RESUMO
INTRODUCTION: The incorporation of selenium in the structure of nucleosides is a promising strategy to develop novel therapeutic molecules. OBJECTIVE: To assess the toxic effects of three AZT derivatives containing organoselenium moieties on human erythrocytes. METHODOLOGY: Freshly human erythrocytes were acutely treated with AZT and selenium derivatives SZ1 (chlorophenylseleno), SZ2 (phenylseleno) and SZ3 (methylphenylseleno) at concentrations ranging from 10 to 500⯵M. Afterwards, parameters related to membrane damage, redox dyshomeostasis and eryptosis were determined in the cells. RESULTS: The effects of AZT and derivatives toward erythrocytes differed considerably. Overall, the SZ3 exhibited similar effect profiles to the prototypal AZT, without causing cytotoxicity. Contrary, the derivative SZ1 induced hemolysis and increased the membrane fragility of cells. Reactive species generation, lipid peroxidation and thiol depletion were also substantially increased in cells after exposure to SZ1. δ-ALA-D and Na+/K+-ATPase activities were inhibited by derivatives SZ1 and SZ2. Additionally, both derivatives caused eryptosis, promoting cell shrinkage and translocation of phosphatidylserine at the membrane surface. The size and granularity of erythrocytes were not modified by any compound. CONCLUSION: The insertion of either chlorophenylseleno or, in a certain way, phenylseleno moietes in the structure of AZT molecule was harmful to erythrocytes and this effect seems to involve a pro-oxidant activity. This was not true for the derivative encompassing methylphenylseleno portion, making it a promising candidate for pharmacological studies.
Assuntos
Azidas/efeitos adversos , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Selênio/metabolismo , Zidovudina/efeitos adversos , Azidas/química , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/metabolismo , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Glycosylation of 1,2,4 lambda 3-diazaphosphole (4) under Lewis acid catalyzed conditions gave 1-alpha-D-ribofuranosyl-1,2,4 lambda 3-diazaphosphole (5) as the only product. Ethyl 1,2,4 lambda 3-diazaphosphole-3-carboxylate (10) was synthesized by the cyclocondensation of ethyl (chlorophosphinidene)(trimethylsilyl)acetate (8) with (trimethylsilyl)diazomethane and subsequent desilylation with tetra-n-butylammonium fluoride. Reaction of 10 with methanolic ammonia at 80 degrees C gave 1,2,4 lambda 3-diazaphosphole-3-carboxamide. Glycosylation of 10 using trimethylsilyl triflate catalyst followed by ammonlysis gave the ribavirin (1) analogue 1-beta-D-ribofuranosyl-1,2,4 lambda 3-diazaphosphole-3-carboxamide (11). Acetylation of 11 and subsequent treatment with phosphorus pentasulfide gave 2',3',5'-tri-O-acetyl-1-beta-D-ribofuranosyl-1,2,4 lambda 3-diazaphosphole-3- thiocarboxamide (13). Deprotection with methanolic ammonia gave 1-beta-D-ribofuranosyl-1,2,4 lambda 3-diazaphosphole-3-thiocarboxamide (14). Compound 14 gave a 25% increase in life span (ILS) against L1210 in female BDF1 mice. The anomeric configuration and site of glycosylation of 5 and 13 were established by single-crystal X-ray crystallography.
Assuntos
Antineoplásicos/síntese química , Azidas/síntese química , Nucleosídeos/síntese química , Compostos Organofosforados/síntese química , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Azidas/efeitos adversos , Azidas/uso terapêutico , Fenômenos Químicos , Química , IMP Desidrogenase/antagonistas & inibidores , Camundongos , Modelos Moleculares , Neoplasias Experimentais/tratamento farmacológico , Compostos Organofosforados/efeitos adversos , Compostos Organofosforados/uso terapêutico , Relação Estrutura-Atividade , Análise de Sobrevida , Difração de Raios XRESUMO
A total of 68 patients were treated in a phase I study of meta-azidopyrimethamine ethanesulphonate (MZPES)--a novel lipophilic dihydrofolate reductase (DHFR) antagonist. The dose was increased from 5.4 mg/m2 to 460 mg/m2 given as a 1-h infusion, with 460 mg/m2, 600 mg/m2 and 800 mg/m2 given as a 24-h infusion. The dose-limiting toxicity was nausea and vomiting, which was marked at doses above 360 mg/m2 by 1-h infusion and 600 mg/m2 by 24-h infusion. Above 250 mg/m2 patients also described subjective neurological symptoms, although no objective signs were apparent. Myelosuppression was not consistent at any dose level. No objective responses were seen. In view of the lack of anti-folate activity at toxic levels, no phase II trials are currently proposed; toxicological and in vitro studies will continue.
Assuntos
Antineoplásicos/uso terapêutico , Azidas/uso terapêutico , Antagonistas do Ácido Fólico , Pirimetamina/análogos & derivados , Pirimidinas/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Azidas/administração & dosagem , Azidas/efeitos adversos , Relação Dose-Resposta a Droga , Avaliação de Medicamentos , Humanos , Infusões Intravenosas , Neoplasias/tratamento farmacológico , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversosRESUMO
The number of cycles of alcohol detoxification is suggested to be an important variable in the predisposition to severe withdrawal seizures in alcohol-dependent individuals. Several clinical studies have suggested that exposure to repeated alcohol withdrawals may lead to increased severity of subsequent withdrawal episodes. Consistent with these observations, exposure to multiple cycles of ethanol withdrawal in our previous study significantly increased sensitivity to the convulsive effects of the GABA(A) receptor inverse agonist, Ro15-4513, in comparison to continuous ethanol exposure with no intermittent withdrawals. There was also a selective increase in the occurrence of spontaneous spike and sharp wave (SSW) activity in the EEG recorded from hippocampal area CA(3) in proportion to the number of withdrawal episodes experienced. It is hypothesized that during such repeated episodes of ethanol intoxication and withdrawal, changes in neuronal excitation during prior withdrawals could serve as initially subconvulsive kindling stimuli that might eventually result in the increased severity of the withdrawal syndrome. There is some evidence of the successful suppression of such neuronal excitation during acute ethanol withdrawal by positive modulators of the GABA(A) receptor. In the present study, the benzodiazepine agonist, diazepam, at a dose (4.0 mg/kg) that suppresses acute withdrawal symptoms, when administered during intermittent withdrawals, did not alter seizure sensitivity during a subsequent nonmedicated withdrawal. Diazepam treatment during prior withdrawals also did not have any effect on the multiple withdrawal-associated increase in SSW activity in hippocampal area CA(3) during an untreated withdrawal. This finding suggests that suppression of acute withdrawal symptoms by diazepam does not prevent long-lasting changes in CNS function resulting from repeated exposures to ethanol withdrawal.
Assuntos
Convulsões por Abstinência de Álcool/tratamento farmacológico , Anticonvulsivantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Depressores do Sistema Nervoso Central/efeitos adversos , Diazepam/uso terapêutico , Etanol/efeitos adversos , Marcadores de Afinidade/efeitos adversos , Convulsões por Abstinência de Álcool/sangue , Convulsões por Abstinência de Álcool/induzido quimicamente , Animais , Azidas/efeitos adversos , Benzodiazepinas/efeitos adversos , Encéfalo/fisiopatologia , Depressores do Sistema Nervoso Central/sangue , Eletroencefalografia , Etanol/sangue , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Sixteen 1-(2-naphthyloxyacetyl)-4-substituted-3-thiosemicarbazide, 2-(2-naphthyloxymethyl)-5-substitutedamino-1,3,4-oxadiazole, 2-(2-naphthyloxymethyl)-5-substitutedamino-1,3,4-thiadiazole and 5-(2-naphthyloxymethyl)-4-substituted-1,2,4-triazole-3thione derivatives have been prepared and evaluated as orally active anti-inflammatory agents with reduced side-effects. The structures of the compounds were confirmed by IR and 1H NMR spectral data and microanalysis. The anti-inflammatory and ulcerogenic activities of the compounds were compared with naproxen, indomethacin and phenylbutazone. In carrageenan-induced foot pad edema assay, 2-(2-naphthyloxymethyl)-5-methylamino-1,3,4-oxadiazole, 5-(2-naphthyloxymethyl)-4-methyl-1,2,4-triazole-3-thione and 5-(2-naphthyloxymethyl)-4-ethyl-1,2,4-triazole-3-thione showed an interesting anti-inflammatory activity. In the air-pouch test, 1,3,4-oxadiazole and 1,2,4-triazole-3-thione derivatives reduced total number of leukocytes of the exudate that indicates excellent inhibition of prostaglandin production. Side effects of the compounds were examined on gastric mucosa, liver and stomach and none of the compounds showed significant side effects compared with reference nonsteroidal anti-inflammatory drugs (NSAIDs).
Assuntos
Anti-Inflamatórios/síntese química , Azidas/síntese química , Azidas/farmacologia , Tiadiazóis/síntese química , Tiadiazóis/farmacologia , Tionas/síntese química , Tionas/farmacologia , Administração Oral , Ar , Animais , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Azidas/efeitos adversos , Azidas/uso terapêutico , Edema/induzido quimicamente , Edema/patologia , Edema/prevenção & controle , Pé/patologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Estômago/efeitos dos fármacos , Tiadiazóis/efeitos adversos , Tiadiazóis/uso terapêutico , Tionas/efeitos adversos , Tionas/uso terapêuticoAssuntos
Alérgenos/efeitos adversos , Corantes/efeitos adversos , Dermatite Alérgica de Contato/epidemiologia , Fenilenodiaminas/efeitos adversos , Alérgenos/imunologia , Azidas/efeitos adversos , Azidas/imunologia , Reações Cruzadas , Dermatite Alérgica de Contato/diagnóstico , Dermatite Alérgica de Contato/etiologia , Dermatite Alérgica de Contato/imunologia , Inglaterra/epidemiologia , Humanos , Testes do Emplastro/estatística & dados numéricos , Fenilenodiaminas/imunologia , Fatores de RiscoRESUMO
UNLABELLED: Effective anticancer therapy induces tumor cell death through apoptosis. Noninvasive monitoring of apoptosis during therapy may provide predictive outcome information and help tailor treatment. A caspase-3-specific imaging radiotracer, (18)F-(S)-1-((1-(2-fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-5-(2(2,4-difluorophenoxymethyl)-pyrrolidine-1-sulfonyl)isatin ((18)F-ICMT-11), has been developed for use in PET studies. We report the safety, biodistribution, and internal radiation dosimetry profiles of (18)F-ICMT-11 in 8 healthy human volunteers. METHODS: (18)F-ICMT-11 was intravenously administered as a bolus injection (mean ± SD, 159 ± 2.75 MBq; range, 154-161 MBq) to 8 healthy volunteers (4 men, 4 women). Whole-body (vertex to mid thigh) PET/CT scans were acquired at 6 time points, up to 4 h after tracer injection. Serial whole blood, plasma, and urine samples were collected for radioactivity measurement and radiotracer stability. In vivo (18)F activities were determined from quantitative analysis of the images, and time-activity curves were generated. The total numbers of disintegrations in each organ normalized to injected activity (residence times) were calculated as the area under the curve of the time-activity curve, normalized to injected activities and standard values of organ volumes. Dosimetry calculations were then performed using OLINDA/EXM 1.1. RESULTS: Injection of (18)F-ICMT-11 was well tolerated in all subjects, with no serious tracer-related adverse events reported. The mean effective dose averaged over both men and women was estimated to be 0.025 ± 0.004 mSv/MBq (men, 0.022 ± 0.004 mSv/MBq; women, 0.027 ± 0.004 mSv/MBq). The 5 organs receiving the highest absorbed dose (mGy/MBq), averaged over both men and women, were the gallbladder wall (0.59 ± 0.44), small intestine (0.12 ± 0.05), upper large intestinal wall (0.08 ± 0.07), urinary bladder wall (0.08 ± 0.02), and liver (0.07 ± 0.01). Elimination was both renal and via the hepatobiliary system. CONCLUSION: (18)F-ICMT-11 is a safe PET tracer with a dosimetry profile comparable to other common (18)F PET tracers. These data support the further development of (18)F-ICMT-11 for clinical imaging of apoptosis.
Assuntos
Apoptose/fisiologia , Azidas/farmacocinética , Caspase 3/metabolismo , Indóis/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Idoso , Azidas/efeitos adversos , Feminino , Humanos , Indóis/efeitos adversos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Especificidade de Órgãos , Doses de Radiação , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Distribuição TecidualRESUMO
Sodium azide (NaN3) is a highly reactive, toxic, widely used chemical. Although industrial exposure is common, fatal ingestion is rare. We describe the case of a 30-year-old man who ingested 15 to 20 g of sodium azide. He became comatose within two hours and eventually expired from a combination of acidosis, respiratory depression, and ventricular fibrillation. In sufficient doses, sodium azide is rapidly fatal and there is no effective treatment.
Assuntos
Azidas/intoxicação , Suicídio , Administração Oral , Adulto , Azidas/efeitos adversos , Humanos , Masculino , Equipe de Assistência ao Paciente , Ressuscitação/métodos , Azida SódicaRESUMO
While it is well established that the disposal of laboratory wastes containing sodium azide might be hazardous, evidence proving such a risk when the wastes are disposed of properly remains inconclusive. The Scientific Apparatus Makers Association and the Pharmaceutical Manufacturers Association oppose any general policy requiring the elimination of the preservative from laboratory reagents. Rather, they endorse the concept of alerting users to its presence and advising them of proper handling procedures. The following position paper, prepared by the SAMA/PMA Task Force, explains these suggestions.
Assuntos
Azidas/efeitos adversos , Explosões/prevenção & controle , Laboratórios/normas , Esgotos , Eliminação de Resíduos Líquidos , Hospitais , Humanos , Indicadores e Reagentes/efeitos adversos , Segurança , Estados UnidosRESUMO
The water used for dialysate (dialysis fluid) in hemodialysis centers is produced by water treatment systems (WTS), which require careful and frequent monitoring. On November 3, 1988, nine patients receiving hemodialysis treatments at a single dialysis center suddenly developed hypotension within 30 minutes of onset of dialysis. Eight patients exhibited symptoms and two experienced syncopal episodes; there were no deaths. The incidence of dialysis-associated hypotension occurring within 30 minutes after dialysis onset for these patients was significantly higher during outbreak treatments than during preoutbreak (September 1 through November 2, 1988) treatments, (9 of 9 vs. 0 of 238, P less than 0.00001, Fisher's t-test). Sodium azide, a potent hypotensive agent, was identified as the probable contaminant within the WTS of the dialysis center at the time of the outbreak because: 1) it was mixed with glycerine as the preservative solution of each of the four ultrafilters that were put on-line in the WTS without rinsing, 12 hours before the outbreak; and 2) high levels of total organic carbons were detected from dialysis water collected at point-of-use sites at the time of the outbreak, suggesting contamination of the WTS with the sodium azide-glycerine preservative solution. To prevent similar occurrences, we recommend that ultrafilters (and other components of the WTS) be rinsed free of potentially toxic chemicals prior to use. Dialysis center personnel need to be aware of the potential affects that each modification of disinfection of the WTS may have upon the product water used to prepare dialysate for patient treatments.
Assuntos
Instituições de Assistência Ambulatorial , Azidas/efeitos adversos , Soluções para Diálise , Soluções para Hemodiálise , Hipotensão/induzido quimicamente , Diálise Renal , Poluição Química da Água , Idoso , Surtos de Doenças , Feminino , Humanos , Indicadores e Reagentes/efeitos adversos , Masculino , Pessoa de Meia-Idade , New York , Azida Sódica , Ultrafiltração/instrumentaçãoRESUMO
The ubiquitous use of sodium azide has resulted in widespread occupational exposure to it in both laboratory and industrial settings, despite a lack of knowledge of the risks which may be involved. Explosive, toxic, and mutagenic hazards have been shown at even low-dose exposures. These effects occur in many species, from cellular damage through pathology of whole systems, and human fatalities have been reported. The advantages to its availability for applicable uses precludes reaching a "no exposure" level, but efforts to decrease unnecessary exposure can reduce its risk; therefore a quantitative procedure for determining human exposure is necessary. However, for various reasons present methods for this type of evaluation of azide are unsatisfactory, and minimizing hazard is dependent upon good laboratory hygiene and motivated personnel. The increasing use of azide and proportionally increasing occupational and accidental exposure in the future warrants the undertaking of chronic exposure studies, which hopefully will result in more explicit guidelines for human protection.
Assuntos
Azidas/efeitos adversos , Mutagênicos , Doenças Profissionais/induzido quimicamente , Acidentes , Animais , Azidas/toxicidade , Fenômenos Químicos , Físico-Química , Humanos , Indústrias , Laboratórios , Azida SódicaRESUMO
Report on the results of the clinical trial of a new trichomonacide in ambulatory patients in a gynaecological practice. A report is given on a new drug for the treatment of vaginal trichomoniasis, which has been tried in 87 patients of a gynaecological practice under outpatient conditions. The rate of failures was 5.7% (5 of 87 cases). The advantages over alternative preparations is to be seen in the short duration of treatment (24 hours at the most), and in the favourable tolerance in spite of high doses.
Assuntos
Antitricômonas/uso terapêutico , Nitroimidazóis/uso terapêutico , Ornidazol/uso terapêutico , Vaginite por Trichomonas/tratamento farmacológico , Adolescente , Adulto , Assistência Ambulatorial , Antitricômonas/administração & dosagem , Antitricômonas/efeitos adversos , Azidas/efeitos adversos , Ensaios Clínicos como Assunto , Esquema de Medicação , Feminino , Humanos , Concentração de Íons de Hidrogênio , Pessoa de Meia-Idade , Ornidazol/administração & dosagem , Fatores de TempoRESUMO
The development of an occupational health system for a plant manufacturing sodium azide has had to confront biological and hygienic difficulties related to the nature of sodium azide. Sodium azide in pellet form is used as the nitrogen generant for automobile air bags; however, it is manufactured as a very fine powder making exposure control more difficult. Sodium azide is a rapidly active, vasodilatory hypotensive agent that causes headaches and drops in blood pressure. Occupational health assessment of the plant and its employees demonstrated the need for exposure control, based on inspection, interviews, health data, process and site review. Targeted studies demonstrated the nature and magnitude of health effect problems at this plant and the relationship to azide exposure. Engineering and hygiene changes were developed in response to the evidence of worker exposure demonstrated by the targeted studies. The occupational health surveillance system provided a monitor for temporal changes. Results appear to demonstrate over the period of the development of the program, the following changes: (1) reductions in evidence of subjective symptoms from azide exposure (health incident reports of headaches and other symptoms), (2) reductions in objective signs of effects from azide exposure (drops in cross-shift mean arterial blood pressures), and (3) reductions in measured levels of azide exposure. Future studies need to validate the evidence of exposure changes and to further identify additional sources of exposure. Interventions designed to reduce exposures need to be demonstrated to be effective and need to be monitored to demonstrate continuing effectiveness.
Assuntos
Azidas/efeitos adversos , Indústria Química , Monitoramento Ambiental/métodos , Indicadores e Reagentes/efeitos adversos , Doenças Profissionais/prevenção & controle , Exposição Ocupacional/estatística & dados numéricos , Gestão de Riscos/métodos , Azidas/síntese química , Indústria Química/tendências , Coleta de Dados , Previsões , Humanos , Indicadores e Reagentes/síntese química , Doenças Profissionais/induzido quimicamente , Doenças Profissionais/diagnóstico , Exposição Ocupacional/prevenção & controle , Saúde Ocupacional , Medição de Risco , Azida Sódica , UtahRESUMO
Twenty patients with paralysis agitans took part in a double-blind, cross-over investigation of CB 154 (2-bromo-alpha-ergocryptine) and Madopar (L-Dopa + benserazid (a peripheral decarboxylase inhibitor), dose ratio 4:1). Each treatment phase lasted for 8 weeks. Modapar was found to be significantly superior to CB 154 in the treatment of the Parkinson state as a whole (Webster total score) and the individual symptoms of hypokinesia, rigidity and tremor. Compared with pretreatment score, CB 154 had a weak, but significant effect on tremor, but not on the Webster total score, hypokinesia and rigidity. The effect of CB 154, however, varied: four patients preferred CB 154 to Madopar on account of its satisfactory therapeutic effect and fewer side-effects ("on-off" phenomena, hyperkinesia, psychiatric complications); other patients showed neither therapeutic effect nor side-effects of CB 154, which in some cases may be related to too low a dose-level of CB 154 (median 30 mg daily, range 20-60 mg). In the four cases first mentioned which showed a good effect of CB 154, the ratio between the dose of CB 154 and the dose of L-Dopa (in Madopar) was 3.5-10 mg/100 mg, i.e. in certain cases it must be assumed that the maximum dose of CB 154 lies around 120 mg daily.
Assuntos
Benserazida/uso terapêutico , Bromocriptina/uso terapêutico , Ergolinas/uso terapêutico , Hidrazinas/uso terapêutico , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Idoso , Azidas/administração & dosagem , Azidas/efeitos adversos , Bromocriptina/administração & dosagem , Bromocriptina/efeitos adversos , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Humanos , Hipercinese/induzido quimicamente , Levodopa/administração & dosagem , Levodopa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Psicoses Induzidas por SubstânciasRESUMO
Sodium azide is the principal gas-generating agent used to inflate automobile supplemental restraint systems, more commonly called airbags. Although sodium azide is known to affect the cardiovascular system by causing peripheral vasodilation, there is no published literature describing occupational exposures to sodium azide in the rapidly growing automobile airbag industry. In 1994-1995, the National Institute for Occupational Safety and Health (NIOSH) conducted a cross-sectional study of health complaints reported by sodium azide production workers at the only continuous sodium azide production facility in the United States. The NIOSH evaluation consisted of a plant industrial hygiene survey, a symptom questionnaire, ambulatory blood pressure monitoring, and blood azide analysis. Personal breathing zone air monitoring revealed exposures to sodium azide and hydrazoic acid (a reactant product) at levels greater than the NIOSH Recommended Exposure Limits (RELs). In some cases, exposures exceeded the REL despite the use of air-supplied respirators. The questionnaire revealed that most workers reported headache (10 of 11 [91%]), episodes of low blood pressure (9 of 11 [82%]), and palpitations (8 of 11 [73%]) occurring in the production areas within the 6 months preceding the study. Mild headache (4 of 11 [36%]) was the only symptom reported during our 24-hr medical survey. Ambulatory blood pressure monitoring revealed one asymptomatic employee with a drop in blood pressure (defined as a drop in systolic [at least 20 mm Hg] and diastolic [at least 10 mm Hg] blood pressure) during a period of exposure to sodium azide at a level five times the NIOSH REL. Improvements in plant engineering controls, increased attention to employee hygiene practices, and a more comprehensive respiratory protection program were recommendations made by NIOSH to reduce exposures at the plant. All facilities handling sodium azide should be aware of the potential toxicity of sodium azide and hydrazoic acid.