to assure that food was not contaminated, andenjoined the defendants to examine all foods on hand at thewarehouse, to have FDA make necessary analyses, and todestroy or otherwise bring into compliance all contaminatedfoods. (Inj. No. 1022; S. No. 78-140-783 et al.; S.J. No. 14)
M I S C E L L A N E O U S A C T I O N S
SUBJECT: Red No. 2 as a color additive and FDA's denialof its permanent listing. District of Columbia Circuit Courtof Appeals, Washington, D.C.; No. 80-1403.PETITIONED 4-14-80 by Certified Color ManufacturersAssn., Washington, D.C., against HEW Secretary PatriciaR. Harris in a petition for judicial review: That the FDA commissioner's decision against permanent listing of the color additive FD&C Red No. 2 should be reversed because the commissioner had not applied the proper standard for determining color additive safety and because the commissioner'sdenial was not adequately and fairly supported by the adm i n i s t r a t i v e r e c o r d .DISPOSITION: The petitioner argued that FD&C Red No.2 was a water-soluble food coloring that had been widely usedfor over 70 years, had been one of the first food colors approved under the Food and Drugs Act of 1906, and was themost thoroughly tested food color; that, after the Color Additive Amendments of 1960, FD&C Red No. 2 had continuedin use as a provisionally listed color additive and, in 1969,FDA's Bureau of Foods concluded that "results of extensivetoxicological and biochemical testing of FD&C Red No. 2(amaranth) demonstrate the safety of this color additive."
However, Russian investigations on male rats conducted
b e t w e e n 1 9 6 8 a n d 1 9 7 0 o n a s u b s t a n c e i d e n t i fi e d a s"amaranth" (FD&C Red No. 2 is known as amaranth in itsnonpurified, industrial form) created a concern that FD&CRed No. 2 might be a carcinogen, although there was substantive evidence before an FAO/WHO committee that the Russian amaranth was not FD&C Red No. 2 and although boththe FAO/WHO Joint Expert Committee on Food Additivesand FDA's toxicologists rejected the Russian study.
In an attempt to duplicate the results of the Russian studiesof amaranth, FDA began its own tests of Red No. 2. ThisFDA study (the Taylor/Monlux study) was an extensive long-term chronic animal feeding study that involved feeding RedNo. 2 to rats whose dams had been exposed to Red No. 2since birth. In 1976, the FDA commissioner received astatistical analysis by Dr. David W. Gaylor of the data fromthe ongoing Taylor/Monlux study which showed a statisticallysignificant increase in malignant tumors in female rats in thehighest dosage group. Although the provisional listing of RedNo. 2 had just been extended, the commissioner proceededto end the provisional listing; his action was affirmed in Certified Color Manufacturers Ass'n v. Mathews, 543 F.2d 284(D.C. Cir. 1976); and the color additive was removed fromt h e m a r k e t .
Nevertheless, the petitioner persisted by objecting to thedenial of a pending color additive petition for permanentlisting of Red No. 2 and by requesting a formal hearing beforean administrative law judge. On March 30, 1978, Administrative Law Judge Daniel J. Davidson found that, althoughthe tests of Red No. 2 showed many negative results, andseveral equivocally positive results, the data before FDAneither established Red No. 2 as being safe nor establishedit as not being a carcinogen in man or animals.
The petitioner appealed to the FDA commissioner who,after review of the entire record, denied the permanent listingof Red No. 2. The petitioner then appealed to the CircuitCourt of Appeals, arguing that permanent listing had beenimproperly denied because the commissioner had adopted a"conservative approach" requiring more proof than areasonable certainty, and because the commissioner had selectively parsed the record rather than basing his decision "upona fair evaluation of the entire record" as required by statute.
The Court of Appeals, without an opinion, upheld the administrative law judge and the commissioner and affirmedthe denial of permanent listing of Red No. 2. (Misc. No. 584;S.J. No. 15)
48 / February 1984 / FDA Consumer U.S. GOVERNMENT PRINTING OFFICE 1984-421-174/101
It starts quite innocently: you convince what his symptoms mean. And he doesn'tyourself the symptoms aren't serious. So want to seem silly,if you sought medical help you'd just Please, learn the warning signals of alook foolish. And later it's too late. heart attack. And, if you experience any of
Each year 350,000 Americans die from them, get help. Call a paramedic at once,heart attacks before reaching the Or, if you can get to an emergency roomhospital. Often after a deadly, unnecess- faster another way, do so. Without a sec-ary delay. In fact, the average victim ond thought.waits over three hours before consulting After all, saving face means nothinga doctor. Because he doesn't realize compared to saving your life.
W A R N I N G S I G N A L S O F A H E A R T A T T A C K
1. An uncomfortable pressure, fullness, squeezing orpain in the center of your chest behind thebreastbone.
2. The sensation may spread to your shoulders, neck orarms. If it lasts for two minutes or more, you couldbe having a heart attack.
3. Severe pain, dizziness, fainting, sweating, nausea orshortness of breath may also occur, but are notalways present.
WE'RE FIGHTING FOR VOUR LIFE
^American Heart Association
