Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.014
Filtrar
1.
Drug Des Devel Ther ; 14: 4263-4276, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116414

RESUMO

Purpose: Anisodine hydrobromide (Ani) is isolated from the medicinal plant Anisodus tanguticus (Maxim.) Pascher for clinical use. Although considerable research regarding Ani has been reported, the safety profiles of Ani are currently unknown. This study investigated the cardiorespiratory effects of Ani in conscious dogs to provide clinicians a detailed safety profile of Ani on the cardiorespiratory system. Materials and Methods: Using the Latin square design, the study was divided into six phases, where in each phase, six telemetered beagle dogs received one dose of normal saline or sotalol hydrochloride or Ani (0.1, 0.4, 1.6, or 6.4 mg/kg). Electrocardiogram, blood pressure (BP) and respiratory parameters were collected before and after administration for 24 hours. Statistical comparisons were performed at scheduled time-points. Results: The heart rate was significantly increased, PR and QTCV intervals were significantly shortened in Ani 0.4, 1.6, 6.4 mg/kg treatment group after drug administration. Compared with the saline group, a significant increase in heart rate and shortening of PR, QTCV intervals were observed in the Ani 1.6, 6.4 mg/kg treatment groups from 5 min to 4 h time-points. Diastolic and mean BP were significantly increased in Ani 1.6, 6.4 mg/kg from 1 h to 2 h time-points compared to those of the saline control. Accelerated breathing was observed in the first 20 min after Ani 0.4, 1.6, and 6.4 mg/kg treatment, although not statistically significant. Furthermore, no significant differences were observed in any of the corresponding indexes of Ani 0.1 mg/kg treatment group at different time-points compared to those of the saline group. Conclusion: Ani may have adverse effects on the cardio-respiratory systems of dogs at doses above 0.4 mg/kg, whereas Ani 0.1 mg/kg was devoid of potentially deleterious effects on cardiorespiratory function.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Respiração/efeitos dos fármacos , Derivados da Escopolamina/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Anti-Inflamatórios não Esteroides/toxicidade , Pressão Sanguínea/efeitos dos fármacos , Estado de Consciência , Cães , Eletrocardiografia , Feminino , Frequência Cardíaca/efeitos dos fármacos , Masculino , Derivados da Escopolamina/toxicidade , Sotalol/farmacologia , Telemetria
4.
J Pharm Biomed Anal ; 183: 113145, 2020 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-32058292

RESUMO

The European Pharmacopoeia (Ph. Eur.) described two separate HPLC methods for determination of organic impurities in oxitropium bromide, a synthetic anticholinergic agent used by inhalation in the treatment of asthma and other bronchial disorders, and a potentiometric titration assay method which is not a stability indicating method. During synthetic process development and analytical studies of oxitropium; besides known Ph. Eur.-impurities new process related and degradation impurities were determined, identified by LC-MS, synthesized, characterized, and then used in development and validation studies of oxitropium analytical methods. As a result of these studies, a single HPLC related substances method was developed and validated according to international conference on harmonisation (ICH) guidelines for determination of all oxitropium related substances by using an inertsil ODS-4 (250 mm × 4.6 mm, 5 µm) column at 15 °C with 50 µL injection volume at a wavelength of 210 nm with gradient elution of phosphate-buffer/acetonitrile mixture flowing at a rate of 1.2 mL/min during 60 min. Also, a stability indicating HPLC assay method was developed and validated by using an XBridge C18 (150 mm × 4.6 mm, 3.5 µm) column at 25 °C with 10 µL injection volume at a wavelength of 210 nm and with phosphate-buffer/acetonitrile (85/15) mixture flowing at a rate of 1.0 mL/min during 10 min. Stress-testing and stability studies of oxitropium bromide was carried out and samples were analyzed by using newly developed stability-indicating HPLC assay and related substances methods.


Assuntos
Derivados da Escopolamina/química , Derivados da Escopolamina/síntese química , Cromatografia Líquida de Alta Pressão/métodos , Contaminação de Medicamentos , Estabilidade de Medicamentos , Espectrometria de Massas/métodos , Reprodutibilidade dos Testes
5.
Pharmacology ; 105(7-8): 369-376, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31655826

RESUMO

INTRODUCTION: Benzodiazepine anxiolytics are believed to cause urination disorders due to their anticholinergic effects. OBJECTIVE: This study was carried out to investigate the potential inhibitory effects of 15 clinically available anxiolytics in Japan on acetylcholine (ACh)-induced contractions in rat detrusor smooth muscle (DSM) to predict whether these anxiolytics could induce urination disorders. METHODS: -Effects of anxiolytics on contractions induced by ACh and 80 mmol/L KCl solution in rat DSM and effects of anxiolytics on specific binding of [N-methyl-3H]scopolamine ([3H]NMS) in mouse cerebral cortex were investigated. RESULTS AND CONCLUSIONS: ACh-induced contractions in rat DSM were inhibited by clotiazepam and diazepam (benzodiazepine anxiolytics) at concentrations that were clinically relevant. These contractions were also significantly inhibited by paroxetine, escitalopram (selective serotonin reuptake inhibitors -[SSRIs]), and hydroxyzine (a histamine H1 receptor antagonist), albeit at concentrations that substantially exceeded clinically achievable blood levels. At a concentration of 10-5 mol/L, paroxetine, escitalopram, and hydroxyzine inhibited 80 mmol/L high-KCl solution-induced rat DSM contractions but not clotiazepam and diazepam. Paroxetine, escitalopram, and hydroxyzine also inhibited specific binding of [3H]NMS in mouse cerebral cortex but clotiazepam and diazepam did not. In contrast to the effects of the abovementioned anxiolytics, ACh-induced contractions were not significantly affected by tofisopam, alprazolam, lorazepam, bromazepam, oxazolam, chlordiazepoxide, clonazepam, ethyl loflazepate (benzodiazepine anxiolytics), fluvoxamine (an SSRI), or tandospirone (a serotonin 5-HT1A receptor agonist). These findings suggest that most clinically used anxiolytics are not likely to result in anticholinergic-induced urination disorders within their clinically achievable blood concentration ranges. However, clotiazepam and diazepam may induce urination disorders within their clinical dose ranges via nonanticholinergic inhibition of DSM contractility.


Assuntos
Acetilcolina/antagonistas & inibidores , Ansiolíticos/toxicidade , Benzodiazepinas/toxicidade , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Bexiga Urinária/efeitos dos fármacos , Animais , Masculino , Camundongos , Contração Muscular/fisiologia , Músculo Liso/fisiologia , Ratos , Ratos Wistar , Derivados da Escopolamina/metabolismo , Bexiga Urinária/fisiologia , Transtornos Urinários/induzido quimicamente
6.
Chin J Nat Med ; 17(7): 490-497, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31514980

RESUMO

Current study systematically investigated the interaction of two alkaloids, anisodine and monocrotaline, with organic cation transporter OCT1, 2, 3, MATE1 and MATE2-K by using in vitro stably transfected HEK293 cells. Both anisodine and monocrotaline inhibited the OCTs and MATE transporters. The lowest IC50 was 12.9 µmol·L-1 of anisodine on OCT1 and the highest was 1.8 mmol·L-1 of monocrotaline on OCT2. Anisodine was a substrate of OCT2 (Km = 13.3 ± 2.6 µmol·L-1 and Vmax = 286.8 ± 53.6 pmol/mg protein/min). Monocrotaline was determined to be a substrate of both OCT1 (Km = 109.1 ± 17.8 µmol·L-1, Vmax = 576.5 ± 87.5 pmol/mg protein/min) and OCT2 (Km = 64.7 ± 14.8 µmol·L-1, Vmax = 180.7 ± 22.0 pmol/mg protein/min), other than OCT3 and MATE transporters. The results indicated that OCT2 may be important for renal elimination of anisodine and OCT1 was responsible for monocrotaline uptake into liver. However neither MATE1 nor MATE2-K could facilitate transcellular transport of anisodine and monocrotaline. Accumulation of these drugs in the organs with high OCT1 expression (liver) and OCT2 expression (kidney) may be expected.


Assuntos
Monocrotalina/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Derivados da Escopolamina/metabolismo , Transporte Biológico , Permeabilidade da Membrana Celular , Expressão Gênica , Células HEK293 , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Monocrotalina/química , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/genética , Derivados da Escopolamina/química
7.
Anal Chim Acta ; 1049: 1-9, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30612639

RESUMO

A simple and cheap design for interfacing thin layer chromatography (TLC) with electrospray ionization mass spectrometry (ESI/MS) was developed to scan and characterize compounds on TLC plate. The developed TLC plate was rapidly and easily modified into two sawtooth-edged pieces that were positioned on an XYZ stage so that one of the triangular tips was pointed toward the MS inlet. A drop of methanol and high DC voltage was applied at the tip to induce ESI. After the analytes in the first tip were analyzed, the TLC piece was moved so that the second triangular tip was pointed toward the MS inlet for analysis. The process was repeated until all the triangular tips on the piece were analyzed. In this manner, the analytes, no matter visible or non-visible bands, were scanned and characterized. Since a 4.8 cm long TLC track were cut to 32 triangles on two sawtooth pieces for analysis, the spatial resolution of using the sawtooth TLC-ESI/MS for analysis is 1.5 mm/band. A mixture of dye standards and Datura metel flower extract was analyzed to demonstrate the capability of sawtooth TLC-ESI/MS on scanning and characterizing chemical compounds on the TLC plates. The limits of detection of the dye standards were between 0.25 and 2.5 ng/band. TLC bands containing alkaloids such as scopolamine and norscopolamine from the Datura metel flower extract were not visualized on the developed TLC track, but were successfully detected at different triangular tips using sawtooth TLC-ESI/MS. Based on these results, the Rf values of scopolamine and norscopolamine were determined.


Assuntos
Cromatografia em Camada Delgada/métodos , Corantes/análise , Extratos Vegetais/análise , Espectrometria de Massas por Ionização por Electrospray/métodos , Cromatografia em Camada Delgada/instrumentação , Datura metel/química , Técnicas Eletroquímicas/métodos , Flores/química , Limite de Detecção , Escopolamina/análise , Derivados da Escopolamina/análise
8.
Int J Chron Obstruct Pulmon Dis ; 13: 2147-2156, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30034230

RESUMO

Background: The DYNAGITO study was a Phase IIIb, randomized, double-blind, multicenter, active-controlled, parallel-group, 52-week study designed to determine the efficacy and safety of tiotropium and olodaterol combination therapy (TIO+OLO 5/5 µg) versus tiotropium monotherapy (TIO 5 µg) for reducing moderate-to-severe exacerbations of COPD. This is a prespecified analysis of the DYNAGITO data in Japanese patients. Patients and methods: Enrolled patients had a diagnosis of COPD with at least one moderate-to-severe exacerbation in the previous 12 months. Of the total 7,880 treated patients in the DYNAGITO study, 461 (TIO+OLO 5/5 µg: n=226, TIO 5 µg: n=235) were Japanese. The primary endpoint was the annualized rate of moderate-to-severe COPD exacerbations. The key secondary endpoint was the time to first moderate-to-severe COPD exacerbation, and other secondary endpoints included the annualized rate of exacerbations leading to hospitalization, time to first COPD exacerbation leading to hospitalization, and all-cause mortality. Safety data were analyzed descriptively. Results: Combination therapy with TIO+OLO resulted in a 29% lower rate of moderate-to-severe COPD exacerbations relative to TIO monotherapy (rate ratio 0.71; 99% CI: 0.46, 1.10; p=0.0434). The risk of a first moderate-to-severe COPD exacerbation was 19% lower with TIO+OLO combination therapy than with TIO monotherapy (HR 0.81; 99% CI: 0.57, 1.17; p=0.1379), although this difference was not statistically significant. The annualized rate of COPD exacerbations requiring hospitalization was 14% lower in the TIO+OLO arm than in the TIO arm (rate ratio 0.86; 95% CI: 0.52, 1.42; p=0.5654). The adverse event incidence was balanced between treatment arms. Conclusion: In a prespecified subgroup analysis of Japanese patients in the DYNAGITO study, combination therapy with TIO+OLO was more effective than TIO in reducing exacerbations. Both treatments were well tolerated.


Assuntos
Benzoxazinas/uso terapêutico , Progressão da Doença , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Brometo de Tiotrópio/uso terapêutico , Administração por Inalação , Idoso , Benzoxazinas/administração & dosagem , Broncodilatadores , Causas de Morte , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Volume Expiratório Forçado , Hospitalização , Humanos , Masculino , Doença Pulmonar Obstrutiva Crônica/mortalidade , Derivados da Escopolamina , Fatores de Tempo , Brometo de Tiotrópio/administração & dosagem , Resultado do Tratamento
9.
Medicine (Baltimore) ; 97(25): e11253, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29924056

RESUMO

BACKGROUND: Endoscopic inspection of colonic mucosa is disturbed by colonic folds and peristalsis, which may result in missed polyps. Cimetropium bromide, an antispasmodic agent, inhibits peristalsis and colonic spasms, which may improve polyp detection. The purpose of this randomized, double-blind, placebo-controlled study was to investigate whether cimetropium bromide could improve polyp and adenoma detection in the colorectum and right colon. METHODS: Patients undergoing screening or diagnostic colonoscopy were randomized to receive intravenous cimetropium bromide (5 mg) or placebo after cecal intubation. The primary outcomes were the number of polyps per patient (PPP) and adenomas per patient (APP); secondary outcomes were the polyp detection rate (PDR), adenoma detection rate (ADR), and advanced neoplasm detection rate (ANDR). RESULTS: A total of 181 patients were analyzed; 91 patients received cimetropium bromide and 90 patients received placebo. Cimetropium bromide and placebo groups did not significantly differ in the PPP and APP for the colorectum (1.38 ±â€Š1.58 vs 1.69 ±â€Š2.28, P = .298; 0.96 ±â€Š1.27 vs 1.11 ±â€Š1.89, P = .517, respectively) and right colon (0.70 ±â€Š0.95 vs 0.78 ±â€Š1.21, P = .645; 0.47 ±â€Š0.81 vs 0.51 ±â€Š0.81, P = .757, respectively). Two groups also did not significantly differ in the PDR, ADR, and ANDR for the colorectum and right colon. Furthermore, there were no difference between groups in the PPP, APP, PDR, ADR, and ADNR in a sub-analysis of expert and non-expert endoscopists. CONCLUSIONS: Cimetropium bromide did not improve polyp and adenoma detection in the colorectum and right colon during colonoscope withdrawal, regardless of the expertness of the endoscopist. However, its use may be helpful in patients with active peristalsis or for beginning endoscopists during standard colonoscopy without a transparent cap.


Assuntos
Adenoma/diagnóstico , Pólipos do Colo/diagnóstico , Colonoscópios/estatística & dados numéricos , Neoplasias Colorretais/diagnóstico , Derivados da Escopolamina/administração & dosagem , Adenoma/patologia , Administração Intravenosa , Idoso , Pólipos do Colo/patologia , Colonoscopia/métodos , Neoplasias Colorretais/patologia , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Parassimpatolíticos/administração & dosagem , Peristaltismo/efeitos dos fármacos
18.
CNS Neurol Disord Drug Targets ; 16(10): 1111-1119, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29076436

RESUMO

BACKGROUND: Chronic cerebral hypoperfusion is a common pathophysiological state in various cerebrovascular diseases. Anisodine has been reported to exert neuroprotective effects in cerebral ischemia/reperfusion (I/R) animal model. However, it is unclear whether anisodine hydrobromide, the hydrobromide format of anisodine, one of the tropic alkanes alkaloids, exhibits the same neuroprotective effect on chronic cerebral hypoperfusion(CCH) rats. Herein, we tried to unravel these issues. METHODS: CCH model in adult male Sprague-Dawley rats was established by permanent ligation of the bilateral common carotid arteries [two-vessel occlusion (2-VO)] surgery. Rats were randomly divided into six groups: sham, 2-VO, 2-VO + Butyl phthalide and sodium chloride injection (NBP, as positive control group), 2-VO + anisodine hydrobromide (AH)1.2mg/kg, 2-VO +AH0.6mg/kg, 2-VO +AH0.3mg/kg. Cognitive behavior was examined by Morris Water Maze Test. Neuronal survival and apoptosis were evaluated by Nissl staining and Terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL staining). The relative monoamine neurotransmitter (5-hydroxytryptamine (5-HT), norepinephrine (NA)), the content of Ach, the activity of acetylcholin esterase (AchE) were measured in cholinergic system, and the protein expressions of Bcl-2, Bax, p-Akt and p-GSK-3ßwere detected by Western blot assay. RESULTS: The results showed that there is significant memory impairment and a remarkable neuron necrosis and apoptosis, along with the dysfunction of the neurotransmitter systems and central cholinergic system in CCH rats. AH treatment could significantly improve cognitive deficits, while reducing neuron necrosis and apoptosis, apart from increasing the content of 5-HT and decreasing the activity of AchE markedly. Further study revealed that AH could promote the protein expression of Bcl-2, phosphorylation of Akt and GSK-3ß, and downregulate the protein of Bax. CONCLUSION: AH was demonstrated to ameliorate memory deficits by revising the imbalance of the monoamine neurotransmitter and cholinergic dysfunction. Moreover, AH can attenuate neuronal cell death and apoptosis by activating the Akt/GSK-3ßsignaling pathway.


Assuntos
Isquemia Encefálica/prevenção & controle , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Derivados da Escopolamina/administração & dosagem , Derivados da Escopolamina/farmacologia , Acetilcolinesterase/metabolismo , Animais , Apoptose/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Isquemia Encefálica/psicologia , Artéria Carótida Primitiva/cirurgia , Sobrevivência Celular/efeitos dos fármacos , Córtex Cerebral/metabolismo , Hipocampo/metabolismo , Ligadura , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Proteínas do Tecido Nervoso/biossíntese , Neurônios/efeitos dos fármacos , Neurotransmissores/metabolismo , Ratos
19.
Zhonghua Jie He He Hu Xi Za Zhi ; 40(8): 596-603, 2017 Aug 12.
Artigo em Chinês | MEDLINE | ID: mdl-28810313

RESUMO

Objective: To evaluate the efficacy and safety of tiotropium Respimat in the treatment of chronic obstructive pulmonary disease (COPD) according to the Cochrane systematic evaluation. Methods: The Cochrane Library, PubMed, EMbase, CNKI, VIP and CBM, Wanfang Data were searched(from the foundation date to Jan. 2016) for the randomized controlled trials (RCTs) of tiotropium Respimat in the treatment of patients with COPD. Two reviewers independently retrieved the RCTs according to the inclusion and exclusion criteria, assessed the methodological quality of the included trials.and performed statistical analysis on the data using RevMan 5.3 software. Results: Totally 11 RCTs on efficacy were finally included.The results of the combined analysis showed that FEV(1) was significantly improved in the tiotropium Respimat group than that in the placebo group[MD=0.12, 95%CI(0.10-0.14), P<0.000 01], while FEV(1) was similar between the tiotropium Respimat group and the tiotropium HandiHaler group[5 µg: MD=0.00, 95%CI(-0.04-0.04), P=0.94; 2.5 µg: MD=-0.04, 95%CI(-0.10-0.01), P=0.12; 10 µg: MD=0.02, 95%CI(-0.06-0.09), P=0.66]. FVC was significantly improved in the tiotropium Respimat group than that in the placebo group[MD=0.18, 95%CI(0.09-0.28), P=0.0002], while FVC was similar between the tiotropium Respimat group and the HandiHaler group[2.5 µg: MD=-0.06, 95%CI(-0.16-0.04), P=0.24; 5 µg: MD=-0.00, 95%CI(-0.08-0.08), P=1.00; 10 µg: MD=0.02, 95%CI(-0.14-0.19), P=0.78]. The risk of acute exacerbations was lower in the tiotropium Respimat group (5 µg / kg) than in the placebo group [OR=0.72, 95%CI(0.60-0.86), P=0.000 3]. It was similar in the tiotropium Respimat group (5 µg) and the HandiHaler group[OR=1.01, 95%CI(0.94-1.09), P=0.71]. The SGRQ total score of the tiotropium Respimat group (5 µg) was significantly different from that of the placebo group[MD=-3.6, 95%CI(-3.88--3.32), P<0.000 01]. C(max, ss) and AUC(0-6 h, ss) were also similar between the tiotropium Respimat group and the HandiHaler group[MD=0.2, 95%CI(-5.1-5.5), P=0.94]; MD=-1.01, 95%CI(-11.78-9.77), P=0.85]. Nine RCTs were included in the evaluation of the incident rates of adverse drug reactions(ADR). There was no significant difference between the tiotropium Respimat group HandiHaler group and the placebo group[RR=0.95, 95%CI(0.89-1.00), P=0.05], [OR=1.07, 95%CI(1.00-1.16), P=0.06]. Conclusions: The efficacy and safety of tiotropium Respimat was similar to tiotropium HandiHaler in the treatment of COPD. They can effectively improve the pulmonary function and clinical symptoms of patients. But the long-term efficacy and safety of tiotropium Respimat still need to be confirmed by higher quality and larger RCTs with long-term follow-up.


Assuntos
Broncodilatadores/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Brometo de Tiotrópio/uso terapêutico , Administração por Inalação , Volume Expiratório Forçado , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Derivados da Escopolamina , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...