Publications by authors named "Stephen Hyslop"

108 Publications

Are Silver Nanoparticles Useful for Treating Second-Degree Burns? An Experimental Study in Rats.

Adv Pharm Bull 2021 Jan 7;11(1):130-136. Epub 2020 Nov 7.

Graduate Program in Pharmaceutical Sciences, University of Sorocaba (UNISO), Sorocaba, SP, Brazil.

In this work, the potential usefulness of silver nanoparticles (AgNPs) for treating burn wounds was examined. Second-degree burns were induced in male Wistar rats by touching the skin with a heated (70°C) metallic device for 10 s, after which the animals were randomly allocated to one of two groups: control (n=8, treated with sterile saline) and experimental (n=8, treated with AgNPs, 0.081 mg/mL; 50 µL applied to the burn surface). Seven, 14, 21 and 28 days after lesion induction two rats from each group were killed and blood samples were collected for a complete blood count and to assess oxidative stress. The livers were examined macroscopically and skin samples were collected for histological analysis. Macroscopically, wound healing and skin remodeling in the experimental group were similar to the saline-treated rats. Likewise, there were no significant differences in the histological parameters between the two groups. However, treatment with AgNPs caused a persistent reduction in white blood cell (WBC) counts throughout the experiment, whereas platelet counts increased on days 7 and 28 but decreased on days 14 and 21; there was also an increase in the blood concentration of reduced glutathione on day 7 followed by a decrease on days 21 and 28. There were no significant changes in blood glutathione peroxidase (GSH-Px) and catalase (CAT) activities or in the serum concentration of thiobarbituric acid reactive substances. The findings of this study raise questions about the potential transitory effects of AgNPs based on the changes in WBC and platelet counts, blood glutathione concentrations and macroscopic hepatic alterations.
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http://dx.doi.org/10.34172/apb.2021.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961217PMC
January 2021

Chemical and functional analyses of Rhinella icterica (Spix, 1824) toad secretion screened on contractions of the heart and oviduct in Locusta migratoria.

J Insect Physiol 2021 Feb-Mar;129:104192. Epub 2021 Jan 16.

Laboratório de Neurobiologia e Toxinologia (LANETOX), Programa de Pós-Graduação em Ciências Biológicas (PPGCB), Universidade Federal do Pampa (UNIPAMPA), São Gabriel, RS, Brazil; Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica (PPGBTox), Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil. Electronic address:

Rhinella icterica is a Brazilian toad with a parotoid secretion that is toxic to insects. In this work, we examined the entomotoxicity of this secretion in locust (Locusta migratoria) semi-isolated heart and oviduct preparations in vitro. The parotoid secretion caused negative chronotropism in semi-isolated heart preparations (at the highest dose tested: 500 μg) and markedly enhanced the amplitude of spontaneous contractions and tonus of oviduct muscle (0.001-100 μg). In addition, the secretion enhanced neurally-evoked contractions of oviduct muscle, which was more sensitive to low concentrations of secretion than the semi-isolated heart. The highest dose of secretion (100 μg) caused neuromuscular blockade. In zero calcium-high magnesium saline, the secretion still enhanced muscle tonus, suggesting the release of intracellular calcium to stimulate contraction. Reverse-phase HPLC of the secretion yielded eight fractions, of which only fractions 4 and 5 affected oviduct muscle tonus and neurally-evoked contractions. No phospholipase A activity was detected in the secretion or its chromatographic fractions. The analysis of fractions 4 and 5 by LC-DAD-MS/MS revealed the following chemical compounds: suberoyl arginine, hellebrigenin, hellebrigenin 3-suberoyl arginine ester, marinobufagin 3-pimeloyl arginine ester, telocinobufagin 3-suberoyl arginine ester, marinobufagin 3-suberoyl arginine ester, bufalin 3-adipoyl arginine, marinobufagin, bufotalinin, and bufalitoxin. These findings indicate that R. icterica parotoid secretion is active in both of the preparations examined, with the activity in oviduct possibly being mediated by bufadienolides.
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http://dx.doi.org/10.1016/j.jinsphys.2021.104192DOI Listing
January 2021

Entomotoxicity of jaburetox: revisiting the neurotoxic mechanisms in insects.

J Venom Res 2020 15;10:38-44. Epub 2020 Sep 15.

Centro Interdisciplinar de Pesquisa em Biotecnologia (CIPBiotec), Universidade Federal do Pampa (UNIPAMPA), Avenida Antônio Trilha 1847, Campus São Gabriel, São Gabriel 97300-000, RS, Brazil.

Ureases are metalloenzymes that hydrolyze urea to ammonia and carbamate. The main urease isoforms present in the seeds of (jack bean urease - JBU and canatoxin) exert a variety of biological activities. The insecticidal activity of JBU is mediated, at least in part, by jaburetox (Jbtx), a recombinant peptide derived from the JBU amino acid sequence. In this article, we review the neurotoxicity of Jbtx in insects. The insecticidal activity of Jbtx has been investigated in a variety of insect orders and species, including Blattodea (the cockroaches , , e ), Bruchidae ( - cowpea weevil), Diptera ( - mosquito), Hemiptera ( - cotton stainer bug; - large milkweed bug, and the kissing bugs and ), Lepidoptera ( - fall army worm) and Orthoptera ( - locust). In , the injection of Jbtx induces marked alteration of locomotor and grooming behavior, whereas in Jbtx causes leg paralysis, an extension of the proboscis and abnormal antennal movements. Electromyographical analysis showed that Jbtx causes complete neuromuscular blockade in . The same treatment in and causes a decrease in the action potential firing rate. Jbtx forms membrane pore-channels compatible with cations in bilipid membranes. A study using voltage-gated sodium (Nav1.1) channels that were heterologously expressed in oocytes correlated the entomotoxicity of Jbtx with the activation of these channels. Taken together, these findings demonstrate the potential of this peptide as a natural pesticide.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659472PMC
September 2020

Kinetic profile of N,N-dimethyltryptamine and β-carbolines in saliva and serum after oral administration of ayahuasca in a religious context.

Drug Test Anal 2021 Mar 3;13(3):664-678. Epub 2020 Nov 3.

Department of Physiological Sciences, Santa Casa de São Paulo School of Medical Sciences, São Paulo, SP, Brazil.

Ayahuasca is a beverage obtained from Banisteriopsis caapi plus Psychotria viridis. B. caapi contains the β-carbolines harmine, harmaline, and tetrahydroharmine that are monoamine oxidase inhibitors and P. viridis contains N,N-dimethyltryptamine (DMT) that is responsible for the visionary effects of the beverage. Ayahuasca use is becoming a global phenomenon, and the recreational use of DMT and similar alkaloids has also increased in recent years; such uncontrolled use can lead to severe intoxications. In this investigation, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to study the kinetics of alkaloids over a 24 h period in saliva and serum of 14 volunteers who consumed ayahuasca twice a month in a religious context. We compared the area under the curve (AUC), maximum concentration (C ), time to reach C (T ), mean residence time (MRT), and half-life (t ), as well as the serum/saliva ratios of these parameters. DMT and β-carboline concentrations (C ) and AUC were higher in saliva than in serum and the MRT was 1.5-3.0 times higher in serum. A generalized estimation equations (GEEs) model suggested that serum concentrations could be predicted by saliva concentrations, despite large individual variability in the saliva and serum alkaloid concentrations. The possibility of using saliva as a biological matrix to detect DMT, β-carbolines, and their derivatives is very interesting because it allows fast noninvasive sample collection and could be useful for detecting similar alkaloids used recreationally that have considerable potential for intoxication.
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http://dx.doi.org/10.1002/dta.2955DOI Listing
March 2021

Cardiovascular activity of Micrurus lemniscatus lemniscatus (South American coralsnake) venom.

Toxicon 2020 Oct 2;186:58-66. Epub 2020 Aug 2.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161Cathedral Street, G4 0RE, Glasgow, UK. Electronic address:

Envenomation by coralsnakes (Micrurus spp.) is characterized by blockade of peripheral neurotransmission mediated by the presence of α- and β-neurotoxins. However, little is known about their cardiovascular activity. Micrurus lemniscatus lemniscatus is a coralsnake found in the Amazon basin and occasionally causes envenomation in humans. In this study, we examined the hemodynamic, vascular and atrial responses to M. l. lemniscatus venom. Anesthetized rats were used for hemodynamic and electrocardiogram (ECG) recordings; in vitro experiments were carried out in rat isolated thoracic aorta and atria preparations. In vivo, venom (0.1 and 0.3 mg/kg) caused immediate and persistent hypotension that was maximal within the first minute with both doses being lethal after ~40 and ~20 min, respectively. ECG, heart and respiratory rates were not altered during the transient hypotension phase induced by venom but all altered prior to death. There was no evidence of myonecrosis in cardiac muscle tissue, pulmonary hemorrhage nor thrombosis in anesthetized rats exposed to venom. In vitro, venom (10 μg/ml) did not contract aortic strips nor affected the maximal responses to pre-contraction with phenylephrine (PE, 0.0001-30 μM) in strips with and without endothelium. However, venom (10 μg/ml) relaxed aortic strips with endothelium pre-contracted with PE. In aortic strips pre-contracted with PE, venom prevented acetylcholine (0.0001-30 μM)-induced relaxation in strips with endothelium without affecting relaxation induced by sodium nitroprusside (0.1-100 nM) in strips without endothelium. Venom (30 μg/ml) produced a transient increase of atrial contractile force without affecting atrial rate. Taken together these findings indicate a predominantly vascular action of the venom, most likely involving toxins interacting with muscarinic receptors.
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http://dx.doi.org/10.1016/j.toxicon.2020.07.019DOI Listing
October 2020

Chemical and Pharmacological Screening of (Spix 1824) Toad Parotoid Secretion in Avian Preparations.

Toxins (Basel) 2020 06 15;12(6). Epub 2020 Jun 15.

Laboratório de Neurobiologia e Toxinologia, Programa de Pós-Graduação em Ciências Biológicas (PPGCB), Universidade Federal do Pampa (UNIPAMPA), Avenida Antônio Trilha 1847, São Gabriel RS 97300-000, Brazil.

The biological activity of parotoid secretion (RIPS) and some of its chromatographic fractions (RI18, RI19, RI23, and RI24) was evaluated in the current study. Mass spectrometry of these fractions indicated the presence of sarmentogenin, argentinogenin, (5,12)-12,14-dihydroxy-11-oxobufa-3,20,22-trienolide, marinobufagin, bufogenin B, 11α,19-dihydroxy-telocinobufagin, bufotalin, monohydroxylbufotalin, 19-oxo-cinobufagin, 3α,12,25,26-tetrahydroxy-7-oxo-5-cholestane-26--sulfate, and cinobufagin-3-hemisuberate that were identified as alkaloid and steroid compounds, in addition to marinoic acid and -methyl-5-hydroxy-tryptamine. In chick brain slices, all fractions caused a slight decrease in cell viability, as also seen with the highest concentration of RIPS tested. In chick neuromuscular preparations, RIPS and all four fractions significantly inhibited junctional acetylcholinesterase (AChE) activity. In this preparation, only fraction RI23 completely mimicked the pharmacological profile of RIPS, which included a transient facilitation in the amplitude of muscle twitches followed by progressive and complete neuromuscular blockade. Mass spectrometric analysis showed that RI23 consisted predominantly of bufogenins, a class of steroidal compounds known for their cardiotonic activity mediated by a digoxin- or ouabain-like action and the blockade of voltage-dependent L-type calcium channels. These findings indicate that the pharmacological activities of RI23 (and RIPS) are probably mediated by: (1) inhibition of AChE activity that increases the junctional content of Ach; (2) inhibition of neuronal Na/K-ATPase, leading to facilitation followed by neuromuscular blockade; and (3) blockade of voltage-dependent Ca channels, leading to stabilization of the motor endplate membrane.
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http://dx.doi.org/10.3390/toxins12060396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354542PMC
June 2020

Neurotoxicity of Tityus bahiensis (brown scorpion) venom in sympathetic vas deferens preparations and neuronal cells.

Arch Toxicol 2020 09 16;94(9):3315-3327. Epub 2020 Jun 16.

Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil.

Systemic scorpion envenomation is characterized by massive neurotransmitter release from peripheral nerves mediated primarily by scorpion venoms neurotoxins. Tityus bahiensis is one of the medically most important species in Brazil, but its venom pharmacology, especially regarding to peripheral nervous system, is poorly understood. Here, we evaluated the T. bahiensis venom activity on autonomic (sympathetic) neurotransmission by using a variety of approaches, including vas deferens twitch-tension recordings, electrophysiological measurements (resting membrane potentials, spontaneous excitatory junctional potentials and whole-cell patch-clamp), calcium imaging and histomorphological analysis. Low concentrations of venom (≤ 3 μg/mL) facilitated the electrically stimulated vas deferens contractions without affecting postsynaptic receptors or damaging the smooth muscle cells. Transient TTX-sensitive sustained contractions and resting membrane depolarization were mediated mainly by massive spontaneous ATP release. High venom concentrations (≥ 10 μg/mL) blocked the muscle contractions and induced membrane depolarization. In neuronal cells (ND7-23wt), the venom increased the peak sodium current, modified the current-voltage relationship by left-shifting the Na-channel activation curve, thereby facilitating the opening of these channels. The venom also caused a time-dependent increase in neuronal calcium influx. These results indicate that the sympathetic hyperstimulation observed in systemic envenomation is presynaptically driven, probably through the interaction of α- and β-toxins with neuronal sodium channels.
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http://dx.doi.org/10.1007/s00204-020-02799-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415753PMC
September 2020

Near-fatal poisoning after ricin injection.

Clin Toxicol (Phila) 2021 Feb 1;59(2):158-168. Epub 2020 Jun 1.

Campinas Poison Control Center, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil.

Objective: To report a near-fatal poisoning after intentional injection of ricin from a castor bean () extract.

Case Report: A 21 year-old man self-injected ∼3 mL of a castor bean extract intramuscularly and subcutaneously in the left antecubital fossa. Upon admission to our ED (1 h post-exposure; day 1, D1) he was awake and alert, but complained of mild local pain and showed slight local edema and erythema. He evolved to refractory shock (∼24 h post-exposure) that required the administration of a large volume of fluids and high doses of norepinephrine and vasopressin, mainly from D2 to D4. During this period, he developed clinical and laboratory features compatible with systemic inflammatory response syndrome, multiple organ dysfunction, capillary leak syndrome, rhabdomyolysis, necrotizing fasciitis and possible compartment syndrome. The patient underwent forearm fasciotomy on D4 and there was progressive improvement of the hemodynamic status from D7 onwards. Wound management involved several debridements, broad-spectrum antibiotics and two skin grafts. Major laboratory findings within 12 days post-exposure revealed hypoalbuminemia, proteinuria, thrombocytopenia, leukocytosis and increases in cytokines (IL-6, IL-10 and TNF-α), troponin and creatine kinase. Ricin A-chain (ELISA) was detected in serum up to D3 (peak at 24 h post-exposure), with ∼79% being excreted in the urine within 64 h post-exposure. Ricinine was detected in serum and urine by LC-MS up to D5. A ricin A-chain concentration of 246 µg/mL was found in the seed extract, corresponding to the injection of ∼738 µg of ricin A-chain (∼10.5 µg/kg). The patient was discharged on D71, with limited range of motion and function of the left forearm and hand.

Conclusion: Ricin injection resulted in a near-fatal poisoning that evolved with septic shock-like syndrome, multiple organ dysfunction and necrotizing fasciitis, all of which were successfully treated with supportive care.
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http://dx.doi.org/10.1080/15563650.2020.1771358DOI Listing
February 2021

Toxinological characterization of venom from Leptodeira annulata (Banded cat-eyed snake; Dipsadidae, Imantodini).

Biochimie 2020 Jul 14;174:171-188. Epub 2020 Apr 14.

Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, 13083-887, Campinas, SP, Brazil. Electronic address:

We investigated the histology of Duvernoy's venom gland and the biochemical and biological activities of Leptodeira annulata snake venom. The venom gland had a lobular organization, with secretory tubules formed by serous epithelial cells surrounding each lobular duct. The latter drained into a common lobular duct and subsequently into a central cistern. In contrast, the supralabial gland was mucous in nature. SDS-PAGE revealed a profile of venom components that differed from pitviper (Bothrops spp.) venoms. RP-HPLC also revealed greater complexity of this venom compared to Bothrops venoms. The venom had no esterase, l-amino acid oxidase or thrombin-like activity, but was proteolytic towards elastin-Congo red, fibrin, fibrinogen, gelatin and hide powder azure. The venom showed strong α-fibrinogenase and fibrinolytic activities and reduced the rate and extent of plasma recalcification. The proteolytic activity was inhibited by EDTA and 1,10-phenanthroline (metalloproteinase inhibitors) but not by AEBSF and PMSF (serine proteinase inhibitors). The venom had phospholipase A (PLA) activity that was inhibited by varespladib. The venom cross-reacted with antivenoms to lancehead (Bothrops spp.), coralsnake (Micrurus spp.) and rattlesnake (Crotalus durissus terrificus) venoms. The venom did not aggregate rat platelets or inhibit collagen-induced aggregation, but partially inhibited thrombin-induced aggregation. The venom was hemorrhagic (inhibited by EDTA) and increased the vascular permeability (inhibited by varespladib) in rat dorsal skin. In gastrocnemius muscle, the venom caused myonecrosis and increased serum creatine kinase concentrations. In conclusion, L. annulata venom has various enzymatic and biological activities, with the local effects being mediated primarily by metalloproteinases and PLA.
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http://dx.doi.org/10.1016/j.biochi.2020.04.006DOI Listing
July 2020

Biochemical characterization and cytotoxic effect of the skin secretion from the red-spotted Argentina frog (Anura: Hylidae).

J Venom Anim Toxins Incl Trop Dis 2020 Mar 30;26:e20190078. Epub 2020 Mar 30.

Protein Research Laboratory (LabInPro), IQUIBA-NEA CONICET, National University of the Northeast, Corrientes, Argentina.

Background: (red-spotted Argentina frog) is a casque-headed tree frog species belonging to the Hylidae family. This species has a complex combination of anti-predator defense mechanisms that include a highly lethal skin secretion. However, biochemical composition and biological effects of this secretion have not yet been studied.

Methods: The skin secretion samples were analyzed by mass spectrometry and chromatographic analysis (MALDI-TOF/MS, RP-HPLC and GC-MS). Proteins were also studied by SDS-PAGE. Among the biological activities evaluated, several enzymatic activities (hemolytic, phospholipase A, clotting, proteolytic and amidolytic) were assessed. Furthermore, the cytotoxic activity (cytolysis and fluorescence staining) was evaluated on myoblasts of the C2C12 cell line.

Results: The MALDI-TOF/MS analysis identified polypeptides and proteins in the aqueous solution of skin secretion. SDS-PAGE revealed the presence of proteins with molecular masses from 15 to 55 kDa. Steroids, but no alkaloids or peptides (less than 5 KDa), were detected using mass spectrometry. Skin secretion revealed the presence of lipids in methanolic extract, as analyzed by CG-MS. This secretion showed hemolytic and phospholipase A activities, but was devoid of amidolytic, proteolytic or clotting activities. Moreover, dose-dependent cytotoxicity in cultured C2C12 myoblasts of the skin secretion was demonstrated. Morphological analysis, quantification of lactate dehydrogenase release and fluorescence staining indicated that the cell death triggered by this secretion involved necrosis.

Conclusions: Results presented herein evidence the biochemical composition and biological effects of skin secretion and contribute to the knowledge on the defense mechanisms of casque-headed frogs.
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http://dx.doi.org/10.1590/1678-9199-JVATITD-2019-0078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112748PMC
March 2020

Experimental model for removal of snake venom via hemoperfusion in rats.

J Vet Emerg Crit Care (San Antonio) 2020 May 29;30(3):286-294. Epub 2020 Feb 29.

Post-Graduate Program in Pharmaceutical Sciences, University of Sorocaba (UNISO), Sorocaba, São Paulo, Brazil.

Objective: To examine the efficiency of hemoperfusion in removing South American rattlesnake (Crotalus durissus terrificus) venom from rats compared with neutralization by antivenom.

Design: An exploratory experimental investigation in rats involving the injection of snake venom with or without subsequent hemoperfusion or antivenom administration.

Setting: Basic animal research laboratory in a private university.

Animals: Normal, healthy male Wistar rats (0.29-0.40 kg, 3-6 months old) from a commercial breeder.

Interventions: Four experimental groups of randomly allocated rats (n = 3/group) were studied: Group 1: rats were injected with a single dose of venom (5 mg/kg, IM, in the right thigh) with no other treatment; blood samples were collected minutes before death to determine leukocyte, platelet, and erythrocyte counts; Group 2 (Control): rats underwent hemoperfusion alone for 60 min using a hemoperfusion cartridge designed for protein adsorption (by granulated charcoal) and protein precipitation (by tannic acid); Group 3 (Venom + antivenom): rats were injected with venom (5 mg/kg, IM) and, 10 min later, were treated with antivenom at the venom:antivenom ratio recommended by the manufacturer; Group 4 (Venom + hemoperfusion): Rats were injected with venom (5 mg/kg, IM) and, 10 min later, were hemoperfused for 60 min. In groups 2-4, blood samples were collected for leukocyte, platelet, and erythrocyte counts 24 h after venom.

Measurements And Main Results: Rats injected with venom alone (Group 1) developed signs of neurotoxicity and ataxia and died in 9.0 ± 0.43 h but showed no changes in leukocyte or erythrocyte counts. In contrast, there were no deaths in groups 2-4. The lack of deaths in Groups 3 and 4 indicated that antivenom and hemoperfusion, respectively, protected against the lethal effects of the venom.

Conclusions: Hemoperfusion with a double-action hemoperfusion cartridge capable of protein adsorption and precipitation protected rats against C. d. terrificus venom.
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http://dx.doi.org/10.1111/vec.12949DOI Listing
May 2020

Inhibition of Kv2.1 Potassium Channels by MiDCA1, A Pre-Synaptically Active PLA-Type Toxin from Coral Snake Venom.

Toxins (Basel) 2019 06 12;11(6). Epub 2019 Jun 12.

Interdisciplinary Centre for Research in Biotechnology (CIPBiotec), Federal University of Pampa (UNIPAMPA), Campus São Gabriel, São Gabriel 97300-000, RS, Brazil.

MiDCA1, a phospholipase A (PLA) neurotoxin isolated from coral snake venom, inhibited a major component of voltage-activated potassium (Kv) currents (41 ± 3% inhibition with 1 μM toxin) in mouse cultured dorsal root ganglion (DRG) neurons. In addition, the selective Kv2.1 channel blocker guangxitoxin (GxTx-1E) and MiDCA1 competitively inhibited the outward potassium current in DRG neurons. MiDCA1 (1 µM) reversibly inhibited the Kv2.1 current by 55 ± 8.9% in a oocyte heterologous system. The toxin showed selectivity for Kv2.1 channels over all the other Kv channels tested in this study. We propose that Kv2.1 channel blockade by MiDCA1 underlies the toxin's action on acetylcholine release at mammalian neuromuscular junctions.
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http://dx.doi.org/10.3390/toxins11060335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628393PMC
June 2019

Neurotoxicity of Micrurus lemniscatus lemniscatus (South American coralsnake) venom in vertebrate neuromuscular preparations in vitro and neutralization by antivenom.

Arch Toxicol 2019 07 23;93(7):2065-2086. Epub 2019 May 23.

Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, Campinas, SP, 13083-887, Brazil.

We investigated the effect of South American coralsnake (Micrurus lemniscatus lemniscatus) venom on neurotransmission in vertebrate nerve-muscle preparations in vitro. The venom (0.1-30 µg/ml) showed calcium-dependent PLA activity and caused irreversible neuromuscular blockade in chick biventer cervicis (BC) and mouse phrenic nerve-diaphragm (PND) preparations. In BC preparations, contractures to exogenous acetylcholine and carbachol (CCh), but not KCl, were abolished by venom concentrations ≥ 0.3 µg/ml; in PND preparations, the amplitude of the tetanic response was progressively attenuated, but with little tetanic fade. In low Ca physiological solution, venom (10 µg/ml) caused neuromuscular blockade in PND preparations within ~ 10 min that was reversible by washing; the addition of Ca immediately after the blockade temporarily restored the twitch responses, but did not prevent the progression to irreversible blockade. Venom (10 µg/ml) did not depolarize diaphragm muscle, prevent depolarization by CCh, or cause muscle contracture or histological damage. Venom (3 µg/ml) had a biphasic effect on the frequency of miniature end-plate potentials, but did not affect their amplitude; there was a progressive decrease in the amplitude of evoked end-plate potentials. The amplitude of compound action potentials in mouse sciatic nerve was unaffected by venom (10 µg/ml). Pre-incubation of venom with coralsnake antivenom (Instituto Butantan) at the recommended antivenom:venom ratio did not neutralize the neuromuscular blockade in PND preparations, but total neutralization was achieved with a tenfold greater volume of antivenom. The addition of antivenom after 50% and 80% blockade restored the twitch responses. These results show that M. lemniscatus lemniscatus venom causes potent, irreversible neuromuscular blockade, without myonecrosis. This blockade is apparently mediated by pre- and postsynaptic neurotoxins and can be reversed by coralsnake antivenom.
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http://dx.doi.org/10.1007/s00204-019-02476-9DOI Listing
July 2019

Consecutive envenomation of two men bitten by the same coral snake ().

Clin Toxicol (Phila) 2020 02 13;58(2):132-135. Epub 2019 May 13.

Campinas Poison Control Center, School of Medical Sciences, State University of Campinas (UNICAMP), Campinas, Brazil.

To report two patients who developed systemic neurotoxicity after consecutive bites by the same coral snake. Two previously healthy men (32-year-old and 34-year-old) found a coral snake in a woodpile while collecting wood for a barbecue. During the barbecue, both men became drunk and "played" with the snake, believing that they were handling a false coral snake, and were bitten within a few minutes of each other. Both patients were admitted to a referral tertiary care hospital (175 km from where the bites occurred) 16 hours and 19 hours postbite; both showed similar features of envenomation: palpebral ptosis, muscle weakness, dysphagia, and generalized myalgia. No fang marks or local pain were detected in either case. The patients were successfully treated with Brazilian coral snake antivenom (Fab´) and discharged one-day postadmission, with improvement of myasthenia, but still showing palpebral ptosis. The offending snake was identified as a 42-cm-long . During follow-up, both patients reported a transitory loss of taste that lasted approximately 3-4 weeks postbite. Consecutive bites by the same coral snake may cause systemic neurotoxicity (acute myasthenia) in more than one person, as well as transitory loss of taste, an underreported complication of snakebites.
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http://dx.doi.org/10.1080/15563650.2019.1610568DOI Listing
February 2020

Scorpion venom increases acetylcholine release by prolonging the duration of somatic nerve action potentials.

Neuropharmacology 2019 07 14;153:41-52. Epub 2019 Apr 14.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Robertson Trust Wing Building, Room 601, 161 Cathedral Street, G4 0RE, Glasgow, UK. Electronic address:

Scorpionism is frequently accompanied by a massive release of catecholamines and acetylcholine from peripheral nerves caused by neurotoxic peptides present in these venoms, which have high specificity and affinity for ion channels. Tityus bahiensis is the second most medically important scorpion species in Brazil but, despite this, its venom remains scarcely studied, especially with regard to its pharmacology on the peripheral (somatic and autonomic) nervous system. Here, we evaluated the activity of T. bahiensis venom on somatic neurotransmission using myographic (chick and mouse neuromuscular preparations), electrophysiological (MEPP, EPP, resting membrane potentials, perineural waveforms, compound action potentials) and calcium imaging (on DRG neurons and muscle fibres) techniques. Our results show that the major toxic effects of T. bahiensis venom on neuromuscular function are presynaptically driven by the increase in evoked and spontaneous neurotransmitter release. Low venom concentrations prolong the axonal action potential, leading to a longer depolarization of the nerve terminals that enhances neurotransmitter release and facilitates nerve-evoked muscle contraction. The venom also stimulates the spontaneous release of neurotransmitters, probably through partial neuronal depolarization that allows calcium influx. Higher venom concentrations block the generation of action potentials and resulting muscle twitches. These effects of the venom were reversed by low concentrations of TTX, indicating voltage-gated sodium channels as the primary target of the venom toxins. These results suggest that the major neuromuscular toxicity of T. bahiensis venom is probably mediated mainly by α- and β-toxins interacting with presynaptic TTX-sensitive ion channels on both axons and nerve terminals.
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http://dx.doi.org/10.1016/j.neuropharm.2019.04.013DOI Listing
July 2019

Effects of Two Fractions of Swietenia macrophylla and Catechin on Muscle Damage Induced by BothropsVenom and PLA₂.

Toxins (Basel) 2019 01 14;11(1). Epub 2019 Jan 14.

Microbiology School, Universidad de Antioquia, Medellín 050010, Colombia.

Plant natural products can attenuate the myonecrosis caused by snake venom and their phospholipases A₂ (PLA₂). In this study, we evaluated the effects of two fractions (F4 and F6) from and purified catechin on the muscle damage caused by a myotoxic PLA₂ from Colombian venom (BaColPLA₂) in mice and by venom from Brazil in mouse phrenic nerve-diaphragm muscle (PND) preparations in vitro. Male mice were injected with PLA₂ (50 µg) in the absence or presence of F4, F6, and catechin, in the gastrocnemius muscle and then killed 3, 7, 14, and 28 h later for histopathological analysis of myonecrosis, leukocyte infiltration, and the presence of collagen. Fractions F4 and F6 (500 µg) and catechin (90 µg) significantly reduced the extent of necrosis at all-time intervals. These two fractions and catechin also attenuated the leukocyte infiltration on day 3, as did catechin on day 14. There was medium-to-moderate collagen deposition in all groups up to day 7, but greater deposition on days 14 and 28 in the presence of F6 and catechin. venom (100 µg/mL) caused slight (~25%) muscle facilitation after 10 minutes and weak neuromuscular blockade (~64% decrease in contractile activity after a 120-minute incubation). Pre-incubation of venom with F4 or F6 abolished the facilitation, whereas catechin, which was itself facilitatory, did not. All three fractions attenuated the venom-induced decrease in muscle contractions. These findings indicate that fractions and catechin from can reduce the muscle damage caused by venom and PLA₂. These fractions or their components could be useful for treating venom-induced local damage.
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http://dx.doi.org/10.3390/toxins11010040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356255PMC
January 2019

Acute kidney injury caused by the intraperitoneal injection of venom in rats.

Nat Prod Res 2020 Sep 22;34(17):2533-2538. Epub 2018 Dec 22.

Post-Graduate Program in Pharmaceutical Sciences, University of Sorocaba (UNISO), Sorocaba, SP, Brazil.

We examined the ability of venom (12.5 mg/kg) injected intraperitoneally (i.p.) to cause acute kidney injury (AKI) in rats. Blood urea and creatinine (AKI biomarkers, in g dL) were elevated after 2 h in venom-treated rats (urea: from 0.41 ± 0.1 to 0.7 ± 0.03; creatinine from 46.7 ± 3.1 to 85 ± 6.7;  < 0.05;  = 3 each), with no change in circulating reduced glutathione. Venom-treated rats survived for ∼6 h, at which point platelets were reduced (×10 µL; from 763.8 ± 30.2 to 52.5 ± 18.2) whereas leukocytes and erythrocytes were slightly increased (from 4.7 ± 0.3 to 6.6 ± 0.1 × 10 µL and from 8.38 ± 0.1 to 9.2 ± 0.09 × 10 µL, respectively;  < 0.05); blood protein (5.2 ± 0.4 g dL) and albumin (2.7 ± 0.1 g dL) were normal, whereas blood and urinary urea and creatinine were increased. All parameters returned to normal with antivenom given 2 h post-envenomation. The i.p. injection of venom caused AKI similar to that seen with other routes of administration.
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http://dx.doi.org/10.1080/14786419.2018.1543675DOI Listing
September 2020

Management of severe pain after dermal contact with caterpillars (erucism): a prospective case series.

Clin Toxicol (Phila) 2019 05 17;57(5):338-342. Epub 2018 Nov 17.

a School of Medical Sciences , Campinas Poison Control Center, State University of Campinas (UNICAMP) , Campinas , Brazil.

Context: Erucism, envenomation caused by dermal contact with larval forms of moths, may result in intense local pain, mainly after contact with puss caterpillars (family Megalopygidae).

Objective: To evaluate the response to different treatments for controlling severe pain in a case series of erucism in Campinas, southeastern Brazil.

Patients And Methods: Prospective cohort study. A Numeric Pain Rating Scale (NPRS 0-10) was used to assess pain intensity in the Emergency Department (ED). Pain was considered as severe upon ED admission (T0) when the NPRS was ≥8.

Inclusion Criteria: age ≥8 years old, severe pain at T0, with continuous assessment of pain intensity in all patients using the NPRS during the ED stay (T5, T15, T30, T60 min and at discharge).

Results: Fifty-five patients fulfilled the inclusion criteria and were divided into three groups according to the initial treatment at T0: local anesthesia alone with 2% lidocaine (group 1, n = 15), local anesthesia and analgesics (group 2, n = 26) and analgesics without local anesthesia (group 3, n = 14). Most patients were admitted within 2 h after dermal contact with the stinging bristles of caterpillars (median =90 min, IQR: 40-125 min). In 22 cases (40%), the caterpillar was brought for identification (Podalia spp., n = 18; Megalopyge spp., n = 4). There was a significant decrease in pain from T5 onwards with all of the treatments. When the short-term response (T5 and T15) was considered, analgesia was more effective in groups 1 and 2 compared to group 3 (p < .01). Additional analgesia (from T5 until discharge) was frequently required (n = 25/55), mainly in group 1 (n = 11/15). The median length of stay in the ED was 120 min (IQR: 80-173 min).

Conclusions: The association of local anesthesia with analgesics was apparently a good combination for the rapid management of severe pain in the ED.
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http://dx.doi.org/10.1080/15563650.2018.1520998DOI Listing
May 2019

Thrombotic microangiopathy following Bothrops jararaca snakebite: case report.

Clin Toxicol (Phila) 2019 04 16;57(4):294-299. Epub 2018 Nov 16.

c Department of Pharmacology, School of Medical Sciences , State University of Campinas (UNICAMP) , Campinas , Brazil.

Context: Thrombotic microangiopathy (TMA) is an uncommon and severe complication of snakebites, and is similar, in general, to hemolytic-uremic syndrome (HUS). We describe a case of TMA following envenomation by Bothrops jararaca.

Case Details: A 56-y-old-woman with controlled hypertension was transferred from a primary hospital to our ER ∼7 h after being bitten by B. jararaca in the distal left leg. She developed edema extending from the bite site to the proximal thigh, associated with intense radiating local pain, local paresthesia and ecchymosis at the bite site. Laboratory features upon admission revealed coagulopathy (20 min whole blood clotting time - WBCT20 > 20 min), thrombocytopenia (76,000 platelets/mm) and slight increase in serum creatinine (1.58 mg/dL; RV < 1.2 mg/dL). Upon admission, the patient was treated with bothropic antivenom and fluids replacement. During evolution, her thrombocytopenia and anemia worsened, with blood films showing fragmented red cells, haptoglobin consumption, increase in serum lactate dehydrogenase, and progressive increase of serum creatinine (KDIGO stage = 3). No RBC transfusion, renal replacement therapy or plasmapheresis was done. The patient showed progressive improvement from day nine (D9) onwards and was discharged on D20; there was complete recovery of hemoglobin levels at follow-up (D50). ADAMTS-13 activity, assayed 10 months post-bite, was within reference values.

Discussion: TMA following snakebite has been reported mainly in India, Sri Lanka and Australia, with several patients needing renal replacement therapy. Although controversial, plasmapheresis has also been used in some cases. Our patient developed microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury, a triad of features compatible with TMA similar to HUS. Despite the severity, the outcome following conservative treatment was good, with complete recovery.
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http://dx.doi.org/10.1080/15563650.2018.1514621DOI Listing
April 2019

Presynaptic Activity of an Isolated Fraction from Rhinella schneideri Poison.

Adv Pharm Bull 2018 Aug 29;8(3):517-522. Epub 2018 Aug 29.

School of Medicine Faculdade Israelita de Ciências da Saúde Albert Einstein, São Paulo, SP, Brazil.

Rhinella schneideri is a toad found in many regions of the South America. The poison of the glands has cardiotoxic effect in animals and neuromuscular effects in mice and avian preparation. The purpose of this work was to identify the toxin responsible for the neuromuscular effect in avian and mice neuromuscular preparation. The methanolic extract from R. schneideri poison was fractioned by reversed phase HPLC. The purity and molecular mass were determined by LC/MS mass spectrometry. Chick biventer cervicis and mouse phrenic-nerve diaphragm were used as neuromuscular preparations to identify the toxin. The purification resulted in 32 fractions, which 4 of them were active in neuromuscular preparation. The toxin of fraction 20 were chosen for better reproducibility of the whole extract activity and its molecular mass was 730.6 Da. The toxin produced facilitation of the muscle contraction followed by a complete neuromuscular blockade in chick biventer cervicis preparation in 90 min without interfering with the exogenous response to ACh and KCl. The quantal content was increased from 128 ± 13 (control) to 216 ± 44 (after 5 min and sustained until 60 min) in the presence of the toxin. In conclusion, our results demonstrated that the neuromuscular action of the poison of Rhinella schneideri is a multitoxin effect. More, the present work first isolated a 730.6 Da toxin that better represent the whole poison neuromuscular effect, to which is attributed a presynaptic action in avian and mouse neuromuscular preparation.
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http://dx.doi.org/10.15171/apb.2018.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156484PMC
August 2018

Biochemical characterization of venom from Pseudoboa neuwiedii (Neuwied's false boa; Xenodontinae; Pseudoboini).

Comp Biochem Physiol C Toxicol Pharmacol 2018 Nov 30;213:27-38. Epub 2018 Jun 30.

Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, 13083-887 Campinas, SP, Brazil. Electronic address:

In this work, we examined the proteolytic and phospholipase A (PLA) activities of venom from the opisthoglyphous colubrid Pseudoboa neuwiedii. Proteolytic activity (3 and 10 μg of venom) was comparable to that of Bothrops neuwiedii venom but less than Bothrops atrox. This activity was inhibited by EDTA and 1,10-phenanthroline but only slightly affected (≤30% inhibition) by PMSF and AEBSF, indicating it was mediated by snake venom metalloproteinases (SVMPs). The pH and temperature optima for proteolytic activity were 8.0 and 37 °C, respectively. The venom had no esterase activity, whereas PLA activity was similar to B. atrox, greater than B. neuwiedii but less than B. jararacussu. SDS-PAGE revealed venom proteins >100 kDa, 45-70 kDa, 21-24 kDa and ~15 kDa, and mass spectrometry of protein bands revealed SVMPs, cysteine-rich secretory proteins (CRISPs) and PLA, but no serine proteinases. In gelatin zymography, the most active bands occurred at 65-68 kDa (seen with 0.05-0.25 μg of venom). Caseinolytic activity occurred at 50-66 kDa and was generally weaker than gelatinolytic activity. RP-HPLC of venom yielded 15 peaks, five of which showed gelatinolytic activity; peak 7 was the most active and apparently contained a P-III class SVMP. The venom showed α-fibrinogenase activity, without affecting the β and γ chains; this activity was inhibited by EDTA and 1,10-phenanthroline. The venom did not clot rat citrated plasma but reduced the rate and extent of coagulation after plasma recalcification. In conclusion, P. neuwiedii venom is highly proteolytic and could potentially affect coagulation in vivo by degrading fibrinogen via SVMPs.
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http://dx.doi.org/10.1016/j.cbpc.2018.06.003DOI Listing
November 2018

In vitro effects of Crotalus atrox snake venom on chick and mouse neuromuscular preparations.

Comp Biochem Physiol C Toxicol Pharmacol 2018 Jul 28;209:37-45. Epub 2018 Mar 28.

Ikiam - Universidad Regional Amazónica, Km 7 Via Muyuna, Tena, Napo, Ecuador. Electronic address:

The neuromuscular effect of venoms is not a major clinical manifestation shared between rattlesnakes native to the Americas, which showed two different venom phenotypes. Taking into account this dichotomy, nerve muscle preparations from mice and chicks were used to investigate the ability of Crotalus atrox venom to induce in vitro neurotoxicity and myotoxicity. Unlike crotalic venoms of South America, low concentrations of C. atrox venom did not result in significant effects on mouse neuromuscular preparations. The venom was more active on avian nerve-muscle, showing reduction of twitch heights after 120 min of incubation with 10, 30 and 100 μg/mL of venom with diminished responses to agonists and KCl. Histological analysis highlighted that C. atrox was myotoxic in both species of experimental animals; as evidenced by degenerative events, including edematous cells, delta lesions, hypercontracted fibers and muscle necrosis, which can lead to neurotoxic action. These results provide key insights into the myotoxicity and low neurotoxicity of C. atrox in two animal models, corroborating with previous genomic and proteomic findings and would be useful for a deeper understanding of venom evolution in snakes belonging to the genus Crotalus.
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http://dx.doi.org/10.1016/j.cbpc.2018.03.008DOI Listing
July 2018

Photobiomodulation of local alterations induced by BthTX-I, a phospholipase A myotoxin from Bothrops jararacussu snake venom: In vivo and in vitro evaluation.

Int J Biol Macromol 2018 Feb 14;107(Pt B):2020-2025. Epub 2017 Oct 14.

Department of Medicine, Universidade Nove de Julho (UNINOVE), Rua Vergueiro, 235, 01504-000, São Paulo, SP, Brazil. Electronic address:

This report describes the effect of photobiomodulation (PBM) on edema formation, leukocyte influx, prostaglandin E (PGE) biosynthesis and cytotoxicity caused by bothropstoxin-I (BthTX-I), a phospholipase A (PLA) homologue isolated from Bothrops jararacussu snake venom. Swiss mice or C2C12 cells were irradiated with low-level laser (LLL) at 685nm wavelength, an energy density of 4.6J/cm and an irradiation time of 13s. To evaluate the effect on edema formation and leukocyte influx, LLL was applied to the site of inoculation 30min and 3h post-injection. C2C12 cells were exposed to BthTX-I and immediately irradiated. PBM significantly reduced paw edema formation, peritoneal leukocyte influx and PGE synthesis, but increased the viability of C2C12 muscle cells after BthTX-I incubation. These findings demonstrate that PBM attenuated the inflammatory events induced by BthTX-I. The attenuation of PGE synthesis could be an important factor in the reduced inflammatory response caused by laser irradiation. The ability of LLL irradiation to protect muscle cells against the deleterious effects of BthTX-I may indicate preservation of the plasma membrane.
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http://dx.doi.org/10.1016/j.ijbiomac.2017.10.076DOI Listing
February 2018

Functional β-adrenoceptors in rat left atria: effect of foot-shock stress.

Can J Physiol Pharmacol 2017 Sep 30;95(9):999-1008. Epub 2017 Apr 30.

a Department of Biosciences, Federal University of São Paulo (UNIFESP), Santos, SP, Brazil.

Altered sensitivity to the chronotropic effect of catecholamines and a reduction in the β/β-adrenoceptor ratio have previously been reported in right atria of stressed rats, human failing heart, and aging. In this report, we investigated whether left atrial inotropism was affected by foot-shock stress. Male rats were submitted to 3 foot-shock sessions and the left atrial inotropic response, adenylyl cyclase activity, and β-adrenoceptor expression were investigated. Left atria of stressed rats were supersensitive to isoprenaline when compared with control rats and this effect was abolished by ICI118,551, a selective β-receptor antagonist. Schild plot slopes for the antagonism between CGP20712A (a selective β-receptor antagonist) and isoprenaline differed from unity in atria of stressed but not control rats. Atrial sensitivity to norepinephrine, as well as basal and forskolin- or isoprenaline-stimulated adenylyl cyclase activities were not altered by stress. The effect of isoprenaline on adenylyl cyclase stimulation was partially blocked by ICI118,551 in atrial membranes of stressed rats. These findings indicate that foot-shock stress equally affects inotropism and chronotropism and that β-adrenoceptor upregulation contributes to the enhanced inotropic response to isoprenaline.
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http://dx.doi.org/10.1139/cjpp-2016-0622DOI Listing
September 2017

Local and hematological alterations induced by Philodryas olfersii snake venom in mice.

Toxicon 2017 Jun 24;132:9-17. Epub 2017 Mar 24.

Department of Bioengineering and Biomedical Engineering, Brazil University, Rua Carolina Fonseca, 584/235 (Campus I and II), Vila Santana, 08230-030, Itaquera, São Paulo, SP, Brazil.

Envenomation by the South American opisthoglyphous snake Philodryas olfersii causes local pain, edema, erythema and ecchymosis; systemic envenomation is rare. In this work, we examined the inflammatory activity of P. olfersii venom (10, 30 and 60 μg) in mouse gastrocnemius muscle 6 h after venom injection. Intramuscular injection of venom did not affect hematological parameters such as red cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration. The venom caused thrombocytopenia (at all three doses), leukopenia and lymphopenia (both at the two highest doses), as well as neutrophilia (30 μg), monocytosis (30 μg) and basophilia (10 μg). Of the cytokines that were screened [IL-1β, IL-6, IL-10, IL-13, IL-17, TNF-α, IFN-γ, MIP-2 and KC] and IGF-1, only IGF-1 showed a significant increase in its circulating concentration, seen with 60 μg of venom; there were no significant changes in the cytokines compared to control mice. Histological analysis revealed the presence of edema, an inflammatory infiltrate and progressive myonecrosis. Edema and myonecrosis were greatest with 60 μg of venom, while the inflammatory infiltrate was greatest with 10 μg of venom. All venom doses caused the migration of polymorphonuclear and mononuclear leukocytes into muscle, but with no significant dose-dependence in the response. These findings show that, at the doses tested, P. olfersii venom does not cause hematological alterations and has limited effect on circulating cytokine concentrations. These data also confirm that the principal effects of the venom in mice are local edema, inflammatory cell infiltration and myonecrosis.
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http://dx.doi.org/10.1016/j.toxicon.2017.03.013DOI Listing
June 2017

Antidote availability in the municipality of Campinas, São Paulo, Brazil.

Sao Paulo Med J 2017 Jan-Feb;135(1):15-22. Epub 2017 Mar 13.

MD, MSc, PhD. Professor, Campinas Poison Control Center, School of Medical Sciences, Universidade Estadual de Campinas (Unicamp), Campinas (SP), Brazil.

Context And Objective:: The lack of availability of antidotes in emergency services is a worldwide concern. The aim of the present study was to evaluate the availability of antidotes used for treating poisoning in Campinas (SP).

Design And Setting:: This was a cross-sectional study of emergency services in Campinas, conducted in 2010-2012.

Methods:: The availability, amount in stock, place of storage and access time for 26 antidotal treatments was investigated. In the hospitals, the availability of at least one complete treatment for a 70 kg adult over the first 24 hours of admission was evaluated based on stock and access recommendations contained in two international guidelines.

Results:: 14 out of 17 functioning emergency services participated in the study, comprising pre-hospital services such as the public emergency ambulance service (SAMU; n = 1) and public emergency rooms for admissions lasting ≤ 24 hours (UPAs; n = 3), and 10 hospitals with emergency services. Six antidotes (atropine, sodium bicarbonate, diazepam, Phytomenadione, flumazenil and calcium gluconate) were stocked in all the services, followed by 13 units that also stocked activated charcoal, naloxone and diphenhydramine or biperiden. No service stocked all of the recommended antidotes; only the regional Poison Control Center had stocks close to recommended (22/26 antidotal treatments). The 10 hospitals had almost half of the antidotes for starting treatments, but only one quarter of the antidotes was present with stocks sufficient for providing treatment for 24 hours.

Conclusion:: The stock of antidotes for attending poisoning emergencies in the municipality of Campinas is incomplete and needs to be improved.
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http://dx.doi.org/10.1590/1516-3180.2016.00171120816DOI Listing
August 2017

Erratum to "Bothrops fonsecai snake venom activities and cross-reactivity with commercial bothropic antivenom" [Comp. Biochem. Physiol. C 191 (2017) 86-100].

Comp Biochem Physiol C Toxicol Pharmacol 2017 06 6;196:53. Epub 2017 Mar 6.

Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, 13083-887 Campinas, SP, Brazil.

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http://dx.doi.org/10.1016/j.cbpc.2017.03.001DOI Listing
June 2017

A Highly Polar Phytocomplex Involving Rutin is Responsible for the Neuromuscular Facilitation Caused by Casearia sylvestris (guaçatonga).

Curr Pharm Biotechnol 2016 ;17(15):1360-1368

Post-Graduate Program in Pharmaceutical Sciences and Pharmacy Course, University of Sorocaba, Rodovia Raposo Tavares, km 92,5 18023-000, Sorocaba, SP, Brazil.. Brazil.

Background: Of the various biological activities ascribed to extracts from Casearia sylvestris (guaçatonga), its facilitatory activity, i.e., ability to increase skeletal muscle contractile amplitude, has promising therapeutic applications. In this work, we investigated the components responsible for the previously described neurofacilitation caused by C. sylvestris leaves.

Methods: The methanolic fraction of C. sylvestris leaves was initially fractionated by column chromatography and partitioned in a MeOH:H2O gradient. The resulting fractions were analyzed by analytical HPLC and yielded fraction 5:5 (F55) that was subjected to solid phase extraction and preparative HPLC. Of the seven resulting subfractions, only F55-6 caused muscle facilitation. Subfractions F55-6 and F55-7 (similar in composition to F55-6 by TLC analysis, but inactive) were analyzed by 1H-NMR to identify their constituents.

Results: This analysis identified a rutin-glycoside phytocomplex that caused neurofacilitation, a property that commercial rutin alone did not exhibit.

Conclusion: F55-6 apparently caused neurofacilitation by the same mechanism (presynaptic action) as the methanolic fraction since its activity was also inhibited in tetrodotoxin-pretreated preparations.
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http://dx.doi.org/10.2174/1389201017666161117145947DOI Listing
January 2016

Hemodynamic responses to Lachesis muta (South American bushmaster) snake venom in anesthetized rats.

Toxicon 2016 Dec 5;123:1-14. Epub 2016 Oct 5.

Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, 13083-887, Campinas, SP, Brazil. Electronic address:

In this work, we examined the hemodynamic responses to Lachesis muta (South American bushmaster) venom in anesthetized male Wistar rats. Venom (1.5 mg/kg, i.v.) caused immediate hypotension that was followed by a gradual return towards baseline over 60 min; there were no significant changes in heart rate, ECG parameters and respiratory rate. A higher dose (3 mg/kg, i.v.) caused sustained hypotension, variable bradycardia, respiratory depression and fluctuations in ECG; death occurred within 10-60 min. Venom injected intramuscularly (15 mg/kg) produced a smaller decrease in blood pressure that was more persistent than with 1.5 mg/kg (i.v.). Pre-treatment with atenolol (selective β-adrenergic receptor antagonist) potentiated the response to venom (1.5 mg/kg, i.v.) and resulted in a hemodynamic profile similar to that seen with 3 mg/kg (i.v.). Macroscopically, systemic hemorrhage was seen only in the ileum, whereas histological analysis revealed extensive pulmonary hemorrhage; the heart, liver and kidney were generally unaffected. Intravascular pulmonary thrombosis occurred with venom given i.v. and i.m., but was less marked with the latter route. In rat isolated perfused hearts, venom caused a persistent decrease in left ventricular developed pressure but no change in heart rate, coronary flow or ECG; there was tissue necrosis and release of CK-MB that were abolished by pre-treating venom with the PLA inhibitor p-bromophenacyl bromide. These results show that in rats L. muta venom causes hypotension, bradycardia and respiratory depression, depending on the dose and route of administration. The hemodynamic responses apparently do not involve direct cardiotoxicity and are modulated by the adrenergic system.
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http://dx.doi.org/10.1016/j.toxicon.2016.10.001DOI Listing
December 2016

Pharmacological analysis of hemodynamic responses to Lachesis muta (South American bushmaster) snake venom in anesthetized rats.

Toxicon 2016 Dec 5;123:25-44. Epub 2016 Oct 5.

Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitária Zeferino Vaz, 13083-887, Campinas, SP, Brazil. Electronic address:

In this work, we examined some mechanisms involved in the hypotension caused by Lachesis muta (South American bushmaster) venom in anesthetized rats. Venom (1.5 mg/kg, i.v.) caused immediate hypotension that was maximal after 5 min and gradually returned to baseline over 60 min. Pretreatment of rats with the non-selective nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME) did not attenuate the early phase of venom-induced hypotension, but abolished the recovery phase and resulted in rapid death; a similar effect was observed with the soluble guanylate cyclase (sGC) inhibitor ODQ. In contrast, the hemodynamic responses to venom were not attenuated by the non-selective NOS inhibitor N-monomethyl-L-arginine, the inducible NOS inhibitor aminoguanidine, the phosphodiesterase 5 inhibitor sildenafil, the adenylate cyclase (AC) inhibitor SQ-22.536, the non-selective muscarinic receptor antagonist atropine, the bradykinin B2 receptor antagonist HOE-140 and the non-selective cyclooxygenase inhibitor indomethacin. Preincubation of venom with the PLA inhibitor pBPB had no effect on the immediate hypotension but tended to improve the recovery phase. Neither AEBSF (a serine proteinase inhibitor) nor EDTA (a metalloproteinase inhibitor) prevented the venom-induced hypotension, but AEBSF and not EDTA protected against the lethality of a high dose (3.0 mg/kg, i.v.). There were no marked changes in the ECG parameters with the various treatments, except with L-NAME and ODQ that increased the RR interval. Pulmonary thrombus formation was markedly enhanced by L-NAME and ODQ, and to a lesser extent by pBPB, especially in small vessels, whereas AEBSF and EDTA inhibited thrombus formation. Venom relaxed phenylephrine-precontracted thoracic aorta and pulmonary artery in vitro, with the latter being more sensitive. The relaxation was endothelium-dependent and was inhibited by ODQ but not by H-89, a protein kinase A (PKA) inhibitor. Together, these findings indicate involvement of the NO/sGC/cGMP, but not the AC/cAMP/PKA signaling pathway, in the hemodynamic responses to L. muta venom in rats. Muscarinic mechanisms, kinins and arachidonic acid metabolites are apparently not involved.
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http://dx.doi.org/10.1016/j.toxicon.2016.10.002DOI Listing
December 2016