Sequential randomised and double blind trial of promethazine prophylaxis against early anaphylactic reactions to antivenom for bothrops snake bites. (1/183)

OBJECTIVE: To investigate the efficacy of the H1 antihistamine promethazine against early anaphylactic reactions to antivenom. DESIGN: Sequential randomised, double blind, placebo controlled trial. SETTING: Public hospital in a venom research institute, Sao Paulo, Brazil. PARTICIPANTS: 101 patients requiring antivenom treatment after being bitten by bothrops snakes. INTERVENTION: Intramuscular injection of promethazine (25 mg for adults and 0.5/kg for children) or placebo given 15-20 min before starting intravenous infusion of antivenom. MAIN OUTCOME MEASURES: Incidence and severity of anaphylactic reactions occurring within 24 hours after antivenom. RESULTS: Reactions occurred in 12 of 49 patients treated with promethazine (24%) and in 13 of 52 given placebo (25%); most were mild or moderate. Continuous sequential analysis indicated that the study could be interrupted at the 22nd untied pair, without preference for promethazine or placebo. CONCLUSION: Prophylaxis with promethazine does not prevent early reactions. Patients should be observed carefully during antivenom infusion and the subsequent few hours.  (+info)

Crystallization and preliminary X-ray diffraction analysis of a myotoxic phospholipase A(2) homologue from Bothrops neuwiedi pauloensis venom. (2/183)

Crystals of a myotoxic phospholipase A(2) from Bothrops neuwiedi pauloensis have been obtained. They diffracted at 2.5 A resolution using a synchrotron radiation source and belong to space group P3(1)21. Preliminary analysis shows that there are two molecules in the asymmetric unit.  (+info)

"RKKH" peptides from the snake venom metalloproteinase of Bothrops jararaca bind near the metal ion-dependent adhesion site of the human integrin alpha(2) I-domain. (3/183)

Integrin alpha(1)beta(1) and alpha(2)beta(1) are the major cellular receptors for collagen, and collagens bind to these integrins at the inserted I-domain in their alpha subunit. We have previously shown that a cyclic peptide derived from the metalloproteinase domain of the snake venom protein jararhagin blocks the collagen-binding function of the alpha(2) I-domain. Here, we have optimized the structure of the peptide and identified the site where the peptide binds to the alpha(2) I-domain. The peptide sequence Arg-Lys-Lys-His is critical for recognition by the I-domain, and five negatively charged residues surrounding the "metal ion-dependent adhesion site" (MIDAS) of the I-domain, when mutated, show significantly impaired binding of the peptide. Removal of helix alphaC, located along one side of the MIDAS and suggested to be involved in collagen-binding in these I-domains, does not affect peptide binding. This study supports the notion that the metalloproteinase initially binds to the alpha(2) I-domain at a location distant from the active site of the protease, thus blocking collagen binding to the adhesion molecule in the vicinity of the MIDAS, while at the same time leaving the active site free to degrade nearby proteins, the closest being the beta(1) subunit of the alpha(2)beta(1) cell-surface integrin itself.  (+info)

Histologic and functional renal alterations caused by Bothrops moojeni snake venom in rats. (4/183)

Acute renal failure (ARF) is the main cause of death following snake bites by Bothrops species. In this study, we investigated the morphologic and functional renal disturbances caused by Bothrops moojeni venom in rats. Renal function was assessed based on creatinine and lithium clearances and on histologic examination of renal tissue 5 hr after the intravenous administration of 0.2 mg of venom/kg and 5 hr, 16 hr, and 48 hr after 0.4 mg of venom/ kg. A venom dose of 0.4 mg/kg produced renal tubule disturbances, including acute impairment of proximal and post-proximal tubule sodium handling associated with acute tubule necrosis. The glomerular filtration rate (GFR) decreased significantly and was accompanied by severe morphologic disturbances in the renal glomeruli. These functional and morphologic findings were observed in the absence of any change in mean arterial blood pressure. The decrease in GFR was not related to the presence of fibrin deposits in the glomerular capillary loops. These results suggest an early nephrotoxic action of B. moojeni venom involving significant morphologic and functional changes similar to those observed in snakebite-induced ARF in humans.  (+info)

Two phospholipase A2 inhibitors from the plasma of Cerrophidion (Bothrops) godmani which selectively inhibit two different group-II phospholipase A2 myotoxins from its own venom: isolation, molecular cloning and biological properties. (5/183)

Myotoxic phospholipases A(2) (PLA(2)s; group II) account for most of the muscle-tissue damage that results from envenomation by viperid snakes. In the venom of the Godman's viper (Cerrophidion godmani, formerly Bothrops godmani), an enzymically active PLA(2) (myotoxin I) and an inactive, Lys-49 variant (myotoxin II) induce extensive muscle damage and oedema. In this study, two distinct myotoxin inhibitor proteins of C. godmani, CgMIP-I and CgMIP-II, were purified directly from blood plasma by selective binding to affinity columns containing either myotoxin I or myotoxin II, respectively. Both proteins are glycosylated, acidic (pI=4) and composed of 20-25-kDa subunits that form oligomers of 110 kDa (CgMIP-I) or 180 kDa (CgMIP-II). In inhibition studies, CgMIP-I specifically neutralized the PLA(2) and the myotoxic, oedema-forming and cytolytic activities of myotoxins I, whereas CgMIP-II selectively inhibited the toxic properties of myotoxin II. N-terminal amino acid sequence analysis and sequencing of cDNAs encoding the two inhibitors revealed that CgMIP-I is similar to gamma-type inhibitors, which share a pattern of cysteine residues present in the Ly-6 superfamily of proteins, whereas CgMIP-II shares sequence identity with alpha-type inhibitors that contain carbohydrate-recognition-like domains, also found in C-type lectins and mammalian PLA(2) receptors. N-terminal sequencing of myotoxin I revealed a different primary structure from myotoxin II [De Sousa, Morhy, Arni, Ward, Diaz and Gutierrez (1998) Biochim. Biophys. Acta 1384, 204-208], which provides insight into the nature of such pharmacological specificity.  (+info)

Antibody from mice immunized with DNA encoding the carboxyl-disintegrin and cysteine-rich domain (JD9) of the haemorrhagic metalloprotease, Jararhagin, inhibits the main lethal component of viper venom. (6/183)

Envenoming by the Brazilian pit viper, Bothrops jararaca, induces extensive local and systemic haemorrhage in humans. The severe and occasionally lethal outcome of envenoming is prevented only by administration of antivenom which is conventionally prepared by hyperimmunization of large animals with an individual venom or a range of venoms. Since snake venoms typically consist of numerous molecules, only some of which are toxic, antivenoms are antigenically crude preparations whose therapeutic value would theoretically be enhanced by restricting antibody specificity to toxic venom molecules. We report here that high-titre IgG antibody from mice immunized by the GeneGun with DNA encoding the carboxy-terminal JD9 domain of Jararhagin, a haemorrhage-inducing metalloprotease in B. jararaca venom, extensively neutralized the main lethal component of B. jararaca venom. This is to our knowledge the first study to apply DNA-based methods to preparation of antivenom; it represents a novel approach with greater immunological specificity and fewer hazards than conventional systems of antivenom production.  (+info)

Basic residues of human group IIA phospholipase A2 are important for binding to factor Xa and prothrombinase inhibition comparison with other mammalian secreted phospholipases A2. (7/183)

Human secreted group IIA phospholipase A2 (hGIIA) was reported to inhibit prothrombinase activity because of binding to factor Xa. This study further shows that hGIIA and its catalytically inactive H48Q mutant prolong the lag time of thrombin generation in human platelet-rich plasma with similar efficiency, indicating that hGIIA exerts an anticoagulant effect independently of phospholipid hydrolysis under ex vivo conditions. Charge reversal of basic residues on the interfacial binding surface (IBS) of hGIIA leads to decreased ability to inhibit prothrombinase activity, which correlates with a reduced affinity for factor Xa, as determined by surface plasmon resonance. Mutation of other surface-exposed basic residues, hydrophobic residues on the IBS, and His48, does not affect the ability of hGIIA to inhibit prothrombinase activity and bind to factor Xa. Other basic, but not neutral or acidic, mammalian secreted phospholipases A2 (sPLA2s) exert a phospholipid-independent inhibitory effect on prothrombinase activity, suggesting that these basic sPLA2s also bind to factor Xa. In conclusion, this study demonstrates that the anticoagulant effect of hGIIA is independent of phospholipid hydrolysis and is based on its interaction with factor Xa, leading to prothrombinase inhibition, even under ex vivo conditions. This study also shows that such an interaction involves basic residues located on the IBS of hGIIA, and suggests that other basic mammalian sPLA2s may also inhibit blood coagulation by a similar mechanism to that described for hGIIA.  (+info)

Local haemorrhage induced by Bothrops jararaca venom: relationship to neurogenic inflammation. (8/183)

We investigated morphological alterations induced by s.c. injection of 2.5 microg of Bothrops jararaca venom in rats. Intense disorganisation of collagen fibres was observed 1 min after the venom injection, particularly at regions near vessels and nerves. Mast cells were degranulated, and erythrocytes were seen leaving venules throughout the endothelial junctions. At this time, damaged endothelial cells were not observed. In rats envenomed as above, but immediately after cardiorespiratory failure induced by deep ether anaesthesia, alterations in the connective tissue structures, as previously described, were not observed. The mediation of this haemorrhage was investigated by injecting the venom into the foot pad of mice and compared to the mediation of oedema. Local haemorrhage was significantly reduced in mice pre-treated with capsaicin or guanethidine or submitted to a surgical section of sciatic and saphenous nerves. In these animals, oedema was not affected. Groups treated with methysergide or morphine showed both haemorrhage and oedema significantly reduced. Indomethacin or dexamethasone pre-treatments significantly reduced the oedema, but not the haemorrhage. Moreover, in animals treated with promethazine or mepyramine, oedema and haemorrhage were not affected. These data suggest that local haemorrhage induced by Bothrops jararaca venom is partially controlled by serotonin and neurohumoral mediators. Furthermore, results indicate that haemorrhage and oedema are mediated by different pharmacological systems.  (+info)

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