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TOXICOLOGYLETTER
The NY State Poison Centers
October2007
A Quarterly Publication Vol. XII No. 4
Program Announcements Ruth A. Lawrence: Monthly conference:
every 4 weeks onThursdays (11 am to noon), and every 4 weeks on
Tuesdays(10 am-11 am).
UNY: Our Eleventh Annual Toxicology Teaching Day willbe held on
November 14, 2007 at the Genesee Grand Hotel in
Syracuse. Please mark your calendar!
NYC: Consultants Case Conference The rst Thursday of the
Month from 2-4pm
Long Island Regional Poison and Drug Information
CenterToxicology Teaching Conferences 2007
Pre-Registration is required. Please contact Mr. Denis Jao
at 516-663-2650 to register. Both Telephone and
Televideobroadcasts will be available.
Target Audience: Physicians, Pharmacists, Nurses,
NursePractitioners, Physician-Assistants, Laboratory
technicians,
EMS staff, medical/nursing/pharmacy students and otherhealthcare
professionals.
Times for ALL Conferences are: 12:15 PM-1:45 PM
Wednesday: November 7, 2007
TOPIC: Update of Common Poisonings and Treatments
Speaker: Michael McGuigan, MD, FACMT, FAAP; Professor of
Emergency Medicine, State University of New York at StonyBrook,
Medical Consultant Long Island Regional Poison
Center at Winthrop University Hospital,
Wednesday: December 5, 2007
TOPIC:Food Poisoning
Speaker: Daniel Kuhles, MD, MPH; Clinical Instructor,
State University of New York at Stony Brook, Department
ofPreventive Medicine. Assistant Director, Division of
DiseaseControl Nassau County Department of Health
Location:
New Life Conference Rooms B&CWinthrop-University Hospital259
First Street
Mineola, Long Island, New York 11501
State
Poison
Centers
1-800-222-1222
New York
Please call administrative telephonenumbers for more
information.
Administrative Phone Numbers - To obtain a consult inyour area,
call 1.800.222.1222.
Western New York Poison Center (WNY)
716.878.7871 http://wnypoison.org
Ruth A. Lawrence NY Poison Center (FL)
585.273.4155 www.FingerLakesPoison.org
Upstate New York Poison Center (UNY)
315.464.7078 www.upstatepoison.org
New York City Poison Control Center (NYC)
212.447.8152
Long Island Poison & Drug Info Center (LI)
516.663.4574 www.LIRPDIC.org
Toxicology Advice Centers
Case Report:
Continuedonpag
MethotrexatePoisoning
Contributed by: Silas Smith, MD, New York City PoisonControl
Center, New York, NY
A 10-year-old boy with osteosarcoma received an ap-propriate
four-hour infusion of high dose-methotrexate(12.8 grams/m2). A
post-infusion methotrexate concentra-tion was uninterpretable, but
this result was not appreci-ated by the treating clinicians. The
child developed blurrvision, painful mucositis, stomatitis, and
facial blistering.serum methotrexate concentration was 287 mol/L 31
houpost-infusion and 171 mol/L 48 hours post infusion.
Hiscreatinine rose from 0.57 mg/dL pre-infusion to 2.76 mg/42 hours
post infusion.
What is the mechanism of action ofmethotrexate?
Folate (vitamin B9) must be activated prior to utilizatioin the
one-carbon metabolic pathway necessary for DNA
synthesis. It is reduced rst by dihydrofolate reductase to
didrofolate (FH2), and then again by dihydrofolate reductase
toactive tetrahydrofolate (FH4). FH4 obtains a carbon fromserine to
form 5,10-methylene-FH4. Thymidylate synthase thutilizes
5,10-methylene-FH4 to make thymidine from urac5,10-methylene-FH4 is
converted back to FH2 in the proce
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Methotrexate Poisoning Continuedfrompag
Continued on pag
Methotrexate competitively inhibits dihydrofolate re-ductase
such that neither FH2 nor active FH4 can be generat-ed from folate,
nor can existing FH2 be recycled. Methotrex-ate metabolites
additionally inhibit thymidylate synthase,further inhibiting
thymidine synthesis. Rapidly proliferatingcells (e.g. malignancies
and those in the gastrointestinaltract, bone marrow or skin) which
rely heavily on de novonucleotide creation for DNA replication and
RNA synthesis
are most affected by methotrexate. Because of its ability
toimpair cellular replication, methotrexate has uses in addi-tion
to conventional chemotherapy regimens (e.g. breastcarcinoma,
choriocarcinoma, lymphoma, and osteosar-coma). These include the
treatment of rheumatoid arthritisand psoriasis, and as an ablative
therapy for ectopic preg-nancy. Methotrexate may be administered
via oral, intrave-nously, or intrathecal routes.
How does methotrexate poisoning withtherapeutic dosing
occur?
Methotrexates primary route of elimination is renal. Pa-tients
with existing or the potential for impaired renal func-
tion (e.g. those taking nephrotoxic drugs) are at increasedrisk
of developing methotrexate poisoning. In addition, pre-cipitation
of methotrexate or its relatively insoluble metabo-lites in the
renal tubules can cause acute renal failure andtubular necrosis,
further impairing excretion. Persistentlyelevated serum
concentrations lead to hematological abnor-malities, such as
myelosupression, and nonhematologicaleffects, which commonly
include stomatitis/mucositis anddiarrhea, dermatitis, and
hepatotoxicity. Pulmonary toxic-ity and neurotoxicity (after either
high-dose intravenoustherapy or intrathecal use) are less
common.
How is a patient with suspected methotrexate
toxicity evaluated and treated?Any of the above symptoms should
prompt the clinician
to obtain a serum methotrexate concentration, as well as as-sess
renal, hematological, and hepatic function.
Intravenous uids should be administered to reverseany volume
depletion and to maintain brisk diuresis (>60mL/hour) and are
critical to maximizing methotrexateelimination. Since methotrexates
urinary precipitation isenhanced by aciduria, intravenous sodium
bicarbonate isroutinely given along with aggressive hydration to
maxi-mize urinary solubility. At pH 7.5 methotrexate is ten
timesmore soluble than at pH 5.5.
Folate is an ineffective antidote because methotrexateblocks the
enzymes responsible for its activation (althoughfolate will inhibit
renal resorption of methotrexate). Leuco-vorin (5-formyl-FH4;
folinic acid; citrovorum factor) is effec-tive, bypassing the
blocked pathways and maintaining thefolate cycle. The 10 mg/m2
intravenous dose of leucovorinfor chemotherapeutic rescue therapy
must be increasedsignicantly in patients with elevated methotrexate
con-centrations. Leucovorin intravenous doses of 100 mg/m2,1000
mg/m2, or even higher every six hours (at a rate notto exceed 160
mg/min in adults) may be required. In the
absence of a methotrexate concentration, empiric
leucovo(molecular weight 511) should be given to obtain a
plasmconcentration equal to or greater than that of the
estimatemethotrexate (MW 455) concentration. In patients not
beintreated with methotrexate for malignancy, leucovorin
iscontinued until the serum methotrexate concentration isless than
10 nmol/L, or less than 50-100 nmol/L in patientreceiving
methotrexate therapeutically. Leucovorin loses
efcacy at methotrexate concentrations above 100 mol/LLeucovorin
must not be administered intrathecally.
High ux hemodialysis or charcoal hemoperfusion is dicated for
patients at risk for developing methotrexate toicity despite
leucovorin treatment, particularly those withworsening renal
function. Clinically signicant quantitieof methotrexate can be
removed, although there is often arebound in methotrexate
concentration secondary to reditribution. Peritoneal dialysis is
ineffective. Carboxypepti-dase (see below) is largely replacing the
need for dialysis.
Thymidine rescue (thymidylate salvage) provides thessential
nucleoside downstream from the sites of inhibi-
tion. However, thymidine is rapidly cleared and must begiven by
continuous infusion. The investigational dose fothymidine is 8
grams/m2 per day IV. It is available from tNational Cancer
Institute (NCI: 888-624-1937 or 301-496-5725). Carboxypeptidase
(see below) is replacing the needfor thymidine rescue.
Glutamate carboxypeptidase (CPDG2, glucarpidase), abacterial
derived, zinc-dependent metallo-enzyme, directcleaves methotrexate
into inactive 4-amino-4-deoxy-10-methylpteroic acid (DAMPA) and
glutamate. The typicaldose for an adult is 50 units per kilogram
intravenouslyover ve minutes. Administration of CPDG2 producesrapid
reduction of serum methotrexate concentrations (by95-99%). DAMPA is
known to cross-react with most com-mercial methotrexate
immunoassays, such that persistentelevated concentrations of
methotrexate may be reportedif an immunological-based assay is
subsequently used.High performance liquid chromatography must be
usedto determine actual serum methotrexate concentrations.CPDG2 has
at least a ten-fold higher afnity for methotrexate than it does for
leucovorin. Despite this, many protocorecommend that leucovorin not
be administered for 2 houbefore, and for up to 2 hours after CPDG2
is provided. Asecond dose of CPDG2 may be administered at 48
hoursbecause CPDG2 acts only on extracellular methotrexate
and slow redistribution of methotrexate from the intracellular
compartment may occur. This necessitates continueleucovorin therapy
(many protocols suggest 250 mg/m2 fo48 hours after the second dose
of carboxypeptidase). Thenleucovorin is continued based on
methotrexate concentration until it is less then 50 nmol/L.
CPDG2 is available in the US on a compassionate-usebasis from
the NCI and under an open-label treatment prtocol. Emergency
inquiries and supply details may also bdirected to AAIPharma:
866-918-1731 (intravenous emerg
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NYStatePoisonCenters1.800.222.1222
Propofol-InducedSeizure-likePhenomenon
Contributed by: Sini Cherian, Pharm D Candidate, St.
JohnsUniversity College of Pharmacy; Mary Ann Howland, PharmD,
DABAT, FAACT, Clinical Professor of Pharmacy, FacultyMentor, St.
Johns University College of Pharmacy, Consultant,New York City
Poison Control Center, Consultant, BellevueHospitals Emergency
Services
Propofol (DiprivanRx) is an intravenous anesthetic agentused for
induction and maintenance of general anesthesiaand for sedation.
Its rapid onset and fast recovery timehave made it one of the most
frequently used agents in theUnited States.1,2 Although its
mechanism of action is notcompletely understood, propofol is
believed to act primar-ily through both enhancing GABAA receptor
function andby inhibiting the NMDA subtype of glutamate receptor.1,
2 Propofol is very lipid soluble and virtually insoluble
in water, and was initially prepared with Cremophor EL.However,
since this formulation was believed responsiblefor anaphylactoid
reactions,1 propofol is now formulated inan emulsion containing 1%
(weight/volume) propofol, 10%soybean oil, 2.25% glycerol, and 1.2%
puried egg phos-phatide with either disodium edetate (0.005%) or
meta-bisulte added to limit bacterial growth.1
Propofol causes a number of adverse effects includ-ing
oversedation, respiratory depression, bradycardia,hypotension,
movement disorders, injection site pain, andhyperlipemia.. In
addition, opisthotonus is an uncommonbut well recognized side
effect of propofol anesthesia.1
Opisthotonus is described as tetanic spasms of the backin which
excessive contraction of the extensors of the spinecauses the body
to arch until it rests on the heels and thehead.3 Symptoms such as
facial twitching and athetoidmovements of the neck and limbs are
seen, followed byarching of the back. Opisthotonus may occur alone
or withother neuroexcitatory events like generalized
tonic-clonicseizures, focal motor seizures and involuntary
dystonicmovements. Since the symptoms resemble seizures, andEEG
monitoring is usually not available, they have beentermed
seizure-like phenomena (SLP) or spontaneous excit-atory
movements.4,5,6 In a systematic review published in2002, there were
8 patients with opisthotonus out of 81 pa-
tients with SLP. Similar to other cases of SLP, opisthotonusmay
occur during induction, emergence or delayed greaterthan 30 minutes
after the end of anesthesia, and can occurin patients with and
without a prior history of epilepsy. An-other review, this time of
the pediatric literature, revealed12 case reports of patients who
ranged in age from 2 weeksto 16 years old who developed what
appeared to be seizuresor SLP. Most of the SLP reported in these 12
cases occurredduring the recovery period or hours after the
induction.Only one out of the twelve cases occurred during
induction.These SLP can last from minutes to days.
The mechanism for SLP is unclear. Theories includedistubances in
subcortical structures 5 and imbalances between inhibitory and
excitatory neurons, perhaps with lodoses favoring glycine
inhibition.6 There is no rm conclusion on treatment strategies but
many patients were treatsuccessfully with benzodiazepines.
In conclusion, opisthotonus is a rare side effect associ-ated
with the administration of propofol for anesthesia.Opisthotonus may
occur along with other SLP. These SLPoften occur during the
recovery phase or may be delayedhours after the propofol infusion
is stopped. Manifesta-tions may last for minutes to days. Treatment
with benzoazepines is often successful.
References:
Miller RD, ed: Millers Anesthesia. 6th ed. Elsevier,
IPhiladelphia 2005.
Dukes MNG, Aronson JK. Meylers Side Effects OfDrugs. 14th ed.
New York: Elsevier; 2000
Sneyd JR. Excitatory events associated with propofol anaes
thesia: a review. Journal of the Royal Society of Medicine1992;
85: 288-291
Walder B, Tramer MR, Seeck M. Seizure-like phenomenaand
propofol: A systematic review.Neurology. 2002; 58:1327-1332
Borgeat A, Wilder-Smith OHG, Despland PA et al:Spontaneous
excitatory movements during recovery from propoanaesthesia in an
infant: An EEG evaluation.Br J Anaesthesi1993;70:459-61.
Hickey K, Martin D, Chuidian F: Propofol-induced seizulike
phenomena.J Emerg Med 2005;25:447-449.
S P I C O R N E R :
FDA Safety SummarieAugust2007
Continued on pag
http://www.fda.gov/medwatch/safety/2007/safety07.htm#chronological
Axcil and Desirin (marketed as dietary supplements)
Babys Bliss Gripe Water, Apple avor
Haloperidol (marketed as Haldol, Haldol decanoate, anHaldol
lactate)
Fentora (fentanyl buccal tablet)Viracept (nelfnavir
mesylate)
Zencore Tabs
METABOLISM Apple Cider Vinegar Brand DietarySupplement
Capsules
Codeine Products Used By Nursing Mothers
Warfarin (marketed as Coumadin)
Nonprescription Cough and Cold Medicine Use inChildren
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UpstateNYPoisonCenter
750EastAdamsStreet
Syracuse,NY
13210
Methotrexate Poisoning Continuedfrompag
cies) or Protherics Inc: 888-327-1027 (intrathecal
emergen-cies). Specialty cancer centers which may have access to
thisantidote might also serve as a source. Common adverseeffects
include feeling of warmth, tingling ngers, ushing,shaking, burning
of the face and extremities, and pruritus.
How did the patient do?
The patient received saline hydration, urinary alkalini-
zation with sodium bicarbonate, and leucovorin (1500 mg/m2).
CPDG2 (50 U/kg) was given at 68 hours post-infusionfollowed by a
second identical dose 48 hours later. Themethotrexate concentration
by immunoassay dropped byapproximately 90%. The patients creatinine
peaked at 2.95mg/dL; aminotransferases (AST and ALT) rose to 815
U/Land 1574 U/L with a bilirubin of 3.5 mg/dL. Within 24 hoursof
CPDG2 administration, renal and hepatic dysfunctionstabilized and
began trending downward. He did developabdominal pain which
required parenteral opioids for sev-eral days. Visual symptoms
rapidly resolved. Ultimately hewas discharged and was able to
undergo his next chemo-therapy cycle.
Suggested Reading
Bleyer WA.Methotrexate: clinical pharmacology, current sta-tus,
and therapeutic guidelines. Cancer Treat Rev. 1977;4:87-101.
Buchen S, et al. Carboxypeptidase G2 rescue in patientswith
methotrexate intoxication and renal failure.Br J
Cancer.2005;92:480-7.
Goto E, et al.Methotrexate poisoning with acute
hepatorendysfunction.J Toxicol Clin Toxicol. 2001;39:101-4.
Widemann BC, et al. High-dose methotrexate-induced nephtoxicity
in patients with osteosarcoma. Cancer. 2004;100:1111-3
Continuedfrompag
FDA Safety Summaries
Avandia (rosiglitazone maleate) TabletsActos (pioglitazone
hydrochloride) TabletsAvandaryl (rosiglitazone maleate and
glimepiride)TabletsAvandamet (rosiglitazone maleate and
metforminhydrochloride) TabletsKaletra (lopinavir/ritonavir) Oral
Solution
Omeprazole (marketed as Prilosec and generic productsOmeprazole
+ Sodium Bicarbonate (marketed as ZegeriNexium (esomeprazole)
Rocephin (ceftriaxone sodium) for Injection
Invanz (ertapenem sodium) Injection
Colistimethate (marketed as Coly-Mycin M and
genericproducts)
Propofol (marketed as Diprivan and generic products)
RotaTeq (Rotavirus, Live, Oral, Pentavalent) Vaccine
Long Weekend Dietary Supplement
