Biomedical subjects
D A Warrell
Publications and source records attributed to D A Warrell.
Successful in-vitro cultivation of Borrelia recurrentis.
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Development of alpha-neurotoxin antibodies in patients envenomed by the monocellate Thai cobra (Naja kaouthia).
Serum samples from 50 patients envenomed by the Thai cobra (Naja kaouthia) were tested by enzyme immune assay for the presence of antibodies against the principal neurotoxin. Samples were taken between 1 month and 19 years after the bite. Only 16% (8/50) of the samples were positive for antibodies against neurotoxin, while 76% (38/50) were positive for antibodies against whole venom. There was no clear correlation between the presence of antibodies against neurotoxin and clinical features.
Biological properties of the venom of the Papuan black snake (Pseudechis papuanus): presence of a phospholipase A2 platelet inhibitor.
The whole venom of Pseudechis papuanus, in addition to its anticoagulant activity, powerfully inhibited platelet aggregation induced by ADP, adrenaline, collagen, ristocetin and thrombin. High levels of phospholipase A2 (PLA2) activity were detected. A mild procoagulant activity was also observed. Following exposure of platelets to P. papuanus venom, platelet factor 3 (procoagulant platelet phospholipid) showed decreased cofactor activity in factor X activation by Russell's viper, venom suggesting that the venom PLA2 plays a major role in the inhibition of the coagulation mechanism. In vivo rodent assays confirmed the inhibitory effect on platelets and the haemorrhagic and neurotoxic activities. It is possible that PLA2 is responsible for anticoagulation and that this, combined with the effect on platelet aggregation, a mild procoagulant and a moderately potent haemorrhagin, is responsible for the haemorrhagic diathesis observed in systemically envenomed patients. Polyvalent (Australia-Papua New Guinea) Commonwealth Serum Laboratories antivenom, currently used for clinical treatment of snakebite in Papua New Guinea, proved highly effective against P. papuanus venom in rodent and in vitro assays, despite the absence of this particular venom from the immunising mixture.
Neurotoxicity and haemostatic disturbances in patients envenomed by the Papuan black snake (Pseudechis papuanus).
Among 335 patients presenting with snakebites in Central Province, Papua New Guinea, nine were proved by enzyme immunoassay to have been bitten by Papuan black snakes (Pseudechis papuanus). Seven showed clinical evidence of envenoming. Early symptoms included vomiting and tender local lymph nodes. Five patients had neurotoxic signs and one required mechanical ventilation. Spontaneous systemic bleeding occurred in two patients. Coagulation studies in four patients showed thrombocytopenia, prolongation of prothrombin time, mild defibrination and depletion of other clotting factors with elevated fibrin(ogen) degradation products and other evidence of fibrinolysis. One patient developed mild renal dysfunction. There was no evidence of intravascular haemolysis or rhabdomyolysis. These clinical observations, which do not distinguish victims of P. papuanus from those of taipans (Oxyuranus scutellatus canni), suggest that the venom contains neurotoxic, haemorrhagic and mild procoagulant activities. Only two other cases of proven envenoming by this species have been reported. There appears to have been a decline in the abundance of this species, and hence its medical importance, over the last 25 years.
Neurotoxicity, haemostatic disturbances and haemolytic anaemia after a bite by a Tunisian saw-scaled or carpet viper (Echis 'pyramidum'-complex): failure of antivenom treatment.
A young man in Germany was bitten by a large captive saw-scaled viper (Echis 'pyramidum'-complex) of Tunisian origin. During the first few hours after the bite he developed evidence of disseminated intravascular coagulation and fibrinolysis, and bled spontaneously. Despite being given a total of 310 ml of three different Echis-specific antivenoms (together with large amounts of fresh frozen plasma and concentrated clotting factors), venom antigenaemia (measured by enzyme immunoassay) and coagulopathy persisted for more than 10 days, and he developed a haemolytic anaemia and mild renal dysfunction. Transient bilateral ptosis was attributed to envenoming. The venom of the snake responsible for the bite was immunologically distinct from that of Nigerian E. ocellatus and was clearly not neutralised by the three monospecific antivenoms which had been administered. This case is another illustration of the geographical variation in snake venoms and the need for pooling venoms from snakes from different parts of the geographical range in the preparation of antivenoms. Envenoming by North African Echis species may not be reversible by available antivenoms.
Reliability of the simple 20 minute whole blood clotting test (WBCT20) as an indicator of low plasma fibrinogen concentration in patients envenomed by Bothrops snakes. Butantan Institute Antivenom Study Group.
Reliability of the simple 20 minute whole blood clotting test (WBCT20) as an indicator of low plasma fibrinogen concentration in patients envenomed by Bothrops snakes. Toxicon 32, 1045-1050, 1994.--A simple whole blood clotting test (WBCT20) was assessed for its efficacy in determination of severe defibrinogenation in patients envenomed by Bothrops snakes in Brazil. There was a close relationship between the results of the WBCT20 and plasma fibrinogen levels in 69 moderately envenomed patients. The advantage of the WBCT20 over estimation of plasma fibrinogen concentrations in patients is that it is a simpler, faster and more reliable test. It is also of use in assessing the effectiveness of antivenom therapy in relation to the restoration of blood coagulability.
Imported falciparum malaria in British troops returning from Kenya.
The objective of this study was to report on a breakthrough of Plasmodium falciparum infection following a military exercise in central Kenya and the treatment regimens used. A series of case reports are presented from the three UK hospitals involved. Among 150 British soldiers who had been on exercises for five weeks in central Kenya, taking proguanil/chloroquine anti-malarial prophylaxis, seven developed symptomatic falciparum malaria. Initial symptoms, which started between 2 and 10 days before their return to England, included faintness, sweating, shivering, diarrhoea, headache and myalgia. Diagnosis was delayed from between 5 and 13 days after the first symptom. One patient was severely ill with 50% parasitaemia: he required intensive care, exchange blood transfusion and haemofiltration for acute renal failure. Compliance with chemoprophylaxis was not measured and anti-mosquito measures were not generally practised. However, British Army policy was amended in June 1993 so that mefloquine will be used in future rather than proguanil/chloroquine. It was concluded therefore that even in an educated and motivated population simple preventive measures are not observed. Chemoprophylactic compliance could be improved by changing to a simpler regime. Falciparum malaria is a medical emergency that requires urgent admission for confirmation of diagnosis, supportive and curative treatment. Its presence should be suspected in any ill traveller.
Severe and fatal mass attacks by 'killer' bees (Africanized honey bees--Apis mellifera scutellata) in Brazil: clinicopathological studies with measurement of serum venom concentrations.
In São Paulo State, Brazil, five males, aged between 8 and 64 years, were attacked by 'Africanized' honey bees (Apis mellifera scutellata). The estimated number of stings received by each patient ranged from > 200 to > 1000. All five were transferred to intensive care units in São Paulo City. Clinical features included intravascular haemolysis, respiratory distress with ARDS, hepatic dysfunction, rhabdomyolysis (with myoglobinaemia and myoglobinuria), hypertension and myocardial damage (perhaps explained by release of endogenous catecholamines by venom phospholipase A2 and mellitin), shock, coma, acute renal failure and bleeding. Laboratory findings included gross neutrophil leucocytosis, elevated serum enzymes [AST, ALT, LDH, CPK (predominantly CPK-MM)] and creatinine. Clotting times were slightly prolonged. Despite treatment with antihistamines, corticosteroids, bronchodilators, vasodilators, bicarbonate, mannitol and mechanical ventilation, three of the patients died between 22 and 71 h after the attacks, with histopathological features of ARDS, hepatocellular necrosis, acute tubular necrosis, focal subendocardial necrosis and disseminated intravascular coagulation. Whole bee venom and phospholipase A2 (PLA2) antigen concentrations were measured in serum and urine for the first time, using enzyme immunoassay. High venom and PLA2 concentrations were detected in serum and urine for more than 50 h after the stings in two fatal cases, in one of which the total circulating unbound whole venom was estimated at 27 mg, one hour after the attack. An antivenom should be developed to treat the increasing numbers of victims of mass attacks by Africanized 'killer' bees in USA, Middle and South America.
Disorders of neuromuscular transmission due to natural environmental toxins.
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Action of snake venom components on the haemostatic system.
Among the components in snake venom are a number which have profound effects (either stimulatory or inhibitory) on haemostatic mechanisms, including coagulation, fibrinolysis, platelet function and vascular integrity. As a consequence, human victims of snakebite may suffer severe and sometimes fatal haemorrhagic and/or thrombotic sequelae. Many of these venom components have been isolated and their precise mechanisms of action established. Apart from direct fibrinolysins, procoagulants predominate, most of these exerting their effect late in the clotting cascade, activating factor X or prothrombin or directly converting fibrinogen to fibrin. Some of the procoagulants are, or have the potential to be, used as therapeutic agents. Some venom components have been put to use as laboratory reagents for diagnostic purposes or for characterising molecular defects of haemostasis, although because they often have unphysiological actions, results must be interpreted with caution. These and other useful constituents e.g. protein C activator and platelet aggregating agents are discussed.
Venomous bites and stings.
Travellers to tropical countries are often extremely concerned about the risk of bites and stings by venomous animals. This fear prompts many enquiries, usually at the last moment before departure, about the possibility of carrying first aid kits and antivenoms. In fact, these accidents are extremely rare because most travellers wear shoes and are far less exposed to venomous animals than indigenous peoples for whom bites and stings may be important causes of death or morbidity.
Hypoglycaemia and counterregulatory hormone responses in severe falciparum malaria: treatment with Sandostatin.
The mechanism and response to treatment of severe life-threatening hypoglycaemia (plasma glucose 1.15 +/- 0.73 mM/l [+/- SD]) was studied in eight Thai patients with falciparum malaria. Plasma insulin concentrations were inappropriately high (range 1.0-21.8 mU/l), lactic acidosis was common (arterial blood lactic acid concentration 1.44-17.8 mM/l), but the glucose counterregulatory response, indicated by plasma cortisol, growth hormone, catecholamines and glucagon concentrations, was intact. Hyperinsulinaemia was successfully treated in five patients by a continuous intravenous infusion of the long-acting somatostatin analogue Sandostatin (SMS 201-995), 50 micrograms/h. In volunteer studies a single intramuscular injection of Sandostatin (100 micrograms) suppressed quinine-induced hyperinsulinaemia within 15 min; this effect was maintained for 6 h. These results suggest that Sandostatin may be a safe and effective way of correcting the hyperinsulinaemic hypoglycaemia complicating quinine treatment of falciparum malaria. This treatment could be particularly useful in fluid-overloaded patients with recurrent hypoglycaemia despite dextrose infusions.
Rabies vaccine: economical regimens.
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Treatment of primaquine-resistant Plasmodium vivax malaria.
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Cerebral malaria.
Cerebral malaria is the most important manifestation of severe Plasmodium falciparum infection. The clinical picture in South East Asian adults differs from that in African children. The children are more likely to have abnormal brain stem reflexes, signs suggestive of cerebral herniation, and raised CSF opening pressure, and to suffer persistent neurological sequelae. The mortality remains high at about 20%. The diagnosis must be considered in all patients with fever and impaired consciousness who may have been exposed to the infection. The pathophysiology of cerebral malaria may involve mechanical obstruction of the cerebral circulation by parasitized erythrocytes which have adhered to the vascular endothelium. Cytokines such as tumor necrosis factor may also contribute. The most important element of treatment is early, optimal chemotherapy with quinine, but artemisinine derivatives may prove even more effective.
Comparison of the potency of three Brazilian Bothrops antivenoms using in vivo rodent and in vitro assays. BIASG (Butantan Institute Antivenom Study Group).
Three Brazilian polyspecific Bothrops antivenoms were compared using standard W.H.O. rodent in vivo and in vitro assays of their ability to neutralize the principal venom activities of pooled whole Bothrops jararaca venom. On a volume basis, the antivenoms were equally effective in neutralizing lethal activity in mice, and there were only minor differences in their ability to neutralize venom-induced haemorrhage, necrosis and procoagulant activity. Antivenom efficacy in neutralizing defibrinogenation varied. However, when equal amounts of antivenom IgG were compared, it was found that the FUNED antivenom best neutralized lethality, haemorrhage, necrosis and fibrinogen clotting activity. Vital Brazil and FUNED antivenoms were equally effective in neutralizing plasma coagulant activity but Vital Brazil antivenom was the more effective in neutralizing defibrinogenation.