Journal of Ethnopharmacology 97 (2005) 175–181

Review

Atractylis gummiferaL. poisoning: an ethnopharmacological review

C. Danielea,∗, S. Dahamnab, O. Firuzia, N. Sekfalib, L. Sasoa, G. Mazzantia

a Department of Pharmacology of Natural Substances and General Physiology, University of Rome “La Sapienza”, P.le Aldo Moro 5, 00185 Rome, Italyb Department of Biology, University of Setif, Algeria

Received 15 March 2004; received in revised form 15 November 2004; accepted 16 November 2004Available online 13 January 2005

Abstract

Atractylis gummiferaL. (Asteraceae) is a thistle located in the Mediterranean regions. Despite the plant’s well-known toxicity, its ingestioncontinues to be a common cause of poisoning. The toxicity ofAtractylis gummiferaresides in atractyloside and carboxyatractyloside,two diterpenoid glucosides capable of inhibiting mitochondrial oxidative phosphorylation. Both constituents interact with a mitochondrialprotein, the adenine nucleotide translocator, responsible for the ATP/ADP antiport and involved in mitochondrial membrane permeabilization.

adache and

hiothreitolproachesmponents

176

76

177

8

78

180

180

180

Poisoned patients manifest characteristic symptoms such as nausea, vomiting, epigastric and abdominal pain, diarrhoea, anxiety, heconvulsions, often followed by coma. No specific pharmacological treatment forAtractylis gummiferaintoxication is yet available and all thecurrent therapeutic approaches are only symptomatic. In vitro experiments showed that some compounds such as verapamil, or ditcould protect against the toxic effects of atractyloside, but only if administered before atractyloside exposure. New therapeutic apcould come from immunotherapy research: some studies have already tried to produce polyclonal Fab fragments against the toxic coof Atractylis gummifera.© 2004 Elsevier Ireland Ltd. All rights reserved.

Keywords: Atractylis gummiferaL.; Poisoning; Atractyloside; Asteraceae; Toxicology

Contents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2. Botany and ethnopharmacology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

3. Phytochemistry. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4. Clinical aspects ofAtractylis gummiferapoisoning. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

5. Toxicology and pharmacology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

6. Treatment ofAtractylis gummiferapoisoning and studies on possible therapeutic approaches. . . . . . . . . . . . . . . . . . . . . . . . . . . 179

7. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Acknowledgment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author. Tel.: +39 06 49912903; fax: +39 06 49912480.E-mail address:claudia.daniele@uniroma1.it (C. Daniele).

0378-8741/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.jep.2004.11.025

176 C. Daniele et al. / Journal of Ethnopharmacology 97 (2005) 175–181

1. Introduction

In some regions of the world, plant poisoning continues tobe an infrequent though important problem causing clinicalmorbidity and mortality. Among plants occasionally involvedin human poisonings isAtractylis gummiferaL. (Fig. 1), es-pecially in countries where the plant grows spontaneously(Hamouda et al., 2000). BecauseAtractylis gummiferaL.is easily confused with a wild artichoke most poisoningsare unintentional. Many of the victims are children becauseAtractylis gummiferahas sweet tasting juice and children en-joy chewing the root-like chewing gum (Stickel et al., 2000).

Here we review the botany, ethnopharmacology and tox-icology of Atractylis gummiferaand discuss possible phar-macological therapy for intoxication.

2. Botany and ethnopharmacology

Atractylis gummiferais a thistle distributed worldwide butespecially abundant in the Mediterranean regions: in North-ern Africa (Algeria, Morocco and Tunisia) and in SouthernEurope (Italy, Greece, Spain and Portugal).

The plant has a long rhizome that can reach a length of30–40 cm with a diameter of 7–8 cm. The leaves are deeplyd Thefl d byb ish-w ,1 em.T llinem cretinl

ongtsb and

Dioscorides. The species is also known asAcarna gummiferaW. andCarlina gummiferaLess. Two varieties ofCarlinagummiferawere proposed:�-typical and�-Fontanesii (Fioriand Paoletti, 1973), which differ in morphology and geo-graphical position:�-typical grows in the south of Italy andSicily whereas�-Fontanesii is found especially in Sardiniaand Corsica.

Atractylis gummiferawas known as ‘masticogna’ (Si-cilian), ‘musciurida’ (Sardinian), ‘chardona glu’ (Franch)and ‘el-heddah’ (Arabian). Other common names are ‘bird-lime’, ‘blue thistle’ and ‘chamaelon’, because its flowerscontinually change colour. The court-physician and botanist-pharmacologist of the khalif el-Hakim of Cahira, Mesue theYounger (1000a.d.), called it ‘mezereon’; the same author,in his ‘De Simplicibus’ commented that the Persians namedthis deadly plant ‘rapiens vitam’ (Santi and Luciani, 1978).

The therapeutic as well as the toxic properties ofAtractylisgummiferahave long been recognized. In the first cen-tury a.d., the Greek pharmacologist and physician PedaniusDioscorides of Anazarbos gave a thorough description ofthe plant and its properties. Theophrastus (300b.c.) alsonoted the toxicological effects of the plant in animals; hedescribed two kinds of ‘chamalaeon’, white and dark, dif-fering in the colour of their root and properties. The root ofthe ‘chamalaeon’ variety is white, thick and sweet and has

rootandarkhasand

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stedarstoil

oneonethe

resh

ers,nal

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ivided into prickly lobes and grouped into rosettes.owers are pink and grouped into capitulum surrounderacts covered with spikes. After the fruit is ripe, a yellowhite latex exudes from the base of the bracts (Bruneton999). The rhizome contains the plant’s lactiferous systhe parenchymal cells of the rhizome abound in crystaasses and the cortical parenchyma has numerous se

acunae.Linnaeus named the species and classified it am

he Asteraceae, in theAtractylis genus and asgummiferapecies. He also proposed thatAtractylis gummiferacoulde the white chamaleon described by Theophrastus

Fig. 1. Atractilis gummiferaL.

g

a strong smell. Theophrastus also wrote that the whitehad been used against worms, and when mixed with oil‘mountain cabbage’, as a poison for dogs and pigs. The d‘chamalaeon’ variety resembles white chamelaeon, butsmaller and smoother leaves; the root is thick and blackwas known for its properties against leprosy (Theophrastus,1949). Galen recommended the plant only for externalplications (Bruneton, 1999). In the renaissance the plant waalso well known, especially with the name of ‘chameleonin his book Matthioli described the ‘chameleone bianco’a sweet, aromatic plant with a strong odour. He suggeusing its root for various purposes: boiled in wine, vinegand wild marjoram as a vermifuge; drunk in wine againsnake poison and mixed with ‘polenta’, sugar, water andas poison against dogs, pigs and mice (Matthioli, 1957). Inanother renaissance book (Durante, 1585), the author accu-rately described both ‘chameleone bianco’ and ‘chamelenero’. He recommended a root decoction of ‘chamelebianco’ against urinary retention, and somnolence; androot of ‘chameleone nero’ to decrease toothache, to refthe breath and to remove skin stains such as freckles.

In folk medicine,Atractylis gummiferahas been used totreat several conditions including intestinal parasites, ulcsnake-bite poisoning, hydropsy and drowsiness. In traditioArabic medicine it was used to cauterize abscesses. Thewas also known for its antipyretic, diuretic, purgative aemetic properties (Larrey and Pageaux, 1995). In the popularmedicine of Northern African, it is still used to treat syphilitulcers, induce abortion and bleach the teeth (Capdevielle andDarraq, 1980; Georgiou et al., 1988). It is also used againsparasites in folk veterinary medicine (Viegi et al., 2003). The

C. Daniele et al. / Journal of Ethnopharmacology 97 (2005) 175–181 177

Fig. 2. Toxic compounds fromAtractylis gummifera.

dry rhizome is also usually burned in Arabic countries asincense to ward off bad fate (Hamouda et al., 2004).

3. Phytochemistry

All the underground parts of this plant contain two toxicditerpenoid glucosides: atractyloside (ATR) and carboxya-tractyloside (CATR) (Fig. 2).

ATR was isolated from the roots ofAtractylis gummiferafor the first time byLefranc (1868). The correspondingaglycone (atractyligenine) is a non-volatile diterpene of the(−) kaurene family, with a perhydrophenanthrenic structure.The carbohydrate portion consists of a singled (+) glucosemolecule, with only one free hydroxyl group (C-6); it is linkedin C-2′ to a residue of isovaleric acid, in C-3′ and C-4′ to tworesidues of sulphuric acid and in C-1′, through a�-linkage,to the C-hydroxyl of atractyligenin (Piozzi, 1978).

CATR was isolated for the first time in 1964 and calledgummiferin (Stanisls and Vignais, 1964) and subsequentlyidentified as 4-carboxyatractyloside (Danieli et al., 1971).CATR differs from ATR owing to the presence of a secondcarboxylic group in position C-4′ of the diterpene ring. CATRis present in fresh but not in dried plants because it is decar-boxylated to ATR during ageing or desiccation. CATR is alsom

tiono flu-e omeo dlyege i-z um-m rve

TCd

dry

S

S

Fig. 3. Chemical structure of atratylosides ofCoffea arabica.

substances and active compounds in the underground part ofa plant during the time of quiescence. And last, a quantita-tive study showed thatAtractylis gummiferaof Sicilian originhad a higher ATR content than that of Sardinian origin, eventhough the two plants had been acclimatized in the same ter-ritory different from the original habitat (Toth, 1964).

ATR and CATR have also been also isolated from otherplants from different genera includingCallilepsis laureola,Xanthium strumarium, Iphiona aucheri, andWedeila glauca(Obatomi and Bach, 1998). ATR analogues were also foundin aqueous extracts of green and roasted beans ofCoffeaarabica. In particular, three glycosides were identified: 2-O-(2-O-isovaleryl-beta-d-glucopyranosyl)-atractyligenin, 2-O-beta-d-glucopyranosyl-atractyligenin and 2-O-(3-O-beta-d-glucopyranosyl-2-O-isovaleriyl-beta-d- glucopyranosy)-atractyligenin (Fig. 3) (Obermann and Spiteller, 1976; Richerand Spiteller, 1978). Green beans ofCoffea arabicacontain34.5–624 mg/kg of ATR analogues whereas the roasted beanscontain only 17.5–32.5 mg/kg (Obatomi and Bach, 1998). Nopublished information is available on the ATR plant levels re-quired to produce toxicity. Considering the quantity of ATRanalogues present in coffee beans and the fact that some ofthem are non-toxic (Fontana et al., 1994), the risk related tocoffee consumption is presumably negligible. Indeed, no pub-lished reports have described cases of coffee-induced ATRt

cei xic( heg y in-c ofA andt o un-d ATR.O ar-b toa TRt duc-t thanA R,C ont itoryp l ofi ctive

ore toxic than ATR (Luciani and Carpenedo, 1978).Several factors, including the climate, the composi

f the soil, the time of harvest and genetic factors, innce the content of diterpenoid glucosides in the rhizf Atractylis gummifera. For example, differences reportexist between the rhizome content of ATR fromAtractylisummiferagrown in Sardinia or in Sicily (Table 1) (Fassinat al., 1962). A higher amount of ATR was found in rhomes collected in autumn or winter, than in spring or ser (Table 1), in agreement with the higher content of rese

able 1ontents of atractyloside in rhizomes ofAtratylis gummiferaL. from Sar-inia and Sicily in different time of the years (Fassina et al., 1962)

Time of the harvest ATR content gram% weight

ardinia June 0.12± 0.013October 0.19± 0.036December 0.33± 0.045

icily May 1.21± 0.038December 1.57± 0.101

oxicity even in heavy coffee drinkers.ATR inhibits the oxidative phosphorylation of ADP. Sin

ts genin, atractyligenin, which is about 150-fold less toVignais et al., 1978), has a similar but weaker activity, tlucose moiety, disulphoric and isovaleric acids probablrease the inhibitory effect of the atracyligenin moietyTR. Various atractyloside analogues were prepared

ested, to evaluate structure–activity relationships and terstand better the mechanism underlying the action ofne of the most crucial groups for ATR toxicity is the coxyl group in C-4′ of the diterpene ring: its reductionlcohol produces a non-toxic compound, atractylitriol. A

oxicity depends also on the C-16 methylene group: its reion leaves a compound two- or three-fold less potentTR. Acetylation of the two free hydroxyl groups of AT-15 of atractyligenin and the C-6 free hydroxyl group

he glucose molecule, decreases by 100-fold the inhibotency of ATR. The derivatives obtained by the remova

sovaleric acid or the sulphate groups are also less effe

178 C. Daniele et al. / Journal of Ethnopharmacology 97 (2005) 175–181

than ATR (Vignais et al., 1978). For example,Fontana etal. (1994)studied the effects of two atractylosides ofCof-fea arabica 2-O-(2-O-isovaleryl-beta-d-glucopyranosyl)-atractyligenin and 2-O-beta-d-glucopyranosyl-atractyligeninon carbohydrate metabolism in rats by measuring blood glu-cose levels, lactate and pyruvate, as well as hepatic, muscu-lar and cardiac glycogen. In this study, the ATR analogueswere used at a dose of about 150 mg/kg, corresponding tothe ATR DL50 in rats, when administered by the s.c. route(Luciani and Carpenedo, 1978); 2-O-(2-O-isovaleryl-beta-d-glucopyranosyl)-atractyligenin showed the same activity asatractyloside, conversely the other analogue glycoside with-out the isovaleric group, was nearly inactive.

4. Clinical aspects ofAtractylis gummiferapoisoning

About 100 cases ofAtractylis gummiferapoisoning havebeen described in the literature since the XIXth century(Hamouda et al., 2004). Larribaud (1954)reported theintoxication of two children aged 4 and 6 years, afteringestion ofAtractylis gummiferarhizome in a region ofDellys (Algeria). The children arrived at the hospital withviolent abdominal colic and abundant vomiting, followedby generalized contractions, cyanosis, agony and coma.T gicfi datesa

g ofs ses( ficc

twocT us-c val-u Hgi chil-d cyten ss

, ad-mg eree nt’sc t, theb

nfu-s .T fail-u e butt se

3t edi-c sive

care unit for poisoning with 11 species of plants. The prin-cipal plants involved wereAtractylis gummifera(18 cases;32%) Datura stramoniumL. (14 cases; 25%) andRicinuscommunisL. (5 cases; 9%). Of these 56 cases 16 were lethaland all of them involvedAtractylis gummifera.

These case reports provide useful information on thesymptoms and laboratory findings that help to identify vic-tims ofAtractylis gummiferapoisoning. The symptoms be-gin 6–36 h after the ingestion of the extract ofAtractylisgummiferarhizome (Capdevielle and Darraq, 1980). Thetypical symptoms are gastrointestinal problems includingnausea, vomiting, epigastric and abdominal pain, and di-arrhoea (Capdevielle and Darraq, 1980; Georgiou et al.,1988). Some reports also describe general anxiety, headache,drowsiness, arrhythmia and convulsions (Hamouda et al.,2000). In several cases, these symptoms are followed bycoma (Capdevielle and Darraq, 1980). The laboratory find-ings (marked increased in SGOT, SGPT and bilirubin) mayindicate severe hepatocellular damage and acute renal fail-ure (Georgiou et al., 1988; Nogue et al., 1992). Post-mortemhistopathologic examination discloses massive gastrointesti-nal haemorrhage, diffuse necrosis of the hepatic parenchymawith collapse of the interstitial connective tissue and accu-mulation of macrophages (Caravaca-Magarinos et al., 1985).

5

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Tb harged -a hos-p p ofA nsedr

ntc ibitst tions kingo ac-to ility

he next morning both children died. The histopatholondings showed congested intestine, peritoneal exund haemorrhages in stomach and kidney.

In 1955, a report describing the accidental poisonineveral Italian school children including three fatal caSanti and Cascio, 1955) raised the interest of the scientiommunity inAtractylis gummifera.

In 1969, Catanzano described the intoxication ofhildren who drank a decoction ofAtractylis gummifera.he observed symptoms were vomiting, convulsions, mular hypertonia and mydriasis; the arterial pressurees were 100/50 mm Hg in one child and 100/75 mm

n the other and the pulse rate was 100 bpm for bothren. The laboratory findings showed increased leucoumbers (20,000/mm3) while the histopathologic findinghowed hepatic necrosis.

Georgiou described another case of a 7-year-old boyitted to hospital 2 days after drinking an extract ofAtractylisummifera, taken to treat oxyuriasis. The symptoms wpigastric pain, vomiting and general anxiety. The patieondition progressively worsened and, despite treatmenoy died 8 days after admission (Georgiou et al., 1988).

In Spain, five people were poisoned after taking an iion ofAtractylis gummifera, owing to a misidentificationhe patients suffered extensive liver damage and kidneyre. One of them died after gastrointestinal haemorrhag

he other four survived after dialysis (Caravaca-Magarinot al., 1985).

A report byHamouda et al. (2000)stated that from 198o 1998 the Tunisian Poisoning Center collected 56 mal records of patients admitted to the toxicological inten

. Toxicology and pharmacology

The toxic effect ofAtractylis gummiferaarises from ATRpowerful inhibitor of oxidative phosphorylation in mi

hondria. This action is exerted especially in cells ricitochondria such as hepatocytes and in proximal tubula

thelial cells, which contain carriers that allow ATR to crhe cell membrane.

ATR interacts with the adenine nucleotide translocANT) (Roux et al., 1996), a mitochondrial protein containn the inner membrane. ANT has two major functions:esponsible for the antiport of ATP and ADP, an imporystem for oxidative phosphorylation and it is part ofermeability transition pore complex, a non-specific porolved in mitochondrial membrane permeabilization, anortant event during apoptosis (Haouzi et al., 2002).

ATR and ADP both interact in a similar way with ANecause they resemble one another in geometric and cistribution (Stewart and Steenkamp, 2000): the polar charcter of the sulphate groups in ATR corresponds to the phate group in ADP; the glucose in the glycoside grouTR corresponds to the ribose of ADP, and the condeings of ATR resemble the purine moiety of adenine.

The selective binding of ATR to ANT has two importaonsequences. First, ATR inhibits ADP transport and inhhe access of extra mitochondrial ADP to a phosphorylaite located in the mitochondrial compartment, thus blocxidative phosphorylation and Krebs cycle oxidative re

ions (Quintanilla et al., 1979; Kholodenko et al., 1988). Sec-nd, ATR induces opening of the mitochondrial permeab

C. Daniele et al. / Journal of Ethnopharmacology 97 (2005) 175–181 179

transition ATN-containing pores leading to membrane per-meabilization and release of soluble intermembrane proteins,including cytochromec. The translocation of cytochromecfrom mitochondria to the cytosol is a crucial step in Fas-induced apoptosis (Vancompernolle et al., 1998).

The toxic effects due to the inhibition of mitochondrialphosphorylation are hepatic necrosis and renal failure in an-imals and humans. The acute toxicity of ATR neverthelessdiffers according to the animal species and route of admin-istration. Toxicity is higher in dogs than in mice and rats,suggesting an even higher toxicity in humans (Luciani andCarpenedo, 1978). Renal toxicity also differs among the var-ious species: for example, rabbits and guinea pigs show norenal necrosis at ATR doses that are nephrotoxic for rats(Carpenedo et al., 1974). Toxicity differs also in male rats be-tween albino and Wistar strains: in albino rats ATR is not toxicat doses up to 200 mg/kg, whereas in Wistar strains 60 mg/kgcan lead to death.Luciani and Carpenedo (1978)describedthe action of ATR in different species. The major effects areon glycidic metabolism: ATR depletes glycogen in vivo byinhibiting glycogen synthesis, it increases blood lactic acidconcentrations and decreases oxygen consumption. Animalspoisoned with ATR usually die in hypoglycaemic convul-sions. An interesting feature of ATR poisoning is the longlatency between the administration of ATR and the appear-a undi asec lyco-g onseq press lactica insad vouss

tso ion.T a-a ma-gt ratst es( erateg hesee ey,a lear-a t un-c andiia

Rc ie -l via-b ed

glutathione (GSSG) and reduced glutathione (GSH) levels inkidney and liver tissues from different animals. ATR nephro-toxicity involved only the proximal tubule cells, whereasthe glomerular cells appeared unaffected (Carpenedo et al.,1974). In the proximal tubule cells, ATR caused a signifi-cant concentration-dependent decrease in ATP content anda depletion of cellular GSH (Obatomi and Bach, 1998). Theinvestigators proposed that ATR could act by interfering withcell transport; the presence of a sulphate moiety, suggestedthat ATR may undergo anion transport and then accumulatein the renal cells. ATR also inhibited organic anion uptakein a dose- and time-dependent manner (Koechel and Krejci,1992; Obatomi et al., 1998). In the liver, the major effectsare lipid peroxidation, GSH depletion and GSSG elevation.These changes suggest that ATR may induce its toxic effectsthrough an oxidative process involving its methylene moietythus producing a free radical. The reactive intermediate pro-duced has not been identified, but reactive oxygen speciessuch as superoxide anion, hydrogen peroxide or hydroxylradicals may be involved (Obatomi et al., 1998).

6. Treatment ofAtractylis gummiferapoisoning andstudies on possible therapeutic approaches

ail-a -t ent,c l andc andr p,2 ctices on,g (

entsf dsw yo twop ogs( usa lu-c cy-t in-is mia,h ad-m udy,I itya eetga rosst sided nesisa amil( re

nce of the first toxic symptoms, also when the compos given intravenously. After an initial hyperglycaemic phaused by depletion of skeletal muscle and hepatic gen a hypoglycaemic phase ensues that has important cuences on the whole organism, such as respiratory deion, hypoxaemia, acidosis due to increased plasmacid, and finally convulsions. Because ATR toxicity remafter vagotomy and pancreatectomy (Santi, 1958) it cannotepend either on an interaction with the autonomic nerystem or on glands implicated in glycaemic control.

In a study in rats,Hopps et al. (1997)described the effecf the ATR and some of its derivatives on renal functhey determined the urinary excretion of enzymes (betN-cetyl-d-glucosaminidase, alanine amino peptidase, gamlutamyltransferase) and electrolytes (Na+, K+ and Cl−), and

he blood and urinary concentrations of creatinine inreated with ATR, atractyligenin and two ATR derivativone lacking both the sulphate groups and the isovalroup, the other lacking the sulphate groups alone). Txperiments showed that ATR highly toxic to the kidns shown by enzymuria and reduction of creatinine cnce, whereas atractyligenin leaves renal function almoshanged. ATR toxicity is related to its chemical structure

ncreases when the hydroxyl groups in C-4′ is esterified withsovaleric acid or when the hydroxyl groups in C-3′ and C-4′re esterified with sulphuric acid.

Other important information on the toxic effects of ATomes from in vitro studies using tissue slices (Obatomt al., 1998; Obatomi and Bach, 1998). This method al

owed comparison of enzyme leakage, mitochondrialility, changes in ATP levels, lipid peroxidation, oxidiz

--

No specific pharmacological treatment is currently avble to treatAtractylis gummiferaintoxications. All therapeu

ic approaches, including fluid and electrolyte replacemardiovascular and respiratory support, seizure controonventional therapeutic methods for severe hepaticenal failure, are symptomatic (Stewart and Steenkam000). Some recommend that standard therapeutic prahould include induction of vomiting, bowel evacuatiastric lavage and administration of activated charcoalBen

Salah et al., 2001).In an attempt to develop better pharmacological treatm

or Atractylis gummiferaintoxication, various compounere evaluated.Catanzano et al. (1969)showed the inefficacf hydrocortisone (500 and 25 mg i.v.) administered tooisoned children. In vivo experiments performed in dChardon et al., 1964) evaluated the efficacy of an intravenodministration of 100 ml of a solution containing 6–7% gose, 0.1% dinitrophenol, 5 mg of ATP and 11.25 mg ofochromecagainst poisoning induced by intravenous admstration of an extract or dry root ofAtractylis gummiferainaline solution. This treatment corrected the hypoglycaeypotension and anuria and delayed death only wheninistered immediately after the extract. In an early st

shii and Bracht (1986)investigated the protective activgainst ATR-induced liver toxicity of stevioside, a swlycoside isolated from the plantStevia rebaudiana(Aster-ceae) that can interfere with the transport of ATR ac

he cell membrane. In isolated perfused rat liver, stevioecreased the effects of ATR on glycolysis, gluconeogend oxygen uptake. The cytoprotective effects of verapVRP) and dithiothreitol (DTT) against ATR toxicity we

180 C. Daniele et al. / Journal of Ethnopharmacology 97 (2005) 175–181

investigated using precision-cut renal and liver slices assays(Obatomi et al., 2001a). The beneficial effect of VRP reflectsits ability to reduce the ATR-induced increase in cytosolicCa2+. VRP, a well-known calcium-channel blocker, com-pletely blocked ATR-induced cell death, depletion of ATP,inhibition of gluconeogenesis in both kidney and liver slices,and provided protection against ATR-induced depletion ofGSH in liver slices but not in kidney slices. Dithiothreitol(DTT), a sulphydryl-reducing agent and a metal chelator,reduced the reactive methylene double bond of ATR. DTTprotected against ATR-induced enzyme linkage, inhibitionof gluconeogenesis and depletion of GSH in kidney but ex-erted no protective effects against GSH and ATP depletionin the liver slices. Both verapamil and dithiothreitol never-theless had protective effects only if used 30 or 60 min be-fore ATR exposure, but were ineffective after the exposureto ATR. Hence they cannot be used for therapeutic purposes.In another study,Obatomi et al., (2001b)compared the roleof ADP, calpain inhibitor I (CPI), stevioside and probenecidin protecting against ATR-induced toxicity in rat renal cor-tical slices. ADP, CPI and stevioside prevented the deple-tion of ATP and the reduction in gluconeogenesis, whereasprobenecid gave no protection at all. Both in vivo and invitro Haouzi et al., (2002)showed that ATR-permeabilitytransition is counteracted by cyclosporin A (CsA) and GSH.C hu-m rsorN . Inv cesm inoa thel pa-t

7

-l usly.T e tot ctedbsi ymp-t diesa educ-i re-i e toA entsw ronict

re-s usedi ntsc ean-d

Fab fragments are highly effective also inThevetia peruvianapoisoning, a recurrent phenomenon in Sri Lanka (Eddlestonand Persson, 2003). A study conducted in Tunisia has al-ready attempted to produce polyclonal Fab fragments againsttoxic components ofAtractylis gummifera, (Hamouda et al.,2004). This immunotherapy approach will probably be saferbut more expensive than conventional treatments. Anotherpractical approach would be to spread information about thetoxicity of Atractylis gummifera, teaching children to recog-nize dangerous plants they should keep away from.

Acknowledgment

The Authors wish to thank Prof. Mauro Ballero, Uni-versity of Cagliari, for having provided the photograph ofAtractylis gummifera.

References

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. Conclusion

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