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Home , Banded rubber frog, Bufotoxin, Cardiotoxicity, Phrynomantis, Raucous toad

ORIGINAL ARTICLES

NO~OUSTOADSANDFROGSOF all over the body, whereas granular glands are localised in special regions, such as the paratoid poison glands behind the head in . Because of their locality the paratoid glands, which do not secrete saliva, are often erroneously referred to as L Pantanowitz, TW aude, A Leisewitz 'parotid' glands. Granular glands produce a thicker, more toxic secretion. However, secretion from both mucous and granular glands may be poisonous.' While nearly all have a The major defence mechanism in is via the secretion of trace of in their skin: this is not equally developed in the from their skin. In humans, intoxication may occur different genera. Both gland types are under the control of when part of the integument is ingested, as in the sympathetic nerves and discharge following a variety of l form of herbal medicines. Two groups of South African frogs stimuli. " Mucous glands secrete mainly when stimulated by have skin secretions that are potentially lethal to humans and dryness, whereas granular glands require pressure, injury or . (BlIfo and Schismademla pecies), the any stress to the to cause secretion."'" With some amphibian with which man and his pets most frequently exceptions, notably BI/fv lIlaril/lIS (not a South African toad), have contact, secrete potent toxins with pre-metamorphic larvae lack toxic properties as granular activity. Topical and systemic intoxication, while seen in glands develop only at metamorphosis." humans, remains predominantly a veterinary problem. Amphibians are not equipped for speed, nor do they have Intoxication by the red-banded rubber , which secretes an any armament; as such they rely predominantly on chemical unidentified cardiotoxin, is far less common. The probable defence to deter predators.'"-" As well as being unpalatable, the mechanisms of intoxication and management of a poisoned sticky, viscous properties of secretions may confer a protective patient are discussed. advantage. This is seen in some of Brroiceps (rain frog),I" whose defensive white secretions have earned it the name 5 Afr Med 11998; 88: 1408-1414. 'melk padda'. Such sticky toad secretions have given rise to the false superstition that handling of toads causes warts. Poisoning may cause local and/or systemic toxicity. ln domestic and wild animals poisoning usually occurs following Reports of human and veterinary toxicity eau ed by mouthing or ingestion of the amphibian. In humans, poisoning amphibians are not common in the literature.'4 However, little is likely to occur when secretions are brought into contact with has been published on noxious South African amphibians, skin, mucosa or conjunctiva.»u Absorption of directly probably because the occurrence of toxicity is low and/or into the circulation may occur where cuts or abrasions are because toxicity has previously not been diagnosed. Anurans present.7.L1 Intoxication may also occur when part of the (frogs and toads) are the only amphibians indigenous to South amphibian integument is ingested, as in the form of herbal Africa. (toads), Schisl1laderma (red toads) and PJzryllol1lantis medicines," or when saliva containing toxins is inspired.'; (rubber frogs) are the only genera of tOXicological importance. Systemic toxicity following topical application of venom to The highly toxic tropical dendrobatid frogs u ed for dart intact skin has not been documented. However, anuran venom poison' do not occur in South Africa. Toxicity remains introduced intradermally, rather than topically, causes a more primarily a veterinary problem. However, in view of the fact marked and painful dermal reaction.'" The fascinating practice that humans have considerable contact with amphibians, of smoking dried toad skin and licking toads for their particularly toads, physicians should have some knowledge of hallucinogenic effects has also been reported." 0 amphibian their toxicity. causes actual mechanical trauma, except for the bullfrog Only skin secretions of amphibians are considered (Pyxicepltallls) which may inflict a nasty bite'" with its teeth-like poisonous, although venom has been isolated from the plasma odontoids on the lower jaw. and eggs of some toads.~' The amphibian skin houses mucous and granular ('poison') glands. Mucous glands are dispersed BIOCHEMISTRY AD PHARMACOLOGY Amphibians secrete a wide range of substances belonging to CI"is Hani Bamgu'lIlath Hospital and University ofti,e Witwatersrand. many chemical classes with varied pharmacological activities. Johannesburg Many of these compounds could serve the frog in defence as L Pantanowitz, BSc Hons (Zoology), MB BCh chemical irritants'" '" secondary to a physiological role'l 12 They Departmmt of PllOrmacolog,v and Toxicology, FaCIlity of Vt'lcrinary Science, include biogenic amines (e.g. catecholamines), various peptides Ullil'ersity of Prt'loria (e.g. bradykinin, physalaemin and caerulein), TW aude. BVSc, MSc Agric (Biochemistry) indolealkylamines (e.g. ), (one of the Dqmrtlllmt of Medicille. Faculty of Veterinary Scimce, Ullil'crsitv of Pretoria cardiac aglycones) and alkaloids.""" There are cardiotoxins, A Leisewitz, BVSc Hons, MMed (Ve') Med

o\'ember 199 ,Vol. , j\;o. 11 AM) , sympathomimetics, pressor agents, local Digitalis is used in humans and animals to treat congestive anaesthetics and hallucinogens present in frog secretions."·"'-" cardiac failure and to slow the ventricular heart rate in the The indolealkylamines (bufotenines or related presence of atrial fibrillation and flutter. In toxic amounts alkaloids) exert primarily oxytocic and pressor effects and are digitalis causes arrhythmias and asystole..... Knowledge of toad responsible for causing hallucinations." Peptides from skin toxicity dates back to ancient times where physicians used secretions of the South African platanna (Xenopus laevis) have dried toad skins to treat dropsy (oedema) and as a cardiotonic, even shown similarity to toxins'"' Secretions from even before digitalis was introduced....'"'" Dried skin extracts of Xenoplls makes it unpalatable as prey to other animals and also toads are still employed in herbal medicines today by the toxic to other frogs in contact with it. Intoxication of mammals Chinese (known as Ch'all 5u) and Japanese (called 5enso)" to by Xenopus, however, is not known (W D Haacke - personal treat congestive ." Bufadienolides, like digitalis in communication). At high enough dosages all these compounds toxic doses, initially cause bradycardia, followed by a may be poisonous. Their equivalents in mammalian tissues sequential first-, second- and third-degree atrioventricular occur in lower concentrations and are often less active:""" For block and terminally asystole'+'-'i3·70 Extracardiac effects of example, the amount of stored in the paratoid bufadienolides also mimic digitalis toxicity. Effects include glands of Bufo guttllrnlis (formerly B. regularis,'" namely 10.7 mg nausea, emesis, diarrhoea and a bitter taste. However, no single per toad, is equivalent to the amount of adrenaline found in the substance is entirely responsible for the clinical signs of toad adrenals of sheep, and greater than that found in man'"" toxicity, as the exogenous catecholamines found in toad When isolated from toad-skin secretions the cardio-active secretions have a marked additive effect on the toxicity of aglycones () and their ." derivatives, the bufotoxins, are structurally analogous to the well-known bufadienolide and cardenolide cardiac glycosides, such as those respectively fOlmd in medicinally TOADS applied squill (plant of the lily family) and digitalis."';! The Toads are the most common amphibians that man and his pets pharmacological activity of all cardiac glycosides is vested in have contact with. There are 11 species of Bufo (Fig. 2) and one the aglycone. The sugar moeity probably only influences lipid of 5cJlismaderma (Fig. 3) in the South African Bufonidae. solubility, and thus absorption. The stereospecificity essential Requiring water only to breed and for their tadpole stage, they for digitalis-like cardio-activity is present in both the are terrestrial animals inhabiting most of the country. Toads are cardenolides (with a 5-membered, singly unsaturated lactone common in urban areas and suburban gardens. Because all Bufo ring at position C" of the steroid skeleton), and bufadienolides species are poisonous to some extent and capable of causing (with a 6-membered, doubly unsaturated lactone ring in tJtis toxicity, species identification is unnecessary. Compared with position). Both have the stereospecific configuration essential other frogs, toads are stout, slower-moving creatures with short for cardiac activity/' and therefore the same pharmacological limbs and little webbing on their feet. Their dorsal skin, with and toxicological actions.";" Furthermore, in the cardiac cryptic colouration, is rough with numerous wart-like dermal glycosides there is always a glycosidic-bound sugar moiety at protuberances. Their paratoid glands are conspicuous, pitted position C, of the teroid structure, but in the toad toxins this is replaced by an ester linkage to suberyl-arginine (Fig. 1). The pharmacological receptor for all cardiac glycosides is the membrane-bOlmd a-, K--adenosine triphosphate ( Ta', K- ­ ATPase) enzyme.;'-a

o o o

o o o I I I [Rhamnose] (SuberlC acid] [Digito$

DIGOXIN SCILUlREN A A Fig. 1. The structurnl formulae of the medicinal cardellolide (digoxin) Fig. 2. Bufo gutturalis (gutturnl toad). The parntoid glands situated and bllfadienolide (scillaren A) cardiac glycosides in comparison with behind the elJes and the wart-like dorsal dermal skin glands are very a typical bufadienolide toad toxin (bufotoxin). distinct (photo - VC Carruthers). ORIGINAL ARTICLES

usually brick-red in colour and lacks the large warts of other toads. The same type of toxins, however, are still secreted from their dorsal skin glands (T W aude, AR Schultz ­ unpublished data). The mouthing of South African toads by dogs is known to cause intoxication, often with fatal outcome.73-74 The development of clinical signs varies according to the victim's age, concurrent disease, amount of toxin absorbed in relation to body weight and the length of time following exposure." Because toxins are rapidly absorbed through buccal and gastric mucosa, clinical symptoms are usually evident within a short period of contact with the toad." Distasteful poisons cause a burning sensation and inflammation of the buccal and pharyngeal mucosa, forcing the animal to drop the toad. In cases of mild poisoning no other toxic effects occur'· Profuse salivation (which helps remove toxins), head shaking, vomiting, abdominal pains, diarrhoea (which may be Fig. 3. Schismaderma carens has a conspicuous glandular ridge haemorrhagic), pyrexia, laboured respiration (with possible running dorsolaterally down each side ofits body. The dorsum is pulmonary oedema), cyanosis and cardiac arrhythmias are brick red in colour and granular. There are no paratoid glands (photo - VC Carruthers). cardinal clinical signs of systemic toxicity in dogs and cats. Neurological effects, including ataxia and seizures, occur with 77 ridges located behind each eye. Toads emit secretions more severe poisoning. Seizure activity is usually a precursor containing bufadienolides from these paratoid glands when to death. Death in domestic animals has been known to occur frightened or injured (Fig. 4). The presence of cardiac glycoside within 15 minutes of the onset of symptoms, and in most cases 47 activity in the secretions of the four largest South African Bufo ventricular fibrillation is the cause of death. Toxicity may 77 species has been confirmed by digoxin-specific fluorescence persist for a week, resulting in exhaustion of the animal. polarisation immunoassay (T W Naude, AR Schultz, Toad toxicity in humans is less common. Ingestion of toad Toxicology Division, Ondestepoort Veterinary Institute ­ poisons by humans also causes local oral irritation with profuse unpublished data). Smaller amounts of poison are secreted salivation, vomiting, dizziness, blurred vision, general from dorsal dermal glands, which explains why mammals that weakness, cyanosis, mental confusion and hallucinations, peri­ prey on toads frequently consume only the ventral parts, oral numbness, seizures, transient focal neurological signs and rejecting the dorsal skin.n Paratoid glands are absent in metabolic disturbances.""'" It is unclear whether convulsions are Schismaderma (the red toad). The dorsal skin in this species is due to direct stimulation of the central nervous systemS! or to a secondary mechanism such as arrhythmia. Cardiac manifestations of toad toxicity in humans include severe bradycardia, both hypertension and hypotension, arrhythmias and cardiopulmonary arrest. Electrocardiographic features of bufotoxins on the mammalian heart include bradycardia, P-R prolongation, T-wave inversion, ectopic beats, secondary ventricular tachycardia and ventricular fibrillation.46.70 Evidently the most important toxic effects in terms of risk to the patient are those involving the heart. Hence patients with premorbid cardiac disease are at increased risk. Other factors likely to increase sensitivity to bufadienolides are poor excretion of toxin (renal disease) and electrolyte disturbances, 82 particularly potassium abnormalities. -83 Children and immature animals, however, seem to tolerate higher concentrations of cardiac glycosides than do adults.84-85 Toad toxicity during pregnancy does not appear to be teratogenic"" even though components of bufadienolides have been shown to modulate cellular differentiation and angiogenesis.87 Significant ocular effects have occurred in humans following Fig. 4. Bufo rangeri (raucous toad) secreting sticky white toxins eye exposure to toad secretions. Pain, chemical conjunctivitis, from its paratoid glands (photo - WR Branch).

ovember 199 , Vol. 88, o. 11 SAMJ ORIGINAL ARTICLES

swelling of the eyelids, clouding of the cornea, and changes in intra-ocular pressure have all been reported after toxic secretions were inadvertently brought into contact with the eyes....·! There is also a report of a toad 'squirting' venom a distance of 2 - 3 feet into the eyes of a man, resulting in temporary blindness.92 Application of toad venom to the mammalian eye initially causes painful irritation, followed 30 - 60 minutes later by mydriasis, swelling of the eyelids and local anaesthesia. Initially conjunctival congestion is absent. Conjunctivitis rarely persists for longer than 24 hours. Venom passing via the nasolacrimal ducts into the nose and mouth can cause salivation and sneezing.'" Systemic poisoning can also occur with the absorption of venom from the eye.'"

RED- Frogs of the genus (rubber frogs) are found on the African continent south of the Sahara. Their skin is smooth and rubbery to the touch. In South Africa, only skin secretions of the red-banded rubber frog Phrynomantis bifasciatus (formerly Phrynomerus bifasciatus) are toxic. The dorsum of this frog has aposematic (warning) red or pink markings and a ventral surface which is grey with white spots (Fig. 5). Although their digits have expanded terminal discs, these Gevic~reepersare not arboreal in habit. Their milky secretions, produced in great quantities when disturbed, can cause both local irritation and systemic toxicity in humans.!9.93 Their secretions are also poisonous to other frog species that come in dose contact with them.'·93 Skin irritation after handling this frog causes an erythematous rash with temporary inflammation.·"'" Paraesthesia of the hands is also experienced (G van Aswegen - personal communication). More prolonged contact with the frog results in throbbing pain which may persist for up to 10 Fig. 5. (Top) Phrynomantis bifasciatus is readily identified by its hours.95 No fatalities are recorded in the literature. Only one striking red to pink dorsal markings against a black background. serious toxic reaction attributed to P. bifasciatus has been Adults are usually 5 cm in size. (Bottom) The ventral surface is grey with white spots (photos - V C Carruthers). documented." Thirty minutes after contact with the toxin the scratches on the victim's hand became painfully inflamed and anaphylaxis usually start shortly after allergen administration, oedematous. One hour later he developed systemic symptoms. and the most common manifestations are usually Painless muscle contractions of the chest and abdomen resulted dermatological. More serious reactions involve the respiratory in respiratory difficulty and inability to stand. One-and-a-half and cardiovascular systems. It is surprising that the victim in hours later the victim experienced a headache, dizziness, this case did not experience any significant cardiorespiratory tachycardia, diaphoresis and nausea. Four hours after initial symptoms, as skin secretions of the red-banded rubber frog are contact, toxicity appeared to subside gradually, except for a known to be cardiotoxic.98 Biochemical analysis of P. bifasciatus persistent myalgia. An intense burning sensation of the eyes skin secretions, however, has failed to demonstrate any also occurred following contact with secretions. The severity of identifiable active toxins 0 VlSser - personal communication). this reaction, described by the author as an anaphylactoid This frog is probably of little potential danger to humans; reaction," was thought to be related to the absorption of toxic firstly because people are unlikely to come into contact with secretions directly into the bloodstream through the open this nocturnal species, which spends much of its time in scratches on the victim's skin. concealed places, and secondly because knowledgeable The symptoms in the aforementioned case are not typical of handlers with many years' experience appear never to have anaphylaxis, although humans do vary in their clinical suffered any ill effects while handling specimens (N I expression of anaphylaxis!7 Clinical manifestations of Passmore, JVlS5er - personal communication). ORIGINAL ARTICLES

MANAGEMENT OF INTOXICATION important in assessing severity of intoxication. Hyperkalaemia is often suggestive of acute ingestion of cardiac glycosideslO,.1(\J General and supportive measures Because the chemical structure of bufadienolides is similar to To prevent possible reactions, one should avoid direct contact that of digoxin, toad toxins will frequently cross-react with while handling poisonous specimens. Handlers should keep digoxin antibodies used in digoxin immunoassays.lt>l hands away from their eyes, noses and mouths. Treatment of In cases of systemic envenomation, or when the diagnosis of intoxication depends on correct diagnosis. This is often toad intoxication is in doubt, actual measurement of serum difficult, particularly with paediatric and veterinary victims cardiac glycoside levels by immunoassay is required. While where a history is unreliable and many other conditions could competitive radio-immunoassays with antibodies of broad be confused with poisoning. After suspected poisoning, urgent specificity to cardiac glycosides have proved successful in medical (or veterinary) attention should be sought as mortality confirming the diagnosis of poisoning from the Bufo may occur within as little as 15 minutes from time of exposure marimls,"" commercially available monoclonal digoxin in dogs. Monitoring of the patient for 12 - 24 hours may be immunoassays appear to be of little help.I" Nevertheless there necessary, as delayed tissue distribution occurs with cardiac is enough cross-reactivity between digoxin and bufotoxins to glycosides.85 The principles of treatment in veterinary and qualitatively confirm cardiac glycoside activity by digoxin­ human patients are unlikely to differ. In fact, the specific fluorescence polarisation immunoassay in skin pharmacokinetics of cardiac glycosides in normal human secretions of toads, and in the organs of dogs that died from subjects is similar to that in canines.99-IOO intoxication (T W Naude, AR Schultz - unpublished results). Local skin irritation is self-limiting and unlikely to require These immunoassays will also permit the rapid screening of topical antihistamines, hydrocortisone and analgesics. other anuran species suspected of containing cardiac Applying cold ice-packs offers some relief from pain.'" glycosides. Vigorous oral irrigation and a dilute sodium bicarbonate Sympatholytics, acting on both a- and ~-adrenergic 77 mouthwash may help to relieve local oral symptoms. If eyes receptors, are effective in the treatment of toad poisoning.7l If become exposed to secretions immediate copious irrigation life-threatening arrhythmias are present, they will respond to with clean water or saline is essential. Because the eye tends to appropriate medications. Various drugs advocated include clear up after 24 hours no additional treatment is required, atropine, propranolol, diphenylhydantoin, lidocaine and unless infection or complications develop. Inducing emesis'OI is calcium gluconate."·7l·'I1l·' Although atropine treats bradycardia, probably of little value once signs of toxicity are evident, as heart block and hypotension from 811fo intoxication, the vomiting commonly occurs as a result of toad poisoning. sialogogic effects of toad poisoning do not appear to be Gastric lavage, activated charcoal and cathartics have also been appreciably influenced by its administration. A temporary used to limit the absorption of ingested toad toxins' True cardiac pacemaker in cases of persistent symptomatic anaphylaxis, although unlikely, will need to be treated with bradycardia may be required." Working on the treatment of respiratory support, adrenaline and intravenous fluids. dogs poisoned with the cardiac glycoside and catecholarnine­ Parenteral fluids will also be required to treat shock and containing skin secretions of 811fo marinlls, researchers found excessive vomiting, in volumes sufficient to guarantee an that total adrenergic blockade with propranolol and optional diuresis. Additional therapies include systemic dibenamine protected animals against the toxic effects of up to corticosteroids and antihistamines," even though immune 100 times the lethal dose of crude toad toxins.7l The possibility n reactions are insignificant. Sedatives, tranquillisers and of using acetyl promazine (as an a-blocker) in conjunction with n systemic analgesics are of no proven benefit. Treatment with propranolol (as a ~-blocker) as a combination therapy seems magnesium salts plus agents that chelate calcium, such as worthwhile investigating. Propranolol is thought to antagonise ethylenediaminetetra-acetic acid (EDTA), might decrease the the stimulatory effect of glycosides on sympathetic nerves, thus toxicity of bufadienolides." Convulsions can be treated with blocking the release of endogenous catecholamines. This action diazepam and pentobarbitone. Pentobarbital-induced then limits the intoxication to a purely cardiac glycoside anaesthesia has been shown to increase canine tolerance to Bllfo intoxication. I!>! Propranolol also has anti-arrhythmic properties, intoxication." Although unlikely, intubation and ventilation not directly related to its ~-receptor-blocking action"" may also be necessary.211 Fortunately, in many cases recovery Administering potassium in the presence of hypokalaemia will usually occurs without any therapeutic assistance. further antagonise cardiotoxic effects. Potassium, however, should be avoided if there is heart block. There is currently no Cardiac management known antidote to toad toxins. The administration of The most toxic aspects of toad poisoning are the cardiac effects. commercially available digoxin-specific antibodies may

1I A baseline ECG may help in evaluating the patient's condition antagonise some of the cardiotoxic effects of toad . tJ.1I1 by detecting treatable cardiac abnormalities. Continuous ECG However, more work in this field is still required before the use monitoring will also help to establish a response to treatment. of antibodies becomes an accepted form of treatment. Blood chemistry, in particular potassium levels, is also

'O\'ember 199 , Vol. , 0.11 SAM] ORIGINAL ARTICLES

The authors thank DE van Dijk (Department of Zoology, 42. Witkop B. New directions in tht> chemistry of natural products: The organic chemist as a pathfinder for biochemistry and medicine. Experimtia 1971; 27: 1121-1138. University of Stellenbosch), NI Passmore (Department of Zoology, 43. Kolbe HVj. Huber A. Cordier P, 8 nl. Xenoto'<.ins, a family of peptides from dorsal gland University of the Witwatersrand), A Channing (Department of secretions of Xenopus lal!i.'is related to snake \enom cytotoxins and neurotoxins. JBioi Chem 1993; 268: 16r 16464. Biochemistry, University of the Western Cape), G van Aswegen +to Erspamer V, Melchiorri P. Acti\·e polypeptides of the amphibian skin and their synthetic (Department of Anatomy, University of Potchefstroom), WD analogues. Pure Applied Cllemi:itry 1973; 35: -1-63-49--1. Haacke (Transvaal Museum of Natural History, Pretoria), and J 45. Lichtstein D, Gati t Babila T, Haver E, Katz U. Effect of salt acdimation on digita1i::.-like compounds in the toad. Biochem BiopJrys Acta 1991; 1073: 65-68. Visser (Durbanville), for their assistance with this review, as well as -1-6. Tandy M, Keith R. BuJo in Africa. In: Blair WF, eel. Emlution of the Genus BlIJo. Austin: VC Carruthers and WR Branch for photographs. University of Texas Press, 1972: 119·170. 47. Chen KK, Chen L. The phYSiological action of the principles isolated from the secretion of the South African toad (Bufo regularis). JPhann Exp Therap 1933; 49: 503-513. References 48. MO€' GK, Farah AE. Digitalis and allied cardiac glycosides. In: Goodman LS, Gillman AL, eds. Thf PhnmlacologicaI Basis ofTherapeutics. ~ew York: Macmillan, 1965. 1. Alien ER, Neill WT. Effect of marine toad toxins on man. Herpetologica 1956; 12: 150-151. 49. Jensen H, Westphal U. Chemical structure and interrelationship of toad poisons. In: Buckley 2. Banner W. Bites and stings in the pediatric patient. Curr ProbI Pediatr 1988; 18: 1--69. EE, Porges N, eds. Venoms: First IllteTtlational Conference on Vel'loms. 1965: 75-83 (reference kept 3. Yei CC, Deng JF. Toad or toad cake intoxication in Taiwan: report of four cases. J Fonnos Med at the Biophysics library. University of the Wihvatersrand). AS50C 1993; 92: 5135-5139. SO. Klyne W. The Chemistry ofthe . London: Metheum, 1957. -l. Daly.f\V. Myers CW, \\'hittaker N. Further classification of skin alkaloids from neotropical 51. Ode RH, Pettit GR, Kamano Y. Cardenolides and Bufadienolides. In: Hey OH, lohns WF, eds. poison frogs (Dendrobatidae), with a general sun'ey of toxic/noxious substances in the StmJids (Orgallic Chemistry. Series Two). London: Bunenvorth, 1976: 1-t.5-171. arnphibia. Toricon 1987; 25: 1023-1095. 52. Chen. KK, Henderson FG. Pharmacology of si),t}'·four cardiac glycosides and aglycones. J 5. Myers CW. Daly JW. Dart-poison frogs_ Sa Am 1983; 248, 97-105. PllImn Exp Thmp 1954; 111, 365-" 6. Licht LE. Unpalatability and toxicity of toad eggs. Herpetologica 1968; 24: 93-98. 53. Chen KK, Chen L. Similarity and dis-similarity of bufagins, bufotoxins, and digitaloid 7. Lutz B. Venomous toads and frogs. In: Bucherl W, Buckley EE, eds. Veflomous Animals and glucosides. J Phnml Exp Tllerap 1933; 49: 561·579. Their Vmoms. Vo12. New York: Academic Press, 1971: 423-473. 54. shoppee CW, Shoppee E. Steroids: Cardiotonic glycosides and aglycones. Toad poisons: S. Noble GK. The Biology of the Amphibia. USA: Dover Publications, 1931. Steroid saponins and sapogenins. In: Rood EH. 00. Chemistry ofCarbon Compounds. Vol lIB. 9. Cochran OM. Living Amphibians of the World. London: Hamish Hamilton. 1961. Amsterdam: EIse\"ier, 1953: 9 1049. A. 10. Tyler M), Stone DJM. Bowie}H. A novel methcx:i for the release and collection of dermal, 55. Chen KK, Kovariko\·a Pharmacology and toxicology of toad venom. JPhaml Sri 1967; 56: 1535-1541. glandular secretions from the skin of frogs. JPharmacol Toxicol Methods 1992; 28: 199-200. 56. Hoffman BF, Bigger Digitalis and allied cardiac glycosides. In: Goodman LS, Gillman AL. 11. Toledo RC, Jared C, Brumer A. Morphology of the large granular alveoli of the parotid fT. eels. 7th 00. New York: Macmillan, 19 ~: 716-747. glands in toads (Bufo ictencus) before and after compression. Toxicon 1992; 30: 745-753. The PlrnTl1U1cologicaI Basis o/Therapeutics. 12. Habermehl GG. Exocytosis of toxins in amphibians and . Ann NY Acad Sri 1994; no: 57. 5chwartz A. Is the cell membrane Na·. K·-ATPase enzyme system the pharmacological 149-152. receptor for digitalis? Circ Res 1976; 39: 2+7. 58. Flier J, Edwards ~1\V, Oaly JW. Myers CW. Widespread occurrence in frogs and toads of skin 13. Oaly]\V. The chemistry of poisons in amphibian skin. Proc Natl Acad SCI USA 1995; 92.: 9-13. compounds interacting with the ouabain site of. a·. K--ATPase. Science 1980; 208: 503-505. 14. Smart cr. BuIoto),ins and buIogenins - their effectivity in protecting their producer and 59. lichtstein D, Kachalsky 5, Deutsch J. Identificabon of a ouabain-like compound in toad skin their potential as aversive conditioning agents. J H~ Assoc Ajnca 1981; 26: 3-6. and plasma as a bufcx:iienolide derivative. Lifr Sei 1986; 38: 1261-1270. 15. Daly lW, Myers CW. Toxicity of Panamanian poison frogs (Dendrobates): Some biological 60. Cruz J5, Matsuda H. Arenbufagin. a compound in toad venom, blocks Na C)-K· pump and chemical aspects. Scif71ce 1967; 156: 970-973. current in cardiac myocytes. Eur JPlIarnrncoll993; 239: 223-226. 16. Barthalmus GT, Zielinski WJ. Xellopus skin mucus induces oral dyskinesias that promote 61. Akera R. Larsen Fs, Brody TM. Correlation of cardiac sodium- and potassium-activated escape from snakes. Pharmacol Biochem BeJun l 1988; 30: 957-959. adenosine triphosphate activity with ouabain-induced inotropic stimulation. JPhann Exp 17. Groves F. Fatal toad poisoning in snakes. Herp Rev 1978; 9: 19-20. Therap 1970; 173: 145·151. 18. Licht LE, Low B. Cardiac response of snakes after ingestion of toad parotoid venom. Copeia 62. 5himoni Y, Gotsman M, Deutsch J, Kachalsky 5, lichstem D. Endogenous ouabain-like 1968; 1: 547-551. compound increases heart muscle contractility. .'·ature 1984; 307: 369·371. 19. Passmore l\'l, Caruthers Vc. South African Frogs. A Complete Gude. 2nd eel. Johannesburg: 63. Shimoni Y, Gotsman M. Epstein M, Kachabky S, Deutseh 1, lichstein O. Further Witwatersrand University Press, 1995. characterisation of the inotropic effect of a bufodienolide glycoside - an endogenous 20. Prescott CW. Ticks, , insects, cane toads, platypus. Venom intoxications 11. Aust Vet ouabain like compound Cardiac RI!S 1986; 20: 229-239. PractiI1984; 14, 111-116. 64. Rosen MR. WitAl, Hoffman BF. Electrophysiology and pharmacology of cardiac 21. Janzen OH. Injury caused by toxic secretions of Phrynohyas spilomma. CopeiJl1962; 1: 657. arrhythmias. IV Cardiac antiarrhythmic and toxic effects of digitalis. Am Heart J 1975; 89: 391­ 22. Agosti A. 8ertaccini G. ~asa1 absorption of caerulein.LAncet 1969; 1: 580-581. 399. 23. Gebhart L. A plague of toads. Sa Ne-.os 1967; 9Z," 39. 65. Mever K, Linde H. Collection of toad \"enoffi5, and chemistrv of the toad venom steroids. In: Bi.i~erl V~oms. ~e\ 24. Boericke W. Pockd Manual ofHomeopathic MilterUi Medica . . lew Delhi: B. Jain Publishers, 1994: W, Buckley EE, eds. Venomous Ammals alld Thnr Vol 2. .., York.: Academic 135-136_ Press, 1971: 521-556. 25. Palumbo NE, Perri 5, Read G. Experimental induction and treatment of toad poisoning in the 66. Kwan T, Paiusco AD, Kohl L. Digitalis toxidty caused by toad venom. Chest 1992; 102: 949­ dog. JAm Vet Med Assoc 1975; 167,1000-1005. 950. 26. Brodie EO. Hedgehogs use toad venom in their own defence. Nature 1977; 268: 627-628. 67. De Klobusitzky D. AnimaJ venoms in therapy. In: Bucher! W. Buckley EE, eds. Venomous Animals and nwr Vet/Orris. Vo13. l'.:ew York: Academic Press, }Q71: 443-47 . 27. ~1ack RE. Kiss me and the world is mine. Toad toxins. NC Med J 1990; 51: 375-377. 68. Sakanashi M, Xoguchi K. Chibana T, Ojiri Y, shoji M. Effects of mtraduOOenaJ administration 28. Wager VA. The Frogs 0 South Africa. Cape Town: Pumell & Sons. 1965. of 'kyushin', a sense (toad venomkontaining drug. on systemic hemoJynamics, cardiac 29. Kaiser E, Krame.r R. Biochemistry of the cytotoxic action of amphibian poisons. In: Russel FE. function and myocardial oxygen co~urnption m anaesthetized dogs Am JChin Med 1993; 21: Saunders PR, OOs. Animal Toxins. Oxford: Pergamon Press. 1967: 389-394. 7-16. 30. Daly JW. Witkop B. Chemistry and pharmacology of frog venoms. In, Bucher! W. Buckley EE. 69. Morishita 5. SI- oji M, Oguni Y, Ito C. t\:oguchi K, Sakanashi M. Congesb\·e heart failure eds. Venomous Animals and TJutrr Vmoms. Vo12. New York: Academic Press, 1971: 497-519. model in rabbits: effects of digoxin and a drug containing toad venom. Jprl JPharnwcoI1991; 31. Flier J5. Ouabain·like activity in toad skin and its implications for endogenous regulation of 56,427-432. ion transport. Nature 1978; 274: 285-286. 70. Chen KK, Chen L. The a(ti\'e groupings in the molecules of rino- and marino-buIagins and 32 Flier J5. Moratos-Flier E. Pallotta JA, McIsaac D. Endogenous digitalis·Jike activity in the cino- and vulgaro-buIotoxins. JPJrnrm Exp Therap 1933; 49: 548-579. plasma of the toad Bufo marinus. Nature 1979; 279: J.U·3-t3. n. Otani A, Palumbo N, Read G. Pharmaccx:iynamics and treatment of mammals poisoned by 33. ZeLnik R. Ziti L~1. lltin-layer chromatography. Chromatoplate analysis of the bufadienolides BuJv mannus Mxin. Am J Vet Res 1969; 30: 1865-18n. isolated from toad \·enoms. JChromatog 1962; 9: 371-373. 72. Channing A, \·an Dijk DE. Amphibla. In: Cowan Cl, ed Wet1.lnds ofSouth Africa. Pretoria: 34. Deulofeu V. RuvOOa EA. The basic constituents of toad venoms. in: Bucherl W, Buckley EE. Department of En\'irorunental Affairs and Tounsm, 1995: 193-206. eds. Venomous Ammals and Their Venoms. VoI2.1\'ew York: Academic Press, 1971: 475-495. 73. f\aude TVV. Bula-intoxication in dogs. Proceedings of a symposium on veterinary aspects of 35. Cei]M, Erspamer V, Roseghini M. Biogenic amines. In: Blair WF. ed. Emlutio1f ofthe Genus some zootoxins in . Department of Pharmacology and Toxicology, Faculty of Bufo. Austin: Uni\'ersity of Texas Press, 1972: 233-2·B. Veterinary Science, University of Pretoria, 1992.

36. Erspamer V. Biogenic amines and active polypeptides of the amphibian skin. Ann Rro Pharm 74. :\ewlands C, de Meillon E. Venomow; Creaturl'$ ofSou thenI Africa. Cape Town: 5truik, 1997. 1971; 11, 327-350. 73. ~tacdonald B. Terrier toad toxicity syndrome. Aust Vet Practit 1990; 20: 11 37. Erspamer V. Half a century of comparative research on biogenic amines and al..1:ive peptides 76. HomIeldt CS. Toad toxicity in small animals. Vet Practiu 1993; 5: 12·H. in amphibian skin and mollusc:an tissues. Comp Biochem Physio119S4; 79C: 1-7. 17. Bedford PGC. Toad venom toxicity and its clinical occurrence in small animals in the United 38. Erspamer V. Erspamer GE tazzanti G. Endean R. Active peptides in the skin of one hundred Kingdom. Vet Rec 1974; 94, 613-614. amphibian species from Australia and Papua New Guinea. Comp PfOChem PhySIo/198-l; ne: 78. Hit! M. Ettinger DD. Toad toxicity. N Engl JM'd 1986; 314,1517-1518. 99-1 79. (hem M, Ray C, Wu D. Biologic mtoxication due to digitalis·1ike substance after ingestion of 39. Nakajima T. Active peptides in amphibian skin. Trends Pharmacol So 1981; 2: 202-206. cooked toalJ soup. Am 1CardIo11991; 6i: 4-lJ-4..l.-t. -W. Habermehl GC. Venoms of amphibia. In: Florkin M, Scheer BT. eds. Amph!bia and Reptl1w Ko Rj. Greenwald ~1 • Loscutoff S~l. et al. Lethal Ulgestion of chinese herbal tea containing (Otemical Zoology, \'ollX). ~ew York; Academic Press, 197·t 101-1 Ch·an Su. IV,,! I Akd 1996; 16-1, 71-75. 41. Bradley D. Frog \'enom cocktail yields a one-handed painkiller. Saence 1993; 261: 1117. ORIGINAL ARTICLES

1. Bagetta G, De Sarm G. Corasaniti ~tZ. Robrott 0, l\istico G. Epileptogenic effects of skin extracts from the Australic:n frog Pseudophryne coriacea after intracerebral microinfusion in SPECIAL ARTICLE rats. TarieD" 1992; 30: 197-201. 82. Beller GA, Smith TV\', Abelmann WH, HabeT E, Hood WB. Digitalis intoxication. .l\' Engl / Med 1971; 284, 989·997. 3. Doherty JE. Digitalis glycosides. Pharmacokinetics and their clinical implications. Ann Intern M'd 1973; 79,2..?9--238. PROBLEM-BASED LEARNING IN 84. GLantz SA, Kemoff R, Goldrnan RH. Age-related changes in ouabain pharmacology. Cire Res ,p 1976; 39, 407414. 85. Benowitz Nl. Cardiac glycosides. In: Olson KR ed. PObollillg and Drug Overdose. London: CLINICAL CLERKSHIP - THE Prentice Hall. 19901: 124-125. 86. Chan WY, Ng TB, Yeung HW. Examination for toxicity of a Chinese drug, the toad glandular secretory product Chan su, in pregnant mice and embryos. Bioi NOOll11te 1995; 67: 376-380. EXPERIENCE AT THE UNIVERSITY 87. Lee DY, Yasuda M, Yamamoto T, Yoshida T, Kwoiwa Y. BuIa.lin inhibits endothelial cell proliferation and angiogenesis in vitro. Life Sei 1997; 60: 127·134. OF TRANSKEI MEDICAL SCHOOL 88. Chen KK, Chen L. Notes on the poisonous secretions of twelve toad species. I Pharm Exp Therop 1932; 47, 281-293. 89. Van littelboom T, Kuhn D, Strauven A. Alteration ocularis par venin de crapaud. JTaxieol Cli" Exp 1988; 8, 95-99. Geoffrey AB Buga 90. Howell KM. Ocular envenomation by a toad in the BuJo regularis species group: effects and first aid. East AI' Not Hist 50<: Bull 1978; july/Aug' 82·84. 91. Grant WM. ToxlColagy ofthe Ey'. 2nd ed. Springfield, UL Charles C Thomas, 1974, 1016-1018. The entire medical course· at the University of Transkei (Unitra) 92. Epstein D. The effects of toad venom on the eye. 5 Afr Med J1932; 6:-lQ.3-.4().t.. Medical School became fully problem-based and community­ 93. Pienaar UV, Passmore l\.'1, Carruthers Vc. The Frogs ofthe Kruger National Park. Pretoria: . ational Parks Board of South Africa, 1976. based in 1997, following the introduction of the innovative 94. Stewart MM Amphibions ofMahmli. New York: State University. lew York Press, 1967. medical curriculum into the 2nd year course in 1993. 95. Colley B. Phrynomerus bifasciatus ~ an unpleasant experience. The Herptile 19 ; 12: 43. 96. Jaeger RG. Toxic reaction to skin secretions of the frog, PhrynOmeTUS bijasciJltus. Copria 1971; 1: Descriptions of this curriculum and the process in the first 3 160-161. I 3 years of training have already been published. . The present 97. Patterson R, Valentine M. Anaphylaxis and related allergic emergencies including reactions due to insect stings.IAMJ\ 1982; 248: 2632-2636. paper complements these earlier reports, and covers mainly 9. Van der Wait MPK, Van Rooyen JM, Oberholzer C, Van Aswegen G. of the problem-based learning (PBl) in the last 3 years of the medical skin of the red-handed rubber frog, Phrynomerus InJaseUltus (Smith 1847). OruIerst'POOrt j Vet Res 1992; 5'), 107·109. course. A separate paper dealing with the details of the 99. Selden R, Smith TW. Ouabain phannacokinetic. in dog and man. Circulation 1972; 45: 1176­ 1182- community-based education (CBE) aspects of the curriculum in 100. Keene BW, Rush)E. Therapy of heart failure. In, Ettinger Sj, Feldman EC, eds. Textbook of the senior years of training is being planned. Veterinary Internal MedIcine. 4th 00. Philadelphia: WB Saunders, 1994: 72-873. 101. Boys F, Smith HM. Poisonous Amphilnans and Rf71tiles. Springfield, nI.: Charles C Thomas, Many established medical schools around the world are 19- . making the transition hom traditional curricula to a PBL/CBE 102. Frahne D, Pfander HJ. A Colour Atlas of Poisonous . London: WoUe Science, 1983. 103. Stopfkuchen H, Gilfrich HJ, lungst BK, Gemp? W. Massive digoxin intoxication in childhood. curriculum. The essential characteristics of the PBL/CBE Intensivt Cart Med 1978; 4: 199-201. curriculum include the use of clinical problems rather than 104. Fushimi R, Tachi j, Amino N, Miyai K. Chinese medicine interfering with digoxin immunoassays. Ltmcet 1989; 1: 339. discipline-based teaching for learning, the integration of basic 105. Radford Dj, GUlies AD, Hinds JA, Duffy P. Naturally occurring cardiac glycosides. Med j Aust and clinical sciences throughout the course, and the 1986; 144, 540-544. 106. Brubacher JR Hoffman RS, Kile T. Toad venom poisoning: failure of a monoclonal digoxin development of higher cognitive skills as well as knowledge. immunoassay to cross-react with the cardioactive steroids. I Toxieol C/in ToxicoI 1996; 34: 529­ 530. Various strategies have been adopted to implement these 107. Knowles TP. The poison toad and the canine. Vet Med 196-l; 59: 39-42. principles. Most PBL medical schools have successfully 108. Ojiri Y, Chibana T, Noguchi K. Sakanashi M. Cardiovascular effect of a sensa (toad venom)· containing drug in anesthetized dogs (2): lnfluence of propranolol. Am I Clin Med 1992; 20: introduced these student-centred, tutorial-based learning U7-155. methods in the early years of their courses. However, few have 109. Hondeghem LM, .Mason ]W. Agents used in cardiac arrhythmias. to: Katzung BC, eel. Basic and Clinical PhaTmllcology. 4th ed. London: Prentice-Hall, 1989: 165-182. achieved the goal of incorporating the PBl philosophy into the 110. Bagrov AY, Roukoyatkina NI, Fedorova QV, Pinaev AC, UkhaHova MV. Digitalis-Like and later clinical clerkship years. Unitra Medical School is one of vasoconstrictor effects of endogenous digoxin-like factor{s) from the venom of Bujo marinu;; toad. Eur / Plulmuu:oll995; 234: 165-172 the few schools that has successfully attempted the 111. Bagrov AY, Roukoyatkina r\r:I, Pinaev AG, Dmitieva Rl, Federova OV. Effects of tv.'o endogenous Na·, K·-ATPase inhibitors, marinobufagin and ouabain, on isolated rat aorta_ introduction of PBL strategies at this latter stage.' This article Eur I PhamuuoI1995; 274: 151-r . describes the clinical PBL programme at Unitra in its present Accepted 14 Feh 1998. form.

PBLI ACTIO The major goals of the innovative curriculum in medical training at Unitra have already been reported elsewhere.'-3 However some of the most important goals of PBL in the clinical setting include: (i) acquiring adequate knowledge of the major disease processes seen in the community; (ii) developing

Department of Obstetrics and Gynaecology, University ofTranskei, Urntata, E Cape GeoffTey AB Buga, MB ChB, MMed, PhD

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