Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 326
Filtrar
1.
Cardiovasc Pathol ; 44: 107154, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31760242

RESUMO

Although the cause of eosinophilic coronary periarteritis (ECPA) remains unclear, an allergic background is present in fewer patients than expected. A 50-year-old man with no history of allergy or symptoms suggestive of cardiac or respiratory disorders suddenly died shortly after oral administration of loxoprofen sodium. Autopsy showed eosinophilic coronary periarteritis in three main branches of the coronary arteries, characterized by eosinophil-predominant inflammation without fibrinoid necrosis or granulomatous change in the adventitia and its surroundings of the three main branches of the coronary arteries, in addition to the localized sign of bronchial asthma in the lung. Immunohistochemical examination showed that many mast cells positive for human mast cell tryptase were evident in the perivascular tissue containing peripheral nerve trunks. Whereas the blood concentration of loxoprofen sodium was within the therapeutic range, significant elevation of the serum histamine and tryptase levels was found. The present case suggests that eosinophilic coronary periarteritis may be caused by a type I allergic reaction in some patients and that loxoprofen sodium can trigger a life-threatening type I allergic reaction, including eosinophilic coronary periarteritis, leading to sudden unexpected death.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Doença da Artéria Coronariana/induzido quimicamente , Vasos Coronários/efeitos dos fármacos , Morte Súbita Cardíaca/etiologia , Hipersensibilidade a Drogas/etiologia , Eosinofilia/induzido quimicamente , Fenilpropionatos/efeitos adversos , Dor de Ombro/tratamento farmacológico , Autopsia , Causas de Morte , Doença da Artéria Coronariana/imunologia , Doença da Artéria Coronariana/patologia , Vasos Coronários/imunologia , Vasos Coronários/patologia , Morte Súbita Cardíaca/patologia , Hipersensibilidade a Drogas/imunologia , Hipersensibilidade a Drogas/patologia , Eosinofilia/imunologia , Eosinofilia/patologia , Evolução Fatal , Humanos , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/patologia , Pessoa de Meia-Idade
2.
Phytomedicine ; 65: 153102, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31654989

RESUMO

BACKGROUND: Euphorbia factor L1 (EFL1) is a lathyrane-type diterpenoid from the medicinal herb Euphorbia lathyris L., and has been reported with intestinal toxicity, but the potential mechanisms remain unknown. PURPOSE: The objective of this study was to investigate the intestinal toxicity of EFL1 and the underlying mechanisms using nematode Caenorhabditis elegans. METHODS: C. elegans were exposed to 0-200 µM EFL1 for 72 h, then the survival rate, body length and body width, locomotion and chemoreception behavior, intestinal ROS and lipofuscin accumulation, intestinal permeability, and defecation rhythm were detected. The γ-aminobutyric acid(GABA) energic neurons AVL and DVB were shown via green fluorescent protein under a laser scanning confocal microscope. The structure of GABA transporter UNC-47 were predicted by homology modeling, and the interaction between EFL1 and UNC-47 was simulated by molecular docking. The mRNA expression of genes related to oxidative stress, intestinal permeability and defecation after EFL1 exposure were detected by RT-qPCR. RESULTS: EFL1 did not induce lethality of nematodes. The general toxicity was characterized by abnormal growth, locomotion and chemoreception. The intestinal barrier was leaky, due to down-regulated cell junction and active cation transport. The mean defecation cycle length in nematodes was decreased, relating to disorder vesicular and ion transport, enhanced rhythm behavior and muscle contraction. The dysfunctional defecation also attributed to injured UNC-47 protein, as well as GABAergic neurons AVL and DVB. Excessive ROS and lipofuscin accumulation were observed in intestine, along with activation of antioxidant enzymes of SOD, COQ7 and CAT. CONCLUSION: This study elucidated the EFL1-induced intestinal toxicity in nematodes, characterized as leaky intestinal barrier and accelerated defecation behavior. The underlying mechanisms were involved in oxidative stress, cell junctions, transportation, rhythm behavior, muscle contraction, and GABAergic neurons.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Defecação/efeitos dos fármacos , Diterpenos/efeitos adversos , Intestinos/efeitos dos fármacos , Fenilpropionatos/efeitos adversos , Animais , Animais Geneticamente Modificados , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans/química , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Diterpenos/química , Regulação da Expressão Gênica , Absorção Intestinal/efeitos dos fármacos , Intestinos/patologia , Simulação de Acoplamento Molecular , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fenilpropionatos/química , Espécies Reativas de Oxigênio/metabolismo , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/química , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismo
4.
Environ Mol Mutagen ; 60(9): 830-836, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31454112

RESUMO

Ortho-phenylphenol (OPP), as an active ingredient of disinfectants, has been worldwide utilized as fungicides and antibacterial agents in hospital, agriculture, wood preservation, and veterinary products. However, little is known about the toxic effects of OPP on male reproduction, especially sperm motility, and the underlying mechanisms. In this study, we chose porcine sperms as in vitro model to investigate the effects and mechanisms of OPP exposure on sperm motility. Our results indicated that porcine sperm motility decreases significantly in a dose-dependent manner after exposed to OPP. Additionally, ATP synthesis deficiency was revealed by downregulation of ATP synthase subunit beta and adenosine 5'-monophosphate-activated protein kinase expression. Furthermore, OPP disturbed the expression of TP53 and PTEN, which contributed to AKT pathway deactivation. OPP exposure also disrupted platelet-derived growth factor receptor A expression, which further inhibited 3-phosphoinositide-dependent protein kinase 1 activation, resulting in protein kinase B and pyruvate dehydrogenase phosphatase catalytic subunit 1 deactivation. In conclusion, these observations suggest that OPP exposure decreases porcine sperm motility by disturbing the AMPK/AKT signaling pathway. Environ. Mol. Mutagen. 2019. © 2019 Wiley Periodicals, Inc.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Fenilpropionatos/efeitos adversos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Motilidade Espermática/efeitos dos fármacos , Adenosina Trifosfatases/metabolismo , Animais , Compostos de Bifenilo/efeitos adversos , Domínio Catalítico/efeitos dos fármacos , Desinfetantes/efeitos adversos , Regulação para Baixo/efeitos dos fármacos , Fungicidas Industriais/efeitos adversos , Masculino , PTEN Fosfo-Hidrolase/metabolismo , Suínos
5.
Cardiovasc Diabetol ; 18(1): 80, 2019 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-31208414

RESUMO

BACKGROUND: Saroglitazar, a novel dual peroxisome proliferator activated receptor (PPAR) agonist, in clinical trials, has shown an improvement in lipid and glycemic parameters through the PPAR-α and γ agonist actions, respectively. It was granted marketing authorization in India in 2013 for diabetic dyslipidemia. This review was conducted to summarize the effects of Saroglitazar in patients with diabetic dyslipidemia in real world clinical studies conducted after marketing authorization in India. METHODS: In this review, we selected real world clinical studies of Saroglitazar published as manuscripts and abstracts presented at scientific conferences. In all these studies, patients with diabetic dyslipidemia were treated with Saroglitazar 4 mg once daily for at least 12 weeks and different lipid and glycemic parameters were measured at the baseline and end of the study. RESULTS: In 18 selected studies (5 published manuscripts and 13 abstracts), a total of 5824 patients with diabetic dyslipidemia were prescribed Saroglitazar 4 mg for a duration ranging from 12 to 58 weeks. Across all the studies, mean age of patients ranged from 49.6 to 59.1 years and the proportion of female patients ranged from 22% to 42%. Across all the studies, there was a consistent mean reduction in triglyceride levels (~ 45% to 62%), total cholesterol levels (~ 17% to 26%), non-high-density lipoprotein cholesterol levels (~ 21% to 36%), low-density lipoprotein cholesterol levels (~ 11% to 27%), and glycosylated hemoglobin levels (~ 0.7% to 1.6%) with an increase in mean high-density lipoprotein cholesterol levels (up to 9%) from baseline to end of the study. Saroglitazar also improved alanine aminotransferase levels and fatty liver (evaluated by FibroScan™) in non-alcoholic fatty liver disease patients with diabetic dyslipidemia. Body weight remained unchanged and no significant adverse events (AEs) were reported in the studies. CONCLUSION: Saroglitazar effectively improved lipid and glycemic parameters without significant AEs in patients with diabetic dyslipidemia in real-world clinical studies of up to 58 weeks duration.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Hipolipemiantes/uso terapêutico , Lipídeos/sangue , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , PPAR alfa/agonistas , PPAR gama/agonistas , Fenilpropionatos/uso terapêutico , Pirróis/uso terapêutico , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Hipolipemiantes/efeitos adversos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , PPAR alfa/metabolismo , PPAR gama/metabolismo , Fenilpropionatos/efeitos adversos , Pirróis/efeitos adversos , Transdução de Sinais , Fatores de Tempo , Resultado do Tratamento
6.
Clin Ther ; 41(6): 1110-1127, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060740

RESUMO

PURPOSE: Pulmonary arterial hypertension (PAH) is a life-threatening disease that typically causes shortness of breath and exercise intolerance. Combination therapy with ambrisentan and tadalafil has proven to be more effective at preventing clinical failure events in patients with PAH than either drug alone. The aim of this study was to evaluate the bioequivalence of an ambrisentan/tadalafil fixed-dose combination (FDC) compared with co-administration of the 2 monotherapies. METHODS: This 3-part, randomized, single-dose, open-label crossover study was conducted in healthy volunteers. The first part of the study consisted of a 5-way crossover that compared the relative bioavailability of 4 FDC formulations (10-mg ambrisentan + 40-mg tadalafil) with co-administered reference monotherapies. One formulation was selected and its relative bioavailability was assessed when produced in 3 different granulation sizes during the second part of the study. In the third part of the study, the bioequivalence of the candidate FDC with the reference monotherapies was evaluated for the 10-mg/40-mg dose strength, in addition to 2 other dose strengths (5 mg/20 mg and 5 mg/40 mg). For all parts of the study, blood samples were taken at regular intervals after each dose, ambrisentan and tadalafil concentrations determined, and pharmacokinetic (PK) parameters (Cmax, AUC0-∞, and AUC0-t) obtained. Test/reference ratios of the geometric means of PK parameters were used to evaluate bioequivalence. Safety and tolerability were assessed by recording adverse events and monitoring vital signs, ECGs, and clinical laboratory data. FINDINGS: Of the 174 subjects screened for eligibility, 112 were allocated to a randomized treatment sequence across all study parts, and 100 completed their full assigned treatments. All 4 FDC formulations tested during part 1 of the study yielded PK parameters similar those of the reference treatments. In part 2, granulation size was found to not affect the relative bioavailability of the selected formulation. In part 3, the selected FDC was found to be bioequivalent to co-administration of the monotherapies in both the fasted and fed states. The FDC was also found to be bioequivalent to the reference treatments at the 2 additional dose strengths. All but one of the adverse events was mild to moderate in intensity, and no serious adverse events were reported. IMPLICATIONS: An ambrisentan/tadalafil FDC was bioequivalent to concurrently administered monotherapies and therefore represents a viable alternative treatment to co-administration. Use of an FDC is likely to be associated with reduced costs and improved patient compliance. ClinicalTrials.gov identifier: NCT02688387.


Assuntos
Fenilpropionatos/farmacocinética , Piridazinas/farmacocinética , Tadalafila/farmacocinética , Disponibilidade Biológica , Estudos Cross-Over , Voluntários Saudáveis , Humanos , Fenilpropionatos/administração & dosagem , Fenilpropionatos/efeitos adversos , Fenilpropionatos/sangue , Piridazinas/administração & dosagem , Piridazinas/efeitos adversos , Piridazinas/sangue , Tadalafila/administração & dosagem , Tadalafila/efeitos adversos , Tadalafila/sangue , Equivalência Terapêutica
7.
Clin Drug Investig ; 39(4): 369-377, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30725315

RESUMO

BACKGROUND AND OBJECTIVE: Loxoprofen (LOX) is a nonsteroidal anti-inflammatory drug (NSAID). Although oral administration of LOX has been widely prescribed, clinical guidelines for osteoarthritis generally recommend topical rather than oral NSAIDs in specific patients. However, there is limited information on the effects of loxoprofen sodium oral (LOX-O) versus loxoprofen sodium hydrogel transdermal patch (LOX-T) in myalgia patients. Hence, this non-inferiority study was designed to compare the efficacy and safety of LOX-O versus LOX-T in Chinese patients with myalgia. METHODS: In this double-blind, double-dummy, parallel-group, randomized controlled trial, 182 Chinese patients were enrolled and randomized equally to either LOX-T or LOX-O treatment for 2 weeks. Patients in the LOX-T group applied one sheet of the active LOX-T once a day on the affected site and took one placebo tablet three times a day immediately after meals, whereas patients in the LOX-O group applied one sheet of the placebo patch once a day and took one active LOX-O three times a day. Primary endpoint was the proportion of patients with 50% overall improvement or higher at the final visit. The cutoff value of a non-inferiority difference was set as - 10%. RESULTS: In the full analysis set, the primary endpoint of final efficacy rate was 81.3% (n = 91) in the LOX-T group and 72.2% (n = 88) in the LOX-O group. The difference between the two groups was 9.1% [95% confidence interval (CI) - 3.1 to 21.3%], which showed that LOX-T was non-inferior compared with LOX-O. No serious adverse events occurred in either group. CONCLUSIONS: This trial showed the non-inferiority of LOX-T compared with LOX-O in efficacy and safety in Chinese patients with myalgia. Also, the characteristic features of topical LOX-T, such as better compliance and lower risk-benefit ratio, make it more favorable for clinical practice. TRIAL REGISTRATION: The study was registered in the isrctn.com registry (ISRCTN trial ID: ISRCTN16227145).


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Hidrogéis/administração & dosagem , Mialgia/tratamento farmacológico , Mialgia/epidemiologia , Fenilpropionatos/administração & dosagem , Adesivo Transdérmico , Administração Oral , Adulto , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , China/epidemiologia , Método Duplo-Cego , Feminino , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/epidemiologia , Humanos , Hidrogéis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mialgia/diagnóstico , Fenilpropionatos/efeitos adversos , Comprimidos , Adesivo Transdérmico/efeitos adversos , Resultado do Tratamento
8.
Curr Mol Pharmacol ; 12(3): 195-201, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30636619

RESUMO

BACKGROUND: Diabetes mellitus and concomitant dyslipidemia, being referred to as 'diabetic dyslipidemia', are the foremost detrimental factors documented to play a pivotal role in cardiovascular illness. Diabetic dyslipidemia is associated with insulin resistance, high plasma triglyceride levels, low HDL-cholesterol concentration and elevated small dense LDL-cholesterol particles. Maintaining an optimal glucose and lipid levels in patients afflicted with diabetic dyslipidemia could be a major task that might require a well-planned diet-management system and regular physical activity, or otherwise an intake of combined antidiabetic and antihyperlipidemic medications. Synchronized treatment which efficiently controls insulin resistance-associated diabetes mellitus and co-existing dyslipidemia could indeed be a fascinating therapeutic option in the management of diabetic dyslipidemia. Peroxisome proliferator-activated receptors α/γ (PPARα/γ) dual agonists are such kind of drugs which possess therapeutic potentials to treat diabetic dyslipidemia. Nevertheless, PPARα/γ dual agonists like muraglitazar, naveglitazar, tesaglitazar, ragaglitazar and aleglitazar have been reported to have undesirable adverse effects, and their developments have been halted at various stages. On the other hand, a recently introduced PPARα/γ dual agonist, saroglitazar is an emerging therapeutic agent of glitazar class approved in India for the management of diabetic dyslipidemia, and its treatment has been reported to be generally safe and well tolerated. CONCLUSION: Some additional and new compounds, at initial and preclinical stages, have been recently reported to possess PPARα/γ dual agonistic potentials with considerable therapeutic efficacy and reduced adverse profile. This review sheds light on the current status of various PPARα/γ dual agonists for the management of diabetic dyslipidemia.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Dislipidemias/complicações , Dislipidemias/tratamento farmacológico , PPAR alfa/agonistas , PPAR gama/agonistas , Fenilpropionatos/uso terapêutico , Pirróis/uso terapêutico , Gerenciamento Clínico , Humanos , Resistência à Insulina , Fenilpropionatos/efeitos adversos , Pirróis/efeitos adversos
9.
Dig Dis Sci ; 64(2): 401-408, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30377885

RESUMO

BACKGROUND: There is considerable individual variability in nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy. AIM: To identify the SNP that is most significantly involved with NSAID-induced enteropathy. METHODS: One hundred fifty human subjects who were known to have a certain degree of loxoprofen- or celecoxib-induced small-intestinal damage from a previous study were enrolled. The subjects were divided into groups based on treatments and also on the increased number of small intestinal mucosal breaks. The candidate SNP was selected by an initial analysis of GWAS among the groups in various combinations. After the initial analysis, the gene including the specified SNP was analyzed in detail using GWAS and genotype imputation. RESULTS: After analysis, 70 subjects receiving the loxoprofen treatment and 69 subjects receiving celecoxib treatment were determined to be eligible for the analysis. The minimum p value in GWAS was detected in the analysis of 16 cases with an increase of five or more mucosal breaks and 123 controls with zero to four mucosal breaks. In the GWAS, five SNPs in the bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) gene showed the lowest p value (p = 2.69 × 10-7 with an odds ratio of 40.9). Of the five SNPs, four were nonsynonymous SNPs (rs2070325: V268I, rs2889732: T320N, rs11699009: F527L, rs11696307: T533I, and rs11696310: intronic). Furthermore, 23 SNPs in BPIFB4 detected by genotype imputation based on the GWAS data also showed suggestive associations (p < 1 × 10-6). CONCLUSION: The results indicate that SNPs in BPIFB4 were associated with NSAID-induced small intestinal mucosal injury (UMIN: 000007936).


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Enteropatias/genética , Mucosa Intestinal/patologia , Intestino Delgado/patologia , Fosfoproteínas/genética , Adulto , Endoscopia por Cápsula , Celecoxib/efeitos adversos , Feminino , Estudo de Associação Genômica Ampla , Humanos , Enteropatias/induzido quimicamente , Enteropatias/patologia , Masculino , Pessoa de Meia-Idade , Fenilpropionatos/efeitos adversos , Polimorfismo de Nucleotídeo Único
10.
Pharmacoepidemiol Drug Saf ; 27(11): 1223-1230, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30232832

RESUMO

PURPOSE: The safety of nonsteroidal anti-inflammatory drugs (NSAIDs) commonly used in Asia-Pacific countries has had limited study. We assessed the risk of hospitalization for gastrointestinal events with loxoprofen and mefenamic acid compared with other NSAIDs in Asia-Pacific populations. METHODS: We conducted a cohort study using a distributed network with a common data model in Australia, Hong Kong, Japan, Korea, and Taiwan. We included patients who initiated diclofenac, loxoprofen, mefenamic acid, or celecoxib and followed them until their first gastrointestinal hospitalization, switch or discontinuation of medication, disenrollment, or end of database coverage. We used Cox proportional hazards models to assess hospitalization risk. RESULTS: We identified 9879 patients in Japan, 70 492 in Taiwan, 263 741 in Korea, and 246 in Hong Kong who initiated an NSAID, and 44 013 patients in Australia, a predominantly Caucasian population. The incidence of gastrointestinal hospitalization was 25.6 per 1000 person-years in Japan, 32.8 in Taiwan, 11.5 in Korea, 484.5 in Hong Kong, and 35.6 in Australia. Compared with diclofenac, the risk of gastrointestinal events with loxoprofen was significantly lower in Korea (hazards ratio, 0.37; 95% CI, 0.25-0.54) but not in Japan (1.65; 95% CI, 0.47-5.78). The risk of gastrointestinal events with mefenamic acid was significantly lower in Taiwan (0.45; 95% CI, 0.26-0.78) and Korea (0.11; 95% CI, 0.05-0.27) but not Hong Kong (2.16; 95% CI, 0.28-16.87), compared with diclofenac. CONCLUSIONS: Compared with diclofenac, loxoprofen was associated with a lower risk of gastrointestinal hospitalizations in Korea and mefenamic acid with a lower risk in Taiwan and Korea.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Celecoxib/efeitos adversos , Diclofenaco/efeitos adversos , Gastroenteropatias/epidemiologia , Ácido Mefenâmico/efeitos adversos , Fenilpropionatos/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Bases de Dados Factuais/estatística & dados numéricos , Feminino , Seguimentos , Gastroenteropatias/induzido quimicamente , Gastroenteropatias/terapia , Hong Kong/epidemiologia , Hospitalização/estatística & dados numéricos , Humanos , Incidência , Japão/epidemiologia , Masculino , República da Coreia/epidemiologia , Taiwan/epidemiologia
11.
J Int Med Res ; 46(6): 2466-2469, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29587554

RESUMO

A 37-year-old man suffered irreversible profound symptomatic bradycardia requiring a pacemaker 3 days after beginning tizanidine/loxoprofen combination therapy for neck pain. This combination therapy is prescribed frequently for joint pain; however, combining loxoprofen with tizanidine could increase the risk of symptomatic bradycardia that is both permanent and severe. Similar cases have not been reported. This case suggests that tizanidine should be used cautiously when combined with loxoprofen, and drug interaction screening should be performed.


Assuntos
Analgésicos/efeitos adversos , Bradicardia/terapia , Estimulação Cardíaca Artificial , Clonidina/análogos & derivados , Cervicalgia/tratamento farmacológico , Fenilpropionatos/efeitos adversos , Adulto , Analgésicos/uso terapêutico , Bloqueio Atrioventricular/induzido quimicamente , Bloqueio Atrioventricular/terapia , Bradicardia/induzido quimicamente , Clonidina/efeitos adversos , Clonidina/uso terapêutico , Quimioterapia Combinada , Humanos , Masculino , Fenilpropionatos/uso terapêutico
12.
Clin Drug Investig ; 38(3): 219-229, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29282676

RESUMO

BACKGROUND AND OBJECTIVE: Pulmonary arterial hypertension (PAH) is an intractable and rare disease and the accumulation of clinical evidence under real-world setting is needed. A post-marketing surveillance for the endothelin receptor antagonist ambrisentan (Volibris tablet) has been conducted by all-case investigation since September 2010. This paper is an interim report on the safety and efficacy of ambrisentan in 702 patients with PAH. METHODS: PAH patients aged 15 years or older were subjected to the analysis. The safety analysis by overall cases or stratification of patient backgrounds and the efficacy analysis were investigated. RESULTS: Regarding patient characteristics, the 702 patients subjected to safety analysis included 543 (77.4%) women and 546 (77.8%) patients at WHO functional class II/III. The mean observational time was 392.7 days. A total of 324 adverse drug reaction (ADR) occurred in 204 (29.1%) patients. Common ADRs (≥ 2%) included anemia (4.6%), peripheral edema (4.1%), headache (3.6%), edema and face edema (2.6% each), abnormal hepatic function (2.3%), and epistaxis (2.1%). There were 82 serious ADRs occurring in 44 (6.3%) patients (385 serious adverse events in 184 (26.2%) patients). Although 11 (1.6%) interstitial lung disease (ILD) cases were reported, all were observed in patients with disease that may contribute to ILD and therefore it is difficult to assess if ambrisentan was associated with these events. There was no difference in safety in relation to the presence/absence of connective tissue disease-related PAH (CTD-PAH) or combination therapy. Among 677 patients subjected to efficacy analysis, those in whom hemodynamic status was determined before and after treatment showed improvement in the mean pulmonary arterial pressure and pulmonary vascular resistance after treatment. CONCLUSION: The interim results showed safety consistent with the known profile of ambrisentan in terms of the types and frequencies of ADRs in patients with PAH in real clinical practice, in comparison with previous clinical trials in Japan and the rest of the world. Thus, these results provided another corroboration of the tolerability of ambrisentan and we continue to monitor proper use information via the post-marketing surveillance to ensure any new safety signals are identified in a timely manner (ClinTrial.gov: NCT01406327).


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/epidemiologia , Fenilpropionatos/uso terapêutico , Vigilância de Produtos Comercializados/métodos , Piridazinas/uso terapêutico , Relatório de Pesquisa , Adulto , Idoso , Anti-Hipertensivos/efeitos adversos , Edema/induzido quimicamente , Antagonistas dos Receptores de Endotelina/efeitos adversos , Antagonistas dos Receptores de Endotelina/uso terapêutico , Feminino , Seguimentos , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Fenilpropionatos/efeitos adversos , Piridazinas/efeitos adversos , Comprimidos , Resultado do Tratamento
13.
Rinsho Shinkeigaku ; 58(1): 25-29, 2018 Jan 26.
Artigo em Japonês | MEDLINE | ID: mdl-29269694

RESUMO

A 19-year-old woman developed high fever, headache, and nausea after taking Loxoprofen for pharyngitis, followed by disturbed consciousness and nuchal stiffness. The patient and her mother had a history of Raynaud's phenomenon. Cerebrospinal fluid (CSF) examination indicated a diagnosis of aseptic meningitis and revealed high levels of Q albumin and IgG index. Anti-RNP antibodies were positive in serum and CSF. Her symptoms disappeared immediately after cessation of Loxoprofen and a drug lymphocyte stimulation test was negative, confirming a diagnosis of non-steroidal anti-inflammatory drugs (NSAIDs)-induced aseptic meningitis. It should be kept in mind that an immune abnormality such as serum and CSF anti-RNP antibodies may play a role in development of NSAIDs-induced aseptic meningitis. A history of usage of NSAIDs and a thorough examination of collagen diseases are useful for identification of the origin of aseptic meningitis in a young woman.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/líquido cefalorraquidiano , Meningite Asséptica/diagnóstico , Meningite Asséptica/etiologia , Fenilpropionatos/efeitos adversos , Ribonucleoproteínas/imunologia , Acetaminofen/administração & dosagem , Adulto , Anti-Inflamatórios não Esteroides/administração & dosagem , Doenças Autoimunes/complicações , Doenças Autoimunes/diagnóstico , Autoimunidade , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Diagnóstico Diferencial , Substituição de Medicamentos , Feminino , Humanos , Resultado do Tratamento , Adulto Jovem
14.
Clin Pharmacol Ther ; 103(5): 888-898, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28857147

RESUMO

We hypothesized that concomitant pharmacological inhibition of the endothelin and adenosine pathway is safe and improves exercise performance in hypoxic humans, via a mechanism that does not involve augmentation of blood oxygenation. To test this hypothesis, we established safety and drug interactions for aminophylline (500 mg) plus ambrisentan (5 mg) in normoxic volunteers. Subsequently, a placebo-controlled study was employed to test the combination in healthy resting and exercising volunteers at simulated altitude (4,267 m). No serious adverse events occurred. Drug interaction was minimal or absent. Aminophylline alleviated hypoxia-induced headaches. Aminophylline, ambrisentan, and their combination all significantly (P < 0.05 vs. placebo) improved submaximal hypoxic exercise performance (19.5, 20.6, and 19.1% >placebo). Single-dose ambrisentan increased blood oxygenation in resting, hypoxic subjects. We conclude that combined aminophylline and ambrisentan offer promise to safely increase exercise capacity in hypoxemic humans without relying on increasing blood oxygen availability.


Assuntos
Aminofilina/efeitos adversos , Aminofilina/uso terapêutico , Endotelinas/efeitos dos fármacos , Exercício Físico/fisiologia , Hipóxia/tratamento farmacológico , Fenilpropionatos/efeitos adversos , Fenilpropionatos/uso terapêutico , Piridazinas/efeitos adversos , Piridazinas/uso terapêutico , Adenosina/metabolismo , Adolescente , Adulto , Altitude , Método Duplo-Cego , Quimioterapia Combinada/efeitos adversos , Endotelinas/metabolismo , Feminino , Humanos , Hipóxia/metabolismo , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Adulto Jovem
15.
Biochem Pharmacol ; 138: 96-106, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28461124

RESUMO

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) controls the expression of genes involved in the regulation of lipid and glucose metabolism, cell proliferation/differentiation as well as inflammatory pathways. Pivotal studies in human sebocytes and isolated sebaceous glands have raised the interesting possibility that compounds acting on PPARγ can modulate sebaceous lipids and inflammation and, as such, may be useful in the treatment of acne. To investigate the role of this receptor in the regulation of lipid synthesis, proliferation and inflammation, we used the SZ95 sebaceous gland cell line stimulated with insulin. In sebocytes, insulin signaling activated the phosphatidylinositide 3-kinase-Akt (PI3K/Akt) and mammalian target of rapamycin (mTOR) pathways, which, in turn, induced high protein/lipid synthesis, increased cell growth and proliferation as well as inflammation. As regards lipogenesis, insulin initially stimulated the formation of unsaturated lipids and then the neosynthesis of lipids. The results showed, that the modulation of PPARγ, counteracted the insulin-induced altered lipogenesis, evident through a decrease in gene expression of key enzymes responsible for the synthesis of fatty acids, and through a reduction of lipid species synthesis analyzed by Oil/Nile Red staining and GC-MS. PPARγ modulation also regulated the insulin-induced proliferation, inhibiting the cell cycle progression and p21WAF1/CIP1 (p21) protein reduction. Moreover, the expression of inflammatory cytokines, induced by insulin or lipopolysaccharide (LPS), was down-modulated. In PPARγ-deficient cells or in the presence of GW9662 antagonist, all these observed effects were abolished, indicating that PPARγ activation plays a role in regulating alteration of lipogenesis, cell proliferation and inflammatory signaling. We demonstrated that selective modulation of PPARγ activity is likely to represent a therapeutic strategy for the treatment of acne.


Assuntos
Regulação da Expressão Gênica , Lipogênese , PPAR gama/metabolismo , Glândulas Sebáceas/metabolismo , Sebo/metabolismo , Transdução de Sinais , Acetanilidas/efeitos adversos , Acetanilidas/farmacologia , Anilidas/efeitos adversos , Anilidas/farmacologia , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/agonistas , Citocinas/metabolismo , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipoglicemiantes/antagonistas & inibidores , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Antagonistas da Insulina/efeitos adversos , Antagonistas da Insulina/farmacologia , Lipogênese/efeitos dos fármacos , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/toxicidade , PPAR gama/agonistas , PPAR gama/antagonistas & inibidores , PPAR gama/genética , Fenilpropionatos/efeitos adversos , Fenilpropionatos/farmacologia , Interferência de RNA , Glândulas Sebáceas/citologia , Glândulas Sebáceas/efeitos dos fármacos , Glândulas Sebáceas/imunologia , Sebo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
16.
Ther Adv Respir Dis ; 11(6): 233-244, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28425346

RESUMO

Pulmonary arterial hypertension (PAH) is a progressive disease defined by an elevation in pulmonary arterial pressure that can lead to right heart failure and death. Ambrisentan is a selective endothelin receptor antagonist approved for the treatment of idiopathic, heritable PAH and connective tissue disease-associated PAH. Ambrisentan has been shown to improve exercise capacity and hemodynamics with an acceptable side-effect profile. It has also proven to be safely used in combination with other PAH-specific medications, especially with phosphodiesterase-5 inhibitors. In the recent randomized trial, AMBITION, it was shown that upfront combination therapy of ambrisentan and tadalafil significantly decreased the risk of clinical failure compared with monotherapy. This review describes the drug profile of ambrisentan and its safety and efficacy in the treatment of PAH.


Assuntos
Anti-Hipertensivos/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Fenilpropionatos/uso terapêutico , Piridazinas/uso terapêutico , Animais , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/efeitos adversos , Quimioterapia Combinada , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/fisiopatologia , Fenilpropionatos/administração & dosagem , Fenilpropionatos/efeitos adversos , Piridazinas/administração & dosagem , Piridazinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Tadalafila/administração & dosagem , Tadalafila/uso terapêutico
17.
Respir Med ; 126: 84-92, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28427554

RESUMO

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a condition which may lead to right ventricular failure and premature death. While recent data supports the initial combination of ambrisentan (a selective ERA) and tadalafil (a PDE5i) in functional class II or III patients, there is no published data describing the safety and efficacy of ambrisentan when added to patients currently receiving a PDE5i and exhibiting a suboptimal response. The ATHENA-1 study describes the safety and efficacy of the addition of ambrisentan in this patient population. METHODS: PAH patients with a suboptimal response to current PDE5i monotherapy were assigned ambrisentan in an open-label fashion and evaluated for up to 48 weeks. Cardiopulmonary hemodynamics (change in PVR as primary endpoint) were evaluated at week 24 and functional parameters and biomarkers were measured through week 48. Time to clinical worsening (TTCW) and survival are also described. RESULTS: Thirty-three subjects were included in the analysis. At week 24, statistically significant improvements in PVR (-32%), mPAP (-11%), and CI (+25%) were observed. Hemodynamic improvements at week 24 were further supported by improvements in the secondary endpoints: 6-min walk distance (+18 m), NT-proBNP (-31%), and maintenance or improvement in WHO FC in 97% of patients. Adverse events were consistent with known effects of ambrisentan. CONCLUSION: The hemodynamic, functional, and biomarker improvements observed in the ATHENA-1 study suggests that the sequential addition of ambrisentan to patients not having a satisfactory response to established PDE5i monotherapy is a reasonable option.


Assuntos
Quimioterapia Combinada/métodos , Hipertensão Pulmonar/tratamento farmacológico , Fenilpropionatos/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Piridazinas/farmacologia , Tadalafila/farmacologia , Adulto , Anti-Hipertensivos/uso terapêutico , Biomarcadores/metabolismo , Relação Dose-Resposta a Droga , Venenos Elapídicos , Antagonistas do Receptor de Endotelina A/uso terapêutico , Tolerância ao Exercício/efeitos dos fármacos , Feminino , Hemodinâmica/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/classificação , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Tipo C/efeitos dos fármacos , Avaliação de Resultados em Cuidados de Saúde , Fenilpropionatos/administração & dosagem , Fenilpropionatos/efeitos adversos , Piridazinas/administração & dosagem , Piridazinas/efeitos adversos , Sobrevida , Tadalafila/administração & dosagem , Resultado do Tratamento
18.
Clin Drug Investig ; 36(9): 771-781, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27444038

RESUMO

Loxoprofen (Loxonin(®), Loxonin(®) Pap, Loxonin(®) Tape) is a prodrug-type NSAID that is available in several formulations, including 60 mg tablets, 100 mg hydrogel patches and 50 or 100 mg tape. In active comparator-controlled trials, oral loxoprofen therapy (ranging from 2 days to 6 weeks' duration depending on the pain type) provided analgesic efficacy that generally did not significantly differ from that of celecoxib for postoperative pain or frozen shoulder, ibuprofen for knee osteoarthritis or naproxen for lumbar pain. In double-blind, double-dummy, multicentre trials, loxoprofen hydrogel patches were noninferior to oral loxoprofen with regard to rates of final overall symptomatic improvement over 1-4 weeks in patients with knee osteoarthritis, myalgia or trauma-induced swelling and pain. Loxoprofen hydrogel patches were also noninferior to other commercially available patches (ketoprofen and indometacin) over 2 or 4 weeks in patients with knee osteoarthritis or myalgia in open-label studies. Oral and topical loxoprofen were generally well tolerated in clinical trials. Thus, loxoprofen is a useful analgesic option for patients with pain and inflammation, with topical loxoprofen potentially reducing the risk of gastrointestinal, cardiovascular and renal complications associated with oral NSAID use.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Fenilpropionatos/uso terapêutico , Anti-Inflamatórios não Esteroides/efeitos adversos , Humanos , Fenilpropionatos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
19.
J Med Case Rep ; 10(1): 128, 2016 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-27225339

RESUMO

BACKGROUND: Loxoprofen is a nonsteroidal anti-inflammatory drug used in the treatment of many diseases. However, there are no case reports about loxoprofen-induced pneumonia. We have encountered a rare case of loxoprofen-induced pneumonia. CASE PRESENTATION: We report the case of a 71-year-old Japanese woman who was initially treated with loxoprofen for fever. She was admitted to our hospital because of worsening of her symptoms, including fever and dyspnea. Her symptoms improved after treatment with ceftriaxone. Seven days after admission, she again developed high fever. She was again treated with loxoprofen and levofloxacin. However, acute respiratory failure developed after initiation of loxoprofen treatment. Chest computed tomography showed peribronchovascular consolidation. She was diagnosed with loxoprofen-induced pneumonia for which she was administered steroids. After treatment, her dyspnea and radiological findings improved. CONCLUSIONS: The findings in this case report reveal an association between treatment with a nonsteroidal anti-inflammatory drug and pneumonia. This rare case was diagnosed after accidental retreatment with loxoprofen. This is the first report of loxoprofen-induced pneumonia.


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Fenilpropionatos/efeitos adversos , Idoso , Feminino , Humanos , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Radiografia Torácica , Tomografia Computadorizada por Raios X
20.
Biomed Res Int ; 2016: 3978010, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27006945

RESUMO

Although the anticonvulsant activity of 3-hydroxy-3-ethyl-3-phenylproionamide (HEPP) is well-known, its use is limited by the pharmacotoxicological profile. We herein tested its fluorinated and chlorinated derivatives (F-HEPP and Cl-HEPP) with two seizure models, maximal electroshock seizures (MES), and intraperitoneal pentylenetetrazole (PTZ) administration. Neurotoxicity was examined via the rotarod test. With in silico methods, binding was probed on possible protein targets-GABAA receptors and the sodium channel Nav1.2. The median effective doses (ED50) of HEPP, F-HEPP, and Cl-HEPP in the MES seizure model were 129.6, 87.1, and 62.0 mg/kg, respectively, and 66.4, 43.5, and in the PTZ seizure model 43.5 mg/kg. The HEPP-induced neurotoxic effect, which occurred at twice the ED50 against MES (p < 0.05), did not occur with F-HEPP or Cl-HEPP. Docking studies revealed that all tested ligands bound to GABAA receptors on a site near to the benzodiazepine binding site. However, on the sodium channel open pore Nav1.2, R-HEPP had interactions similar to those reported for phenytoin, while its enantiomer and the ligands F-HEPP and Cl-HEPP reached a site that could disrupt the passage of sodium. Our results show that, as anticonvulsant agents, parahalogen substituted compounds have an advantageous pharmacotoxicological profile compared to their precursor.


Assuntos
Anticonvulsivantes , Hidrocarbonetos Clorados , Hidrocarbonetos Fluorados , Fenilpropionatos , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Eletrochoque , Hidrocarbonetos Clorados/efeitos adversos , Hidrocarbonetos Clorados/farmacologia , Hidrocarbonetos Fluorados/efeitos adversos , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/farmacologia , Masculino , Camundongos , Simulação de Acoplamento Molecular , Canal de Sódio Disparado por Voltagem NAV1.2/metabolismo , Fenilpropionatos/efeitos adversos , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Convulsões/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA