RESUMO
Clinical induction liability is assessed with human hepatocytes. However, underpredictions in the magnitude of clinical induction have been reported. Unfortunately, in vivo studies in animals do not provide additional insight because of species differences in drug metabolizing enzymes and their regulatory pathways. To circumvent this limitation, transgenic animals expressing human orthologs were developed. The aim of this work was to investigate the utility of mouse models expressing human orthologs of pregnane X receptor, constitutive androstane receptor, and CYP3A4/7 (Tg-Composite) in evaluating clinical induction. Rifampin, efavirenz, and pioglitazone, which were employed to represent strong, moderate, and weak inducers, were administered at multiple doses to Tg-Composite animals. In vivo CYP3A activity was monitored by measuring changes in the exposure of the CYP3A probe substrate triazolam. After the in vivo studies, microsomes were prepared from their livers to measure changes of in vitro CYP3A4 activity. In both in vivo and in vitro, distinction of clinic induction was recapitulated as rifampin yielded the greatest inductive effect followed by efavirenz and pioglitazone. Interestingly, with rifampin, in vivo CYP3A activity was approximately 4-fold higher than in vitro activity. Conversely, there was no difference between in vivo and in vitro CYP3A activity with efavirenz. These findings are consistent with the report that, although rifampin exhibits differential inductive effects between the intestines and liver, efavirenz does not. These data highlight the promise of transgenic models, such as Tg-Composite, to complement human hepatocytes to enhance the translatability of clinical induction as well as become a powerful tool to further study mechanisms of drug disposition. SIGNIFICANCE STATEMENT: Underprediction of the magnitude of clinical induction when using human hepatocytes has been reported, and transgenic models may improve clinical translatability. The work presented here showcases the human orthologs of pregnane X receptor, constitutive androstane receptor, and CYP3A4/7 model, which was able to recapitulate the magnitude of clinical induction and to differentiate tissue-dependent induction observed with rifampin but not with efavirenz. These results not only foreshadow the potential application of such transgenic models in assessing clinical induction but also in further investigation of the mechanism of drug disposition.
Assuntos
Indutores do Citocromo P-450 CYP3A/farmacocinética , Alcinos/administração & dosagem , Alcinos/farmacocinética , Animais , Benzoxazinas/administração & dosagem , Benzoxazinas/farmacocinética , Receptor Constitutivo de Androstano/genética , Receptor Constitutivo de Androstano/metabolismo , Ciclopropanos/administração & dosagem , Ciclopropanos/farmacocinética , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Indutores do Citocromo P-450 CYP3A/administração & dosagem , Avaliação Pré-Clínica de Medicamentos/métodos , Interações Medicamentosas , Estudos de Viabilidade , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Microssomos Hepáticos , Pioglitazona/administração & dosagem , Pioglitazona/farmacocinética , Receptor de Pregnano X/genética , Receptor de Pregnano X/metabolismo , Rifampina/administração & dosagem , Rifampina/farmacocinética , Especificidade da Espécie , Triazolam/administração & dosagem , Triazolam/farmacocinéticaRESUMO
BACKGROUND: There is limited clinical trial and/or real-world evidence comparing differences among currently approved fixed-dose combination (FDC) long-acting muscarinic antagonist (LAMA)/long-acting beta2-agonist (LABA) treatments. OBJECTIVE: To compare chronic obstructive pulmonary disease (COPD)-related and all-cause health care resource utilization (HCRU) and costs between COPD patients initiating tiotropium (TIO) + olodaterol (OLO) versus (a) other LAMA + LABA FDCs and (b) umeclidinium (UMEC) + vilanterol (VI), specifically. METHODS: In this retrospective observational study, patients initiating fixed-dose LAMA + LABA therapy (earliest fill date = index date) between January 1, 2014, and September 30, 2018, were identified using administrative claims data from the Optum Research Database. Patients were followed post-index for 1-12 months. Follow-up was censored at the earliest occurrence of index therapy discontinuation or switch, health plan disenrollment, study end date, or reaching the maximum 12-month allowed duration. Propensity score matching of 1:2 was used to balance differences in baseline characteristics between cohorts for each of the 2 comparisons. Annualized population averages of HCRU and costs were calculated for each cohort as [sum of visits (or costs) for all individuals during the follow-up period] ÷ [sum of follow-up on-treatment time for all individuals] × 365 days. RESULTS: After matching, compared with patients who initiated other LAMA + LABAs or UMEC + VI, patients who initiated TIO + OLO had 14.29% and 16.95% fewer mean annualized per-patient COPD-related emergency department (ED) visits (vs. other LAMA + LABAs: 0.49 vs. 0.59, P = 0.005; vs. UMEC + VI: 0.48 vs. 0.56, P = 0.026) and 3.07% and 3.14% fewer mean annualized per-patient pharmacy fills (vs. other LAMA + LABAs: 12.66 vs. 13.07, P = 0.016; vs. UMEC + VI: 12.62 vs. 13.02, P = 0.022), leading to 17.39% and 21.47% lower mean annualized per-patient COPD-related ED costs (vs. other LAMA + LABAs: $289 vs. $368, P = 0.003; vs. UMEC + VI: $285 vs. $345, P = 0.027) and 4.56% and 5.67% lower mean annualized per-patient pharmacy spending (vs. other LAMA + LABAs: $3,570 vs. $3,741, P < 0.001; vs. UMEC + VI: $3,556 vs. $3,770, P < 0.001) in the follow-up period. Similarly, patients in the TIO + OLO cohort had 15.63% and 21.17% fewer mean annualized per-patient all-cause ED visits (vs. other LAMA + LABAs: 1.08 vs. 1.37, P < 0.001; vs. UMEC + VI: 1.08 vs. 1.28, P = 0.001), 8.29% fewer mean annualized per-patient outpatient visits (vs. UMEC + VI: 13.28 vs. 14.48, P = 0.031), 3.41% fewer mean annualized per-patient pharmacy fills (vs. other LAMA + LABAs: 56.92 vs. 58.93, P = 0.028), 19.48% and 22.28% lower mean annualized per-patient all-cause ED costs (vs. other LAMA + LABAs: $755 vs. $971, P < 0.001; vs. UMEC + VI: $749 vs. $930, P < 0.001), and 10.86% lower mean annualized per-patient outpatient setting costs (vs. UMEC + VI: $3,348 vs. $3,756, P = 0.050). There were no statistically significant differences for the other outcome measures. CONCLUSIONS: In a real-world setting, differences in HCRU and costs were observed between FDC LAMA + LABAs, with patients initiating TIO + OLO having lower ED visits/costs, COPD-related pharmacy fills/costs, and all-cause pharmacy use and outpatient visits/costs than those initiating other FDC LAMA + LABAs or UMEC + VI specifically. The remaining HCRU and cost measures were not significantly different. DISCLOSURES: This study was sponsored by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI; Ridgefield, CT). BIPI was given the opportunity to review the manuscript for medical and scientific accuracy, as well as intellectual property considerations. Palli is an employee of BIPI. Xie, Chastek, Elliott, and Bengtson are employees of Optum, which was contracted by BIPI to conduct this study. The authors received no direct compensation related to the development of the manuscript. Part of the results of this study were accepted and presented at the 30th European Respiratory Society (ERS) International Congress (September 7-9, 2020; virtual).
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/economia , Combinação de Medicamentos , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/economia , Aceitação pelo Paciente de Cuidados de Saúde , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/economia , Administração por Inalação , Idoso , Benzoxazinas/administração & dosagem , Álcoois Benzílicos/administração & dosagem , Broncodilatadores , Clorobenzenos/administração & dosagem , Preparações de Ação Retardada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Quinuclidinas/administração & dosagem , Estudos Retrospectivos , Brometo de Tiotrópio/administração & dosagem , Estados UnidosRESUMO
Cannabinoids have been shown to protect the retina from ischemic/excitotoxic insults. The aim of the present study was to investigate the neuroprotective and anti-inflammatory properties of the synthetic cannabinoid (R)-WIN55,212-2 (CB1/CB2 receptor agonist) when administered acutely or subchronically in control and AMPA treated retinas. Sprague-Dawley rats were intravitreally administered (acutely) with vehicle or AMPA, in the absence or presence of (R)-WIN55,212-2 (10-7-10-4M) alone or in combination with AM251 [CB1 receptor antagonist/inverse agonist,10-4M] and AM630 (CB2 receptor antagonist,10-4M). In addition, AMPA was co-administered with the racemic (R,S)-WIN55,212 (10-4Μ). (R)-WIN55,212-2 was also administered subchronically (25,100 µg/kg,i.p.,4d) in control and AMPA treated rats. Immunohistochemical studies were performed using antibodies against the CB1R, and retinal markers for retinal neurons (brain nitric oxide synthetase, bNOS) and microglia (ionized calcium binding adaptor molecule 1, Iba1). ELISA assay was employed to assess TNFα levels in AMPA treated retinas. Intravitreal administration of (R)-WIN55,212-2 reversed the AMPA induced loss of bNOS expressing amacrine cells, an effect that was blocked by both AM251 and AM630. (R,S)WIN55,212 had no effect. (R)-WIN55,212-2 also reduced a) the AMPA induced activation of microglia, by activating CB2 receptors that were shown to be colocalized with Iba1+ reactive microglial cells, and b) TNFα levels in retina. (R)-WIN55,212-2 administered subchronically led to the downregulation of CB1 receptors at the high dose of 100 µg/kg(i.p.), and to the attenuation of the WIN55,212-2 induced neuroprotection of amacrine cells. At the same dose, (R)-WIN55,212-2 did not attenuate the AMPA induced increase in the number of reactive microglia cells, suggesting CB2 receptor downregulation under subchronic conditions. This study provides new findings regarding the role of CB1 and CB2 receptor activation by the synthetic cannabinoid (R)-WIN55,212-2, administered acutely or sub-chronically, on neuron viability and microglia activation in healthy and diseased retina.
Assuntos
Anti-Inflamatórios/administração & dosagem , Benzoxazinas/administração & dosagem , Morfolinas/administração & dosagem , Naftalenos/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Retina/metabolismo , Animais , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistas , Retina/efeitos dos fármacos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/toxicidadeRESUMO
The endocannabinoid/CB1R system as well as the central ghrelin signalling with its growth hormone secretagogoue receptors (GHS-R1A) are importantly involved in food intake and reward/reinforcement processing and show distinct overlaps in distribution within the relevant brain regions including the hypothalamus (food intake), the ventral tegmental area (VTA) and the nucleus accumbens (NAC) (reward/reinforcement). The significant mutual interaction between these systems in food intake has been documented; however, the possible role of ghrelin/GHS-R1A in the cannabinoid reinforcement effects and addiction remain unclear. Therefore, the principal aim of the present study was to investigate whether pretreatment with GHS-R1A antagonist/JMV2959 could reduce the CB1R agonist/WIN55,212-2-induced dopamine efflux in the nucleus accumbens shell (NACSh), which is considered a crucial trigger impulse of the addiction process. The synthetic aminoalklylindol cannabinoid WIN55,212-2 administration into the posterior VTA induced significant accumbens dopamine release, which was significantly reduced by the 3 mg/kg i.p. JMV2959 pretreatment. Simultaneously, the cannabinoid-increased accumbens dopamine metabolic turnover was significantly augmented by the JMV2959 pretreament. The intracerebral WIN55,212-2 administration also increased the endocannabinoid arachidonoylethanolamide/anandamide and the 2-arachidonoylglycerol/2-AG extracellular levels in the NACSh, which was moderately but significantly attenuated by the JMV2959 pretreatment. Moreover, the cannabinoid-induced decrease in accumbens γ-aminobutyric acid/gamma-aminobutyric acid levels was reversed by the JMV2959 pretreatment. The behavioural study in the LABORAS cage showed that 3 mg/kg JMV2959 pretreatment also significantly reduced the systemic WIN55,212-2-induced behavioural stimulation. Our results demonstrate that the ghrelin/GHS-R1A system significantly participates in the rewarding/reinforcing effects of the cannabinoid/CB1 agonist that are involved in cannabinoid addiction processing.
Assuntos
Benzoxazinas/administração & dosagem , Dopamina/metabolismo , Grelina/metabolismo , Glicina/análogos & derivados , Morfolinas/administração & dosagem , Naftalenos/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Triazóis/administração & dosagem , Animais , Ácidos Araquidônicos/metabolismo , Avaliação Pré-Clínica de Medicamentos , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Glicina/administração & dosagem , Masculino , Núcleo Accumbens/metabolismo , Alcamidas Poli-Insaturadas/metabolismo , Ratos Wistar , Ácido gama-Aminobutírico/metabolismoRESUMO
BACKGROUND: Smoking worsens underlying asthma inflammation and also induces resistance to inhaled corticosteroids (ICS). Small airways dysfunction measured by impulse oscillometry (IOS) is associated with worse control. OBJECTIVES: We investigated the effects on small airways of adding long-acting beta-agonist (LABA) alone or with long-acting muscarinic antagonist (LAMA) to ICS in asthmatic smokers. METHODS: Sixteen current smokers were enrolled: mean age 44 year, FEV1 84%, FEF25-75 47%, R5 158%, ACQ 1.69, 20 pack year . Patients were converted to a reference ICS as HFA-BDP during initial run-in at median dose of 800 µg/day. Open label olodaterol 5 µg od (OLO) or olodaterol 5 µg/tiotropium 5 µg od (OLO/TIO) was added to HFA-BDP for median duration of 3 weeks in a randomized cross over design, including run-in and washout periods on HFA-BDP. IOS and spirometry were measured after each treatment (BDP/OLO/TIO or BDP/OLO) and at baseline after run-in and washout (BDP). RESULTS: After chronic dosing, IOS outcomes at trough except for R20 were all significantly improved with OLO/TIO compared to OLO. For the primary end-point of total airway resistance (as R5), the mean difference (95%CI) at trough was 0.06 (0.015-0.10) kPa/l/s, peripheral airways resistance (as R5-R20) 0.03 (0.003-0.06) kPa/l/s, peripheral lung reactance area (as AX) 0.38 (0.08-0.68) kPa/l and resonant frequency (as RF) 2.28 (0.45-4.12) Hz. FEF25-75 at trough was also better with OLO/TIO vs TIO: 0.93 (0.86 - 0.95) l/s while FEV1 was not different. CONCLUSIONS: ICS/LABA/LAMA was superior to ICS/LABA on trough small airway outcomes in asthma patients who smoke.
Assuntos
Corticosteroides/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Benzoxazinas/administração & dosagem , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/administração & dosagem , Fumantes , Fumar/efeitos adversos , Brometo de Tiotrópio/administração & dosagem , Administração por Inalação , Corticosteroides/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Adulto , Antiasmáticos/efeitos adversos , Asma/diagnóstico , Asma/fisiopatologia , Benzoxazinas/efeitos adversos , Estudos Cross-Over , Combinação de Medicamentos , Feminino , Humanos , Pulmão/fisiopatologia , Masculino , Antagonistas Muscarínicos/efeitos adversos , Nebulizadores e Vaporizadores , Recuperação de Função Fisiológica , Escócia , Fumar/fisiopatologia , Fatores de Tempo , Brometo de Tiotrópio/efeitos adversos , Resultado do TratamentoRESUMO
INTRODUCTION: The assessment of the abuse potential of CNS-active drugs is a regulatory requirement. Drug discrimination is one of the nonclinical tests that contribute to this assessment by providing information on a drug's potential to induce a discriminative stimulus comparable to that of a known drug of abuse. AIM: The objective was to validate drug discrimination in the rat for the purpose of supporting regulatory submissions for novel drugs with potential cannabinoid-like activity. METHODS: Ten female Lister hooded rats were trained to discriminate no-drug from Δ9-THC (1.5 mg/kg, IP) under a FR10 schedule of reinforcement. Once trained, a Δ9-THC dose-response curve was obtained using doses of 0.25, 0.75, 1.5, and 3 mg/kg, IP. This was followed by evaluation of amphetamine (0.3 mg/kg, SC); morphine (3 mg/kg, IP); midazolam (2.5 mg/kg, PO); and the synthetic cannabinoids WIN55,212-2 (0.75 to 2 mg/kg, IP), CP-47,497 (0.5 to 2 mg/kg, IP), and JWH-018 (1 mg/kg, IP) for their discriminative stimulus similarity to Δ9-THC. RESULTS: Pharmacological specificity was demonstrated by achieving the anticipated dose-response curve for Δ9-THC, and a vehicle-like response for the non-cannabinoid drugs. Although full generalisation was obtained for JWH-018, in contrast to published literature, WIN55,212-2 and CP-47,497 failed to generalise to Δ9-THC. DISCUSSION: Based on the literature review performed in light of the results obtained, contrasting and unpredictable behavioural responses produced by cannabinoids in animals and humans raises the question of the reliability and relevance of including drug discrimination and self-administration studies within an abuse potential assessment for novel cannabinoid-like drugs.
Assuntos
Discriminação Psicológica/efeitos dos fármacos , Dronabinol/efeitos adversos , Transtornos Relacionados ao Uso de Substâncias/prevenção & controle , Anfetamina/administração & dosagem , Anfetamina/efeitos adversos , Animais , Benzoxazinas/administração & dosagem , Benzoxazinas/efeitos adversos , Cicloexanóis/administração & dosagem , Cicloexanóis/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Dronabinol/administração & dosagem , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Injeções Intraperitoneais , Midazolam/administração & dosagem , Midazolam/efeitos adversos , Morfina/administração & dosagem , Morfina/efeitos adversos , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Naftalenos/administração & dosagem , Naftalenos/efeitos adversos , Ratos , Reforço Psicológico , Reprodutibilidade dos Testes , Automedicação , Transtornos Relacionados ao Uso de Substâncias/diagnóstico , Transtornos Relacionados ao Uso de Substâncias/etiologiaRESUMO
BACKGROUND: The 2018 Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends combination long-acting muscarinic antagonists/long-acting beta2-agonists (LAMA + LABA) as preferred maintenance therapy for patients with symptomatic chronic obstructive lung disease (COPD) after monotherapy and stepping up to triple therapy (TT; LAMA + LABA + inhaled corticosteroids [ICS]) in case of further exacerbations. Restrictions on TT recommendations have primarily been driven by higher pneumonia risk associated with regular ICS use. Evidence suggests that TT is overprescribed, which may affect economic and clinical outcomes. OBJECTIVE: To compare health plan-paid costs, COPD exacerbations, and pneumonia diagnoses among patients newly treated with a LAMA + LABA regimen composed of tiotropium (TIO) + olodaterol (OLO) in a fixed-dose combination inhaler (TIO + OLO) or TT in a U.S. Medicare Advantage Part D insured population. METHODS: This retrospective study identified COPD patients aged ≥ 40 years who were initiating TIO + OLO or TT (index regimen) between January 1, 2014, and March 31, 2018, from a national administrative claims database. Continuous insurance coverage for 12 months pretreatment (baseline) and ≥ 30 days posttreatment (follow-up) was required. Patients were followed until the earliest of study end (May 31, 2018), discontinuation of index regimen (≥ 60-day gap in index regimen coverage), switch to a different regimen, or health plan disenrollment. Before analysis of outcomes, TIO + OLO and TT patients were 1:1 propensity score-matched on baseline demographics, comorbidities, COPD medication use, medical resource use, and costs. Cohort differences in post-match outcomes were assessed by Wald Z-test (annualized costs) and Kaplan-Meier method (time to first COPD exacerbation and pneumonia diagnosis). RESULTS: After matching, each cohort had 1,454 patients who were well balanced on baseline characteristics. Compared with TT, the TIO + OLO cohort incurred $7,041 (41.1%) lower mean COPD-related total costs ($10,094 vs. $17,135; P < 0.001); cohort differences in the medical component ($3,666 lower for TIO + OLO) were driven by lower mean acute inpatient costs ($3,053 lower for TIO + OLO). Combined mean COPD plus pneumonia-related medical costs were $5,212 (39.0%) lower for TIO + OLO versus TT ($8,209 vs. $13,421; P = 0.006), and total mean all-cause costs were $9,221 (30.4%) lower for TIO + OLO versus TT ($21,062 vs. $30,283; P < 0.001). Kaplan-Meier analysis found longer time to first severe COPD exacerbation (P = 0.020) and first pneumonia diagnosis (P = 0.002) for TIO + OLO versus TT and a lower percentage of TIO + OLO patients experiencing these events (severe COPD exacerbation: 9.0% vs. 16.1%; pneumonia: 14.5% vs. 19.3%). A secondary analysis, which expanded the TIO + OLO cohort to include any LAMA + LABA regimen, had similar findings for all outcomes. CONCLUSIONS: COPD patients initiating TIO + OLO incurred lower costs to health plans and experienced fewer COPD exacerbation and pneumonia events relative to TT. These findings provide important real-world economic and clinical insight into the GOLD recommendations for TIO + OLO and LAMA + LABA therapy. The study findings also indicate the continued inconsistency between the recommendations and real-world clinical practices pertaining to TT. DISCLOSURES: This study was sponsored by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). Palli and Franchino-Elder are employees of BIPI. Frazer, DuCharme, Buikema, and Anderson are employees of Optum, which was contracted by BIPI to conduct this study. The authors received no direct compensation related to the development of the manuscript. BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.
Assuntos
Benzoxazinas/administração & dosagem , Broncodilatadores/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Brometo de Tiotrópio/administração & dosagem , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Seguimentos , Glucocorticoides/administração & dosagem , Humanos , Masculino , Medicare Part D/economia , Pessoa de Meia-Idade , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/economia , Estudos Retrospectivos , Estados UnidosRESUMO
PURPOSE: The aim of the study was to evaluate organogel nanoparticles as a lipophilic vehicle to increase the oral bioavailability of poorly soluble compounds. Efavirenz (EFV), a Biopharmaceutical Classification System (BCS) Class II, was used as drug model. METHODS: Organogel nanoparticles loaded with EFV were formulated with sunflower oil, 12-hydroxystearic acid (HSA) and polyvinyl alcohol (PVA). Various parameters have been investigated in the current study such as (i) the release profile of organogel assessed by USP 4 cell flow dialysis, (ii) the impact of organogel on intestinal absorption, using Caco-2 cells as in vitro model and jejunum segments as ex vivo assay and (iii) the bioavailability of organogel following oral pharmacokinetic study. RESULTS: 250-300 nm spherical particles with a final concentration of 4.75 mg/mL drug loading were obtained, corresponding to a thousand fold increase in EFV solubility, combined to a very high encapsulation efficiency (>99.8%). Due to rapid diffusion, drug was immediately released from the nanoparticles. The biopharmaceutical evaluation on ex vivo jejunum segments demonstrated an increased absorption of EFV from organogel nanoparticles compare to a native EFV suspension. In vitro assays combining Caco-2 cell cultures with TEM and confocal microscopy demonstrated passive diffusion, while paracellular integrity and endocytosis activity remain expelled. Oral pharmacokinetics of EFV organogel nanoparticles improve oral bioavailability (Fr: 249%) and quick absorption compared to EFV suspension. CONCLUSION: Organogel nanoparticles increase the bioavailability of BCS Class II drugs. The main phenomena is simply oil transfer from the gelled particles through the cell membrane.
Assuntos
Benzoxazinas/química , Portadores de Fármacos/química , Géis/química , Nanocápsulas/química , Álcool de Polivinil/química , Ácidos Esteáricos/química , Óleo de Girassol/química , Alcinos , Animais , Benzoxazinas/administração & dosagem , Benzoxazinas/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Permeabilidade da Membrana Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclopropanos , Difusão , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Excipientes/química , Humanos , Absorção Intestinal , Masculino , Solubilidade , Suspensões/química , Distribuição TecidualRESUMO
The term ultra-LABA indicates once-daily ß2-AR agonists (abediterol, indacaterol, olodaterol and vilanterol) that are single enantiomers of the (R)-configuration. All have a near full-agonist profile at human ß2-AR. They can be prescribed in asthmatics only when associated with an with ICS, although further confirmations need to clarify what really these agents add if used in association to ICS and in what asthmatic patients this association may have more value. They are also under development in triple inhalers that include an ultra-LABA, a LAMA and an ICS. The once-daily posology might increase adherence in long-term treatment of asthma but superiority to twice-daily LABAs has not yet been fully demonstrated. In any case, still no ultra-LABA can be recommended as preferred.
Assuntos
Asma/tratamento farmacológico , Benzoxazinas/administração & dosagem , Álcoois Benzílicos/administração & dosagem , Clorobenzenos/administração & dosagem , Indanos/administração & dosagem , Quinolonas/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2 , Humanos , Cooperação do PacienteRESUMO
Multiple prevention therapy has gained importance for the prevention and treatment of sexually transmitted diseases, especially HIV/AIDS. Antiretroviral drugs encapsulated in nanoparticles have been developed for efficient delivery of the drugs to the vaginal surface. Lactoferrin nanoparticles (LFNPs) encapsulating anticancer or antiretroviral drugs are found to be promising agents to specifically deliver drugs at the target sites. Recent studies indicate that the bioavailability is higher for antiretroviral drugs delivered by LFNPs than when the drugs are administered alone. Although LFNP-mediated drug delivery via the oral or vaginal route for the treatment of HIV/AIDS is promising, the effect of such administrations is not well studied. Drug-loaded LFNPs when administered to rats by the vaginal route did not show any effect on the reproductive performance, fertility, and postnatal development. Oral administration of drug-loaded LFNPs caused a significant decrease in litter size, whereas the reproductive performance and postnatal development remained normal. In our model system, the results indicate that vaginal administration of drug-loaded LFNPs appears safer and can be projected for the delivery of antiretroviral agents via the vaginal route. Abbreviations: LFNPs: lactoferrin nanoparticles; STIs: sexually transmitted diseases infections; NPs: nanoparticles; LF: lactoferrin; DL-LFNPs: drug loaded lactoferrin nanoparticles; MPT: multiple prevention techniques.
Assuntos
Antirretrovirais/administração & dosagem , Benzoxazinas/administração & dosagem , Curcumina/administração & dosagem , Doenças Virais Sexualmente Transmissíveis/tratamento farmacológico , Administração Intravaginal , Alcinos , Animais , Ciclopropanos , Avaliação Pré-Clínica de Medicamentos , Feminino , Lactoferrina , Nanopartículas , Gravidez , RatosRESUMO
Biopharmaceutics classification systems based on the properties of solubility and permeability or the extension of metabolism are very important tools in the early stages of the development and regulatory stages of new products. However, until now, there was no clear understanding between the interplay among these classification systems. Therefore, the main objective of this work was to make a comparison of concepts of BCS and BDDCS to understand what are the key factors that allow for the integration of these biopharmaceutics classification systems. Also, the suitability of an in situ single-pass intestinal perfusion assay in rats (SPIP) development was assessed by us to determine the limit between high and low permeability following what the FDA BCS guidance suggests. An excellent correlation was found between the values of permeability obtained by applying SPIP assays and the extensions of the metabolism of the set of compounds studied in this work, with the exception of three compounds that showed disparity between their permeability coefficients ( Peff), obtained herein by SPIP, and their metabolism (acetazolamide, azithromycin, and efavirenz). Discrepancies allowed us to elucidate the interrelationship between BCS and BDDCS.
Assuntos
Bioensaio/métodos , Biofarmácia/classificação , Mucosa Intestinal/metabolismo , Acetazolamida/administração & dosagem , Acetazolamida/química , Acetazolamida/farmacocinética , Administração Oral , Alcinos , Animais , Azitromicina/administração & dosagem , Azitromicina/química , Azitromicina/farmacocinética , Benzoxazinas/administração & dosagem , Benzoxazinas/química , Benzoxazinas/farmacocinética , Disponibilidade Biológica , Clopidogrel/administração & dosagem , Clopidogrel/química , Clopidogrel/farmacocinética , Ciclopropanos , Avaliação Pré-Clínica de Medicamentos/métodos , Estudos de Viabilidade , Absorção Intestinal , Perfusão/métodos , Permeabilidade , Ratos , SolubilidadeRESUMO
BACKGROUND: Cannabinoids have been used for their analgesic and euphoric effects for millennia, but recently the antipruritic effects of cannabis have been discovered. Considering the similarities between pain and itch sensations, we hypothesized that cannabinoid receptors may play a role in the antipruritic effects of cannabinoids. AIM: To analyse the role of the spinal cannabinoid receptors, CB1 and CB2, in the antipruritic effects of the cannabinoid agonist WIN 55,212-2. METHODS: Male Balb/c mice weighing 20-30 g were used. Scratching behaviour in the mice was produced by injection of serotonin 5 µg/50 µL intradermally into the nape of the neck. Scratching of the site of injection by the hind paws was video-recorded for 30 min. After testing different doses of WIN 55,212-2 [1, 3 and 10 mg/kg intraperitoneally (IP)], the effects of the CB1 receptor antagonist, AM-251 [1 µg/mouse administered intrathecally (IT)] and the CB2 receptor antagonist AM-630 (4 µg/mouse IT) on the antipruritic effects of WIN 55,212-2 were studied using a rotarod apparatus. RESULTS: WIN 55,212-2 (1, 3 or 10 mg/kg IP) dose-dependently decreased serotonin-induced scratches. The receptor antagonist CB1 partially reversed the effects of WIN 55,212-2 (P < 0.05); whereas CB2 had no statistically significant effect. WIN 55,212-2 impaired motor function only at the highest dose given (10 mg/kg, P < 0.05). CONCLUSIONS: Our findings support prior researches indicating that cannabinoids exert antipruritic effects. Moreover, our results show that the antipruritic effects of cannabinoids are partially mediated by spinal CB1 receptors.
Assuntos
Benzoxazinas/uso terapêutico , Agonistas de Receptores de Canabinoides/uso terapêutico , Morfolinas/uso terapêutico , Naftalenos/uso terapêutico , Prurido/tratamento farmacológico , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Medula Espinal/metabolismo , Animais , Benzoxazinas/administração & dosagem , Agonistas de Receptores de Canabinoides/administração & dosagem , Antagonistas de Receptores de Canabinoides/farmacologia , Relação Dose-Resposta a Droga , Indóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Morfolinas/administração & dosagem , Naftalenos/administração & dosagem , Piperidinas/farmacologia , Prurido/induzido quimicamente , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/antagonistas & inibidores , SerotoninaRESUMO
OBJECTIVES: To analyze the cost effectiveness of short-cycle therapy (SCT), where patients take antiretroviral (ARV) drugs 5 consecutive days a week and have 2 days off, as an alternative to continuous ARV therapy for young people infected with human immunodeficiency virus (HIV) and taking efavirenz-based first-line ARV drugs. METHODS: We conduct a hierarchical cost-effectiveness analysis based on data on clinical outcomes and resource use from the BREATHER trial. BREATHER is a randomized trial investigating the effectiveness of SCT and continuous therapy in 199 participants aged 8 to 24 years and taking efavirenz-based first-line ARV drugs in 11 countries worldwide. Alongside nationally representative unit costs/prices, these data were used to estimate costs and quality adjusted life years (QALYs). An incremental cost-effectiveness comparison was performed using a multilevel bivariate regression approach for total costs and QALYs. Further analyses explored cost-effectiveness in low- and middle-income countries with access to low-cost generic ARV drugs and high-income countries purchasing branded ARV drugs, respectively. RESULTS: At 48 weeks, SCT offered significant total cost savings over continuous therapy of US dollar (USD) 41 per patient in countries using generic drugs and USD 4346 per patient in countries using branded ARV drugs, while accruing nonsignificant total health benefits of 0.008 and 0.009 QALYs, respectively. Cost-effectiveness estimates were similar across settings with access to generic ARV drugs but showed significant variation among high-income countries where branded ARV drugs are purchased. CONCLUSION: SCT is a cost-effective treatment alternative to continuous therapy for young people infected with HIV in countries where viral load monitoring is available.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/economia , Análise Custo-Benefício , Infecções por HIV/tratamento farmacológico , Infecções por HIV/economia , Adolescente , Alcinos , Benzoxazinas/administração & dosagem , Benzoxazinas/economia , Criança , Ciclopropanos , Esquema de Medicação , Medicamentos Genéricos/administração & dosagem , Medicamentos Genéricos/economia , Seguimentos , Custos de Cuidados de Saúde , Humanos , Internacionalidade , Anos de Vida Ajustados por Qualidade de Vida , Análise de Regressão , Resultado do Tratamento , Carga Viral , Adulto JovemAssuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Inaladores de Pó Seco , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Benzoxazinas/administração & dosagem , Preparações de Ação Retardada , Combinação de Medicamentos , Volume Expiratório Forçado , Glicopirrolato/administração & dosagem , Humanos , Indanos/administração & dosagem , Masculino , Quinolonas/administração & dosagem , Brometo de Tiotrópio/administração & dosagem , Capacidade VitalRESUMO
PURPOSE OF REVIEW: Recent updates to the GOLD guidelines emphasize the use of combination LABA and LAMA bronchodilators for patients with chronic obstructive pulmonary disease with persistent dyspnea despite monotherapy or frequent exacerbations despite LAMA monotherapy. There are several commercially available LABA/LAMA fixed dose combination inhalers, which are likely to become the principle therapy for many patients with COPD. RECENT FINDINGS: In the last 4 years, there have been a number of large clinical trials evaluating the efficacy and safety of combined LAMA and LABA bronchodilators. LAMA/LABA fixed dose combination therapies have consistently demonstrated clinically significant improvements to airway obstruction, dyspnea, and quality of life whenever compared with placebo, and more modest improvements compared with bronchodilator monotherapies and combined bronchodilator/inhaled corticosteroid therapy. SUMMARY: New guidelines emphasize combination bronchodilators as a mainstay of therapy for many patients with symptomatic COPD and there are several new combination bronchodilator therapies available to patients. It is important for physicians and patients to understand the range and degree of expected clinical effects and the safety profiles of these new medications.
Assuntos
Benzoxazinas/uso terapêutico , Broncodilatadores/uso terapêutico , Glicopirrolato/uso terapêutico , Indanos/uso terapêutico , Antagonistas Muscarínicos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinolonas/uso terapêutico , Brometo de Tiotrópio/uso terapêutico , Administração por Inalação , Benzoxazinas/administração & dosagem , Álcoois Benzílicos/uso terapêutico , Broncodilatadores/administração & dosagem , Clorobenzenos/uso terapêutico , Preparações de Ação Retardada , Combinação de Medicamentos , Fumarato de Formoterol/uso terapêutico , Glicopirrolato/administração & dosagem , Humanos , Indanos/administração & dosagem , Antagonistas Muscarínicos/administração & dosagem , Guias de Prática Clínica como Assunto , Quinolonas/administração & dosagem , Quinuclidinas/uso terapêutico , Brometo de Tiotrópio/administração & dosagem , Tropanos/uso terapêuticoRESUMO
INTRODUCTION: We report the results of the first direct comparison of the once-daily fixed-dose long-acting muscarinic antagonist/long-acting ß2-agonist (LAMA/LABA) combinations umeclidinium/vilanterol (UMEC/VI) and tiotropium/olodaterol (TIO/OLO) in patients with COPD. METHODS: This was a randomized, two-period crossover open-label study in symptomatic patients with COPD [age 40 years or older, postbronchodilator forced expiratory volume in 1 s (FEV1) of 70% or less and 50% or more of predicted normal values, and modified Medical Research Council Dyspnoea Scale score of 2 or greater] not receiving inhaled corticosteroid therapy. Patients were randomized to receive UMEC/VI (62.5/25 µg once daily) via a multidose dry powder inhaler (ELLIPTA) followed by TIO/OLO (5/5 µg once daily) via a soft mist inhaler (Respimat), each for 8 weeks with an interim 3-week washout or vice versa. The primary end point was the change from baseline in trough FEV1 at week 8 with a noninferiority margin of - 50 mL in the per-protocol (PP) population. The incidence of adverse events was also assessed. RESULTS: In total, 236 patients (mean age 64.4 years, 60% male) were included in the intent-to-treat population and 227 were included in the PP population. UMEC/VI treatment was noninferior in the PP population and superior in the intent-to-treat population to TIO/OLO treatment with regard to trough FEV1 at week 8 [FEV1 change from baseline 180 mL vs 128 mL; difference 52 mL (95% confidence interval 28-77 mL); p < 0.001]. Patients receiving UMEC/VI had twofold increased odds of experiencing a clinically meaningful increase (100 mL or more) from baseline in trough FEV1 at week 8 compared with patients receiving TIO/OLO (odds ratio 2.05; 95% confidence interval 1.34-3.14). Adverse events occurred in 25% of patients in the UMEC/VI group and in 31% of patients in the TIO/OLO group. CONCLUSION: In this first direct comparison of two once-daily fixed-dose LAMA/LABA combinations, superiority was observed for the primary end point of trough FEV1 at week 8 with UMEC/VI compared with TIO/OLO in patients with symptomatic COPD. Both treatments had similar safety profiles. These findings confirm the results of previous indirect LAMA/LABA comparisons, and show that an efficacy gradient exists within the LAMA/LABA class. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02799784. FUNDING: GlaxoSmithKline.
Assuntos
Benzoxazinas/uso terapêutico , Álcoois Benzílicos/uso terapêutico , Broncodilatadores/uso terapêutico , Clorobenzenos/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Quinuclidinas/uso terapêutico , Brometo de Tiotrópio/uso terapêutico , Administração por Inalação , Idoso , Benzoxazinas/administração & dosagem , Álcoois Benzílicos/administração & dosagem , Broncodilatadores/administração & dosagem , Clorobenzenos/administração & dosagem , Estudos Cross-Over , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Nebulizadores e Vaporizadores , Quinuclidinas/administração & dosagem , Brometo de Tiotrópio/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: Several neuropsychiatric adverse effects of efavirenz are known. Preventing these adverse effects may improve patients' adherence to antiretroviral therapy (ART). OBJECTIVES: To evaluate the efficacy and safety of valerian in preventing neuropsychiatric adverse effects of efavirenz in HIV-positive patients. METHOD: In this pilot randomized, double-blinded, placebo-controlled, clinical trial, 51 HIV-positive patients who were receiving efavirenz were recruited into the valerian (n = 25) or placebo (n = 26) group. Patients received valerian (530 mg) or placebo nightly 1 hour before sleep for 4 weeks. The neuropsychiatric status (sleep, anxiety, depression, suicidal thought, and psychosis) of patients was assessed at baseline and week 4 using validated questionnaires. RESULTS: Sleep ( P ≤ 0.001) and anxiety ( P = 0.001) significantly improved in the valerian group compared with the placebo group. Dizziness was the most common complaint of patients in first days of the intervention. In the valerian and placebo groups, 92% and 84.6% of patients experienced dizziness, respectively ( P = 0.35). Nausea was the second common adverse effect that 84% and 76.9% of patients in the valerian and placebo groups experienced ( P = 0.39). CONCLUSION: In the first 4 weeks of ART including efavirenz, valerian significantly improved sleep and anxiety in HIV-positive patients. Valerian may be considered as a potential option in preventing neuropsychiatric adverse effects of efavirenz in HIV-positive patients.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Benzoxazinas/efeitos adversos , Infecções por HIV/tratamento farmacológico , Valeriana/química , Adulto , Alcinos , Fármacos Anti-HIV/uso terapêutico , Ansiedade/tratamento farmacológico , Benzoxazinas/administração & dosagem , Ciclopropanos , Depressão/tratamento farmacológico , Método Duplo-Cego , Feminino , Humanos , Hipnóticos e Sedativos/uso terapêutico , Masculino , Cooperação do Paciente , Projetos PilotoRESUMO
INTRODUCTION: The superiority of tiotropium/olodaterol is demonstrated in improvement of lung function, dyspnea, lung hyperinflation, and quality of life compared with either monotherapy in patients with chronic obstructive pulmonary disease (COPD). Japanese Respiratory Society Guidelines for COPD management include improvement of exercise tolerance and daily physical activity as the treatment goals; however, there is limited evidence in Japanese patients with COPD. METHODS: A protocol is developed for the VESUTO® study that investigates the efficacy of tiotropium/olodaterol fixed-dose combination (FDC) compared with tiotropium alone on inspiratory capacity (IC, volume from functional residual capacity to total lung capacity), exercise capacity, and daily physical activity in Japanese patients with COPD. RESULTS: A total of 180 Japanese patients with COPD, aged ≥40 years will be enrolled into the double-blind, multicenter, active-controlled, crossover study (NCT02629965) and will be randomized to receive either tiotropium/olodaterol FDC or tiotropium for 6 weeks each [two puffs via RESPIMAT® (Boehringer Ingelheim, Ingelheim, Germany) inhaler in the morning]. The primary endpoint is IC at rest measured at 60 min post-dose after 6 weeks treatment. The secondary endpoints include the 6-min walk distance (6MWD) at 90 min post-dose and physical activity measured by the activity monitor in the last 2 weeks of the 6-week treatment periods. Lung function tests will also be assessed after 6 weeks treatment. A mixed-effects model repeated measures approach will be used for the primary and secondary endpoints. CONCLUSION: The VESUTO® study is the first randomized interventional study to investigate exercise capacity (6MWD) and physical activity measured by a 3-axis accelerometer in Japanese patients with COPD. The study could provide additional evidence of long-acting muscarinic antagonist (LAMA) + long-acting ß2-agonist (LABA) combination therapy on patients' physical activities as well as lung function. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02629965 (registered on December 1, 2015). FUNDING: The VESUTO study was funded by Nippon Boehringer Ingelheim Co., Ltd., Tokyo, Japan.
Assuntos
Benzoxazinas/administração & dosagem , Benzoxazinas/uso terapêutico , Broncodilatadores/uso terapêutico , Tolerância ao Exercício/efeitos dos fármacos , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Brometo de Tiotrópio/administração & dosagem , Brometo de Tiotrópio/uso terapêutico , Administração por Inalação , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Testes de Função RespiratóriaRESUMO
Objectives: We compared the pharmacokinetics of moxifloxacin during rifampicin co-treatment or when dosed alone in African patients with drug-susceptible recurrent TB. Methods: Patients in the intervention arm of the Improving Retreatment Success (IMPRESS) randomized controlled TB trial received 400â mg of moxifloxacin, with rifampicin, isoniazid and pyrazinamide in the treatment regimen. Moxifloxacin concentrations were measured in plasma during rifampicin-based TB treatment and again 4â weeks after treatment completion, when given alone as a single dose. Moxifloxacin concentration-time data were analysed using non-linear mixed-effects models. Results: We included 58 patients; 42 (72.4%) were HIV co-infected and 40 (95%) of these were on efavirenz-based ART. Moxifloxacin pharmacokinetics was best described using a two-compartment disposition model with first-order lagged absorption and elimination using a semi-mechanistic model describing hepatic extraction. Oral clearance (CL/F) of moxifloxacin during rifampicin-based TB treatment was 24.3â L/h for a typical patient (fat-free mass of 47â kg), resulting in an AUC of 16.5â mg·h/L. This exposure was 7.8% lower than the AUC following the single dose of moxifloxacin given alone after TB treatment completion. In HIV-co-infected patients taking efavirenz-based ART, CL/F of moxifloxacin was increased by 42.4%, resulting in a further 30% reduction in moxifloxacin AUC. Conclusions: Moxifloxacin clearance was high and plasma concentrations low in our patients overall. Moxifloxacin AUC was further decreased by co-administration of efavirenz-based ART and, to a lesser extent, rifampicin. The clinical relevance of the low moxifloxacin concentrations for TB treatment outcomes and the need for moxifloxacin dose adjustment in the presence of rifampicin and efavirenz co-treatment need further investigation.
Assuntos
Antibióticos Antituberculose/uso terapêutico , Benzoxazinas/uso terapêutico , Fluoroquinolonas/farmacocinética , Infecções por HIV/complicações , Rifampina/uso terapêutico , Tuberculose Pulmonar/complicações , Tuberculose Pulmonar/tratamento farmacológico , Adulto , África , Alcinos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Antibióticos Antituberculose/administração & dosagem , Antibióticos Antituberculose/efeitos adversos , Antibióticos Antituberculose/farmacocinética , Benzoxazinas/administração & dosagem , Benzoxazinas/sangue , Coinfecção/tratamento farmacológico , Coinfecção/microbiologia , Coinfecção/virologia , Ciclopropanos , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Fluoroquinolonas/administração & dosagem , Fluoroquinolonas/sangue , Fluoroquinolonas/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Masculino , Moxifloxacina , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/uso terapêutico , Rifampina/administração & dosagem , Rifampina/efeitos adversos , Rifampina/sangue , Tuberculose Pulmonar/metabolismo , Tuberculose Pulmonar/microbiologiaRESUMO
Hypothalamic oxytocin (OXT) and arginine vasopressin (AVP) are known to act oppositely on hypothalamic-pituitary-adrenal (HPA) axis, stress response and gastrointestinal (GI) motility. In rodents, exposure to restraint stress (RS) delays gastric emptying (GE), however, repeated exposure to the same stressor (chronic homotypic stress (CHS)), the delayed GE is restored to basal level, while hypothalamic OXT is upregulated. In contrast, when rats are exposed to chronic heterotypic stress (CHeS), these adaptive changes are not observed. Although the involvement of central OXT in gastric motor adaptation is partly investigated, the role of hypothalamic AVP in CHeS-induced maladaptive paradigm is poorly understood. Using in-vivo brain microdialysis in rats, the changes OXT and AVP release from hypothalamus were monitored under basal non-stressed (NS) conditions and in rats exposed to acute stress (AS), CHS and CHeS. To investigate the involvement of central endogenous OXT or AVP in CHS-induced habituation and CHeS-induced maladaptation, chronic central administration of selective OXT receptor antagonist L-371257 and selective AVP V1b receptor antagonist SSR-149415 was performed daily. OXT was measured higher in AS and CHS group, but not in CHeS-loaded rats, whereas AVP significantly increased in rats exposed to AS and CHeS. Additionally, the response of the hypothalamic OXT- and AVP-producing cells was amplified following CHS and CHeS, respectively. In rats exposed to AS for 90min solid GE significantly delayed. The delayed-GE was completely restored to the basal level following CHS, however, it remained delayed in CHeS-loaded rats. The CHS-induced restoration was prevented by L-371257, whereas SSR-149415 abolished the CHeS-induced impaired GE. A significant correlation was observed between GE and (i) OXT in CHS-loaded rats (rho=0.61, p<0.05, positively), (ii) AVP in CHeS-loaded rats (rho=0.69, p<0.05, negatively). Under long term stressed conditions, the release of AVP and OXT from hypothalamus may vary depending on the content of the stressors. Central AVP appears to act oppositely to OXT by mediating CHeS-induced gastric motor maladaptation. Long term central AVP antagonism might be a pharmacological approach for the treatment of stress-related gastric motility disorders.