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1.
J Ethnopharmacol ; 238: 111853, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-30954613

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Fritillariae Bulbus ("Beimu" in Chinese) is a famous traditional Chinese medicine used to treat cough, expectoration and asthma for more than 2000 years, which belongs to the Fritillaria genus in Liliaceae family. Bulbs of Fritillaria cirrhosa D.Don (BFC) and bulbs of Fritillaria pallidiflora Schrenk (BFP) are two important drugs of Beimu. Due to the significant similarities in their outward appearance characters and chemical profiles, BFC has often been adulterated with BFP in Chinese Traditional Medicine markets. AIM OF THE STUDY: This study aims to compare the oral acute toxicity and the traditional pharmacological activities including antitussive, expectorant and anti-inflammatory effects between the extract of BFC and BFP, to clear and definite if the BFP can be used as a substitute of the BFC in the application of traditional medicine. MATERIALS AND METHODS: The extracts were prepared through refluxing with 80% ethanol solvent. For the acute toxicity tests, graded doses of BFP extracts and the maximum dose of BFC extracts were administered orally to mice. The animals were observed for toxic symptoms and mortality daily for 14 days. For the pharmacological activities tests, graded doses of BFP and BFC extracts were administered orally to mice. To observe the effects relieving cough, expelling phlegm and lessening the ear swelling of BFC extracts and BFP extracts through ammonia liquor inducing cough, phenol red apophlegmating in mice and the xylene-induced auricular swelling of mouse, respectively. RESULTS: In the acute toxicity study, the LD50 value of BFP in mice was calculated to be 213.57 g/kg body weight, and the maximum feasible dose (MFD) value of BFC in mice was 452.14 g/kg. Histopathological analysis has shown inflammatory cells infiltration and cells edema in liver, multinucleated giant cell proliferation in spleen, perivascular exudate and hemorrhage in lung, glomerulus atrophy in kidney of mice after oral administrations of BFP extracts. But only liver cells edema was observed in BFC group. Both BFC extract and BFP extract significantly increased latent period of cough and inhibited cough frequency in mice induced by ammonia. Besides, the two extracts also obviously enhanced mice's tracheal phenol red output in expectorant assessment and inhibited the development of ear edema in anti-inflammatory evaluation assay. CONCLUSION: To summarize, the BFP has the significant similarities in morphological characteristics, chemical profiles and traditional pharmacological activities compared with the BFC. The result of this study provide some valid scientific support for using BFP as a plant substitute of the BFC, but considering the toxicity of BFP is much higher than BFC, we don't recommend long-term oral administration of BFP or exceeding recommended dosage of Chinese Pharmacopoeia 2015.


Assuntos
Anti-Inflamatórios , Antitussígenos , Tosse/tratamento farmacológico , Edema/tratamento farmacológico , Expectorantes , Fritillaria , Extratos Vegetais , Administração Oral , Animais , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/toxicidade , Antitussígenos/uso terapêutico , Antitussígenos/toxicidade , Expectorantes/uso terapêutico , Expectorantes/toxicidade , Feminino , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Medicina Tradicional Chinesa , Camundongos , Extratos Vegetais/uso terapêutico , Extratos Vegetais/toxicidade , Raízes de Plantas , Baço/efeitos dos fármacos , Baço/patologia , Testes de Toxicidade Aguda
2.
Toxicol Pathol ; 46(6): 683-692, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30033829

RESUMO

Benzonatate is a peripheral oral antitussive that dampens the activity of cough stretch receptors. Rodent carcinogenicity studies were performed in Tg.rasH2 mice and Wistar Han rats. Mice were orally gavaged benzonatate at 10, 30, 75, and 100 mg/kg/day for males and 5, 15, and 50 mg/kg/day for females. Rats were gavaged at 10, 30, and 90 mg/kg/day for males and 5, 15, and 50 mg/kg/day for females. Higher doses in males were due to differences in maximum tolerated doses in dose-ranging studies. In both species, benzonatate was not detected in plasma because of rapid ester hydrolysis producing 4-(butylamino) benzoic acid (BBA) and methylated polyethylene glycol polymer. This metabolism was similar in human plasma; therefore, plasma BBA was used to show systemic exposure. Both species had no evidence of a benzonatate-related increase in any neoplasm. A slight increase in nasal cavity exudative inflammation was present in benzonatate-dosed male mice. Retinal atrophy was observed in male rats at ≥30 mg/kg/day, but the incidence was within historical control data range and not related to benzonatate. In conclusion, benzonatate and its 2 major metabolites were not carcinogenic in rodent carcinogenicity studies at BBA exposures of ≥32 and 70 times a 200 mg human benzonatate dose, respectively.


Assuntos
Antitussígenos/toxicidade , Butilaminas/toxicidade , Neoplasias Experimentais/induzido quimicamente , Administração Oral , Animais , Antitussígenos/sangue , Butilaminas/sangue , Testes de Carcinogenicidade , Relação Dose-Resposta a Droga , Feminino , Genes ras , Masculino , Dose Máxima Tolerável , Camundongos Transgênicos , Ratos Wistar
3.
Artigo em Inglês | MEDLINE | ID: mdl-29704989

RESUMO

Benzonatate (TESSALON®) is a peripherally acting oral antitussive. It undergoes rapid ester hydrolysis producing 4-(butylamino) benzoic acid (BBA) and methylated polyethylene glycol (MPG) metabolites, which are eliminated in urine and feces. The nonclinical and clinical efficacy of Benzonatate has been demonstrated over the last 60 years, but its safety was not fully assessed. In this study, we tested the genotoxicity of Benzonatate and its major metabolite BBA in an in vitro bacterial reverse mutation and in vivo micronucleus assays. A chromosomal aberration assay was also performed on Benzonatate and BBA. In the reverse mutation assay, Benzonatate and BBA doses 1.5-5000 µg/plate ±â€¯S9 metabolic activation were used and the numbers of revertants/plate were compared to various controls. Chromosomal aberration assays with human peripheral blood lymphocytes used Benzonatate and BBA concentrations 25-2000 and 62.5-1930 µg/mL, respectively. A CByB6F1 mouse bone marrow micronucleus assay was performed as part of a 28-day oral toxicology study at up to 250 mg/kg/day. The frequencies of micronuclei in polychromatic erythrocytes in treated groups were compared with the control group. Neither Benzonatate nor BBA induced significant mutagenicity in any of the bacterial strains, with or without metabolic activation. They also did not produce any biologically relevant structural or numerical aberrations in human chromosomes. Benzonatate and its BBA and MPG metabolites rapidly produced from esterase activity did not produce any significant increase in the incidence of micronucleated polychromatic erythrocytes. In conclusion, Benzonatate and its major metabolite BBA were not mutagenic and did not cause numerical or structural chromosome alterations. While the MPG metabolite was not tested, studies on structural analogues indicated it was also unlikely to be genotoxic. This was supported by oral rodent carcinogenicity assays showing no increase in malignancies.


Assuntos
Antitussígenos/toxicidade , Células da Medula Óssea/efeitos dos fármacos , Butilaminas/toxicidade , Linfócitos/efeitos dos fármacos , Adulto , Animais , Células da Medula Óssea/citologia , Aberrações Cromossômicas , Relação Dose-Resposta a Droga , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Feminino , Humanos , Linfócitos/citologia , Masculino , Camundongos , Micronúcleos com Defeito Cromossômico/induzido quimicamente , Testes para Micronúcleos , Testes de Mutagenicidade , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Adulto Jovem
4.
Brain Res Bull ; 134: 10-17, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28645861

RESUMO

Dextromethorphan (DXM) is one of the common drugs abused by adolescents. It is the active ingredient found in cough medicine which is used for suppressing cough. High dosage of DXM can induce euphoria, dissociative effects and even hallucinations. Chronic use of DXM may also lead to depressive-related symptoms. Lycium barbarum, commonly known as wolfberry, has been used as a traditional Chinese medicine for the treatment of ageing-related neurodegenerative diseases. A recent study has shown the potential beneficial effect of Lycium barbarum to reduce depression-like behavior. In the present study, we investigated the role of Lycium barbarum polysaccharide (LBP) to alleviate DXM-induced emotional distress. Sprague Dawley rats were divided into 4 groups (n=6 per group), including the normal control (vehicles only), DXM-treated group (40 mg/kg DXM), LBP-treated group (1 mg/kg LBP) and DXM+ LBP-treated group (40 mg/kg DXM and 1 mg/kg LBP). After two-week treatment, the DXM-treated group showed increased depression-like and social anxiety-like behaviors in the forced swim test and social interaction test respectively. On the other hand, the adverse behavioral effects induced by DXM were reduced by LBP treatment. Histological results showed that LBP treatment alone did not promote hippocampal neurogenesis when compared to the normal control, but LBP could lessen the suppression of hippocampal neurogenesis induced by DXM. The findings provide insights for the potential use of wolfberry as an adjunct treatment option for alleviating mood disturbances during rehabilitation of cough syrup abusers.


Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Transtorno Depressivo/tratamento farmacológico , Dextrometorfano/toxicidade , Medicamentos de Ervas Chinesas/farmacologia , Fármacos Neuroprotetores/farmacologia , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Animais , Antitussígenos/toxicidade , Transtornos de Ansiedade/induzido quimicamente , Transtornos de Ansiedade/patologia , Transtornos de Ansiedade/fisiopatologia , Transtorno Depressivo/induzido quimicamente , Transtorno Depressivo/patologia , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiopatologia , Masculino , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/fisiologia , Psicotrópicos/farmacologia , Distribuição Aleatória , Ratos Sprague-Dawley , Comportamento Social , Transtornos Relacionados ao Uso de Substâncias/patologia , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia
5.
J Pharmacol Sci ; 132(2): 166-170, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27802908

RESUMO

Dextromethorphan (DM) administered at supra-antitussive doses produce psychotoxic and neurotoxic effects in humans. We administered DM (80 mg/kg) to rats intraperitoneally to determine the ultrastructural change induced by DM, because intraperitoneal route is sensitive for the behavioral responses. Treatment with DM resulted in mitochondrial dysfunction and formation of myelinoid bodies in the hippocampus. MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] attenuated DM-induced cytosolic oxidative burdens. However, neither MK-801 nor naloxone affected DM-induced mitochondrial dysfunction and formation of myelinoid bodies, indicating that the neurotoxic mechanism needs to be further elucidated. Therefore, the spectrum of toxicological effects associated with DM need to be reassessed.


Assuntos
Antitussígenos/toxicidade , Dextrometorfano/toxicidade , Hipocampo/efeitos dos fármacos , Hipocampo/ultraestrutura , Bainha de Mielina/ultraestrutura , Animais , Antitussígenos/administração & dosagem , Citosol/efeitos dos fármacos , Citosol/patologia , Citosol/ultraestrutura , Dextrometorfano/administração & dosagem , Hipocampo/patologia , Injeções Intraperitoneais , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Mitocôndrias/ultraestrutura , Bainha de Mielina/patologia , Ratos
6.
Pediatr. aten. prim ; 17(66): e137-e139, abr.-jun. 2015.
Artigo em Espanhol | IBECS | ID: ibc-137530

RESUMO

Los medicamentos antitusivos son de uso habitual dentro del ámbito pediátrico, a pesar de que su eficacia no está claramente demostrada. La mayoría de las ingestas accidentales no suelen asociarse a complicaciones severas; sin embargo, en ocasiones pueden presentarse efectos secundarios potencialmente graves. Se presenta un caso de intoxicación con un producto antitusivo (AU)


Antitussive drugs are commonly used in Pediatrics, although their effectiveness is not clearly demonstrated. Most of the accidental intakes do not tend to be associated with severe complications; however sometimes potentially serious side effects may occur. A case of poisoning is presented with a cough suppressant product (AU)


Assuntos
Pré-Escolar , Feminino , Humanos , Antitussígenos/toxicidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/complicações , Dextrometorfano/toxicidade , Dextrometorfano/uso terapêutico , Pseudoefedrina/toxicidade , Taquicardia/complicações , Taquicardia/diagnóstico , Hipertensão/complicações , Midríase/complicações , Cefaleia/complicações , Alucinações/complicações
8.
Int J Biol Macromol ; 69: 214-21, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24875316

RESUMO

A dark brown polymeric complex was isolated from flowering parts of medicinal plant Arnica montana L. by hot alkaline extraction followed by neutralization and multi-step extractions with organic solvents. It was recovered in 5.7% yield, on GPC showed two peaks of molecular mass of 9 and 3.5kDa. The compositional analyses of Arnica complex revealed the presence of carbohydrates (26%), uronic acids (12%), phenolics (1.25mM or 213mg of GAE/1g), and low protein content (∼1%). The carbohydrate moiety was rich mainly in rhamnogalacturonan and arabinogalactan. The antitussive tests showed the reduction of the cough efforts by Arnica complex, however, its total antitussive effect was lower compared with that of codeine, the strongest antitussive agent. The bronchodilatory activity of Arnica complex was similar to salbutamol, a classic antiasthmatic drug, and was confirmed by significantly decreased values of specific airways resistance in vivo and by considerably attenuated the amplitude of acetylcholine and histamine-induced contractions in vitro. Arnica complex did not show any cytotoxic effect on mouse fibroblast cultures and human lung cells, up to the dose of 500µg/mL.


Assuntos
Antitussígenos/farmacologia , Arnica/química , Extratos Vegetais/farmacologia , Animais , Antitussígenos/química , Antitussígenos/isolamento & purificação , Antitussígenos/uso terapêutico , Antitussígenos/toxicidade , Linhagem Celular , Ácido Cítrico/efeitos adversos , Tosse/induzido quimicamente , Tosse/tratamento farmacológico , Cobaias , Humanos , Masculino , Camundongos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiopatologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Extratos Vegetais/toxicidade , Reflexo/efeitos dos fármacos , Sistema Respiratório/efeitos dos fármacos
9.
J Ethnopharmacol ; 149(1): 297-302, 2013 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-23816499

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Root of Sorghum bicolor (L.) Moench (RSB) is an herbal medicine in Traditional Chinese Medicine, still used in some rural areas in Central China as an alternative remedy to treat cough and asthma. AIM OF THE STUDY: The study was aimed at evaluating the antitussive, expectorant and bronchodilating effects of ethanol extract of RSB, support its folk use with scientific evidence, and lay a foundation for its further researches. MATERIALS AND METHODS: RSB was extracted with 80% ethanol aqueous in reflux conditions, solutions were concentrated in reduced pressure, and lyophilized in vacuum to yield the RSB extract. Antitussive evaluations were carried out with three different models including ammonia liquor induced mice cough, capsaicin induced mice cough, and citric acid induced guinea pigs cough; phenol red secretion experiments in mice were performed to evaluate the expectorant ability; bronchodilating effects were evaluated with a bronchoconstrictive challenge induced by acetylcholine chloride and histamine in guinea pigs. RESULTS: In all the three antitussive tests, treatment of RSB significantly inhibited the frequency of cough, and prolonged the cough latent period in animals. And high dose of RSB (200mg/kg in mice and 100mg/kg in guinea pigs) created therapeutic activities as good as standard antitussive drug codeine phosphate (20mg/kg). In the expectorant evaluation, 50, 100 and 200mg/kg RSB treatment had significantly increased the amount of phenol red output for 0.39, 1.18, and 1.96 folds in mice tracheas. In the bronchodilating test, RSB treatment at 100mg/kg extended the preconvulsive time for 44.84% compared with that of before treatment in guinea pigs. CONCLUSIONS: RSB is an effective alternative medicine for the treatment of cough with potent antitussive, expectorant and bronchodilating activities.


Assuntos
Antitussígenos/uso terapêutico , Broncodilatadores/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Expectorantes/uso terapêutico , Sorghum/química , Animais , Antitussígenos/isolamento & purificação , Antitussígenos/toxicidade , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/isolamento & purificação , Broncodilatadores/toxicidade , Tosse/tratamento farmacológico , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/toxicidade , Etanol/química , Etnofarmacologia , Expectorantes/isolamento & purificação , Expectorantes/toxicidade , Feminino , Cobaias , Masculino , Camundongos , Camundongos Endogâmicos , Raízes de Plantas/química , Testes de Toxicidade Aguda
10.
Environ Toxicol Pharmacol ; 31(3): 485-9, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21787720

RESUMO

The toxicokinetic characteristics of naringin were investigated in rats that had been orally administered naringin extract, a candidate for oral treatment of cough, prepared from Citrus grandis "Tomentosa", at 50, 250, or 1250 mg/kg/day in a repeated-dose study for 1, 32, 93, or 184 days. Increased values of the mean systemic exposure were approximately proportional to increases in dose levels during all collection intervals; no saturation was observed. No significant differences in mean systemic exposure were observed between male and female rats. Results provide a reference for interpretation of toxicology findings and relevance to clinical safety issues.


Assuntos
Antitussígenos/farmacocinética , Antitussígenos/toxicidade , Flavanonas/farmacocinética , Flavanonas/toxicidade , Administração Oral , Animais , Área Sob a Curva , Comportamento Animal/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Masculino , Espectrometria de Massas , Ratos , Ratos Sprague-Dawley
11.
Pharm Biol ; 49(6): 627-32, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21554006

RESUMO

CONTEXT: Ballota limbata Benth. (Lamiaceae) (syn, Otostegia limbata Hook.f.) is a species grown in the North West Frontier Province and the lower hills of West Punjab, Pakistan. Ballota species are renowned for their antispasmodic, antiulcer, diuretic, vermifuge, and especially sedative effects. However, little is known about the biological activity of B. limbata. OBJECTIVE: Evaluation of antitussive activity and safety profile of dried B. limbata extract. MATERIALS AND METHODS: Whole air-dried plants were partitioned with various solvents and the butanol fraction was subjected to antitussive evaluation using a sulfur dioxide (SO(2))-induced cough model in mice. Codeine and dextromethorphan were used as positive control. Safety profile of the testing material was established using standard toxicity tests. RESULTS: B. limbata extract inhibited cough provoked by SO(2) gas in mice in a dose-dependent manner. The extract exhibited maximum protection against SO(2)-induced cough after 60 min of administration. B. limbata offered maximum cough suppressive effects, that is, number of coughs during 60 min was 11.66 ± 1.2 (mean ± SEM), after s.c. administration of 800 mg/kg, as compared with codeine 10 mg/kg, s.c., dextromethorphan 10 mg/kg, s.c., and saline showing a frequency of cough of 11.75 ± 1.18, 12.25 ± 0.83, and 46.25 ± 1.52, respectively. LD(50) value of B. limbata was greater than 5000 mg/kg. No sign of neural impairment was observed at antitussive doses and the extract has been well-tolerated at higher doses. DISCUSSION AND CONCLUSION: This study demonstrates that the extract of B. limbata has shown strong cough suppressive effect in mice without yielding any notable toxicity.


Assuntos
Antitussígenos/toxicidade , Antitussígenos/uso terapêutico , Tosse/tratamento farmacológico , Fitoterapia/métodos , Extratos Vegetais/toxicidade , Extratos Vegetais/uso terapêutico , Animais , Ballota/química , Codeína/uso terapêutico , Tosse/induzido quimicamente , Dextrometorfano/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Dose Letal Mediana , Masculino , Medicina Tradicional , Camundongos , Camundongos Endogâmicos , Paquistão
12.
J Appl Toxicol ; 31(2): 157-63, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20737414

RESUMO

Dextromethorphan is widely used in over-the-counter cough and cold medications. Its efficacy and safety for infants and young children remains to be clarified. The present study was designed to use zebrafish as a model to investigate the potential toxicity of dextromethorphan during embryonic and larval development. Three sets of zebrafish embryos/larvae were exposed to dextromethorphan at 24, 48 and 72 h post fertilization (hpf), respectively, during the embryonic/larval development. Compared with the 48 and 72 hpf exposure sets, the embryos/larvae in the 24 hpf exposure set showed much higher mortality rates which increased in a dose-dependent manner. Bradycardia and reduced blood flow were observed for the embryos/larvae treated with increasing concentrations of dextromethorphan. Morphological effects of dextromethorphan exposure, including yolk sac and cardiac edema, craniofacial malformation, lordosis, non-inflated swim bladder and missing gill, were also more frequent and severe among zebrafish embryos/larvae exposed to dextromethorphan at 24 hpf. Whether the more frequent and severe developmental toxicity of dextromethorphan observed among the embryos/larvae in the 24 hpf exposure set, as compared with the 48 and 72 hpf exposure sets, is due to the developmental expression of the phase I and phase II enzymes involved in the metabolism of dextromethorphan remains to be clarified. A reverse transcription-polymerase chain reaction analysis, nevertheless, revealed developmental stage-dependent expression of mRNAs encoding SULT3 ST1 and SULT3 ST3, two enzymes previously shown to be capable of sulfating dextrorphan, an active metabolite of dextromethorphan.


Assuntos
Antitussígenos/toxicidade , Dextrometorfano/toxicidade , Embrião não Mamífero/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Larva/efeitos dos fármacos , Teratogênios/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Bradicardia/induzido quimicamente , Bradicardia/embriologia , Anormalidades Craniofaciais/induzido quimicamente , Anormalidades Craniofaciais/embriologia , Relação Dose-Resposta a Droga , Edema/induzido quimicamente , Edema/embriologia , Edema Cardíaco/induzido quimicamente , Edema Cardíaco/embriologia , Embrião não Mamífero/metabolismo , Embrião não Mamífero/patologia , Comportamento Alimentar/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Larva/metabolismo , RNA Mensageiro/metabolismo , Fluxo Sanguíneo Regional/efeitos dos fármacos , Sulfotransferases/genética , Sulfotransferases/metabolismo , Saco Vitelino/efeitos dos fármacos , Saco Vitelino/patologia , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
13.
Dtsch Med Wochenschr ; 135(4): 133-44; quiz 145-6, 2010 Jan.
Artigo em Alemão | MEDLINE | ID: mdl-20101557

RESUMO

Pharmacogenomics investigates inherited differences in drug responses including beneficial and adverse reactions. While a considerable amount of evidence for genetic influences on drug responses has been accumulated within the last decade, predominantly in small studies, its value in routine therapy is still a matter of debate. The aim of this review is to discuss well established examples where pharmacogenomic techniques can improve routine treatment. Examples include genotyping of CYP2D6 in the context of antidepressant therapy, analysis of TPMT variants for the prediction of mercaptopurine-induced bone marrow depression, VKORC1 and CYP2C9 analyses for a better control of anticoagulant administration and the SLCO1B1 variant in the context of statin-induced myopathies.


Assuntos
Farmacogenética , Medicina de Precisão , Adolescente , Adulto , Alelos , Anticolesterolemiantes/farmacocinética , Anticolesterolemiantes/toxicidade , Anticoagulantes/farmacocinética , Anticoagulantes/toxicidade , Antitussígenos/farmacocinética , Antitussígenos/toxicidade , Hidrocarboneto de Aril Hidroxilases/genética , Disponibilidade Biológica , Biotransformação/genética , Codeína/farmacocinética , Codeína/toxicidade , Citocromo P-450 CYP2C9 , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP3A/genética , Inibidores do Citocromo P-450 CYP3A , Quimioterapia Combinada , Feminino , Genótipo , Humanos , Inativação Metabólica/genética , Transportador 1 de Ânion Orgânico Específico do Fígado , Masculino , Taxa de Depuração Metabólica/genética , Metiltransferases/deficiência , Metiltransferases/genética , Pessoa de Meia-Idade , Entorpecentes/farmacocinética , Entorpecentes/toxicidade , Transportadores de Ânions Orgânicos/genética , Fenótipo , Femprocumona/farmacocinética , Femprocumona/toxicidade , Mutação Puntual/genética , Polimorfismo Genético/genética , Sinvastatina/farmacocinética , Sinvastatina/toxicidade , Varfarina/farmacocinética , Varfarina/toxicidade
14.
J Cardiovasc Pharmacol ; 52(6): 494-9, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19034038

RESUMO

A common over-the-counter (OTC) non-opioid antitussive drug, clobutinol, was recently withdrawn from the market due to its potential to induce cardiac arrhythmias by a blockade of the potassium channel coded by the human ether-à-go-go-related gene (hERG). In this study, we investigated the effects of a number of antitussive compounds on the hERG ion channel current using patch-clamp electrophysiology, and compared the effects to that of clobutinol. The compounds clobutinol, pentoxyverine, dextromethorphan, and codeine inhibited the outward current in hERG transfected cells with half-maximal inhibition concentrations (IC50) of 1.9 microM, 3.0 microM, 5.1 microM, and 97 microM, respectively. For theobromine, no significant effect on the hERG current at a concentration up to 100 microM was detected. Safety margins between the effects of the drugs on the hERG ion channel current and their calculated maximal free therapeutic plasma concentration were calculated. These results were compared to assess potential risks of the compounds to induce torsade de pointes-type arrhythmias.


Assuntos
Antitussígenos/toxicidade , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/efeitos adversos , Potássio/metabolismo , Torsades de Pointes/induzido quimicamente , Amino Álcoois/toxicidade , Animais , Células CHO , Codeína/toxicidade , Cricetinae , Cricetulus , Ciclopentanos/toxicidade , Dextrometorfano/toxicidade , Relação Dose-Resposta a Droga , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/genética , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Potenciais da Membrana , Teobromina/toxicidade , Fatores de Tempo , Torsades de Pointes/metabolismo , Transfecção
15.
Intern Med ; 47(11): 1013-5, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18520112

RESUMO

We report a 35-year-old man who was referred to our hospital with generalized convulsion and mixed acidosis presumably caused by abuse of SS-BRON tablets, an over-the-counter (OTC) antitussive medication sold in Japan. These tablets contain dihydrocodeine phosphate, methylephedrine, chlorpheniramine, and caffeine. Although it is difficult to discern which component caused these symptoms, it seems that dihydrocodeine phosphate or methylephedrine was involved in the addiction to SS-BRON and chlorpheniramine may have caused the generalized convulsion. It should be recognized that an OTC antitussive, which is quite easy to obtain, can be abused and subsequently induce serious intoxication.


Assuntos
Acidose/induzido quimicamente , Antitussígenos/toxicidade , Clorfeniramina/toxicidade , Codeína/análogos & derivados , Convulsões/induzido quimicamente , Adulto , Codeína/toxicidade , Efedrina/análogos & derivados , Efedrina/toxicidade , Humanos , Japão , Masculino , Medicamentos sem Prescrição/toxicidade , Transtornos Relacionados ao Uso de Substâncias/complicações
16.
Regul Toxicol Pharmacol ; 50(3): 285-93, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18160193

RESUMO

Dextromethorphan (DMP) is an effective and widely used antitussive drug. While DMP has over a 50 year safe-marketing history, the only available genotoxicity data was an unpublished, negative Ames assay (Roche). Lack of a complete genotoxicity profile on DMP, specifically covering the chromosomal damage endpoint, prompted a regulatory request for an in vitro chromosome aberration assay. In accordance with EC and CPMP Guidance, we evaluated data for a number of chemicals with a structural relationship to DMP. DMP contains no structural alerts for genotoxicity or carcinogenicity using the Deductive Estimation of Risk from Existing Knowledge (DEREK) software tool, confirming the negative results obtained in the existing Ames assay. This is also consistent with the mostly negative genotoxicity and carcinogenicity data available on structurally related chemicals including morphine, codeine, nalbuphine, buprenorphine, naloxone, hydromorphone, levorphanol, and oxycodone. A state-of-the-science, in vitro chromosome aberration assay was also conducted, which demonstrated a lack of genotoxicity for DMP. The overall weight of evidence for DMP and its structural analogues, supports the conclusion that this class of phenanthrene-based chemicals, and DMP, in particular, are not genotoxic in vitro or in vivo, and do not represent a carcinogenic risk to patients.


Assuntos
Antitussígenos/toxicidade , Dextrometorfano/toxicidade , Mutagênicos , Analgésicos Opioides/toxicidade , Animais , Células CHO , Aberrações Cromossômicas/efeitos dos fármacos , Cricetinae , Cricetulus , Bases de Dados Factuais , Internet , Testes de Mutagenicidade , Medição de Risco , Relação Estrutura-Atividade
17.
Indian J Exp Biol ; 45(8): 712-9, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17877148

RESUMO

Dextromethorphan, a noncompetitive blocker of N-methyl-D- aspartate (NMDA) type of glutamate receptor, at 7.5-75 mg/kg, ip did not induce oral stereotypies or catalepsy and did not antagonize apomorphine stereotypy in rats. These results indicate that dextromethorphan at 7.5-75 mg/kg does not stimulate or block postsynaptic striatal D2 and D1 dopamine (DA) receptors. Pretreatment with 15 and 30 mg/kg dextromethorphan potentiated dexamphetamine stereotypy and antagonised haloperidol catalepsy. Pretreatment with 45, 60 and 75 mg/kg dextromethorphan, which release 5-hydroxytryptamine (5-HT), however, antagonised dexamphetamine stereotypy and potentiated haloperidol catalepsy. Apomorphine stereotypy was not potentiated or antagonised by pretreatment with 7.5-75 mg/kg dextromethorphan. This respectively indicates that at 7.5-75 mg/kg dextromethorphan does not exert facilitatory or inhibitory effect at or beyond the postsynaptic striatal D2 and D1 DA receptors. The results are explained on the basis of dextromethorphan (15-75 mg/kg)-induced blockade of NMDA receptors in striatum and substantia nigra pars compacta. Dextromethorphan at 15 and 30 mg/kg, by blocking NMDA receptors, activates nigrostriatal dopaminergic neurons and thereby potentiates dexampetamine stereotypy and antagonizes haloperidol catalepsy. Dextromethorphan at 45, 60 and 75 mg/kg, by blocking NMDA receptors, releases 5-HT and through the released 5-HT exerts an inhibitory influence on the nigrostriatal dopaminergic neurons with resultant antagonism of dexampetamine stereotypy and potentiation of haloperidol catalepsy.


Assuntos
Antitussígenos/farmacologia , Catalepsia/induzido quimicamente , Dextrometorfano/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Estereotipado/efeitos dos fármacos , Animais , Antitussígenos/toxicidade , Apomorfina/farmacologia , Comportamento Animal/efeitos dos fármacos , Dextroanfetamina/farmacologia , Dextrometorfano/toxicidade , Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacocinética , Inibidores da Captação de Dopamina/farmacologia , Haloperidol/toxicidade , Masculino , Ratos , Ratos Wistar , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores Dopaminérgicos/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
18.
Drug Metab Dispos ; 35(10): 1832-9, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17639025

RESUMO

Isoline, a major retronecine-type pyrrolizidine alkaloid (PA) from the Chinese medicinal herb Ligularia duciformis, was suggested to be the most toxic known PA. Its in vitro metabolism was thus examined in rat and mouse liver microsomes, and its toxicity was compared with that of clivorine and monocrotaline after i.p. injection in mice. Isoline was more rapidly metabolized by both microsomes than clivorine and monocrotaline and converted to two polar metabolites M1 and M2, which were spectroscopically determined to be bisline (a deacetylated metabolite of isoline) and bisline lactone, respectively. Both metabolites were formed in the presence or absence of an NADPH-generating system with liver microsomes but not cytosol. Their formation was completely inhibited by the esterase inhibitors, triorthocresyl phosphate (TOCP) and phenylmethylsulfonyl fluoride, but not at all or partially by cytochrome P450 (P450) inhibitors, alpha-naphthoflavone and proadifen (SKF 525A), respectively. These results demonstrated that both metabolites were produced by microsomal esterase(s) but not P450 isozymes. The esterase(s) involved showed not only quite different activities but also responses to different inhibitors in rat and mouse liver microsomes, suggesting that different key isozyme(s) or combinations might be responsible for the deacetylation of isoline. Isoline injected i.p. into mice induced liver-specific toxicity that was much greater than that with either clivorine or monocrotaline, as judged by histopathology as well as serum alanine aminotransferase and aspartate aminotransferase levels. Isoline-induced hepatotoxicity was remarkably enhanced by the esterase inhibitor TOCP but was reduced by the P450 inhibitor SKF 525A, indicating that rodent hepatic esterase(s) played a principal role in the detoxification of isoline via rapid deacetylation in vivo.


Assuntos
Asteraceae/química , Esterases/antagonistas & inibidores , Alcaloides de Pirrolizidina/metabolismo , Alcaloides de Pirrolizidina/toxicidade , Alanina Transaminase/sangue , Animais , Antitussígenos/metabolismo , Antitussígenos/toxicidade , Aspartato Aminotransferases/sangue , Benzoflavonas/farmacologia , Inibidores das Enzimas do Citocromo P-450 , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/toxicidade , Esterases/metabolismo , Expectorantes/metabolismo , Expectorantes/toxicidade , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Microssomos Hepáticos/metabolismo , Monocrotalina/metabolismo , Monocrotalina/toxicidade , Fluoreto de Fenilmetilsulfonil/farmacologia , Proadifeno/farmacologia , Ratos , Ratos Sprague-Dawley , Tritolil Fosfatos/farmacologia
19.
Addict Biol ; 10(4): 325-7, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16318953

RESUMO

As part of a synthesis of evidence regarding the abuse and addiction liability of dextromethorphan (DM), an over-the-counter cough medicine available in over 140 preparations, an uncommonly published case of dextromethorphan dependence (addiction) is described, with specific, rarely published complications. The individual was interviewed and several medical databases were also reviewed (Medline, 1966-present; PubMed) for all content relating to the Keywords: dextromethorphan, abuse, dependence, cough medicine, addiction, withdrawal, psychosis. The patient evidenced history suggesting substance dependence, substance-induced psychosis and substance withdrawal in relation to DM. A literature review revealed that DM has specific serotonergic and sigma-1 opioidergic properties. Dextrorphan (DOR), the active metabolite of DM, has similar properties; however, DOR is a weaker sigma opioid receptor agonist, and a stronger NMDA receptor antagonist. DM and DOR display specific biological features of addiction, and are capable of inducing specific psychiatric sequelae. A specific, reproducible toxidrome with significant psychiatric effects occurred, when DM was abused at greater than indicated doses, with more profound and potentially life-threatening effects at even higher doses. DM withdrawal appears evident. DM's active metabolite, DOR, has pharmacodynamic properties and intoxication effects similar to dissociatives, and may be more responsible for the dissociative effect that this DM abuser sought. However, it is this same metabolite that may be fraught with the potentially life-threatening psychoses and dissociative-induced accidents, as well as addiction. While DM has been hypothesized as the most commonly abused dissociative, health-care providers seem largely unaware of its toxidrome and addiction liability.


Assuntos
Analgésicos Opioides/toxicidade , Antitussígenos/toxicidade , Dextrometorfano/toxicidade , Medicamentos sem Prescrição/toxicidade , Psicoses Induzidas por Substâncias/etiologia , Síndrome de Abstinência a Substâncias/etiologia , Transtornos Relacionados ao Uso de Substâncias/etiologia , Adulto , Delusões/induzido quimicamente , Dextrorfano/toxicidade , Relação Dose-Resposta a Droga , Tolerância a Medicamentos , Feminino , Alucinações/induzido quimicamente , Humanos , Psicoses Induzidas por Substâncias/reabilitação , Receptores sigma/agonistas , Recidiva , Síndrome de Abstinência a Substâncias/reabilitação , Transtornos Relacionados ao Uso de Substâncias/reabilitação
20.
Indian J Exp Biol ; 43(7): 620-5, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16053268

RESUMO

Dextromethorphan, a noncompetitive blocker of the N-methyl-D-aspartate (NMDA) type of glutamate receptor, at 45, 60 and 75 mg/kg, ip doses induced a behavioural syndrome characterised by reciprocal forepaw treading, lateral head-weaving, hind-limb abduction and flat body posture. Such type of behavioural syndrome is induced by 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT) by directly stimulating the central postsynaptic 5-hydroxytryptamine (5-HT, serotonin) receptors of the 5-HT1A type. Pretreatment with buspirone (5, 10 mg/kg, ip) and l-propranolol (10, 20 mg/kg, ip) antagonised the behavioural syndrome induced by 8-OH-DPAT and dextromethorphan. Pretreatment with p-chlorophenylalanine (100 mg/kg/day x 4 days) antagonised the behavioural syndrome induced by dextromethorphan and dexfenfluramine but had no significant effect on 8-OH-DPAT induced behavioural syndrome. This indicates that dextromethorphan induces the behavioural syndrome by releasing 5-HT from serotonergic neurons with resultant activation of the postsynaptic 5-HT1A receptors by the released 5-HT. Pretreatment with fluoxetine (10 mg/kg, ip) significantly potentiated the behavioural syndrome induced by dextromethorphan and 5-hydroxytryptophan but significantly antagonised dexfenfluramine induced behavioural syndrome. This indicates that dextromethorphan releases 5-HT by a mechanism which differs from that of dexfenfluramine. Dextromethorphan may be releasing 5-HT by blocking the NMDA receptors and thereby counteracting the inhibitory influence of l-glutamate on 5-HT release.


Assuntos
Comportamento Animal/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Dextrometorfano/toxicidade , 8-Hidroxi-2-(di-n-propilamino)tetralina/toxicidade , Animais , Antitussígenos/toxicidade , Comportamento Animal/fisiologia , Buspirona/farmacologia , Sistema Nervoso Central/fisiopatologia , Dexfenfluramina/toxicidade , Fluoxetina/farmacologia , Masculino , Propranolol/farmacologia , Ratos , Ratos Wistar , Serotonina/fisiologia , Agonistas do Receptor de Serotonina/toxicidade , Síndrome
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