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2.
Artigo em Inglês | MEDLINE | ID: mdl-32164969

RESUMO

Carbetapentane citrate, a non-opioid centrally-acting antitussive drug, is a common treatment for cough associated with other diseases such as common cold and respiratory tract infections. Its mode of action is very close to that of atropine; since it acts at the level of the peripheral parasympathetic nerve endings. The drug reaches its maximum plasma concentration (Cmax) 2h after administration, and it has a plasma half-life of 2.3h in case of oral administration. Due to its clinical importance, there are many analytical methods in the literature for carbetapentane determination. In addition, it is crucial to collect its analytical results in a single chapter so as to allow researchers to easily interpret their experimental data. Here, we provide the analytical profile of carbetapentane citrate with a brief description/interpretation of each analysis.


Assuntos
Antitussígenos/farmacologia , Ciclopentanos/farmacologia , Tosse/tratamento farmacológico , Humanos
3.
Biomed Chromatogr ; 34(2): e4736, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31696526

RESUMO

Chimonanthus nitens Oliv. leaf (CNOL), as a traditional Chinese medicine, has been widely used for the treatment of influenza and colds over a long history. However, the mechanism of colds related to the effects of CNOL have been little studied. In this study, the anticomplement and antitussive activities of different polarity extracts of CNOL were evaluated. Ethyl acetate extract (EAE) among different extracts not only significantly decreased cough times by 21-58% (P < 0.01), but also had anticomplement effects demonstrated by the CH50 values of 0.100 mg/ml. A total of 28 constituents (10 coumarins, 13 flavonoids and five phenolics) were identified in EAE based on the ultra-high-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry technique. Eight compounds in EAE were evaluated by an ammonia-induced cough model to reveal the antitussive mechanisms and classical anticomplement pathway. The results indicated that the antitussive effects of scopoletin, kaempferol-3-O-rutinoside and kaempferol may depend on central mechanisms and that flavonoids such as compounds of kaempferol-3-O-rutinoside and kaempferol have better anticomplementary activity than coumarins like compounds of scopolin, scopoletin and isofraxidin. Taken together, kaempferol-3-O-rutinoside and kaempferol could be important chemical markers in the present study that might be used to evaluate the quality and biological activity of CNOL.


Assuntos
Antitussígenos , Calycanthaceae/química , Proteínas Inativadoras do Complemento , Extratos Vegetais , Animais , Antitussígenos/química , Antitussígenos/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Proteínas Inativadoras do Complemento/química , Proteínas Inativadoras do Complemento/farmacologia , Tosse/induzido quimicamente , Tosse/fisiopatologia , Modelos Animais de Doenças , Cobaias , Quempferóis , Masculino , Camundongos , Camundongos Endogâmicos ICR , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Espectrometria de Massas em Tandem/métodos
4.
Xenobiotica ; 50(2): 135-144, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30896275

RESUMO

Levodropropizine (LDP) is a non-opioid anti-tussive. The stereoselective pharmacokinetics and tissue distribution (TD) of LDP vs. dextrodropropizine (DDP) have been characterized after oral and intravenous (IV) administration of LDP and rac-dropropozine in rats.Oral/IV doses of 50/5.0 mg/kg and 25/2.5 rac-dropropizine and LDP were employed. TD study focused on tissues such as liver, lung and kidney. Blood samples were collected for pharmacokinetic and TD evaluation. Validated methods were used to quantitate LDP, DDP and rac-dropropizine.No stereoselectivity in pharmacokinetics was observed between LDP vs. DDP following rac-dropropizine. However, LDP pharmacokinetics after LDP administration (oral/IV) appeared to be different compared to LDP derived from rac-dropropizine.TD data were similar between the two enantiomers regardless of oral/IV rac-dropropizine administration. When LDP alone was administered, levels were comparable to those derived for LDP from rac-dropropizine after oral/IV. However, in the lung and kidney tissues, the exposure after oral dosing was higher for LDP alone as compared to LDP from rac-dropropizine.In summary, complete characterization of stereoselective pharmacokinetics and TD of rac-dropropizine has been reported after oral/IV routes. It was evident that the presence of DDP, increased the plasma/tissue exposure of LDP which was evident after oral rac-dropropizine dosing.


Assuntos
Antitussígenos/farmacocinética , Propilenoglicóis/farmacocinética , Administração Intravenosa , Administração Oral , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Estereoisomerismo
5.
Biomed Pharmacother ; 118: 109188, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31315072

RESUMO

Pulmonary dysfunction is tightly associated with cough variant asthma (CVA), a respiratory damage disease. Suhuang antitussive capsule (Suhuang), one of traditional Chinese patent medicines, plays a crucial role in the treatment and complication of CVA in the long clinical application. In this study, we aimed to investigate the protective effects and underlying antitussive mechanisms of Suhuang on pulmonary function in ovalbumin (OVA)-induced CVA rats. Administration (i.g.) of Suhuang significantly alleviated pulmonary damage and dysfunction. Suhuang improved ER stress and PKCε translocation via regulation of Ca2+ trafficking. Suhuang also inhibited NLRP3 inflammasome activation, as evidenced by disrupting the assembly of NLRP3 inflammasome and reducing the expression of cleaved caspase-1, and decreased IL-1ß secretion. Besides, it's identified that TXNIP induction and RIP1-RIP3-Drp1 pathway were required for the inhibitory routes of Suhuang from ER stress to NLRP3 inflammasome activation. Consistent with the in vivo findings, Suhuang also attenuated ER stress/NLRP3 inflammasome activation, and thereby restored pulmonary homeostasis in vitro. Meantime, these functions were diminished by blocking ER stress, indicating that ER stress is essential for the effects of Suhuang on pulmonary function. A further in vivo analysis showed that Suhuang-driven pharmacological inactivation of NLRP3 inflammasome and amelioration of pulmonary dysfunction were reversed by an ER stress inducer tunicamycin, well confirming the beneficial effects of Suhuang on pulmonary function by regulation of ER stress. Collectively, these results indicated that Suhuang contributed to impairing NLRP3 inflammasome activation via inhibition of ER stress, which was responsible for the protection of pulmonary homeostasis. These findings may provide a pharmacological groundwork and important new experimental data regarding the clinical treatment of Suhuang in CVA patients.


Assuntos
Antitussígenos/uso terapêutico , Asma/tratamento farmacológico , Tosse/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Antitussígenos/administração & dosagem , Asma/imunologia , Cápsulas , Tosse/imunologia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/administração & dosagem , Estresse do Retículo Endoplasmático/imunologia , Masculino , Ovalbumina/imunologia , Ratos Wistar , Testes de Função Respiratória
6.
J Med Food ; 22(9): 963-970, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31259654

RESUMO

Naringin and its aglycone, naringenin, occur naturally in our regular diet and traditional Chinese medicines. This study aimed to detect an effective therapeutic approach for cough variant asthma (CVA) through evaluating the relaxant effect of these two bioactive herbal monomers as antitussive and antiasthmatic on rat tracheal smooth muscle. The relaxant effect was determined by measuring muscular tension with a mechanical recording system in rat tracheal rings. Cytosolic Ca2+ concentration was measured using a confocal imaging system in primary cultured tracheal smooth muscle cells. In rat tracheal rings, addition of both naringin and naringenin could concentration dependently relax carbachol (CCh)-evoked tonic contraction. This epithelium-independent relaxation could be suppressed by BaCl2, tetraethylammonium, and iberiotoxin (IbTX), but not by glibenclamide. After stimulating primary cultured tracheal smooth muscle cells by CCh or high KCl, the intracellular Ca2+ increase could be inhibited by both naringin and naringenin, respectively. This reaction was also suppressed by IbTX. These results demonstrate that both naringin and naringenin can relax tracheal smooth muscle through opening big conductance Ca2+-activated K+ channel, which mediates plasma membrane hyperpolarization and reduces Ca2+ influx. Our data indicate a potentially effective therapeutic approach of naringin and naringenin for CVA.


Assuntos
Antiasmáticos/administração & dosagem , Antitussígenos/administração & dosagem , Asma/tratamento farmacológico , Flavanonas/administração & dosagem , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Extratos Vegetais/administração & dosagem , Traqueia/efeitos dos fármacos , Animais , Asma/genética , Asma/metabolismo , Asma/fisiopatologia , Cálcio/metabolismo , Citrus/química , Humanos , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Masculino , Relaxamento Muscular/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Traqueia/fisiopatologia
7.
J Allergy Clin Immunol Pract ; 7(6): 1731-1738, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31279461

RESUMO

Chronic coughing has a significant impact on the sufferer's quality of life. Despite this, licensed therapies are currently lacking, and until recently novel efficacious therapies for the treatment of chronic cough have remained elusive. In recent years, a first in class P2X3 antagonist has been found to be efficacious in patients with refractory chronic cough, stimulating much interest in the development of therapies for this problem. The aim of this review is to summarize the current state of development of novel therapies acting both in the peripheral and central nervous systems. Most programs are focused on treating patients with refractory chronic cough, but chronic coughing is also a problem in common respiratory diseases in spite of standard care. However, unraveling of the pathophysiological mechanisms underlying cough will ultimately be needed to identify the relevant drug targets, better characterize patients, and match them to the most appropriate treatments.


Assuntos
Antitussígenos , Tosse , Doença Crônica , Sistemas de Liberação de Medicamentos , Humanos , Qualidade de Vida
8.
Molecules ; 24(13)2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31247960

RESUMO

Natural products play an important role in drug discovery. This work employed a natural product 1-methylhydantoin as the lead compound to develop novel dual-active drugs. 1-Methylhydantoin was isolated from Oviductus Ranae, which is a traditional Chinese medicine that has been used for tussive and inflammation treatment for a long time. An in silico study screened the more active 1-methylhydantoin derivatives. Antitussive assessment indicated that the newly synthesized agent had similar bioactivity with the natural product. An anti-inflammatory model used xylene induced ear edema model. At the same dosage (100 mg/Kg), the newly prepared agent had an inhibition rate 53.18% which was much higher than that of the lead compound (22.69%). The results might be ascribed to the cyclooxygenases-1 (COX-1) and cyclooxygenases-2 (COX-2) selectivity, and the fitness of the compound, and the binding pocket. The anti-particulate matter (PM 2.5) acute pneumonia was evaluated through an in vivo model constructed by nasal instillation with PM 2.5 suspension. The results of the above models suggested that this novel agent had remarkable antitussive, anti-inflammatory, and anti-PM 2.5 acute pneumonia activities.


Assuntos
Anti-Inflamatórios/farmacologia , Antitussígenos/farmacologia , Produtos Biológicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Hidantoínas/farmacologia , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Antitussígenos/síntese química , Antitussígenos/química , Produtos Biológicos/química , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Desenho de Fármacos , Medicamentos de Ervas Chinesas/síntese química , Medicamentos de Ervas Chinesas/química , Hidantoínas/síntese química , Hidantoínas/química , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade
9.
Spectrochim Acta A Mol Biomol Spectrosc ; 222: 117186, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31176152

RESUMO

Pentoxyverine citrate (PEN-citrate) is an antitussive (cough suppressant) drug used for cough associated with illnesses like common cold. In this work, PEN-citrate is quantified by applying a simple, direct and accurate spectrophotometric method in pure form, pharmaceutical formulation (Cabella®, 2.13 mg/mL) and human serum samples. The formation of a stable yellow ion-pair with sulfonephthalein dyes; bromocresol green (BCG), bromophenol blue (BPB), bromothymol blue (BTB), bromocresol purple (BCP), bromochlorophenol blue (BChPB) and bromoxylenol blue (BXB), in three nonpolar solvents (chloroform, dichloromethane, acetonitrile) is used as the basis for this method. This is the first assay method reported for the quantification of PEN-citrate using the sulfonephthaleins as coloring agents. Diverse parameters were investigated in order to optimize the calibration curve conditions. The strategy was validated with respect to linearity range, precision, accuracy, specificity, robustness and limits of detection (LOD) and quantification (LOQ). In addition, solvents of different polarities were utilized to investigate the color reaction, light absorption and to allow for increasing the method sensitivity. Beer's law is obeyed over a wide concentration range (up to 42.05 µg/mL in case of BTB method). LOD and LOQ values reached 0.22 and 0.72 µg/mL, respectively, upon using BChPB. The relative standard deviation (%RSD) was ≤1.91% while correlation coefficient values (r) were ≥ 0.9974. High molar absorptivity values and low values of Sandell's sensitivity were obtained indicating that the proposed methods are highly sensitive. The validated methods were applied to the analysis of PEN-citrate in the dosage form and human serum samples where the drug was successfully resolved from the pharmaceutical additives and serum components with recoveries ≥98.98%.


Assuntos
Antitussígenos/sangue , Corantes/química , Ciclopentanos/sangue , Fenolsulfonaftaleína/química , Antitussígenos/análise , Ciclopentanos/análise , Humanos , Limite de Detecção , Solventes , Espectrofotometria/métodos , Comprimidos
10.
BMJ Open ; 9(5): e028159, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31101700

RESUMO

INTRODUCTION: Despite the frequent use of therapies in acute bronchitis, the evidence of their benefit is lacking, since only a few clinical trials have been published, with low sample sizes, poor methodological quality and mainly in children. The objective of this study is to compare the effectiveness of three symptomatic therapies (dextromethorphan, ipratropium or honey) associated with usual care and the usual care in adults with acute bronchitis. METHODS AND ANALYSIS: This will be a multicentre, pragmatic, parallel group, open randomised trial. Patients aged 18 or over with uncomplicated acute bronchitis, with cough for less than 3 weeks as the main symptom, scoring ≥4 in either daytime or nocturnal cough on a 7-point Likert scale, will be randomised to one of the following four groups: usual care, dextromethorphan 30 mg three times a day, ipratropium bromide inhaler 20 µg two puffs three times a day or honey 30 mg (a spoonful) three times a day, all taken for up to 14 days. The exclusion criteria will be pneumonia, criteria for hospital admission, pregnancy or lactation, concomitant pulmonary disease, associated significant comorbidity, allergy, intolerance or contraindication to any of the study drugs or admitted to a long-term residence. SAMPLE: 668 patients. The primary outcome will be the number of days with moderate-to-severe cough. All patients will be given a paper-based symptom diary to be self-administered. A second visit will be scheduled at day 2 or 3 for assessing evolution, with two more visits at days 15 and 29 for clinical assessment, evaluation of adverse effects, re-attendance and complications. Patients still with symptoms at day 29 will be called 6 weeks after the baseline visit. ETHICS AND DISSEMINATION: The study has been approved by the Ethical Board of IDIAP Jordi Gol (reference number: AC18/002). The findings of this trial will be disseminated through research conferences and peer-review journals. TRIAL REGISTRATION NUMBER: NCT03738917; Pre-results.


Assuntos
Antibacterianos/uso terapêutico , Antitussígenos/uso terapêutico , Bronquite/tratamento farmacológico , Antagonistas Colinérgicos/uso terapêutico , Dextrometorfano/uso terapêutico , Mel , Ipratrópio/uso terapêutico , Adulto , Tosse/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
11.
Am J Case Rep ; 20: 640-642, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31048669

RESUMO

BACKGROUND Benzonatate is one of the most widely prescribed nonnarcotic antitussives to relieve cough symptoms. As a structurally similar agent to other local anesthetics, including tetracaine and procaine, the risk to the public is not fully appreciated. CASE REPORT A 37-year-old female presented to the Emergency Department (ED) status post cardiac arrest. Advanced cardiac life support (ACLS) protocol was performed, and return of spontaneous circulation (ROSC) was achieved. Total downtime was 30 minutes. The patient was intubated, sedated, and hypothermia protocol was initiated. The patient developed bradyarrhythmia and mild coagulopathy suspicious for disseminated intravascular coagulation (DIC), thus hypothermia protocol was terminated later. A review of laboratory data showed acidosis with pH of 6.87, mixed acidosis secondary to high anion gap metabolic and respiratory acidosis with elevated liver enzymes. It was reported that approximately 2 hours prior to her presentation; the patient had ingested less than 30 pills of benzonatate 200 mg capsules with alcohol. CONCLUSIONS Ingestion of benzonatate, a widely prescribed antitussive, may pose a risk to patients due to the potential for rapid development of life-threatening adverse events and limited treatment options in the overdose setting, not only in children but also in adults. Rational prescribing and patient education are needed.


Assuntos
Antitussígenos/efeitos adversos , Butilaminas/efeitos adversos , Parada Cardíaca/induzido quimicamente , Acidose/induzido quimicamente , Adulto , Overdose de Drogas , Feminino , Humanos
12.
J Pharm Biomed Anal ; 173: 134-143, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31129533

RESUMO

Benzonatate has been used as a non-narcotic oral antitussive drug for many years. Its pharmacokinetics has never been reported due to the technical difficulties in detecting benzonatate by mass spectrometry. However, its concentration can be extrapolated based on the concentration of its metabolite, 4-(butylamino)benzoic acid (BBA). In this study, two sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) methods were developed and fully validated for the determination of the original 4-(butylamino)benzoic acid (method B) and total 4-(butylamino)benzoic acid (containing the original 4-(butylamino)benzoic acid and 4-(butylamino)benzoic acid converted from benzonatate after collection, method A). For both methods, one-step protein precipitation by methanol was performed to extract analytes from the plasma samples. Chromatographic separation was done on an InfinityLab Poroshell 120 Phenyl Hexyl column (2.1 mm × 50 mm, 2.7 µm, Agilent) with initial mobile phase consisting of 5 mM ammonium acetate containing 0.3% formic acid and acetonitrile (60:40, v/v) at a flow rate of 0.3 mL/min. Quantification was achieved by multiple reaction monitoring (MRM) in electron spray ionization (ESI) positive mode with the transitions of m/z 194.2 → 138.1 and 515.3 → 497.3 for 4-(butylamino)benzoic acid and telmisartan (the internal standard), respectively. The two methods exhibited good linearity over the concentration range of 10-10000 ng/mL. Both of the methods were successfully applied to the preliminary pharmacokinetic study in healthy Chinese volunteers after oral administration of benzonatate soft capsule at a single dose of 100 mg. The results showed that 4-(butylamino)benzoic acid and benzonatate were rapidly absorbed and reached a maximum concentration (Cmax) of 1708 ±â€¯457 ng/mL and 1063 ±â€¯460 ng/mL, respectively. The half-life (t1/2) were 1.32 ±â€¯0.29 h for 4-(butylamino)benzoic acid and 1.01 ±â€¯0.41 h for benzonatate. The area under the curve from 0 h to 10 h (AUC0-10) for 4-(butylamino)benzoic acid and benzonatate were 2103 ±â€¯918 ng/mL·h and 1097 ±â€¯559 ng/mL·h, respectively. And the data was valuable for further clinical study.


Assuntos
Antitussígenos/farmacocinética , Butilaminas/farmacocinética , Espectrometria de Massas em Tandem/métodos , para-Aminobenzoatos/sangue , Administração Oral , Antitussígenos/administração & dosagem , Antitussígenos/sangue , Butilaminas/administração & dosagem , Butilaminas/sangue , Cromatografia Líquida de Alta Pressão/métodos , Estabilidade de Medicamentos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Reprodutibilidade dos Testes , para-Aminobenzoatos/metabolismo
13.
J Ethnopharmacol ; 239: 111915, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31039428

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Adenophora triphylla var. japonica is frequently used as an oriental medicinal plant in Korea, China, and Japan for its anti-inflammatory, antitussive, and hepatoprotective effects. AIM OF THE STUDY: In the present study, the antitussive, expectorant, and anti-inflammatory effects of AR powder were investigated using animal models to evaluate their potential to treat respiratory disorders. MATERIALS AND METHODS: AR powder was administered orally to mice once daily for 11 days, at dose levels of 400, 200, and 100 mg/kg. Theobromine (TB), ambroxol (AM) and dexamethasone (DEXA) were used as standard drugs for antitussive effects, expectorant effects and anti-inflammatory effects, respectively. Evaluations of antitussive effects were based on changes in body weight, the number of cough responses and the histopathology of the lung and trachea. Expectorant effects were based on changes in the body weight, macroscopic observations of body surface redness, the mucous secretion of the trachea and histopathology of lung (secondary bronchus). Anti-inflammatory effects were based on changes in the body weight, macroscopic observations involving redness and edema of the treated ear, absolute and relative ear weights and histopathology of the treated ears. RESULTS: Allergic acute inflammation and coughing induced by exposure to NH4OH and symptoms of xylene-induced contact dermatitis were significantly inhibited by treatment with AR powder in a dose-dependent manner. Histological analyses revealed that AR powder decreased the OD values in trachea lavage fluid, reduced body surface redness, thicknesses of intrapulmonary secondary bronchus mucosa, and the number of PAS-positive mucous producing cells. Overall, AR powder administered at 200 mg/kg displayed superior antitussive and expectorant effects as compared to TB (50 mg/kg), and AM (250 mg/kg). At the highest concentration (400 mg/kg) AR powder displayed only moderately improved anti-inflammatory activities as compared to DEXA (1 mg/kg). CONCLUSION: The results obtained in this study suggest that AR powder exerts dose-dependent, favorable antitussive, expectorant, and anti-inflammatory activities achieved through modulation of the activity of mast cells and respiratory mucous production. Therefore, AR powder may serve as a therapeutic agent in various respiratory disorders, especially those that occur as a result of environmental toxicants.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antitussígenos/uso terapêutico , Campanulaceae , Tosse/tratamento farmacológico , Dermatite de Contato/tratamento farmacológico , Expectorantes/uso terapêutico , Hidróxido de Amônia , Animais , Tosse/induzido quimicamente , Tosse/metabolismo , Tosse/patologia , Dermatite de Contato/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos Endogâmicos ICR , Muco/efeitos dos fármacos , Muco/metabolismo , Raízes de Plantas , Pós , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Pele/efeitos dos fármacos , Pele/patologia , Traqueia/efeitos dos fármacos , Traqueia/patologia , Xilenos
14.
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
15.
J Chromatogr Sci ; 57(6): 552-559, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30994883

RESUMO

Two sensitive chromatographic methods have been developed, and validated for chlorpheniramine maleate (CM), phenylephrine (PE) and guaifenesin (GF) determination in their mixture and in presence of GF related substance guaiacol (GL) and preservative namely; sodium benzoate (NaB). The first method was based on thin layer chromatographic separation (TLC) followed by densitometric determination of the separated spots. The separation was achieved using silica gel 60 F254 TLC plates and ethyl acetate: methanol: toluene: ammonia (7:1.5:1:0.5, by volume) as a developing system. Densitometric quantification of the three drugs was carried by the reflectance mode at 270 nm. The second method was based on the use of high-performance liquid chromatography with diode array detection, by which the proposed components were separated on a reversed phase C18 analytical column using phosphate buffer pH 2.9 (containing 0.1 g Heptane-1-sulphonic acid sodium salt) and acetonitrile (85:15, v/v) at 0.8 mL/min for 4 minutes then 1 mL/min till end of the run using flow rate online switching technique. Both methods were validated according to the ICH guidelines and successfully applied for the determination of CM, PE, and GF in pure powder and in combined cough syrup without interference from the excipients.


Assuntos
Antitussígenos/análise , Clorfeniramina/análise , Guaiacol/análise , Guaifenesina/análise , Fenilefrina/análise , Antitussígenos/química , Clorfeniramina/química , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia em Camada Delgada/métodos , Densitometria , Guaiacol/química , Guaifenesina/química , Modelos Lineares , Fenilefrina/química , Conservantes Farmacêuticos/química , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
17.
Pulm Pharmacol Ther ; 56: 15-19, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30872160

RESUMO

Activation of vagal C-fibers is likely involved in some types of pathological coughing, especially coughing that is associated with airway inflammation. This is because stimulation of vagal C-fibers leads to strong urge to cough sensations, and because C-fiber terminals can be strongly activated by mediators associated with airway inflammation. The most direct manner in which a given mediator can activate a C-fiber terminal is through interacting with its receptor expressed in the terminal membrane. The agonist-receptor interaction then must lead to the opening (or potentially closing) of ion channels that lead to a membrane depolarization. This depolarization is referred to as a generator potential. If, and only if, the generator potential reaches the voltage necessary to activate voltage-gated sodium channels, action potentials are initiated and conducted to the central terminals within the CNS. Therefore, there are three target areas to block the inflammatory mediator induced activation of C-fiber terminals. First, at the level of the mediator-receptor interaction, secondly at the level of the generator potential, and third at the level of the voltage-gated sodium channels. Here we provide a brief overview of each of these therapeutic strategies.


Assuntos
Antitussígenos/farmacologia , Tosse/tratamento farmacológico , Fibras Nervosas Amielínicas/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Tosse/fisiopatologia , Humanos , Fibras Nervosas Amielínicas/metabolismo , Nervo Vago/metabolismo , Canais de Sódio Disparados por Voltagem/efeitos dos fármacos , Canais de Sódio Disparados por Voltagem/metabolismo
18.
Pulm Pharmacol Ther ; 56: 79-85, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30872161

RESUMO

Cough is a protective reflex that serves to clear the airways of excessive secretions and foreign matter and which sometimes becomes excessive, and troublesome to patients. Cough is one of the most common reasons why individuals seek medical attention. A range of drugs have been developed in the past with antitussive activity and different mechanisms of action, but there are still very few safe and effective treatments available. The poor tolerability of most available antitussives is closely related to their action on the central nervous system (CNS). An international group of experts specialized in cough met to discuss the need to identify an effective antitussive treatment with a good tolerability profile. The aim of this expert review is to increase the knowledge about the cough mechanism and the activity of levodropropizine, a peripherally acting antitussive drug.


Assuntos
Antitussígenos/administração & dosagem , Tosse/tratamento farmacológico , Propilenoglicóis/administração & dosagem , Animais , Antitussígenos/efeitos adversos , Antitussígenos/farmacologia , Tosse/fisiopatologia , Desenvolvimento de Medicamentos , Humanos , Propilenoglicóis/efeitos adversos , Propilenoglicóis/farmacologia
19.
Pulm Pharmacol Ther ; 56: 56-62, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30902655

RESUMO

BLU-5937 is a small molecule that was shown to be a potent, selective and non-competitive P2X3 homotrimeric receptor antagonist. P2X3 receptors are ATP ion-gated channels located on primary afferent neurons. ATP released from damaged or inflamed tissues in the airways acts on P2X3 receptors of primary afferent neurons, triggering depolarization and action potentials that are transmitted centrally and interpreted as urge to cough. There are strong preclinical and clinical evidence supporting the role of P2X3 receptors in hypersensitization of the cough reflex, leading to chronic cough. By inhibiting P2X3 receptors on the primary sensory neurons, BLU-5937 would inhibit the hypersensitization of the cough reflex and, hence, the exaggerated cough experienced in chronic cough patients. BLU-5937 is being developed for the treatment of unexplained, refractory chronic cough. The high potency and selectivity of BLU-5937 for P2X3 homotrimeric receptors was demonstrated in vitro by inhibiting αß-meATP-evoked P2X3 or P2X2/3 receptor activity in cloned human hP2X3 and hP2X2/3 channels expressed in mammalian cells. The IC50 of BLU-5937 for hP2X3 homotrimeric and hP2X2/3 heterotrimeric receptors was established at 25 nM and >24 µM, respectively. Furthermore, BLU-5937 (500 nM) was able to block αß-meATP-induced sensitization and firing activity of isolated primary nociceptors in rat dorsal root ganglions (DRGs), through P2X3 homotrimeric receptor antagonism. In a guinea pig cough model, BLU-5937 (0.3, 3 and 30 mg/kg, oral) significantly reduced, in a dose-dependent fashion, the histamine-induced enhancement in the number of citric acid-induced coughs. BLU-5937 (3 and 30 mg/kg, oral) was also shown to reduce significantly and dose-dependently the ATP-induced enhancement of citric acid-induced coughs in the guinea pig. These anti-tussive effects were obtained at a plasma concentration known to block P2X3 homotrimeric receptors, but at concentration 50-fold lower than that required to block P2X2/3 heterotrimeric receptors. These results indicate that the anti-tussive effect of BLU-5937 is primarily mediated through the inhibition of P2X3 homotrimeric receptors. In a rat behavioral taste model, BLU-5937 (10-20 mg/kg, IP) did not alter taste perception as compared to control animals. In the same experiment, N-00588 (10-20 mg/kg, IP), a weakly selective antagonist for P2X3 versus P2X2/3 receptors, had a significant inhibitory effect on taste perception. Pharmacokinetic analysis of drug plasma concentrations showed that BLU-5937 did not affect taste function at concentrations up to 30 times the IC50 for P2X3. These results suggest that N-00588 achieved systemic concentration that blocked P2X3 and P2X2/3 receptors expressed on gustatory nerve ending innervating taste buds. The lack of effect of BLU-5937, even at high doses, on taste perception may be attributed to its higher selectivity for the P2X3 versus P2X2/3 receptors on the taste buds. The safety, tolerability and pharmacokinetic profile of BLU-5937 was assessed in a battery of preclinical studies and have revealed that BLU-5937 exhibits excellent drug-like characteristics, including good oral bioavailability, low predicted clearance in human, no blood-brain barrier permeability and high safety margin versus human predicted efficacious exposure. BLU-5937 is currently in clinical phase I development stage. In conclusion, BLU-5937 was selected as a drug candidate for the treatment of chronic cough due to its high potency and selectivity for P2X3 homotrimeric receptors, strong anti-tussive effects, excellent tolerability and predicted pharmacokinetic properties in humans.


Assuntos
Antitussígenos/administração & dosagem , Tosse/tratamento farmacológico , Imidazóis/administração & dosagem , Piperidinas/administração & dosagem , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Piridinas/administração & dosagem , Receptores Purinérgicos P2X3/efeitos dos fármacos , Animais , Antitussígenos/efeitos adversos , Antitussígenos/farmacologia , Doença Crônica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Cobaias , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacologia , Concentração Inibidora 50 , Masculino , Piperidinas/efeitos adversos , Piperidinas/farmacologia , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Antagonistas do Receptor Purinérgico P2X/farmacologia , Piridinas/efeitos adversos , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P2X3/metabolismo , Percepção Gustatória/efeitos dos fármacos
20.
Pulm Pharmacol Ther ; 56: 75-78, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30880151

RESUMO

Chronic cough, or cough lasting >8 weeks, is often associated with underlying medical conditions (ie, asthma, gastroesophageal reflux disease, nonasthmatic eosinophilic bronchitis, and upper-airway cough syndrome). In some patients with chronic cough, treatment of these underlying conditions does not resolve the cough (refractory chronic cough [RCC]), or none of these conditions are present (unexplained chronic cough [UCC]). Despite appropriate medical evaluation, patients with RCC or UCC frequently experience cough persisting for many years, as there are currently no targeted pharmacological approaches approved for the treatment of these conditions. However, the adenosine triphosphate (ATP)-gated P2X3 receptor, a key modulator of the activation of sensory neurons central to the cough reflex, has recently garnered attention as a potential therapeutic target for the treatment of chronic cough. Gefapixant, a first-in-class, non-narcotic, selective antagonist of the P2X3 receptor, recently demonstrated efficacy and was generally well tolerated in phase 2 clinical trials in patients with RCC, validating the utility of targeting this receptor in patients with chronic cough. On the basis of these data, 2 global phase 3 trials, with combined anticipated enrolment exceeding 2000 patients and with treatment durations of up to 1 year, have been initiated. Together, these trials will further evaluate efficacy and safety of gefapixant in the control of cough in patients with RCC or UCC.


Assuntos
Tosse/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Animais , Antitussígenos/efeitos adversos , Antitussígenos/farmacologia , Doença Crônica , Tosse/etiologia , Tosse/fisiopatologia , Humanos , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Pirimidinas/efeitos adversos , Receptores Purinérgicos P2X3/efeitos dos fármacos , Receptores Purinérgicos P2X3/metabolismo , Sulfonamidas/efeitos adversos
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