RESUMEN
The impact of tolvaptan and low-dose dopamine on heart failure (HF) patients with acute kidney injury (AKI) remains uncertain from a clinical standpoint.HF patients with AKI were selected and divided in a 1:1 fashion into the dopamine combined with the tolvaptan group (DTG), the tolvaptan group (TG), and the control group (CG). According to the standard of care, TG received tolvaptan 15 mg orally daily for a week. DTG received combination treatment, including 7 consecutive days of dopamine infusion (2 µg/kgã»minutes) and oral tolvaptan 15 mg. Venous blood and urine samples were taken before and after therapy. The primary endpoint was the cardiorenal serological index after 7 days of treatment.Sixty-five patients were chosen randomly for the DTG (22 patients), TG (20 patients), and CG (23 patients), which were similar before the treatment. The serum indexes related to cardiac function (N-terminal probrain natriuretic peptide and cardiac troponin I) in DTG were decreased, compared with TG and CG (P < 0.05). Furthermore, the serological markers of renal function (serum cystatin C, serum creatinine, and neutrophil gelatinase-associated lipocalin) in DTG were lower than those in TG and CG (P < 0.05). There was no significant difference in the incidence of adverse reactions among groups.Low-dose dopamine combined with tolvaptan can markedly improve patients' cardiac and renal function. This may be considered a new therapeutic method for HF patients with AKI.
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Lesión Renal Aguda , Antagonistas de los Receptores de Hormonas Antidiuréticas , Dopamina , Quimioterapia Combinada , Insuficiencia Cardíaca , Tolvaptán , Humanos , Tolvaptán/administración & dosificación , Tolvaptán/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/complicaciones , Masculino , Femenino , Dopamina/administración & dosificación , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/etiología , Anciano , Persona de Mediana Edad , Antagonistas de los Receptores de Hormonas Antidiuréticas/administración & dosificación , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Péptido Natriurético Encefálico/sangre , Resultado del Tratamiento , Benzazepinas/administración & dosificación , Fragmentos de Péptidos/sangreRESUMEN
The aim of the study was to investigate the stress-reducing effect of a casozepine before a veterinary examination in dogs. It should be examined whether the dogs are less stressed during a standardized veterinary examination after an oral application of casozepine over 2 days and whether the administration has an influence on the salivary concentrations of the stress hormones vasopressin and cortisol. Across the study group (n=36), a significantly lower stress score (P=0.0026) and lower mean (P=0.01) and maximum (P=0.024) pulse rates were seen at follow-up after casozepine administration, in contrast to the placebo group (n=26). Salivary vasopressin concentrations increased during follow-up in the placebo group (P=0.04), whereas they remained the same in the casozepine group. Cortisol concentrations increased during follow-up in the casozepin group (P=0.01). The results indicate that although dogs in both groups remained excited at follow-up, short-term casozepine administration before a veterinary visit had a weak stress-reducing effect in dogs based on subjective stress scoring and pulse rate.
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Hidrocortisona , Estrés Psicológico , Animales , Perros , Masculino , Femenino , Benzazepinas/farmacología , Benzazepinas/administración & dosificación , Benzazepinas/uso terapéutico , Saliva/química , Vasopresinas/administración & dosificación , ImidazolesRESUMEN
Balovaptan is a brain-penetrating vasopressin receptor 1a antagonist previously investigated for the core symptoms of autism spectrum disorder (ASD). A population pharmacokinetic (PK) model of balovaptan was developed, initially to assist clinical dosing for adult and pediatric ASD studies and subsequently for new clinical indications including malignant cerebral edema (MCE) and post-traumatic stress disorder. The final model incorporates one-compartment disposition and describes time- and dose-dependent non-linear PK through empirical drug binding and a gut extraction component with turnover. An age effect on clearance observed in children was modeled by an asymptotic function that predicts adult-equivalent exposures at 40% of the adult dose for children aged 2-4 years, 70% for 5-9 years, and at the full adult dose for ≥ 10 years. The model was adapted for intravenous (IV) balovaptan dosing and combined with in vitro and ex vivo pharmacodynamic data to simulate brain receptor occupancy as a guide for dosing in a phase II trial of MCE prophylaxis after acute ischemic stroke. A sequence of three stepped-dose daily infusions of 50, 25 and 15 mg over 30 or 60 min was predicted to achieve a target occupancy of ≥ 80% in ≥ 95% of patients over a 3-day period. This model predicts both oral and IV balovaptan exposure across a wide age range and will be a valuable tool to analyze and predict its PK in new indications and target populations, including pediatric patients.
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Relación Dosis-Respuesta a Droga , Modelos Biológicos , Humanos , Niño , Preescolar , Adulto , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacocinética , Antagonistas de los Receptores de Hormonas Antidiuréticas/administración & dosificación , Adolescente , Masculino , Femenino , Benzazepinas/farmacocinética , Benzazepinas/administración & dosificación , Adulto Joven , Edema Encefálico/tratamiento farmacológico , Persona de Mediana Edad , Encéfalo/metabolismo , Encéfalo/efectos de los fármacosRESUMEN
BACKGROUND: Growth differentiation factor 15 (GDF-15) is a stress-response cytokine proposed to be associated with body weight regulation. AIMS: The primary aim was to investigate changes of circulating intact GDF-15 (wildtype, non-carrier of the rs1058587 polymorphism coding for the H2O2D mutation) and total GDF-15 (measured irrespective of the mutation) in response to liraglutide (GLP-1 receptor agonist) and lorcaserin (5-HT2C receptor agonist), two pharmacologic agents that induce food intake and weight reduction. In addition, we perform exploratory correlations of total and intact GDF-15 with clinical, hormonal and metabolo-lipidomic parameters in humans with obesity. MATERIALS AND METHODS: We utilized two studies: 1) Study 1, a randomized, double-blinded, cross-over trial of liraglutide and placebo administration for 5 weeks in subjects with obesity (n = 20; BMI = 35.6 ± 5.9 kg/m2), in escalating doses starting at 0.6 mg/day on week 1 and increased every week, up to the highest dose of 3.0 mg/day during week 5. b) Study 2, a randomized, double-blinded trial of lorcaserin 10 mg twice daily, or placebo for 12-weeks in humans with obesity (n = 34 BMI = 37.4 ± 6.1 kg/m2). Total and intact GDF-15 levels were measured with novel enzyme-linked immunosorbent assays and the metabolomics and lipidomics analysis was performed with nuclear magnetic resonance spectroscopy. RESULTS: Total and intact GDF-15 were positively correlated with diabetes risk index and trimethylamine N-oxide and negatively with eGFR. Despite significant changes in body weight, total and intact GDF-15 were not altered in response to liraglutide or lorcaserin treatment in subjects with obesity. CONCLUSIONS: Total and intact GDF-15 levels are not altered in response to liraglutide or lorcaserin therapy and are thus not directly involved in the metabolic feedback loop pathways downstream of GLP1 or 5-HT2C receptor agonists. Since neither total nor intact GDF-15 levels were altered in response to weight loss, future studies are needed to elucidate the pathways activated by GDF-15 in humans and its role, if any, in body weight regulation and energy homeostasis.
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Benzazepinas , Factor 15 de Diferenciación de Crecimiento , Liraglutida , Obesidad , Benzazepinas/administración & dosificación , Peso Corporal , Método Doble Ciego , Factor 15 de Diferenciación de Crecimiento/sangre , Humanos , Liraglutida/administración & dosificación , Obesidad/sangre , Obesidad/tratamiento farmacológico , Receptor de Serotonina 5-HT2C/metabolismo , Agonistas del Receptor de Serotonina 5-HT2/administración & dosificación , Pérdida de PesoRESUMEN
Cannabidiol, as component of cannabis, can potentially hinder the rewarding impact of drug abuse; however, its mechanism is ambiguous. Moreover, the nucleus accumbens (NAc), as a key area in the reward circuit, extensively receives dopaminergic projections from the ventral tegmentum area. To elucidate the role of accumbal D1 and D2 dopamine receptor families in Cannabidiol's inhibitory impact on the acquisition and expression phases of methamphetamine (MET), the conditioned place preference (CPP) procedure as a common method to assay reward characteristics of drugs was carried out. Six groups of rats were treated by various doses of SCH23390 or Sulpiride (0.25, 1, and 4 µg/0.5 µL) in the NAc as D1 or D2 dopamine receptor family antagonists, respectively, prior to infusion of Cannabidiol (10 µg/5 µL) in the lateral ventricle (LV) over conditioning phase in the acquisition experiments. In the second step of the study, animals received SCH23390 or Sulpiride in the NAc before Cannabidiol (50 µg/5 µL) infusion into the LV in the expression phase of MET to illuminate the influence of SCH23390 or Sulpiride on the inhibitory impact of Cannabidiol on the expression of MET-induced CPP. Intra-NAc administration of either SCH23390 or Sulpiride impaired Cannabidiol's suppressive impact on the expression phase, while just Sulpiride could suppress the Cannabidiol's impact on the acquisition phase of the MET-induced CPP. Also, the inhibitory impact of Sulpiride was stranger in both phases of MET reward. It seems that Cannabidiol prevents the expression and acquisition phases of MET-induced CPP partly through the dopaminergic system in the NAc.
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Cannabidiol , Condicionamiento Clásico , Metanfetamina/farmacología , Núcleo Accumbens/efectos de los fármacos , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D2/efectos de los fármacos , Recompensa , Animales , Benzazepinas/administración & dosificación , Cannabidiol/administración & dosificación , Cannabidiol/farmacología , Antagonistas de Dopamina/administración & dosificación , Masculino , Ratas , Sulpirida/administración & dosificación , Área Tegmental Ventral/efectos de los fármacosRESUMEN
Notch signaling plays an important role in development and tissue homeostasis. Deregulation of Notch signaling has been implicated in multiple malignancies. Crenigacestat (LY3039478), a potent Notch inhibitor, decreases Notch signaling and its downstream biologic effects. I6F-MC-JJCD was a multicenter, nonrandomized, open-label, Phase 1b study with 5 separate, parallel dose-escalations in patients with advanced or metastatic cancer from a variety of solid tumors, followed by a dose-confirmation phase in prespecified tumor types. This manuscript reports on 3 of 5 groups. The primary objective was to determine the recommended Phase 2 dose of crenigacestat in combination with other anticancer agents (taladegib, LY3023414 [dual inhibitor of phosphoinositide 3-kinase; mechanistic target of rapamycin], or abemaciclib). Secondary objectives included evaluation of safety, tolerability, efficacy, and pharmacokinetics. Patients (N = 63) received treatment between November 2016 and July 2019. Dose-limiting toxicities occurred in 12 patients, mostly gastrointestinal (diarrhea, nausea, vomiting). The maximum-tolerated dose of crenigacestat was 25 mg in Part B (LY3023414), 50 mg in Part C (abemaciclib), and not established in Part A (taladegib) due to toxicities. Patients had at least 1 adverse event (AE) and 75.0-82.6% were ≥ Grade 3 all-causality AEs. No patient had complete or partial response. Disease control rates were 18.8% (Part B) and 26.1% (Part C). The study was terminated before dose confirmation cohorts were triggered. This study demonstrated that crenigacestat combined with different anticancer agents (taladegib, LY3023414, or abemaciclib) was poorly tolerated, leading to lowered dosing and disappointing clinical activity in patients with advanced or metastatic solid tumors. NCT02784795 and date of registration: May 27, 2016.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias/tratamiento farmacológico , Aminopiridinas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Benzazepinas/administración & dosificación , Bencimidazoles/administración & dosificación , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/patología , Ftalazinas/administración & dosificación , Piridinas/administración & dosificación , Quinolonas/administración & dosificaciónRESUMEN
Preclinical data have shown that treatment with serotonin (5-HT)2C receptor agonists inhibits the behavioral effects of nicotine, including self-administration, reinstatement, and locomotor responses to nicotine. Since the data on the effects of 5-HT2C receptor agonism on nicotine withdrawal signs are limited, we aimed to investigate whether 5-HT2C receptor agonism alleviated the behavioral and neurobiochemical (hippocampal neurogenesis) consequences of nicotine withdrawal in Sprague-Dawley rats. Our data indicate that withdrawal from nicotine self-administration induced locomotor hyperactivity, lengthened immobility time (the forced swim test), induced 'drug-seeking' behavior and deficits in cognition-like behavior (the novel object recognition task). A two-week exposure to the 5-HT2C receptor agonist lorcaserin attenuated locomotor hyperactivity and induced recovery from depression-like behavior. Analyses of brain slices from nicotine-withdrawn animals revealed that lorcaserin treatment recovered the reduced number of doublecortin (DCX)-positive cells, but it did not affect the number of Ki-67- or 5-bromo-2'-deoxyuridine (BrdU)-positive cells or the maturation of proliferating neurons in drug-weaned rats. To summarize, we show that lorcaserin alleviated locomotor responses and depression-like state during nicotine withdrawal. We propose that the modulatory effect of lorcaserin on the 'affective' aspects of nicotine cessation may be linked to the positive changes caused by the compound in hippocampal neurogenesis during nicotine withdrawal.
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Benzazepinas/uso terapéutico , Hipocampo/efectos de los fármacos , Nicotina/efectos adversos , Agonistas de Receptores de Serotonina/uso terapéutico , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Animales , Benzazepinas/administración & dosificación , Benzazepinas/farmacología , Proteína Doblecortina , Comportamiento de Búsqueda de Drogas , Hipocampo/citología , Hipocampo/crecimiento & desarrollo , Locomoción , Masculino , Neuronas/citología , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Agonistas de Receptores de Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
BACKGROUND: Deregulated Notch signaling is implicated in T-cell acute lymphoblastic leukemia (T-ALL)/T-cell lymphoblastic lymphoma (T-LBL). Crenigacestat (LY3039478) prevents cleavage of Notch proteins and may benefit patients with relapsed/refractory T-ALL/T-LBL. METHODS: JJCB was a multicenter, nonrandomized, open-label, dose-escalation, phase 1 study in adult patients with relapsed/refractory T-ALL/T-LBL. Eligible patients received Crenigacestat orally 3 times per week plus dexamethasone at 24 mg twice daily on days 1 to 5 every other week in a 28-day cycle. The starting level of Crenigacestat was 50 mg, and dose escalation was performed with a modified 3+3 scheme for the estimation of dose-limiting toxicity (DLT) at the recommended dose level. RESULTS: In total, 36 patients with T-ALL (n = 31 [86.1%]) or T-LBL (n = 5 [13.9%]) were treated with Crenigacestat and dexamethasone. Six patients (16.7%) experienced DLTs: 2 of 12 (16.7%) in the 75-mg cohort (grade 4 gastrointestinal hemorrhage and grade 3 nausea, vomiting, and diarrhea), 1 of 15 (6.7%) in the 100-mg cohort (grade 3 diarrhea), and 3 of 3 (100%) in the 125-mg cohort (grade 3 diarrhea, nausea, and vomiting). The maximum tolerated dosewas 75 mg plus 24 mg of dexamethasone daily on days 1 to 5. Twenty-eight patients (77.8%) experienced 1 or more treatment-emergent adverse events related to the study treatment. The best overall response was a confirmed response, with 1 patient (2.8%) having a duration of response of 10.51 months. Six patients (16.7%) achieved stable disease, and 12 patients (33.3%) experienced progressive disease. The remaining 17 patients (47.2%) were not evaluable. The median event-free survival was 1.18 months (95% confidence interval, 0.76-2.14 months) among all groups. A pharmacodynamic analysis showed decreased plasma amyloid ß levels. CONCLUSIONS: Crenigacestat demonstrated limited clinical activity at the recommended dose in adult patients with relapsed/refractory T-ALL/T-LBL.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzazepinas/administración & dosificación , Dexametasona/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Adulto , Anciano , Benzazepinas/efectos adversos , Benzazepinas/farmacocinética , Dexametasona/efectos adversos , Dexametasona/farmacocinética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Purpose: This study evaluated the efficacy and safety of once-daily Alcaftadine 0.25% (AGN-229666) for prevention of signs and symptoms of Japanese cedar-pollen allergic conjunctivitis.Methods: This was a single-center, placebo-, and comparator-controlled study using the Ora-CAC® model of allergic conjunctivitis. The primary endpoint was ocular itching 16 hours after Alcaftadine 0.25% instillation; efficacy at 16 hours was compared with 0.1% Olopatadine, 4 hours after instillation. Secondary endpoints included conjunctival hyperemia.Results: 263 Japanese subjects were enrolled; 224 completed the trial. Alcaftadine 0.25% was statistically superior to vehicle for relief of ocular itching at 16 hours (p < .0001). Alcaftadine 0.25% at 16 hours was non-inferior to Olopatadine at 4 hours. Alcaftadine 0.25% was significantly better than vehicle for relief of conjunctival hyperemia. All treatments showed a low frequency of ocular adverse events.Conclusion: Once-daily Alcaftadine 0.25% is safe and effective in preventing signs and symptoms of Japanese cedar-pollen allergic conjunctivitis.
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Benzazepinas/administración & dosificación , Conjuntivitis Alérgica/prevención & control , Cryptomeria/química , Antagonistas de los Receptores Histamínicos H1/administración & dosificación , Imidazoles/administración & dosificación , Polen/efectos adversos , Administración Oftálmica , Adulto , Alérgenos/efectos adversos , Conjuntivitis Alérgica/inducido químicamente , Conjuntivitis Alérgica/diagnóstico , Método Doble Ciego , Femenino , Antagonistas de los Receptores Histamínicos H1 no Sedantes/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Clorhidrato de Olopatadina/administración & dosificación , Soluciones Oftálmicas , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Background Crenigacestat is a potent Notch inhibitor that decreases Notch signaling and its downstream biological effects. Here, we report the results from Part F of study 16F-MC-JJCA designed to evaluate the safety, pharmacokinetics (PK), and antitumor activity of crenigacestat with prednisone in advanced or metastatic cancer. The combination was planned to mitigate gastrointestinal toxicities. Methods Eligible patients (Study Part F) received crenigacestat loading dose (75 mg, escalating to 150 mg) administered thrice weekly (TIW) (F1) or twice weekly (BIW) (F2) for 2 weeks during Cycle 1, followed by 50 mg TIW from week 3 onwards. Prednisone was co-administered for 2 weeks in Cycle 1. Results Twenty-eight patients were enrolled; 11 in F1 (median age, 63 years), 17 in F2 (median age, 50 years). Dose-limiting toxicities were Grade 3 increased serum amylase and Grade 2 fatigue in F1, and Grade 4 hypophosphatemia and Grade 3 rash maculo-papular in F2. The maximum tolerated dose was 75 mg in F1 and 100 mg in F2. Best overall response was stable disease (F1, 6 [54.5%] patients; F2, 11 [64.7%] patients). Pharmacokinetic was dose proportional. Prednisone did not modify PK of crenigacestat, and both F1 and F2 achieved pharmacodynamics effects on evaluable tumor tissue samples. Conclusions This study demonstrated the potential use of prednisone to reduce gastrointestinal (GI) toxicities of a Notch inhibitor without affecting its PK. The safety profile observed was consistent with Notch pathway inhibitors, and the maximum tolerated dose was 75 mg TIW and 100 mg BIW in F1 and F2, respectively. ClinicalTrials.gov: NCT01695005.
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Antineoplásicos/uso terapéutico , Benzazepinas/uso terapéutico , Neoplasias/tratamiento farmacológico , Prednisona/uso terapéutico , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Área Bajo la Curva , Benzazepinas/administración & dosificación , Benzazepinas/efectos adversos , Benzazepinas/farmacocinética , Biomarcadores de Tumor , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Neoplasias/patología , Prednisona/administración & dosificación , Prednisona/efectos adversosRESUMEN
Background This phase 1, single-center, nonrandomized, single-arm, open-label, dose-escalation study, evaluated the tolerability of crenigacestat, a γ-secretase inhibitor as an oral Notch inhibitor in Japanese patients with advanced solid tumors. Methods The study consisted of 2 dose levels of crenigacestat (25 mg and 50 mg), administered orally 3 times per week (TIW) over a 28-day cycle until disease progression, development of unacceptable toxicity, or any other discontinuation criteria were met. The primary objective was to evaluate the tolerability and determine the recommended dose of crenigacestat for Japanese patients. Secondary objectives were to characterize the safety and toxicity, the pharmacokinetic parameters, and to document any antitumor activity of crenigacestat. Results Eleven Japanese patients with advanced solid tumors were enrolled; 4 patients (median age of 64 years) received 25 mg of crenigacestat, and 7 patients (median age of 72 years) received 50 mg of crenigacestat. Median treatment duration was 8 weeks in the 25-mg treatment arm and 4 weeks in the 50-mg treatment arm. There were no dose-limiting toxicities or dose-limiting equivalent toxicities observed. None of the patients had a complete or partial response to the treatment. One patient (14.3%) with a desmoid tumor in the 50-mg treatment arm showed tumor size shrinkage of 22.4% and had stable disease for 22.5 months. Frequent (>14%) treatment-related-adverse events in both treatment arms included diarrhea, malaise, and vomiting. Conclusions Crenigacestat was tolerated in Japanese patients but with limited clinical activity. The recommended crenigacestat dose in Japanese patients is 50 mg TIW.Trial registration: NCT02836600 ( ClinicalTrials.gov ) registered on July 19, 2016.
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Benzazepinas/farmacología , Neoplasias/tratamiento farmacológico , Receptores Notch/antagonistas & inhibidores , Anciano , Benzazepinas/administración & dosificación , Benzazepinas/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Japón , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To assess the protective role of benazepril, an angiotensin-converting enzyme inhibitor, in renal damage caused by prenatal inflammation. METHODS: Saline or lipopolysaccharide were administered intraperitoneally to pregnant Sprague- Dawley rats on gestation days 8, 10, and 12. After birth, offspring received either tap water or benazepril in water between 7 and 68 weeks. Blood pressure, blood urea nitrogen, creatinine, and 24-h urine volume were measured as indices of renal function. Hematoxylin, eosin, periodic acid-Schiff, and Sirius Red staining were used to evaluate renal damage. RESULTS: Postnatal benazepril treatment ameliorated hypertension and restored normal 24-h urine volume and blood urea nitrogen and serum creatinine levels. Benazepril treatment also reduced glycoprotein accumulation and fibrosis in the glomerulus and in tubular epithelial cells and inhibited nuclear factor-kappa B activation. CONCLUSION: Together with our previous findings that postnatal inhibition of nuclear factor-kappa B activation blocks intra-renal renin-angiotensin system activation, our current data demonstrate that intra-renal activation of the renin-angiotensin system interacts with nuclear factor-kappa B activation to cause renal damage in adulthood following prenatal inflammation.
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Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Benzazepinas/administración & dosificación , Riñón/efectos de los fármacos , Exposición Materna/efectos adversos , Efectos Tardíos de la Exposición Prenatal/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Femenino , Humanos , Riñón/inmunología , Riñón/lesiones , Lipopolisacáridos/efectos adversos , Masculino , FN-kappa B/genética , FN-kappa B/inmunología , Embarazo , Efectos Tardíos de la Exposición Prenatal/etiología , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/inmunología , RatasRESUMEN
Animal models have demonstrated a link between dysregulation of the retinal dopamine system and the development of myopia (short-sightedness). We have previously demonstrated that topical application of levodopa in chicks can inhibit the development of form-deprivation myopia (FDM) in a dose-dependent manner. Here, we examine whether this same protection is observed in lens-induced myopia (LIM), and whether levodopa's protection against FDM and LIM occurs through a dopamine D1- or D2-like receptor mechanism. To do this, levodopa was first administered daily as an intravitreal injection or topical eye drop, at one of four ascending doses, to chicks developing LIM. Levodopa's mechanism of action was then examined by co-administration of levodopa injections with D1-like (SCH-23390) or D2-like (spiperone) dopamine antagonists in chicks developing FDM or LIM. For both experiments, levodopa's effectiveness was examined by measuring axial length and refraction after 4 days of treatment. Levodopa inhibited the development of LIM in a dose-dependent manner similar to its inhibition of FDM when administered via intravitreal injections or topical eye drops. In both FDM and LIM, levodopa injections remained protective against myopia when co-administered with SCH-23390, but not spiperone, indicating that levodopa elicits its protection through a dopamine D2-like receptor mechanism in both paradigms.
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Benzazepinas/administración & dosificación , Levodopa/administración & dosificación , Miopía/tratamiento farmacológico , Espiperona/administración & dosificación , Animales , Benzazepinas/farmacología , Pollos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inyecciones Intravítreas , Lentes/efectos adversos , Levodopa/farmacología , Masculino , Miopía/etiología , Miopía/metabolismo , Soluciones Oftálmicas , Receptores de Dopamina D2/metabolismo , Espiperona/farmacologíaRESUMEN
NOTCH signaling represents a promising therapeutic target in chronic lymphocytic leukemia (CLL). We compared the anti-neoplastic effects of the nuclear NOTCH2 inhibitor gliotoxin and the pan-NOTCH γ-secretase inhibitor RO4929097 in primary CLL cells with special emphasis on the individual roles of the different NOTCH receptors. Gliotoxin rapidly induced apoptosis in all CLL cases tested, whereas RO4929097 exerted a variable and delayed effect on CLL cell viability. Gliotoxin-induced apoptosis was associated with inhibition of the NOTCH2/FCER2 (CD23) axis together with concomitant upregulation of the NOTCH3/NR4A1 axis. In contrast, RO4929097 downregulated the NOTCH3/NR4A1 axis and counteracted the spontaneous and gliotoxin-induced apoptosis. On the cell surface, NOTCH3 and CD23 expression were mutually exclusive, suggesting that downregulation of NOTCH2 signaling is a prerequisite for NOTCH3 expression in CLL cells. ATAC-seq confirmed that gliotoxin targeted the canonical NOTCH signaling, as indicated by the loss of chromatin accessibility at the potential NOTCH/CSL site containing the gene regulatory elements. This was accompanied by a gain in accessibility at the NR4A1, NFκB, and ATF3 motifs close to the genes involved in B-cell activation, differentiation, and apoptosis. In summary, these data show that gliotoxin recovers a non-canonical tumor-suppressing NOTCH3 activity, indicating that nuclear NOTCH2 inhibitors might be beneficial compared to pan-NOTCH inhibitors in the treatment of CLL.
Asunto(s)
Gliotoxina/farmacología , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/metabolismo , Receptor Notch2/antagonistas & inhibidores , Receptor Notch3/agonistas , Adulto , Anciano , Anciano de 80 o más Años , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Benzazepinas/administración & dosificación , Benzazepinas/farmacología , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Femenino , Gliotoxina/administración & dosificación , Humanos , Lectinas Tipo C/antagonistas & inhibidores , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/agonistas , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 1 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor Notch2/genética , Receptor Notch2/metabolismo , Receptor Notch3/genética , Receptor Notch3/metabolismo , Receptores de IgE/antagonistas & inhibidores , Elementos Reguladores de la Transcripción , Transducción de Señal/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
Dopamine is the predominant catecholamine neurotransmitter in the mammalian brain which has been shown to play a critical role in antinociceptive process. Previous studies have shown that the role of CA1 region of the hippocampus in antinociception induced by stimulation of the lateral hypothalamus (LH) through the dopaminergic system in tonic pain. In this study, we tried to assess the involvement of intra-hippocampal D1- and D2-like dopamine receptors in the LH stimulation-induced antinociception during the tail-flick test as an animal model of acute pain. Ninety-five male Wistar rats were unilaterally implanted with two separate cannulae into the LH and CA1. Animals received intra-CA1 infusion of SCH-23390 (0.25, 1 and 4 µg/rat), as a D1-like dopamine receptor antagonist and sulpiride (0.125, 0.25, 1 and 4 µg/rat), as a D2-like dopamine receptor antagonist, 2 min before intra-LH administration of carbachol (250 nM/rat). The antinociceptive effects of SCH-23390 and sulpiride were measured by using a tail-flick analgesiometer and represented as the maximal possible effect (%MPE). Also, the locomotion tracking apparatus was used to measure the locomotor activity of animals. Results showed that intra-CA1 administration of SCH-23390 or sulpiride could prevent the intra-LH carbachol-induced antinociception. This effect was a little more dominant after blocking the D2-like dopamine receptor in the CA1. These findings revealed that D1- and D2-like dopamine receptors within the CA1 play an important role in antinociceptive responses induced by chemical stimulation of the LH. It could be suggested that dopamine receptors in the CA1 were triggered by LH orexinergic projections.
Asunto(s)
Dolor Agudo/metabolismo , Modelos Animales de Enfermedad , Área Hipotalámica Lateral/metabolismo , Dimensión del Dolor/métodos , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D2/fisiología , Dolor Agudo/inducido químicamente , Dolor Agudo/tratamiento farmacológico , Animales , Benzazepinas/administración & dosificación , Antagonistas de los Receptores de Dopamina D2/administración & dosificación , Relación Dosis-Respuesta a Droga , Área Hipotalámica Lateral/efectos de los fármacos , Masculino , Microinyecciones/métodos , Dimensión del Dolor/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de Dopamina D1/antagonistas & inhibidores , Estimulación QuímicaRESUMEN
Cocaine use disorder (CUD) is a major public health challenge for which there are no pharmacotherapeutics approved by the United States Food and Drug Administration (FDA). The propensity to relapse in CUD involves several vulnerability factors including sensitivity to cues associated with cocaine-taking. Serotonin (5-hydroxytryptamine, 5-HT) neurotransmission, particularly through the 5-HT2A receptor (5-HT2AR) and 5-HT2C receptor (5-HT2CR), is mechanistically linked to cocaine-seeking in preclinical models. In the present experiments, we employed self-administration assays in male rats to investigate whether acute and/or repeated administration of the FDA-approved selective 5-HT2AR antagonist/inverse agonist pimavanserin, selective 5-HT2CR agonist lorcaserin or their combination would alter cocaine intake and/or cocaine-seeking behavior. We found that acute administration of lorcaserin, but not pimavanserin, attenuated cocaine intake while pimavanserin plus lorcaserin did not impact cocaine self-administration. In contrast, 10-days of repeated administration of pimavanserin, lorcaserin, or pimavanserin plus lorcaserin during forced abstinence from cocaine self-administration, blunted cocaine-seeking, similar to the acute administration of each ligand. Taken together, these data reveal the efficacy of repeated treatment with pimavanserin plus lorcaserin to attenuate factors important to relapse-like behaviors in rodent models of CUD. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.
Asunto(s)
Benzazepinas/administración & dosificación , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Trastornos Relacionados con Cocaína/psicología , Cocaína/administración & dosificación , Piperidinas/administración & dosificación , Urea/análogos & derivados , Animales , Benzazepinas/farmacocinética , Cocaína/farmacocinética , Trastornos Relacionados con Cocaína/metabolismo , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Masculino , Piperidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Recurrencia , Autoadministración , Antagonistas del Receptor de Serotonina 5-HT2/administración & dosificación , Antagonistas del Receptor de Serotonina 5-HT2/farmacocinética , Urea/administración & dosificación , Urea/farmacocinéticaRESUMEN
Introduction: Hepatitis C virus (HCV) is estimated to infect approximately 70 million people worldwide. If left untreated, chronic infection can progress to cirrhosis, liver failure or hepatocellular carcinoma. The advent of new direct-acting antivirals (DAA) has revolutionized patients' chances of treatment and viral elimination. Currently, several DAA options are available on the market.Areas covered: This review focuses on the pharmacokinetics, efficacy, tolerability and safety profile of DCV-TRIO, a twice-daily fixed-dose combination of daclatasvir, asunaprevir and beclabuvir approved in Japan for the treatment of genotype 1 HCV infection.Expert opinion: The DCV-TRIO combination achieved good response rates in genotype 1 patients (SVR12 ≥ 95% in naïve subtype 1b), independently from IL28B genotype, cirrhotic status and prior interferon exposure. On the other hand, unsatisfying response rates were reported in DAA-experienced patients and the risk of RAS selection should not be underestimated. Moreover, DCV-TRIO lacks differentiation from its earlier-launched DAA rivals, presents an inconvenient twice-daily dosing schedule and is not recommended in patients with advanced liver and kidney disease. All these drawbacks considerably limit its effective commercial potential. However, it can be a therapeutic option against HCV in tailored approaches according to the needs of different markets across the world.Abbreviations AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ASV: asunaprevir; AUC: area under the curve; BCRP: Breast Cancer Resistance Protein; BCV: boceprevir; BID: bis in die; CI: confidence intervals; CLcr: creatinine clearance; DAA: direct acting antivirals; DCV: daclatasvir; EC50: Half maximal effective concentration; GT: genotype; HCV: Hepatitis C virus; IFN: Interferon; NHL: non-Hodgkin lymphoma; OATP: Organic anion transporting polypeptides; OR: odds ratio; P-gp: P-glycoprotein; PK: pharmacokinetics; QD: quo die; RAS: resistance-associated substitutions; SVR: sustained virological response; USD: Unites States dollar.
Asunto(s)
Benzazepinas/administración & dosificación , Hepatitis C Crónica/tratamiento farmacológico , Imidazoles/administración & dosificación , Indoles/administración & dosificación , Isoquinolinas/administración & dosificación , Sulfonamidas/administración & dosificación , Antivirales/uso terapéutico , Carbamatos , Combinación de Medicamentos , Genotipo , Hepacivirus/efectos de los fármacos , Humanos , Cirrosis Hepática/prevención & control , Pirrolidinas , Respuesta Virológica Sostenida , Comprimidos , Resultado del Tratamiento , Valina/análogos & derivadosRESUMEN
BACKGROUND: Lorcaserin, a high-affinity 5-HT2C receptor agonist approved for treating obesity, decreased self-administration of oxycodone and cue-induced reinstatement of drug-seeking behavior in preclinical studies. The current investigation is the first clinical trial to evaluate the ability of lorcaserin to alter the reinforcing and subjective effects of oxycodone. METHODS: In this 7-week inpatient trial, 12 non-treatment-seeking volunteers (11 males) with moderate-to-severe opioid use disorder were detoxified from opioids. In a randomized cross-over fashion, participants were first stabilized on lorcaserin (10 mg BID) or placebo (0 mg BID). Participants underwent a two-week testing period during which the reinforcing and subjective effects of intranasal oxycodone were examined in verbal choice, cue-exposure, and progressive-ratio choice sessions. The two testing weeks were identical with the exception that during the first week, active oxycodone (10 mg) was available during verbal choice (self-administration) sessions, and during the second week placebo oxycodone was available. Subsequently, participants were stabilized on the other medication condition (placebo or lorcaserin) and underwent the same testing procedures again. RESULTS: Lorcaserin did not alter oxycodone self-administration. However, lorcaserin had a trend to increase "wanting heroin" when oxycodone was available, and to accentuate oxycodone-induced miosis. CONCLUSION: Under the current experimental conditions, lorcaserin at a dose of 10 mg BID did not reliably decrease the abuse liability of oxycodone, even though the study was sufficiently powered (≥80 %) to detect clinically meaningful differences in the main outcome variables between the placebo and active lorcaserin condition. Future research could explore a wider dose range of lorcaserin and oxycodone.
Asunto(s)
Benzazepinas/administración & dosificación , Conducta de Elección/efectos de los fármacos , Trastornos Relacionados con Opioides/tratamiento farmacológico , Oxicodona/administración & dosificación , Autoadministración/psicología , Administración Intranasal , Adulto , Estudios Cruzados , Señales (Psicología) , Femenino , Heroína , Humanos , Masculino , Trastornos Relacionados con Opioides/psicología , Refuerzo en Psicología , Resultado del TratamientoRESUMEN
Opioid-sparing adjuncts are treatments that aim to reduce the overall dose of opioids needed to achieve analgesia, hence decreasing the burden of side effects through alternative mechanisms of action. Lorcaserin is a serotonin 5-HT2C receptor (5-HT2CR) agonist that has recently been reported to reduce abuse-related effects of the opioid analgesic oxycodone. The goal of our studies was to evaluate the effects of adjunctive lorcaserin on opioid-induced analgesic-like behavior using the tail-flick reflex (TFR) test as a mouse model of acute thermal nociception. We show that whereas subcutaneous (s.c.) administration of lorcaserin alone was inactive on the TFR test, adjunctive lorcaserin (s.c.) significantly increased the potency of oxycodone as an antinociceptive drug. This effect was prevented by the 5-HT2CR antagonist SB242084. A similar lorcaserin (s.c.)-induced adjunctive phenotype was observed upon administration of the opioid analgesics morphine and fentanyl. Remarkably, we also show that, opposite to the effects observed via s.c. administration, intrathecal (i.t.) administration of lorcaserin alone induced antinociceptive TFR behavior, an effect that was not prevented by the opioid receptor antagonist naloxone. This route of administration (i.t.) also led to a significant augmentation of oxycodone-induced antinociception. Lorcaserin (s.c.) did not alter the brain or blood concentrations of oxycodone, which suggests that its adjunctive effects on opioid-induced antinociception do not depend upon changes in opioid metabolism. Together, these data indicate that lorcaserin-mediated activation of the 5-HT2CR may represent a new pharmacological approach to augment opioid-induced antinociception. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.
Asunto(s)
Analgésicos Opioides/administración & dosificación , Analgésicos/administración & dosificación , Benzazepinas/administración & dosificación , Dimensión del Dolor/efectos de los fármacos , Receptor de Serotonina 5-HT2C , Agonistas del Receptor de Serotonina 5-HT2/administración & dosificación , Aminopiridinas/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Indoles/administración & dosificación , Inyecciones Espinales , Masculino , Ratones , Dimensión del Dolor/métodos , Receptor de Serotonina 5-HT2C/metabolismo , Antagonistas del Receptor de Serotonina 5-HT2/administración & dosificaciónRESUMEN
BACKGROUND: The current opioid crisis has reinvigorated preclinical research in the evaluation of non-opioid candidate treatments for opioid use disorder (OUD). Emerging evidence suggests 5-HT2C receptor agonists may attenuate the abuse-related effects of opioids. This study evaluated effectiveness of 7-day treatment with the clinically available 5-HT2C agonist lorcaserin (Belviq®) on heroin-vs.-food choice in rhesus monkeys. Lorcaserin effects were compared to effects produced by 7-day saline substitution and by 7-day treatment with the opioid antagonist naltrexone. METHODS: Adult male (1) and female (6) rhesus monkeys were trained to respond under a concurrent schedule of food delivery (1 g pellets, fixed-ratio 100 schedule) and intravenous heroin injections (0-0.032 mg/kg/injection, fixed-ratio 10 schedule) during daily 2 h sessions. Heroin choice dose-effect functions were determined daily before and following 7-day saline substitution or 7-day continuous treatment with naltrexone (0.0032-0.032 mg/kg/h, IV) or lorcaserin (0.032-0.32 mg/kg/h, IV). RESULTS: Under baseline conditions, increasing heroin doses maintained a dose-dependent increase in heroin choice. Both saline substitution and 7-day naltrexone treatment significantly attenuated heroin choice and produced a reciprocal increase in food choice. Continuous lorcaserin (0.32 mg/kg/h) treatment significantly increased heroin choice. CONCLUSIONS: In contrast to saline substitution and naltrexone, lorcaserin treatment was ineffective to reduce heroin-vs.-food choice. These preclinical results do not support the therapeutic potential and continued evaluation of lorcaserin as a candidate OUD treatment.