RESUMO
BACKGROUND & AIMS: Pharmacologic agents targeting bile acid signaling show promise for treating nonalcoholic steatohepatitis (NASH). However, clinical findings suggest that new treatment strategies with enhanced therapeutic efficacy and minimized undesired effects are needed. This preclinical study investigates whether combining an apical sodium-bile acid transporter (ASBT) inhibitor GSK233072 (GSK672) and fibroblast growth factor-15 (FGF15) signaling activation improves anti-NASH efficacy. METHODS: Mice with high fat, cholesterol, and fructose (HFCFr) diet-induced NASH and stage 2 fibrosis are used as a NASH model. GSK672 or AAV8-TBG-FGF15 interventions are administered alone or in combination to HFCFr diet-fed mice. RESULTS: The combined treatment significantly enhances therapeutic efficacy against steatosis, inflammation, ballooning, and fibrosis than either single treatment. Mechanistically, the synergistic actions of GSK672 and FGF15 on inhibiting gut bile acid reuptake and hepatic bile acid synthesis achieve greater magnitude of bile acid pool reduction that not only decreases bile acid burden in NASH livers but also limits intestinal lipid absorption, which, together with FGF15 signaling activation, produces weight loss, reduction of adipose inflammation, and attenuated hepatocellular organelle stress. Furthermore, the combined treatment attenuates increased fecal bile acid excretion and repressed bile acid synthesis, which underlie diarrhea and hypercholesterolemia associated with ASBT inhibition and FGF19 analogue, respectively, in clinical settings. CONCLUSIONS: Concomitant ASBT inhibition and FGF15 signaling activation produce metabolic changes that partially mimic the bariatric surgery condition whereby lipid malabsorption and increased FGF15/19 signaling synergistically mediate weight loss and metabolic improvement. Further clinical studies may be warranted to investigate whether combining ASBT inhibitor and FGF19 analogue enhances anti-NASH efficacy and reduced treatment-associated adverse events in humans.
Assuntos
Colesterol/metabolismo , Fatores de Crescimento de Fibroblastos/genética , Metilaminas/administração & dosagem , Hepatopatia Gordurosa não Alcoólica/terapia , Tiazepinas/administração & dosagem , Animais , Ácidos e Sais Biliares/metabolismo , Terapia Combinada , Dependovirus/genética , Modelos Animais de Doenças , Frutose/efeitos adversos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Terapia Genética , Vetores Genéticos/administração & dosagem , Vetores Genéticos/farmacologia , Masculino , Metilaminas/farmacologia , Camundongos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/metabolismo , Tiazepinas/farmacologia , Resultado do TratamentoRESUMO
Background: Originally believed to be an atypical antidepressant acting at serotonin transporters, tianeptine is now known to also be an atypical agonist at mu-opioid receptors. Its nonmedical use may be increasing amidst the broader context of novel drug and supplement use.Objectives: To analyze social-media text from current, former, and prospective tianeptine users for better understanding of their conceptualizations of tianeptine, motives for and patterns of use, and reported benefits and harms.Methods: Reddit posts were obtained and thematically coded; additional quantitative analyses were conducted.Results: A total of 210 posts mentioning tianeptine were made between 2012 and 2020. Eighteen thematic categories were identified, 10 of which were consistent with expected themes. Two independent raters coded all text, generating 1,382 unique codes, of which 1,090 were concordant (78.9% interrater agreement). Tianeptine use was frequently associated with use of other drugs, particularly kratom, phenibut, and racetams. People conceptualized and variously used tianeptine as an opioid, antidepressant, and "nootropic" (cognitive enhancer). Between 2014 and 2020, mentions of positive effects decreased, while mentions of adverse effects and withdrawal increased. Motivations for use included substitution or withdrawal mitigation for other drugs (especially opioids) and for kratom itself; self-treatment for psychiatric symptoms; and improvement of quality of life, mood, or performance. Descriptions of tolerance, withdrawal, and addiction were evident. Intravenous use was rare and strongly discouraged, with detrimental effects described.Conclusion: Tianeptine is recognized as an opioid (though not only an opioid) in online communities. Posts describe benefits, acute risks, and patterns of co-use that warrant greater clinical attention.
Assuntos
Usuários de Drogas/psicologia , Mídias Sociais , Tiazepinas/administração & dosagem , Humanos , Receptores Opioides mu/agonistasRESUMO
Tianeptine is an atypical mu-opioid receptor agonist. It is available as an antidepressant outside the United States, but it is also classified as a controlled substance in many other countries. It is not approved by the United States Food and Drug Administration for the treatment of depression but it can be obtained online without a prescription. The case described in this article involved a patient who developed symptoms of psychosis on supratherapeutic doses of tianeptine, highlighting the importance of inquiring into all supplements taken by patients when conducting an initial psychiatric evaluation.
Assuntos
Antidepressivos Tricíclicos , Transtornos Psicóticos/tratamento farmacológico , Tiazepinas , Adulto , Antidepressivos Tricíclicos/administração & dosagem , Antidepressivos Tricíclicos/efeitos adversos , Antipsicóticos/uso terapêutico , Delusões/etiologia , Feminino , Humanos , Palmitato de Paliperidona/uso terapêutico , Receptores Opioides mu/agonistas , Tiazepinas/administração & dosagem , Tiazepinas/efeitos adversos , Estados UnidosRESUMO
This study investigated the kinetics of quetiapine and its metabolite 7-hydroxyquetiapine in guinea pig blood and hair roots during the whole time course of absorption and elimination after intragastric administration of three dosages (25 mg/kg, 50 mg/kg, 100 mg/kg). The mean maximum concentration (Cmax) values of quetiapine in the blood of the low-, medium- and high-dose groups were 334.4, 849.0, and 2751.1 ng/mL, respectively, and those of 7-hydroxyquetiapine were 75.6, 175.5, and 173.7 ng/mL, respectively. The corresponding mean Cmax values of quetiapine in hair roots were 2.0, 5.9, and 14.7 ng/mg, and those of 7-hydroxyquetiapine were 1.0, 1.8, and 6.4 ng/mg. The mean half-lives of quetiapine at the three dosages in blood were 3.8 h, 5.0 h, and 6.0 h, and those in hair roots were 48.2 h, 41.5 h, and 162.3 h; for 7-hydroxyquetiapine, the values were 2.9 h, 4.1 h, and 4.2 h in blood and 77.1 h, 103.6 h, and 385.9 h in hair roots. The levels of quetiapine in blood and hair roots were higher than those of 7-hydroxyquetiapine, and there were significant positive correlations (p<0.05) between the concentrations of quetiapine and 7-hydroxyquetiapine in hair roots and the respective doses within 24 h and 48 h. Quetiapine and 7-hydroxyquetiapine could still be detected in some guinea pigs even after 28 days, which means that drugs remain in the hair roots longer than in the blood. This finding shows that hair roots could be a good alternative or supplemental matrix to common biological samples such as blood and urine, as hair roots substantially extend the detection window from days to months. Moreover, quetiapine and 7-hydroxyquetiapine were detected within 15min after administration in hair roots, which also suggests that the drug enters the hair roots quickly. Therefore, hair root analysis may be a good choice to detect acute poisoning and single-dose administration if other matrices are unavailable or to provide complementary information for other matrices.
Assuntos
Antipsicóticos/farmacocinética , Cabelo/metabolismo , Piperazinas/farmacocinética , Fumarato de Quetiapina/farmacocinética , Tiazepinas/farmacocinética , Administração Oral , Animais , Antipsicóticos/administração & dosagem , Antipsicóticos/sangue , Relação Dose-Resposta a Droga , Cobaias , Cabelo/química , Modelos Animais , Piperazinas/administração & dosagem , Piperazinas/sangue , Fumarato de Quetiapina/administração & dosagem , Fumarato de Quetiapina/sangue , Tiazepinas/administração & dosagem , Tiazepinas/sangueRESUMO
Ziresovir (RO-0529, AK0529) is reported here for the first time as a promising respiratory syncytial virus (RSV) fusion (F) protein inhibitor that currently is in phase 2 clinical trials. This article describes the process of RO-0529 as a potent, selective, and orally bioavailable RSV F protein inhibitor and highlights the in vitro and in vivo anti-RSV activities and pharmacokinetics in animal species. RO-0529 demonstrates single-digit nM EC50 potency against laboratory strains, as well as clinical isolates of RSV in cellular assays, and more than one log viral load reduction in BALB/c mouse model of RSV viral infection. RO-0529 was proven to be a specific RSV F protein inhibitor by identification of drug resistant mutations of D486N, D489V, and D489Y in RSV F protein and the inhibition of RSV F protein-induced cell-cell fusion in cellular assays.
Assuntos
Antivirais/uso terapêutico , Benzazepinas/uso terapêutico , Quinazolinas/uso terapêutico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Tiazepinas/uso terapêutico , Proteínas Virais de Fusão/antagonistas & inibidores , Administração Oral , Animais , Antivirais/administração & dosagem , Antivirais/síntese química , Antivirais/farmacocinética , Benzazepinas/administração & dosagem , Benzazepinas/síntese química , Benzazepinas/farmacocinética , Cães , Descoberta de Drogas , Feminino , Haplorrinos , Masculino , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Estrutura Molecular , Quinazolinas/administração & dosagem , Quinazolinas/líquido cefalorraquidiano , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Ratos Wistar , Vírus Sincicial Respiratório Humano/química , Relação Estrutura-Atividade , Sulfonas , Tiazepinas/administração & dosagem , Tiazepinas/líquido cefalorraquidiano , Tiazepinas/farmacocinética , Proteínas Virais de Fusão/químicaAssuntos
Nootrópicos/administração & dosagem , Nootrópicos/toxicidade , Transtornos Relacionados ao Uso de Substâncias , Tiazepinas/administração & dosagem , Tiazepinas/toxicidade , Adulto , Analgésicos/administração & dosagem , Analgésicos/toxicidade , Dor nas Costas/tratamento farmacológico , Humanos , MasculinoRESUMO
Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a complex neurological disorder, characterized by infantile seizures, impairment of cognitive and motor skills and autistic features. Loss of Cdkl5 in mice affects dendritic spine maturation and dynamics but the underlying molecular mechanisms are still far from fully understood. Here we show that Cdkl5 deficiency in primary hippocampal neurons leads to deranged expression of the alpha-amino-3-hydroxy-5-methyl-4-iso-xazole propionic acid receptors (AMPA-R). In particular, a dramatic reduction of expression of the GluA2 subunit occurs concomitantly with its hyper-phosphorylation on Serine 880 and increased ubiquitination. Consequently, Cdkl5 silencing skews the composition of membrane-inserted AMPA-Rs towards the GluA2-lacking calcium-permeable form. Such derangement is likely to contribute, at least in part, to the altered synaptic functions and cognitive impairment linked to loss of Cdkl5. Importantly, we find that tianeptine, a cognitive enhancer and antidepressant drug, known to recruit and stabilise AMPA-Rs at the synaptic sites, can normalise the expression of membrane inserted AMPA-Rs as well as the number of PSD-95 clusters, suggesting its therapeutic potential for patients with mutations in CDKL5.
Assuntos
Síndromes Epilépticas/tratamento farmacológico , Proteínas Serina-Treonina Quinases/genética , Receptores de AMPA/genética , Espasmos Infantis/tratamento farmacológico , Tiazepinas/administração & dosagem , Animais , Antidepressivos/administração & dosagem , Proteína 4 Homóloga a Disks-Large/genética , Síndromes Epilépticas/genética , Síndromes Epilépticas/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Humanos , Camundongos , Mutação , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fosforilação , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/deficiência , Espasmos Infantis/genética , Espasmos Infantis/patologia , Sinapses/efeitos dos fármacos , Sinapses/genéticaRESUMO
Tianeptine is an atypical antidepressant approved in 25 countries for the treatment of depressive syndromes. Tianeptine abuse among psychiatric patients in the community and at inpatient wards has been increasingly reported in recent years. The purpose of this article is to alert clinicians to tianeptine abuse potential and identify any patterns in the literature. We searched the Academic Search Complete, Google Scholar, MEDLINE, Science Citation Index, Scopus, and the Social Sciences Citation Index for articles published between 1960-2017 in any language containing the keywords: "tianeptine abuse," "tianeptine misuse," "tianeptine dependence." The search retrieved 18 cases. Higher frequency of tianeptine abuse/dependence was observed in women and 30- to 45-year-olds. Most cases (n = 13) reported a previous history of substance abuse. The therapeutic dose of tianeptine was exceeded 110-fold (i.e., up to 4125 mg/day) with a mean of about 1469 mg/day. The most prominent phenomena associated with tianeptine abuse and dependence were marked euphoria and withdrawal symptoms perpetuating further drug misuse. Tianeptine is a drug with potential for abuse and addiction. Caution should be taken when considering the prescription of tianeptine to patients with prior history of substance abuse, and close monitoring for drug misuse is needed during the treatment period.
Assuntos
Antidepressivos Tricíclicos/administração & dosagem , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Tiazepinas/administração & dosagem , Adulto , Antidepressivos Tricíclicos/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Uso Indevido de Medicamentos sob Prescrição/estatística & dados numéricos , Síndrome de Abstinência a Substâncias/epidemiologia , Tiazepinas/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: The mitochondrial Na+/Ca2+ exchanger (mNCX) has been implicated in the pathogenesis of arrhythmogenicity and myocardial reperfusion injury, rendering its inhibition a potential therapeutic strategy. We examined the effects of CGP-37157, a selective mNCX inhibitor, on arrhythmogenesis, infarct size (IS), and no reflow area (NRA) in a porcine model of ischemia-reperfusion. METHODS: Forty pigs underwent myocardial ischemia for 60 minutes, followed by 2 hours of reperfusion. Animals were randomized to receive intracoronary infusion of 0.02 mg/kg CGP-37157 or vehicle, either before ischemia (n=17) or before reperfusion (n=17). Animals were monitored for arrhythmias. Myocardial area at risk (AR), IS, and NRA were measured by histopathology. RESULTS: AR, NRA, and IS were comparable between groups. Administration of CGP-37157 before ischemia resulted in the following: (a) suppression of ventricular tachyarrhythmias (events/pig: 1.5±1.1 vs 3.5±1.9, p=0.014), (b) easier cardioversion of ventricular tachyarrhythmias (defibrillations required for cardioversion of each episode: 2.6±2.3 vs 6.2±2.1, p=0.006), and (c) decreased maximal depression of the J point (0.75±0.27 mm vs 1.75±0.82 mm, p=0.007), compared to controls. Administration of CGP-37157 before reperfusion expedited ST-segment resolution; complete ST-segment resolution within 30 minutes of reperfusion was observed in 7/8 CGP-37157-treated animals versus 1/9 controls (p=0.003). CONCLUSIONS: In a porcine model of myocardial infarction, intracoronary administration of CGP-37157 did not decrease IS or NRA. However, it suppressed ventricular arrhythmias, decreased depression of the J point during ischemia and expedited ST-segment resolution after reperfusion. These findings motivate further investigation of pharmacologic mNCX inhibition as a potential therapeutic strategy to suppress arrhythmias in the injured heart.
Assuntos
Clonazepam , Mitocôndrias Cardíacas , Traumatismo por Reperfusão Miocárdica , Trocador de Sódio e Cálcio , Taquicardia Ventricular , Tiazepinas , Animais , Feminino , Clonazepam/administração & dosagem , Clonazepam/análogos & derivados , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Injeções Intra-Arteriais , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Traumatismo por Reperfusão Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/patologia , Distribuição Aleatória , Trocador de Sódio e Cálcio/antagonistas & inibidores , Suínos , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/metabolismo , Taquicardia Ventricular/prevenção & controle , Tiazepinas/administração & dosagemRESUMO
BACKGROUND: Elobixibat is an oral treatment candidate for chronic constipation with a novel mechanism of action via inhibition of the ileal bile acid transporter. We performed this randomized, double-blind, placebo-controlled, dose-finding phase IIb study in Japanese patients with chronic constipation to determine the optimal clinical dose of elobixibat. METHODS: Japanese patients with chronic constipation were randomized to receive elobixibat (5, 10, or 15 mg) or placebo once daily for 2 weeks. The primary efficacy endpoint was the change from baseline in frequency of spontaneous bowel movements at Week 1 of treatment. Secondary endpoints and adverse events were also examined. RESULTS: Among 226 patients who provided informed consent, 163 patients were randomized and included in the full analysis set. In the 10- and 15-mg groups, frequency of spontaneous bowel movements (±standard deviation) were significantly higher than baseline (5.7 ± 4.2 and 5.6 ± 3.5 times per week, respectively, compared with 2.6 ± 2.9 times per week in the placebo group [P = 0.0005, P = 0.0001, respectively]). Subgroup analysis indicated that elobixibat was equally effective in patients with or without constipation-predominant irritable bowel syndrome. Common adverse events included mild abdominal pain and diarrhea in the elobixibat groups; no serious or severe adverse events occurred. Elobixibat was well tolerated at once-daily oral doses up to 15 mg for 2 weeks. CONCLUSIONS: Our study results suggest that 10 mg of elobixibat is a clinically optimal dose for Japanese patients with chronic constipation. CLINICAL TRIAL REGISTRATION NUMBER: JapicCTI-142608.
Assuntos
Constipação Intestinal/tratamento farmacológico , Dipeptídeos/administração & dosagem , Fármacos Gastrointestinais/administração & dosagem , Tiazepinas/administração & dosagem , Administração Oral , Adulto , Idoso , Proteínas de Transporte/antagonistas & inibidores , Doença Crônica , Constipação Intestinal/fisiopatologia , Defecação/efeitos dos fármacos , Dipeptídeos/efeitos adversos , Dipeptídeos/farmacologia , Dipeptídeos/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/farmacologia , Fármacos Gastrointestinais/uso terapêutico , Humanos , Síndrome do Intestino Irritável/tratamento farmacológico , Síndrome do Intestino Irritável/fisiopatologia , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Pessoa de Meia-Idade , Tiazepinas/efeitos adversos , Tiazepinas/farmacologia , Tiazepinas/uso terapêutico , Adulto JovemRESUMO
Tianeptine is an atypical antidepressant with a unique mechanism of action and recently it has been also reported that its major metabolite, compound MC5, possesses pharmacological activity similar to that of the parent drug. The current study aims to investigate the pharmacokinetics (PK) of both tianeptine and MC5 after intravenous or intraperitoneal administration of the parent drug as well as the metabolic ratio of MC5 in rats. To achieve these goals an LC-MS/MS method using the small sample volume for the quantitation of tianeptine and its active metabolite MC5 in rat plasma and liver perfusate has been developed and validated. Following an intravenous administration of tianeptine pharmacokinetic parameters were calculated by non-compartmental analysis. The average tianeptine volume of distribution at steady state was 2.03 L/kg and the systemic clearance equaled 1.84 L/h/kg. The mean elimination half-lives of tianeptine and MC5 metabolite were 1.16 and 7.53 h, respectively. The hepatic clearance of tianeptine determined in the isolated rat liver perfusion studies was similar to the perfusate flow rate despite the low metabolic ratio of MC5. Mass spectrometric analysis of rat bile indicated that tianeptine and MC5 metabolite are eliminated with bile as glucuronide and glutamine conjugates. Bioavailability of tianeptine after its intraperitoneal administration was 69%. The PK model with a metabolite compartment developed in this study for both tianeptine and MC5 metabolite after two routes of administration may facilitate tianeptine dosage selection for the prospective pharmacological experiments.
Assuntos
Espectrometria de Massas em Tandem/métodos , Tiazepinas/administração & dosagem , Tiazepinas/metabolismo , Tiazepinas/farmacocinética , Animais , Antidepressivos Tricíclicos/administração & dosagem , Antidepressivos Tricíclicos/análise , Antidepressivos Tricíclicos/farmacocinética , Cromatografia Líquida/métodos , Vias de Administração de Medicamentos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Ratos , Ratos Wistar , Tiazepinas/análiseRESUMO
In the rat, we previously demonstrated that serotonin-enhancing drugs impair cortical spreading depression (CSD) and that l-arginine (arginine) treatment enhances CSD. Here, we investigated the interaction between topical application of the serotonin uptake enhancer tianeptine and systemic arginine administration on CSD. From postnatal day 7-28, female Wistar rats (n=40) received by gavage 300mg/Kg/day arginine (n=20) or water (n=20). Half of the arginine- or water-treated rats underwent CSD recording at 30-40days of age (young), while the other half was recorded at 90-120days (adult). Following baseline recording (four episodes of CSD), we applied tianeptine solution (10mg/ml) to a rectangular portion of the intact dura mater for 10-min and then elicited CSD. This procedure was repeated three times. Compared to baseline values, CSD velocities and amplitudes following tianeptine application increased, and CSD duration decreased significantly (p<0.05) in both young and adult rats, regardless of treatment group. CSD acceleration caused by systemic treatment with arginine is in agreement with previous findings. Topical cortical application of tianeptine replicated the effect of systemic application, suggesting a cortically based mechanism for tianeptine's action. However, the absence of interaction between arginine and tianeptine treatments suggests that they probably act through separate mechanisms.
Assuntos
Envelhecimento/fisiologia , Arginina/administração & dosagem , Mapeamento Encefálico , Encéfalo/fisiologia , Depressão Alastrante da Atividade Elétrica Cortical/efeitos dos fármacos , Depressão Alastrante da Atividade Elétrica Cortical/fisiologia , Tiazepinas/administração & dosagem , Animais , Encéfalo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Feminino , Ratos WistarRESUMO
Treatment of depression, a common comorbidity in patients with epilepsy, is restricted as certain antidepressants are considered to be proconvulsants. In contrast, anticonvulsant effects have been reported with some antidepressants. In the present study, the effect of tianeptine, an antidepressant, was evaluated against pentylenetetrazole (PTZ)-induced seizures, cognitive impairment and oxidative stress in rats. Tianeptine was administered in three doses (20, 40 and 80 mg/kg) 30 min before PTZ (60 mg/kg, intraperitoneally). MK801, an N-methyl-D-aspartate antagonist, and naloxone, an opioid receptor antagonist, were administered with tianeptine to evaluate the involvement of N-methyl-D-aspartate and opioid receptors, respectively. Morris water maze, elevated plus maze and passive avoidance tests were performed for behavioural assessment. Brain malondialdehyde and reduced glutathione levels were estimated as markers of oxidative stress. Tianeptine showed dose-dependent protection against PTZ seizures. Coadministration of tianeptine with MK801 potentiated the anticonvulsant effect of tianeptine. The protective effect of tianeptine against PTZ seizures was mitigated when tianeptine was administered with naloxone. Impairment of learning and memory by PTZ was prevented by tianeptine. Tianeptine also attenuated the seizure-induced increased oxidative stress. Thus, tianeptine showed an anticonvulsant effect along with amelioration of seizure-induced cognitive impairment and oxidative stress. Hence, tianeptine could be a useful drug in epileptic patients with depression, with the advantage of having both antidepressant and antiepileptic effects.
Assuntos
Anticonvulsivantes/farmacologia , Disfunção Cognitiva/prevenção & controle , Convulsões/prevenção & controle , Tiazepinas/farmacologia , Animais , Anticonvulsivantes/administração & dosagem , Antidepressivos Tricíclicos/administração & dosagem , Antidepressivos Tricíclicos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Disfunção Cognitiva/etiologia , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Masculino , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Naloxona/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Pentilenotetrazol , Ratos , Ratos Wistar , Convulsões/complicações , Tiazepinas/administração & dosagemRESUMO
BACKGROUND: Pruritus (itch) is a symptom commonly experienced by patients with cholestatic liver diseases such as primary biliary cholangitis (PBC, previously referred to as primary biliary cirrhosis). Bile acids (BAs) have been proposed as potential pruritogens in PBC. The ileal bile acid transporter (IBAT) protein expressed in the distal ileum plays a key role in the enterohepatic circulation of BAs. Pharmacological inhibition of IBAT with GSK2330672 may reduce BA levels in the systemic circulation and improve pruritus. METHODS: This clinical study (BAT117213 study) is sponsored by GlaxoSmithKline (GSK) with associated exploratory studies supported by the National Institute for Health Research (NIHR). It is a phase 2a, multi-centre, randomised, double bind, placebo controlled, cross-over trial for PBC patients with pruritus. The primary objective is to investigate the safety and tolerability of repeat doses of GSK2330672, and explore whether GSK2330672 administration for 14 days improves pruritus compared with placebo. The key outcomes include improvement in pruritus scores evaluated on a numerical rating scale and other PBC symptoms in an electronic diary completed twice daily by the patients. The secondary outcomes include the evaluation of the effect of GSK2330672 on total serum bile acid (BA) concentrations, serum markers of BA synthesis and steady-state pharmacokinetics of ursodeoxycholic acid (UDCA). DISCUSSION: BAT117213 study is the first randomised controlled crossover trial of ileal bile acid transporter inhibitor, a novel class of drug to treat pruritus in PBC. The main strengths of the trial are utility of a novel, study specific, electronic symptom diary as patient reported outcome to measure the treatment response objectively and the crossover design that allows estimating the treatment effect in a smaller number of patients. The outcome of this trial will inform the trial design of future development phase of the IBAT inhibitor drug. The trial will also provide opportunity to conduct metabonomic and gut microbiome studies as explorative and mechanistic research in patients with cholestatic pruritus. TRIAL REGISTRATION: EudraCT number: 2012-005531-84, ClinicalTrials.gov Identifier: NCT01899703 , registered on 3(rd) July 2013.
Assuntos
Cirrose Hepática Biliar/complicações , Metilaminas/uso terapêutico , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Prurido/tratamento farmacológico , Simportadores/antagonistas & inibidores , Tiazepinas/uso terapêutico , Adolescente , Adulto , Idoso , Ácidos e Sais Biliares/sangue , Biomarcadores/sangue , Colagogos e Coleréticos/farmacocinética , Colagogos e Coleréticos/uso terapêutico , Estudos Cross-Over , Quimioterapia Combinada , Feminino , Humanos , Masculino , Metilaminas/administração & dosagem , Metilaminas/efeitos adversos , Metilaminas/farmacocinética , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos Dependentes de Sódio/uso terapêutico , Prurido/etiologia , Simportadores/uso terapêutico , Tiazepinas/administração & dosagem , Tiazepinas/efeitos adversos , Tiazepinas/farmacocinética , Ácido Ursodesoxicólico/farmacocinética , Ácido Ursodesoxicólico/uso terapêutico , Adulto JovemRESUMO
A growing body of evidence has focused on the impact of mitochondrial disturbances in the development of depression, but little data exist regarding the effects of chronic administration of antidepressant drugs on the brain's mitochondrial protein profile. The aim of this study was to investigate the impact of chronic treatment with an atypical antidepressant drug-tianeptine-on the mitochondria-enriched subproteome profile in the hippocampus and the frontal cortex of 3-month-old male rats following a prenatal stress procedure. Rats that were exposed to a prenatal stress procedure displayed depressive- and anxiety-like disturbances based on the elevated plus-maze and Porsolt tests. Moreover, two-dimensional electrophoresis coupled with mass spectrometry showed structure-dependent mitoproteome changes in brains of prenatally stressed rats after chronic tianeptine administration. A component of 2-oxoglutarate and succinate flavoprotein subunit dehydrogenases, isocitrate subunit alpha, was upregulated in the hippocampus. In the frontal cortex, there was a striking increase in the expression of glutamate dehydrogenase and cytochrome bc1 complex subunit 2. These findings suggest that mitochondria are underappreciated targets for therapeutic interventions, and mitochondrial function may be crucial for the effective treatment of stress-related diseases.
Assuntos
Encéfalo/metabolismo , Depressão/tratamento farmacológico , Depressão/patologia , Mitocôndrias/metabolismo , Tiazepinas/administração & dosagem , Tiazepinas/uso terapêutico , Animais , Ansiedade/complicações , Ansiedade/tratamento farmacológico , Comportamento Animal , Depressão/complicações , Modelos Animais de Doenças , Eletroforese em Gel Bidimensional , Feminino , Hipocampo/patologia , Imipramina/uso terapêutico , Proteínas Mitocondriais/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/patologia , Proteoma/metabolismo , Ratos Sprague-DawleyRESUMO
AIMS: To investigate the pharmacodynamics, pharmacokinetics and safety/tolerability of blocking reuptake of bile acids using the inhibitor GSK2330672 (GSK672) in patients with type 2 diabetes (T2D). METHODS: Subjects with T2D taking metformin were enrolled in two studies in which they took metformin 850 mg twice daily for 2 weeks prior to and during the randomized treatment periods. In the first crossover study (n = 15), subjects received GSK672 45 mg, escalating to 90 mg, twice daily, or placebo for 7 days. The second parallel-group study (n = 75) investigated GSK672 10-90 mg twice daily, placebo or sitagliptin for 14 days. RESULTS: In both studies, GSK672 reduced circulating bile acids and increased serum 7-α-hydroxy-4-cholesten-3-one (C4), an intermediate in the hepatic synthesis of bile acids. Compared with placebo, in the parallel-group study 90 mg GSK672 twice daily reduced fasting plasma glucose [FPG; -1.21 mmol/l; 95% confidence interval (CI) -2.14, -0.28] and weighted-mean glucose area under the curve (AUC)0-24 h (-1.33 mmol/l; 95% CI -2.30, -0.36), as well as fasting and weighted-mean insulin AUC0 -24 h . GSK672 also reduced cholesterol (LDL, non-HDL and total cholesterol) and apolipoprotein B concentrations; the maximum LDL cholesterol reduction was â¼40%. There was no change in HDL cholesterol but there was a trend towards increased fasting triglyceride levels in the GSK672 groups compared with placebo. In both studies, the most common adverse events associated with GSK672 were gastrointestinal, mostly diarrhoea (22-100%), which appeared to be independent of dose. CONCLUSIONS: In subjects with T2D on metformin, GSK672 improved glucose and lipids, but there was a high incidence of gastrointestinal adverse events.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Metformina/administração & dosagem , Metilaminas/administração & dosagem , Tiazepinas/administração & dosagem , Adulto , Apolipoproteínas B/metabolismo , Área Sob a Curva , Ácidos e Sais Biliares/metabolismo , Glicemia/metabolismo , LDL-Colesterol , Estudos Cross-Over , Diarreia/induzido quimicamente , Método Duplo-Cego , Esquema de Medicação , Jejum/metabolismo , Feminino , Gastroenteropatias/induzido quimicamente , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Metformina/efeitos adversos , Metformina/farmacologia , Metilaminas/efeitos adversos , Metilaminas/farmacologia , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Simportadores/antagonistas & inibidores , Tiazepinas/efeitos adversos , Tiazepinas/farmacologia , Resultado do TratamentoRESUMO
Omapatrilat (OMA), which simultaneously inhibits the angiotensin-converting enzyme (ACE) and the neutral endopeptidase (neprilysin (NEP)), is widely used in experimental protocols related to hypertension and heart failure. The penetration of OMA across the blood-brain barrier (BBB) and the effects of ACE/NEP inhibition on the recovery from ischaemic stroke have not yet been investigated. Angiotensin (Ang) I injected intracerebroventricularly (ICV) or intravenously (IV) is converted to Ang II by ACE and induces an immediate increase in blood pressure. The pressor responses to OMA administered ICV, orally or IV were studied in male Wistar rats instrumented with an ICV and arterial and venous catheters. OMA infused ICV rapidly appeared in the systemic circulation and more effectively attenuated the systemic than the central pressor responses to Ang I. OMA administered orally (5, 25, 100 µmol/kg body weight) or IV (0.5, 1, 5, 25 µmol/kg body weight) completely abolished increases in blood pressure to IV Ang I up to 2 h after treatment. The pressor responses to ICV Ang I were not altered, indicating that systemically administered OMA does not cross the BBB. To study the effects of ACE and NEP inhibition in the brain on the recovery from ischaemic stroke, OMA was infused ICV over a 5-day period before and 24 h after the occlusion of the middle cerebral artery (MCAO) for 90 min. ICV application of OMA had no effect on infarction volume and marginally improved neurological outcome. We demonstrate for the first time that simultaneous inhibition of ACE and NEP in the brain tissue does not alter the recovery from ischaemic stroke.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Isquemia Encefálica/metabolismo , Piridinas/administração & dosagem , Acidente Vascular Cerebral/metabolismo , Tiazepinas/administração & dosagem , Administração Intravenosa , Administração Oral , Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Infusões Intraventriculares , Masculino , Neprilisina/antagonistas & inibidores , Peptidil Dipeptidase A/metabolismo , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Ratos Wistar , Tiazepinas/farmacocinética , Tiazepinas/farmacologiaRESUMO
BACKGROUND: According to reports in the literature, more than 30% of depressive patients fail to achieve remission. Therapy with the conventional antidepressant drugs may induce the serious adverse reactions. Moreover, its benefits may be seen at least 2-4 weeks after the first dose. Therefore, the alternative strategies for prevention and treatment of depression are sought. The main aim of our study was to assess the effects of ifenprodil given at a non-active dose (10mg/kg) on the activity of antidepressant agents from diverse pharmacological groups. METHODS: The antidepressant-like effect was assessed by the forced swim test in mice. RESULTS: Ifenprodil potentiated the antidepressant-like effect of imipramine (15mg/kg) and fluoxetine (5mg/kg) while did not reduce the immobility time of animals which simultaneously received reboxetine (2.5mg/kg) or tianeptine (15mg/kg). CONCLUSION: The concomitant administration of certain commonly prescribed antidepressant drugs that affect the serotonergic neurotransmission (i.e., typical tricyclic antidepressants and selective serotonin reuptake inhibitors) with a negative modulator selectively binding to the GluN1/N2B subunits of the NMDA receptor complex (i.e., ifenprodil) may induce a more pronounced antidepressant-like effect than monotherapy. However, these findings still need to be confirmed in further experiments.
Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Piperidinas/farmacologia , Animais , Antidepressivos/administração & dosagem , Modelos Animais de Doenças , Sinergismo Farmacológico , Fluoxetina/administração & dosagem , Fluoxetina/farmacologia , Imipramina/administração & dosagem , Imipramina/farmacologia , Camundongos , Morfolinas/administração & dosagem , Morfolinas/farmacologia , Piperidinas/administração & dosagem , Reboxetina , Natação , Tiazepinas/administração & dosagem , Tiazepinas/farmacologiaRESUMO
BACKGROUND: Tianeptine is widely used for controlling depressive symptoms. OBJECTIVE: The aim of this study was to evaluate the bioequivalence between the generic (test) formulation containing tianeptine sodium 12.5 mg and the branded (reference) formulation Stablon® with regard to their pharmacokinetic profiles. METHODS: A randomized, two-sequence, two-treatment crossover study was conducted in healthy male Korean volunteers. All of the enrolled subjects were allocated to one of two sequence groups. They were administered a tablet of the test or reference formulation and then administered the alternative formulation after a 7-day washout period. The blood samples were taken before dosing and at 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, and 10 hours after dosing. The plasma concentrations of tianeptine were analyzed using high-performance liquid chromatography with tandem mass spectrometer. Tolerability was assessed throughout the study. RESULTS: The pharmacokinetic parameters were assessed in the 40 subjects who completed the study. The tianeptine C(max) for the test formulation was 283.13 ± 57.58 ng/mL (mean ± SD) and that for the reference formulation was 272.50 ± 59.00 ng/mL. The AUC(last) of tianeptine was 803.24 ± 180.94 ng×h/mL for the test formulation and 792.27 ± 180.93 ng×h/mL for the reference formulation. The geometric mean ratio (%) of the test to reference formulation was 104.04 (90% CI, 99.66 - 108.61) for C(max) and 101.30 (98.01 - 104.71) for AUC(last). Clinically significant adverse events were not reported during the study. CONCLUSION: The test and reference formulations of tianeptine were bioequivalent with regard to the pharmacokinetic parameters of Cmax and AUC(last). Both formulations were tolerated by all of the participants.
Assuntos
Antidepressivos Tricíclicos/farmacocinética , Medicamentos Genéricos/farmacocinética , Tiazepinas/farmacocinética , Administração Oral , Adulto , Antidepressivos Tricíclicos/administração & dosagem , Antidepressivos Tricíclicos/efeitos adversos , Antidepressivos Tricíclicos/sangue , Área Sob a Curva , Química Farmacêutica , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Medicamentos Genéricos/administração & dosagem , Medicamentos Genéricos/efeitos adversos , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , República da Coreia , Comprimidos , Espectrometria de Massas em Tandem , Equivalência Terapêutica , Tiazepinas/administração & dosagem , Tiazepinas/efeitos adversos , Tiazepinas/sangue , Adulto JovemRESUMO
Increased arterial endothelial cell permeability (ECP) is considered an initial step in atherosclerosis. Atrial natriuretic peptide (ANP) which is rapidly degraded by neprilysin (NEP) may reduce injury-induced endothelial cell leakiness. Omapatrilat represents a first in class of pharmacological agents which inhibits both NEP and angiotensin converting enzyme (ACE). We hypothesized that ANP prevents thrombin-induced increases of ECP in human aortic ECs (HAECs) and that omapatrilat would reduce aortic leakiness and atherogenesis and enhance ANP mediated vasorelaxation of isolated aortas. Thrombin induced ECP determined by I(125) albumin flux was assessed in HAECs with and without ANP pretreatment. Next we examined the effects of chronic oral administration of omapatrilat (12 mg/kg/day, n=13) or placebo (n=13) for 8 weeks on aortic leakiness, atherogenesis and ANP-mediated vasorelaxation in isolated aortas in a rabbit model of atherosclerosis produced by high cholesterol diet. In HAECs, thrombin-induced increases in ECP were prevented by ANP. Omapatrilat reduced the area of increased aortic leakiness determined by Evans-blue dye and area of atheroma formation assessed by Oil-Red staining compared to placebo. In isolated arterial rings, omapatrilat enhanced vasorelaxation to ANP compared to placebo with and without the endothelium. ANP prevents thrombin-induced increases in ECP in HAECs. Chronic oral administration of omapatrilat reduces aortic leakiness and atheroma formation with enhanced endothelial independent vasorelaxation to ANP. These studies support the therapeutic potential of dual inhibition of NEP and ACE in the prevention of increased arterial ECP and atherogenesis which may be linked to the ANP/cGMP system.