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1.
Chem Res Toxicol ; 34(6): 1530-1541, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-33914522

RESUMO

Smoke inhalation from a structure fire is a common route of cyanide poisoning in the U.S. Cyanide inhibits cellular respiration, often leading to death. Its rapid distribution throughout the body can result in injuries to multiple organs, and cyanide victims were reported to experience myocardial infarction and other cardiac complications. However, molecular mechanisms of such complications are yet to be elucidated. While FDA-approved CN antidotes such as sodium thiosulfate and hydroxocobalamin are clinically used, they have foreseeable limitations during mass casualty situations because they require intravenous administration. To facilitate the development of better antidotes and therapeutic treatments, a global view of molecular changes induced by cyanide exposure is necessary. As an exploratory pursuit, we performed oligonucleotide microarrays to establish cardiac transcriptomes of an animal model of nose-only inhalation exposure to hydrogen cyanide (HCN), which is relevant to smoke inhalation. We also profiled cardiac transcriptomes after subcutaneous injection of potassium cyanide (KCN). Although the KCN injection model has often been used to evaluate medical countermeasures, this study demonstrated that cardiac transcriptomes are largely different from that of the HCN inhalation model at multiple time points within 24 h after exposure. Pathway analysis identified that HCN-induced transcriptomes were enriched with genes encoding mediators of pathways critical in modulation of cardiac complications and that a large number of such genes were significantly decreased in expression. We utilized the upstream regulatory analysis to propose drugs that can be potentially employed to treat cyanide-induced cardiac complications.


Assuntos
Traumatismos Cardíacos/complicações , Cianeto de Hidrogênio/intoxicação , Cianeto de Potássio/intoxicação , Animais , Cianeto de Hidrogênio/administração & dosagem , Exposição por Inalação , Injeções Subcutâneas , Masculino , Camundongos , Cianeto de Potássio/administração & dosagem
2.
Clin Toxicol (Phila) ; 59(8): 734-739, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33274646

RESUMO

OBJECTIVE: In this proof-of-concept study, the aim was to evaluate the short-term clinical effectiveness of isosorbide dinitrate (ISDN) oral spray in non-anaesthetized cyanide-poisoned swine. METHODS: A comparative study was conducted using domestic swine. Animals were intravenously poisoned with potassium cyanide (KCN), either 2 mg/kg or 4 mg/kg dose. Two control groups (one for each cyanide dose) were not further treated. Two other groups (one for each cyanide dose) were treated within 1 min after poisoning with ISDN oral spray: 3 spray actuations (averaging a total of 3.75 mg) after the lower cyanide dose and 4 spray actuations (averaging a total of 5.0 mg) after the higher dose. The study outcomes were clinical score, time to death, and blood tests including pH, lactate, and methemoglobin levels. RESULTS: All the animals started to convulse within 20 to 30 sec after KCN poisoning, then became unresponsive and hemodynamically depressed after another 20 to 30 sec. After the KCN 2 mg/kg dose, 3 of 4 control animals survived, while all treated animals survived. Compared with control animals, ISDN-treated animals displayed significantly better clinical scores starting 5 min after KCN poisoning. Acidosis was significantly more pronounced in the untreated animals. After the KCN 4 mg/kg dose, similar survival rates were observed for control and ISDN-treated groups (1/4), but treated animals had longer time to death and better pH and lactate levels. CONCLUSION: ISDN oral spray administration following KCN poisoning in this porcine model did not result in statistically significant increased survival. However, based on clinical scores and clinical laboratory values, ISDN may benefit as a bridging countermeasure until currently-available specific cyanide antidotes can be administered. Further research is warranted to better characterize this potential role of ISDN in cyanide poisoning.


Assuntos
Antídotos/administração & dosagem , Cianetos/intoxicação , Dinitrato de Isossorbida/administração & dosagem , Animais , Antídotos/farmacologia , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Dinitrato de Isossorbida/farmacologia , Ácido Láctico/sangue , Masculino , Metemoglobina/análise , Sprays Orais , Cianeto de Potássio/administração & dosagem , Cianeto de Potássio/intoxicação , Estudo de Prova de Conceito , Taxa de Sobrevida , Suínos
3.
Drug Chem Toxicol ; 42(6): 577-584, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29609494

RESUMO

Cyanide-induced chemical hypoxia is responsible for pronounced oxidative damage in the central nervous system. The disruption of mitochondrial oxidative metabolism has been associated with upregulation of uncoupling proteins (UCPs). The present study addresses the dose- and time-dependent effect of sub-acute cyanide exposure on various non-enzymatic and enzymatic oxidative stress markers and their correlation with inducible-nitric oxide synthase (iNOS) and uncoupling protein-2 (UCP-2) expression. Animals received (oral) triple distilled water (vehicle control), 0.25 LD50 potassium cyanide (KCN) or 0.50 LD50 KCN daily for 21 d. Animals were sacrificed on 7, 14 and 21 d post-exposure to measure serum cyanide and nitrite, and brain malondialdehyde (MDA), reduced glutathione (GSH), glutathione disulfide (GSSG), cytochrome c oxidase (CCO), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and catalase (CA) levels, together with iNOS and UCP-2 expression, and DNA damage. The study revealed that a dose- and time-dependent increase in cyanide concentration was accompanied by corresponding CCO inhibition and elevated MDA levels. Decrease in GSH levels was not followed by reciprocal change in GSSG levels. Diminution of SOD, GPx, GR and CA activity was congruent with elevated nitrite levels and upregulation of iNOS and UCP-2 expression, without any DNA damage. It was concluded that long-term cyanide exposure caused oxidative stress, accompanied by upregulation of iNOS. The upregulation of UCP-2 further sensitized the cells to cyanide and accentuated the oxidative stress, which was independent of DNA damage.


Assuntos
Óxido Nítrico Sintase Tipo II/genética , Estresse Oxidativo/efeitos dos fármacos , Cianeto de Potássio/toxicidade , Proteína Desacopladora 2/genética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Dose Letal Mediana , Cianeto de Potássio/administração & dosagem , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Fatores de Tempo , Regulação para Cima/efeitos dos fármacos
4.
Comp Med ; 68(5): 375-379, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30208987

RESUMO

Cyanide is a readily available and potentially lethal substance. Oral exposure can result in larger doses, compared with other routes. Currently, there are no antidotes specific for use in the treatment of oral cyanide poisoning, and studies cannot be done in humans. We report on a new large animal model of oral cyanide toxicity to evaluate potential antidotes. Six female swine (Sus scrofa; weight, 45 to 55 kg) were anesthetized, intubated, and instrumented. Animals received a KCN bolus of either 5 or 8 mg/kg delivered via orogastric tube. Time to apnea was recorded; parameters monitored included heart rate, respiratory rate, blood pressure, pulse oximetry, end-tidal CO2, arterial blood gasses, and lactate concentrations. The Welch t test was used to calculate confidence intervals, mean, and standard deviation, and a Kaplan-Meier survival curve was used to compare survival between the 2 groups. At baseline, all animals in both groups were similar. Animals in the 5-mg/kg group had a more rapid time to apnea (5.1 ± 2.1 min), longer time to death (48.5 ± 38.1 min), and a greater rate of survival than the 8-mg/kg group (apnea, 10.6 ± 10.7 min; death, 26.1 ± 5.8 min). All animals displayed signs of toxicity (acidemia, hyperlactatemia, hypotension, apnea). We here report a large animal (swine) model of oral cyanide poisoning with dose-dependent effects in regard to time to death and survival rate. This model likely will be valuable for the development of medical countermeasures for oral cyanide poisoning.


Assuntos
Modelos Animais de Doenças , Cianeto de Potássio/toxicidade , Suínos , Administração Oral , Animais , Feminino , Estimativa de Kaplan-Meier , Monitorização Fisiológica/veterinária , Cianeto de Potássio/administração & dosagem , Cianeto de Potássio/intoxicação
5.
Pak J Pharm Sci ; 31(5): 1797-1803, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30150173

RESUMO

The aim of the present study was to determine the deleterious effects of prolonged oral cyanide insult on various organs and tissues in rabbits. For this purpose, 12 locally bred adult male rabbits were allocated into two groups of 6 viz. control and experimental. Rabbits in control group were offered feed only while the rabbits in experimental group received feed plus potassium cyanide (KCN) at 3 mg/kg body weight orally for a period of 40 days. None of the rabbit in both the groups demonstrated any of the gross changes in any organ on postmortem examination. Liver was normal in size, shape, texture and color. Kidneys were also normal in size and color. Histopathological examination revealed severe hepatocyte vacuolation and degeneration in liver of rabbits in experimental group. There was also excessive congestion in liver and bile duct of rabbits in experimental group. Kidneys of rabbits in experimental group demonstrated severe glomerular and tubular necrosis and congestion. In the tubular epithelial cells, pyknotic nuclei were also present. On the other hand, heart and pancreas of rabbits in both control and experimental group did not show any histopathological change in microscopic structures. In conclusion, prolonged oral cyanide administration could have harmful effects on liver and kidney functions.


Assuntos
Coração/fisiologia , Rim/patologia , Fígado/patologia , Pâncreas/patologia , Cianeto de Potássio/toxicidade , Administração Oral , Animais , Esquema de Medicação , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Cianeto de Potássio/administração & dosagem , Coelhos
6.
Cardiovasc Toxicol ; 18(5): 436-449, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29644580

RESUMO

This study was aimed at determining the efficacy of epinephrine, followed by chest compressions, in producing a return of spontaneous circulation (ROSC) during cyanide (CN)- or hydrogen sulfide (H2S)-induced toxic cardiac pulseless electrical activity (PEA) in the rat. Thirty-nine anesthetized rats were exposed to either intravenous KCN (n = 27) or H2S solutions (n = 12), at a rate that led to a PEA within less than 10 min. In the group intoxicated by CN, 20 rats were mechanically ventilated and received either epinephrine (0.1 mg/kg i.v. n = 10) followed by chest compressions or saline (n = 10, "control CN") when in PEA. PEA was defined as a systolic pressure below 20 mmHg and a pulse pressure of less than 5 mmHg for 1 min. In addition, seven spontaneously breathing rats were also exposed to the same CN protocol, but infusion was stopped when a central apnea occurred; then, as soon as a PEA occurred, epinephrine (0.1 mg/kg IV) was administered while providing manual chest compressions and mechanical ventilation (CPR). Finally, 12 rats were intoxicated with H2S, while mechanically ventilated, and received either saline (n = 6, "control H2S") or epinephrine (n = 6) with CPR when in PEA. None of the control-intoxicated animals resuscitated (10 rats in the control CN group and 6 in the control H2S group). In contrast, all the animals intoxicated with CN or H2S that received epinephrine followed by chest compressions, returned to effective circulation. In addition, half of the spontaneously breathing CN-intoxicated animals that achieved ROSC after epinephrine resumed spontaneous breathing. In all the animals achieving ROSC, blood pressure, cardiac output, peripheral blood flow and [Formula: see text]O2 returned toward baseline, but remained lower than the pre-intoxication levels (p < 0.01) with a persistent lactic acidosis. Epinephrine, along with CPR maneuvers, was highly effective in resuscitating rodents intoxicated with CN or H2S. Since epinephrine is readily available in any ambulance, its place as an important countermeasure against mitochondrial poisons should be advocated. It remains critical to determine whether the systematic administration of epinephrine to any victims found hypotensive following CN or H2S intoxication could prevent PEA, decrease post-ischemic brain injury and increase the efficacy of current antidotes by improving the circulatory status.


Assuntos
Agonistas Adrenérgicos/administração & dosagem , Antídotos/administração & dosagem , Circulação Sanguínea/efeitos dos fármacos , Reanimação Cardiopulmonar/métodos , Epinefrina/administração & dosagem , Parada Cardíaca/terapia , Hemodinâmica/efeitos dos fármacos , Sulfeto de Hidrogênio/toxicidade , Cianeto de Potássio/toxicidade , Animais , Parada Cardíaca/induzido quimicamente , Parada Cardíaca/fisiopatologia , Sulfeto de Hidrogênio/administração & dosagem , Infusões Intravenosas , Injeções Intravenosas , Masculino , Cianeto de Potássio/administração & dosagem , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Respiração Artificial
7.
Pak J Pharm Sci ; 31(2): 411-419, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29618429

RESUMO

This study was aimed to compare the efficacy of aqueous garlic extract, sodium nitrite (SNT), sodium thiosulfate (STS) and hydroxocobalamin against oral cyanide exposure in rabbits. For this purpose, forty two adult male rabbits were divided randomly into 7 groups of 6 animals (A-G) each. Rabbits in group A were offered feed only and served as negative control, while the rabbits in group B received feed plus potassium cyanide (KCN) at 3mg/kg orally and were kept as positive control. Animals in group C received feed, KCN and intraperitoneal injection (IP) of aqueous garlic extract at 500mg/kg. Rabbits in group D were given feed, KCN and IP injection of STS at 600mg/kg. Members in group E received feed, KCN and IP injection of both aqueous garlic extract at 500mg/kg and SNT at 20mg/kg. Animals in group F were given feed, KCN and IP injection of both STS at 600mg/kg and SNT at 20mg/kg, while the rabbits in group G received feed, KCN and IP injection of hydroxocobalamin at 300mg/kg. The treatments were given to respective groups for 40 days. The efficacy of the antidotes was measured on the basis of changes in biochemical profile of rabbits in each group. In this study, hydroxocobalamin was found to be significantly more effective cyanide (CNI) antidote than garlic, STS, SNT plus garlic extract, or SNT and STS, either alone or in combination. A combination of SNT and garlic extract was the second most effective CNI antidote. The efficacy of garlic alone was significantly higher than STS alone or in combination with SNT. The efficacy of combined SNT and STS was superior to STS alone in treating rabbits with CNI toxicity. In conclusion, aqueous garlic extract alone or in combination with STS can effectively be used against cyanide toxicity.


Assuntos
Antídotos/farmacologia , Alho/química , Cianeto de Potássio/intoxicação , Nitrito de Sódio/farmacologia , Tiossulfatos/farmacologia , Administração Oral , Alanina Transaminase/sangue , Fosfatase Alcalina/sangue , Animais , Aspartato Aminotransferases/sangue , Bilirrubina/metabolismo , Creatinina/sangue , Hidroxocobalamina/farmacologia , Extratos Vegetais/farmacologia , Cianeto de Potássio/administração & dosagem , Coelhos , Albumina Sérica/metabolismo , Hormônios Tireóideos/sangue
8.
Int J Toxicol ; 35(5): 604-15, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27170681

RESUMO

The Food and Drug Administration Animal Rule requires evaluation of cardiovascular and central nervous system (CNS) effects of new therapeutics. To characterize an adult and juvenile mouse model, neurobehavioral and cardiovascular effects and pathology of a single sublethal but toxic, 8 mg/kg, oral dose of potassium cyanide (KCN) for up to 41 days postdosing were investigated. This study describes the short- and long-term sensory, motor, cognitive, and behavioral changes associated with oral dosing of a sublethal but toxic dose of KCN utilizing functional observation battery and Tier II CNS testing in adult and juvenile mice of both sexes. Selected tissues (histopathology) were evaluated for changes associated with KCN exposure with special attention to brain regions. Telemetry (adult mice only) was used to evaluate cardiovascular and temperature changes. Neurobehavioral capacity, sensorimotor responsivity or spontaneous locomotor activity, and rectal temperature were significantly reduced in adult and juvenile mice at 30 minutes post-8 mg/kg KCN dose. Immediate effects of cyanide included bradycardia, adverse electrocardiogram arrhythmic events, hypotension, and hypothermia with recovery by approximately 1 hour for blood pressure and heart rate effects and by 2 hours for body temperature. Lesions consistent with hypoxia, such as mild acute tubular necrosis in the kidneys corticomedullary junction, were the only histopathological findings and occurred at a very low incidence. The mouse KCN intoxication model indicates rapid and completely reversible effects in adult and juvenile mice following a single oral 8 mg/kg dose. Neurobehavioral and cardiovascular measurements can be used in this animal model as a trigger for treatment.


Assuntos
Comportamento Animal/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Sistema Nervoso/efeitos dos fármacos , Cianeto de Potássio/administração & dosagem , Cianeto de Potássio/toxicidade , Administração Oral , Animais , Pressão Sanguínea/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Modelos Animais de Doenças , Eletrocardiografia , Feminino , Frequência Cardíaca/efeitos dos fármacos , Dose Letal Mediana , Masculino , Camundongos , Camundongos Endogâmicos , Neurônios/efeitos dos fármacos
9.
Chem Phys Lipids ; 183: 159-68, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24995676

RESUMO

Cardiolipin (CL) is a unique anionic, dimeric phospholipid found almost exclusively in the inner mitochondrial membrane and is essential for the function of numerous enzymes that are involved in mitochondrial energy metabolism. While the role of cardiolipin in apoptosis is well established, its involvement in necrosis is enigmatic. In the present study, KCN-induced necrosis in U937 cells was used as an experimental model to assess the role of CL in necrosis. KCN addition to U937 cells induced reactive oxygen species (ROS) formation, while the antioxidants inhibited necrosis, indicating that ROS play a role in KCN-induced cell death. Further, CL oxidation was confirmed by the monomer green fluorescence of 10-N-nonyl acridine orange (NAO) and by TLC. Utilizing the red fluorescence of the dimeric NAO, redistribution of CL in mitochondrial membrane during necrosis was revealed. We also showed that the catalytic activity of purified adenosine triphosphate (ATP) synthase complex, known to be modulated by cardiolipin, decreased following KCN treatment. All these events occurred at an early phase of the necrotic process prior to rupture of the cell membrane. Furthermore, CL-deficient HeLa cells were found to be resistant to KCN-induced necrosis as compared with the wild type cells. We suggest that KCN, an effective reversible inhibitor of cytochrome oxidase and thereby of the respiratory chain leads to ROS increase, which in turn oxidizes CL (amongst other membrane phospholipids) and leads to mitochondrial membrane lipid reorganization and loss of CL symmetry. Finally, the resistance of CL-deficient cells to necrosis further supports the notion that CL, which undergoes oxidation during necrotic cell death, is an integral part of the milieu of events taking place in mitochondria leading to membrane disorganization and mitochondrial dysfunction.


Assuntos
Apoptose/efeitos dos fármacos , Cardiolipinas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Necrose/patologia , Necrose/fisiopatologia , Cianeto de Potássio/administração & dosagem , Relação Dose-Resposta a Droga , Humanos , Células U937
10.
Drug Chem Toxicol ; 37(1): 63-8, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23841473

RESUMO

Cyanide (CN) is an ion that has been well studied in toxicology and has been associated with several intoxication episodes: the ingestion of contaminated foods and water, chemical war, suicides, homicides, occupational exposures and the use of certain medicines. The aim of the present study was to determine the toxicokinetic parameters of thiocyante (SCN), the main metabolite of CN, after oral administration of potassium cyanide (KCN) to female rats at diestrus, gestational and lactational periods. Female Wistar rats were divided into three equal groups: virgins in the diestrus phase of the estrus cycle, females at the 14th day of gestation and females at the 14th day of lactation. Each group of rats received 3.0 mg of potassium cyanide per kilogram (KCN/kg body weight) by gavage, and blood was collected at several time points. We also collected amniotic fluid from pregnant rats and milk from the nursing rats to analyze thiocyanate concentration. The results showed that SCN levels were significantly increased in serum, milk and amniotic fluid after administration of KCN. In conclusion, the results of the present study evidence that the metabolism of CN varies greatly considering the physiologic state of the female rat, being females at estrus probably more exposed by these substances than at gestation and lactation because in these states there are other compartments, fetus and milk, which may capture these substances, as demonstrated by the V(d) values.


Assuntos
Diestro/efeitos dos fármacos , Lactação/efeitos dos fármacos , Gravidez/efeitos dos fármacos , Tiocianatos/farmacocinética , Tiocianatos/toxicidade , Administração Oral , Líquido Amniótico/química , Análise de Variância , Animais , Feminino , Leite/química , Cianeto de Potássio/administração & dosagem , Cianeto de Potássio/metabolismo , Ratos , Ratos Wistar , Tiocianatos/análise , Tiocianatos/sangue , Testes de Toxicidade
11.
Med Tr Prom Ekol ; (3): 36-40, 2013.
Artigo em Russo | MEDLINE | ID: mdl-23785827

RESUMO

Cytochemical analysis of acid phosphatase was used to evaluate lysosomal membranes stability under oral intake of potassium cyanide by rats over one month in daily doses of 1.30 mg/kg (1/10 LD50) and 0.65 mg/kg (1/20 LD50). The authors demonstrated phase-related dose-dependent changes in the lysosomal state, and the main response feature was associated with functional activation that usually followed the membrane alteration.


Assuntos
Modelos Animais de Doenças , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Cianeto de Potássio/toxicidade , Administração Oral , Animais , Masculino , Intoxicação/sangue , Cianeto de Potássio/administração & dosagem , Cianeto de Potássio/sangue , Ratos , Ratos Wistar
12.
Am J Physiol Regul Integr Comp Physiol ; 301(5): R1367-79, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21813868

RESUMO

Serotonin neurons of the caudal raphe facilitate ventilatory and sympathetic responses that develop following blood loss in conscious rats. Here, we tested whether serotonin projections to the caudal portion of the dorsomedial brain stem (including regions of the nucleus tractus solitarius that receive cardiovascular and chemosensory afferents) contribute to cardiorespiratory compensation following hemorrhage. Injections of the serotonin neurotoxin 5,7-dihydroxytryptamine produced >90% depletion of serotonin nerve terminals in the region of injection. Withdrawal of ∼21% of blood volume over 10 min produced a characteristic three-phase response that included 1) a normotensive compensatory phase, 2) rapid sympathetic withdrawal and hypotension, and 3) rapid blood pressure recovery accompanied by slower recovery of heart rate and sympathetic activity. A gradual tachypnea developed throughout hemorrhage, which quickly reversed with the advent of sympathetic withdrawal. Subsequently, breathing frequency and neural minute volume (determined by diaphragmatic electromyography) declined below baseline following termination of hemorrhage but gradually recovered over time. Lesioned rats showed attenuated sympathetic and ventilatory responses during early compensation and later recovery from hemorrhage. Both ventilatory and sympathetic responses to chemoreceptor activation with potassium cyanide injection were attenuated by the lesion. In contrast, the gain of sympathetic and heart rate baroreflex responses was greater, and low-frequency oscillations in blood pressure were reduced after lesion. Together, the data are consistent with the view that serotonin innervation of the caudal dorsomedial brain stem contributes to sympathetic compensation during hypovolemia, possibly through facilitation of peripheral chemoreflex responses.


Assuntos
Barorreflexo , Células Quimiorreceptoras/metabolismo , Hemorragia/metabolismo , Bulbo/metabolismo , Terminações Pré-Sinápticas/metabolismo , Ventilação Pulmonar , Neurônios Serotoninérgicos/metabolismo , Sistema Nervoso Simpático/metabolismo , 5,7-Di-Hidroxitriptamina/administração & dosagem , Adaptação Fisiológica , Animais , Pressão Sanguínea , Células Quimiorreceptoras/efeitos dos fármacos , Modelos Animais de Doenças , Frequência Cardíaca , Hemorragia/patologia , Hemorragia/fisiopatologia , Hipotensão/metabolismo , Hipotensão/fisiopatologia , Hipovolemia/metabolismo , Hipovolemia/fisiopatologia , Injeções , Rim/inervação , Masculino , Bulbo/efeitos dos fármacos , Bulbo/patologia , Bulbo/fisiopatologia , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Cianeto de Potássio/administração & dosagem , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/patologia , Ventilação Pulmonar/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/patologia , Serotoninérgicos/administração & dosagem , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/fisiopatologia , Fatores de Tempo
13.
Auton Neurosci ; 152(1-2): 27-34, 2010 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-19783484

RESUMO

Chemoreflex afferent fibers terminate in the nucleus tractus solitarii (NTS), but the specific location of the NTS neurons excited by peripheral chemoreflex activation remains to be characterized. Here, the topographic distribution of chemoreflex sensitive cells at the commissural NTS was evaluated. To reach this goal, Fos-immunoreactive neurons (Fos-ir) were accounted in rostro-caudal levels of the intermediate and caudal commissural NTS, after intermittent chemoreflex activation with intravenous injection of potassium cyanide [KCN (80microg/kg) or saline (0.9%, vehicle), one injection every 3min during 30min]. In response to intermittent intravenous injections of KCN, a significant increase in the number of Fos-ir neurons was observed specifically in the lateral intermediate commissural NTS [(LI)NTS (82+/-9 vs. 174+/-16, cell number mean per section)] and lateral caudal commissural NTS [(LC)NTS (71+/-9 vs. 199+/-18, cell number mean per section)]. To evaluate the influence of baroreceptor-mediated inputs following the increase in blood pressure during intermittent chemoreflex activation, we performed an intermittent activation of the arterial baroreflex by intravenous injection of phenylephrine [1.5microg/kg iv (one injection every 3min during 30min)]. This procedure induced no change in Fos-ir in (LI)NTS (64+/-6 vs. 62+/-12, cell number mean per section) or (LC)NTS (56+/-15 vs. 77+/-12, cell number mean per section). These data support the involvement of the commissural NTS in the processing of peripheral chemoreflex, and provide a detailed characterization of the topographical distribution of activated neurons within this brain region.


Assuntos
Sistema Nervoso Periférico/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Reflexo/fisiologia , Núcleo Solitário/fisiologia , Agonistas de Receptores Adrenérgicos alfa 1 , Vias Aferentes , Animais , Barorreflexo/efeitos dos fármacos , Barorreflexo/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Mapeamento Encefálico , Citotoxinas/administração & dosagem , Citotoxinas/toxicidade , Frequência Cardíaca/efeitos dos fármacos , Masculino , Neurônios/classificação , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Especificidade de Órgãos , Sistema Nervoso Periférico/efeitos dos fármacos , Fenilefrina/administração & dosagem , Fenilefrina/farmacologia , Cianeto de Potássio/administração & dosagem , Cianeto de Potássio/toxicidade , Ratos , Ratos Wistar , Reflexo/efeitos dos fármacos , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/metabolismo , Estimulação Química , Vasoconstritores/administração & dosagem , Vasoconstritores/farmacologia , Vigília
14.
Drug Metab Lett ; 3(2): 125-9, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19601875

RESUMO

In the early stages of drug discovery, the formation of reactive metabolites is often assessed by co-incubating the drug in liver microsomes with a trapping agent in the presence of NADPH. Our group assessed the capability of commonly used trapping agents to reversibly inhibit major cytochrome P450 (CYP) isoforms. Glutathione and cyanide did not inhibit the enzymes at concentrations up to 10 mM; however methoxylamine did show inhibition, with IC(50) values of 0.53 mM for CYP1A2, 4.12 mM for CYP2C9, 2.04 mM for CYP2C19, 9.72 mM for CYP2D6, and 1.26 and >10 mM for CYP3A4/5 (for testosterone and midazolam, respectively, as substrates).


Assuntos
Inibidores das Enzimas do Citocromo P-450 , Glutationa/farmacologia , Hidroxilaminas/farmacologia , Cianeto de Potássio/farmacologia , Relação Dose-Resposta a Droga , Descoberta de Drogas/métodos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Glutationa/administração & dosagem , Humanos , Hidroxilaminas/administração & dosagem , Concentração Inibidora 50 , Isoenzimas/antagonistas & inibidores , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Midazolam/metabolismo , Cianeto de Potássio/administração & dosagem , Testosterona/metabolismo
15.
J Environ Biol ; 30(4): 515-20, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20120489

RESUMO

Cyanide is a highly toxic cellular poison that requires immediate and aggressive treatments. Combination of sodium nitrite (SN) and sodium thiosulfate (STS) is the treatment of choice but oral treatment of alpha-ketoglutarate (A-KG) has also been shown to significantly antagonize cyanide poisoning in laboratory animals. This study reports the efficacy of various treatment regimens as: (i) repeated doses of A-KG after simultaneous treatment of A-KG and STS, (ii) repeated doses of A-KG after pre-treatment of SN, STS and A-KG, (iii) repeated doses of STS after pre-treatment of SN, STS and A-KG, and (iv) repeated doses of A-KG and STS after pretreatment of SN, STS and A-KG on mortality of female rats exposed to massive doses of potassium cyanide. A maximum of 40-folds protection was observed when A-KG at 1.0 g kg(-1) after 2 hr and 0.5 g kg(-1) after 4 hr was repeated following the pre-treatment of SN (0.025 g kg(-1); subcutaneous;-45 min), STS (1.0 g kg(-1); intraperitoneal; -15 min) andA-KG (2.0 g kg(-1); oral; -10 min). Similar protection was also conferred by repeating 0.5 g kg(-1) each of A-KG and STS 2 hr after pre-treatment of SN, STS and A-KG. Also, 38-folds protection after simultaneous administration of 20 g kg(-1) A-KG and 1.0 g kg(-1) STS, followed by 2.0 g kg(-1) A-KG after 2 hr was noteworthy The results indicate that repeated treatment of A-KG alone after simultaneous treatment of A-KG and STS or repeated treatment of A-KG alone or with STS after pre-treatment of A-KG, SN and STS have immense potential in challenging extremely high doses of cyanide as compared to the antidotes given once. The study has implications in the development of A-KG as an alternate treatment for cyanide poisoning.


Assuntos
Ácidos Cetoglutáricos/farmacologia , Venenos/toxicidade , Cianeto de Potássio/toxicidade , Substâncias Protetoras/farmacologia , Animais , Feminino , Ácidos Cetoglutáricos/administração & dosagem , Venenos/administração & dosagem , Cianeto de Potássio/administração & dosagem , Substâncias Protetoras/administração & dosagem , Ratos , Ratos Wistar , Nitrito de Sódio/administração & dosagem , Nitrito de Sódio/farmacologia , Tiossulfatos/administração & dosagem , Tiossulfatos/farmacologia
16.
Biol Pharm Bull ; 30(3): 514-9, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17329848

RESUMO

We previously demonstrated that tenuifoliside B and 3,6'-disinapoylsucrose in Polygalae Radix, the root of Polygala tenuifolia WILLDENOW, inhibited potassium cyanide (KCN)-induced hypoxia and scopolamine-induced memory impairment in mice. Because both ingredients have a common sinapoyl moiety in their structure, we inferred that the sinapoyl moiety could inhibit hypoxia and memory impairment. In the present study to clarify the hypothesis, sinapic acid inhibited KCN-induced hypoxia and scopolamine-induced memory impairment as well as tenuifoliside B and 3,6'-disinapoylsucrose did. In addition, sinapic acid inhibited decompression- or bilateral carotid artery ligation-induced hypoxia (or mortality) and CO2-induced impairment in mice, and basal forebrain lesion-induced cerebral cholinergic dysfunction (decreases in acetylcholine concentration and choline acetyltransferase activity) in rats. These results, taken together, suggest the possibilities that sinapic acid is not only a very important moiety in the pharmacological activities of tenuifoliside B and 3,6'-disinapoylsucrose but also a candidate for a cerebral protective and cognition-improving medicine.


Assuntos
Cognição/efeitos dos fármacos , Ácidos Cumáricos/farmacologia , Transtornos da Memória/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Acetilcolina/metabolismo , Amnésia/induzido quimicamente , Amnésia/prevenção & controle , Animais , Dióxido de Carbono/administração & dosagem , Dióxido de Carbono/toxicidade , Cognição/fisiologia , Coma/induzido quimicamente , Coma/prevenção & controle , Ácidos Cumáricos/administração & dosagem , Relação Dose-Resposta a Droga , Agonistas de Aminoácidos Excitatórios/administração & dosagem , Agonistas de Aminoácidos Excitatórios/toxicidade , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Lobo Frontal/fisiopatologia , Hipóxia/etiologia , Hipóxia/prevenção & controle , Ácido Ibotênico/administração & dosagem , Ácido Ibotênico/toxicidade , Masculino , Medicina Kampo , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Endogâmicos ICR , Fármacos Neuroprotetores/administração & dosagem , Lobo Parietal/efeitos dos fármacos , Lobo Parietal/metabolismo , Lobo Parietal/fisiopatologia , Cianeto de Potássio/administração & dosagem , Cianeto de Potássio/toxicidade , Ratos , Ratos Wistar , Escopolamina/administração & dosagem , Escopolamina/toxicidade , Taxa de Sobrevida
17.
J Appl Toxicol ; 25(6): 445-50, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16196001

RESUMO

The purpose of this work is to determine and describe the effects of subacute cyanide toxicity to goats. Eight female goats were divided into two groups. The first group of five animals was treated with 8.0 mg KCN kg(-1) body weight day(-1) for seven consecutive days. The second group of three animals was treated with water as controls. Complete physical examination, including observation for behavior changes, was conducted before and after dosing. One treated animal was euthanized immediately after dosing. Later, two of the remaining treated animals and a control goat were euthanized after a 30-day recovery period. Euthanized animals were necropsied and tissues were collected and prepared for histologic studies. Clinical signs in treated goats were transient and included depression and lethargy, mild hyperpnea and hyperthermia, arrhythmias, abundant salivation, vocalizations, expiratory dyspnea, jerky movements and head pressing. Two goats developed convulsions after day 3 of treatment. One animal developed more permanent behavioral changes as she became less dominant and aggressive. Histologic changes included mild hepatocellular vacuolation and degeneration, mild vacuolation and swelling of the proximal convoluted tubules of the kidneys and spongiosis of the white matter (status spongiosis) of the cerebral white tracts, internal capsule, cerebellar peduncles, spinal cord and peripheral nerves. In summary, sub-lethal cyanide intoxication in goats resulted in behavioral changes, and during the treatment period animals showed delayed signs of toxicity. Significant histologic lesions in goats were observed and need to be characterized further.


Assuntos
Comportamento Animal/efeitos dos fármacos , Cabras/fisiologia , Cianeto de Potássio/toxicidade , Animais , Cerebelo/efeitos dos fármacos , Cerebelo/patologia , Feminino , Cabras/sangue , Cabras/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Bulbo/efeitos dos fármacos , Bulbo/patologia , Cianeto de Potássio/administração & dosagem , Cianeto de Potássio/sangue , Convulsões/induzido quimicamente , Tiocianatos/sangue
18.
Theriogenology ; 62(6): 1012-26, 2004 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-15289044

RESUMO

Although exposure to cyanogenic plants or cyanide during pregnancy has adverse effects, no teratological study with cyanide has been conducted in goats or any other ruminant. The objective of the present study was to evaluate the effects of the maternal exposure to potassium cyanide (KCN) during pregnancy on both dams and offspring and furthermore, to develop a model for prenatal toxicological studies in ruminants. Twenty-six pregnant goats were allocated into four groups and given 0, 1.0, 2.0, or 3.0mg KCN/kg body weight per day orally (administered via twice-daily gavage) from Day 24 of pregnancy to term. However, one control dam and another from the 3.0mg KCN/kg per day group were sacrificed on Day 120. At birth, the kids were examined carefully for gross abnormalities. Three months after birth, the male kids and one dam from each group were sacrificed for histopathological study. Although clinical signs of poisoning were observed in dams, cyanide treatment did not alter the length of gestation or the number of live kids. Two prognata kids were born in the 3.0mg KCN/kg group, and one dam from the same group aborted two fetuses. There were histological lesions only in the KCN-treated dam (and its fetuses) sacrificed on Day 120; these consisted of an increased number of resorption vacuoles of thyroid follicular colloid, and status spongiosis of nervous white matter. This study proposes a new animal model for teratogenic trials that could be important to evaluate the effects of chemicals throughout pregnancy in goats and potentially other ruminants.


Assuntos
Anormalidades Induzidas por Medicamentos , Cabras , Modelos Animais , Cianeto de Potássio/toxicidade , Ruminantes , Anormalidades Induzidas por Medicamentos/patologia , Animais , Feminino , Morte Fetal/epidemiologia , Morte Fetal/veterinária , Masculino , Cianeto de Potássio/administração & dosagem , Gravidez , Glândula Tireoide/anormalidades , Glândula Tireoide/patologia , Tiroxina/sangue , Tri-Iodotironina/sangue
19.
Yan Ke Xue Bao ; 20(4): 264-7, 2004 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-15656375

RESUMO

PURPOSE: To investigate the effort of carbamylation, an important post-translational modification of lens proteins, on chaperone activity of alpha-crystallin. METHODS: The alphaL-crystallin and betaL-crystallin were isolated from bovine lens. Carbamylation was performed by different concentrations of potassium [14C] cyanate to alphaL-crystallin at 37 degrees C for 7 days. The binding of cyanate to alphaL-crystallin was determined by measuring the radioactivity incorporated into trichloroacetic acid precipitable protein from potassium [14C] cyanate. In addition, alphaL-crystallin was incubated with unlabelled potassium cyanate (50 and 100 mmol.L(-1)) for 3 and 7 days at 37 degrees C and then its chaperone activity against heat-induced betaL-crystallin aggregation was assayed. Analysis of the carbamylated alphaL-crystallin was further performed by high performance liquid chromatography (HPLC). RESULTS: The rate of binding (cyanate bound /mol of alphaL-crystallin) and the decreased chaperone activity of alphaL-crystallin induced by carbamylation in vitro were dose-dependent and time-dependent. The decreased chaperone activity corresponded with the higher binding of cyanate. After 7 days incubation with 100 mmol.L(-1), almost all chaperone activity was lost compared with a simultaneously incubation control sample. HPLC analysis revealed that aggregation of alphaL-crystallin by potassium cyanate has occurred after 3 days incubation in dose-dependent fashion. CONCLUSION: The alpha-crystallin can be modified in vitro by carbamylation through a high-molecular-weight aggregates formation. The loss of its chaperone activity may result from carbamylation-induced aggregation.


Assuntos
Cianeto de Potássio/administração & dosagem , Processamento de Proteína Pós-Traducional , alfa-Cristalinas/metabolismo , Acilação , Animais , Bovinos , Relação Dose-Resposta a Droga , Técnicas In Vitro , Chaperonas Moleculares/metabolismo , Cianeto de Potássio/química , alfa-Cristalinas/química
20.
Arch Toxicol ; 77(6): 330-4, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12799772

RESUMO

The aim of the present study was to determine the effect of the species on the toxicokinetics of cyanide and its main metabolite, thiocyanate. Forty-two rats, six pigs and six goats were dosed orally with 3.0 mg KCN/kg body weight, and cyanide and thiocyanate concentrations in blood were measured within 24 h. After the single oral dose, KCN was rapidly absorbed by rats and goats, with a time of peak concentration ( T(max)) of 15 min. The maximum plasma concentration ( C(max)) of cyanide was observed in goats (93.5 micro mol/l), whereas the C(max) of thiocyanate was higher in rats (58.1 micro mol/l). The elimination half-life ( t(1/2)) and volume of distribution ( Vd(area)) of both cyanide and thiocyanate were higher in goats (1.28 and 13.9 h, and 0.41 and 1.76 l/kg, respectively). Whereas the area under the curve (AUC) of cyanide was significantly higher in goats (234.6 micro mol.l/h), the AUC of thiocyanate was higher in rats (846.5 micro mol.l/h). In conclusion, the results of the present study support the hypothesis that the metabolism of cyanide and its main metabolite, thiocyanate, is species-linked, with the goat being more sensitive to the toxic effects of cyanide/thiocyanate.


Assuntos
Farmacocinética , Cianeto de Potássio/administração & dosagem , Cianeto de Potássio/farmacocinética , Tiocianatos/sangue , Administração Oral , Animais , Cabras/metabolismo , Masculino , Cianeto de Potássio/sangue , Ratos/metabolismo , Ratos Wistar , Especificidade da Espécie , Suínos/metabolismo , Fatores de Tempo
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