RESUMEN
BACKGROUND: Data suggest that treatment with newer TB drugs (linezolid [LZD], bedaquiline [BDQ] and delamanid [DLM]), used in Khayelitsha, South Africa, since 2012, reduces mortality due to rifampicin-resistant TB (RR-TB).METHODS: This was a retrospective cohort study to assess 6-month mortality among RR-TB patients diagnosed between 2008 and 2019.RESULTS: By 6 months, 236/2,008 (12%) patients died; 12% (78/651) among those diagnosed in 2008-2011, and respectively 8% (49/619) and 15% (109/738) with and without LZD/BDQ/DLM in 2012-2019. Multivariable analysis showed a small, non-significant mortality reduction with LZD/BDQ/DLM use compared to the 2008-2011 period (aOR 0.79, 95% CI 0.5-1.2). Inpatient treatment initiation (aOR 3.2, 95% CI 2.4-4.4), fluoroquinolone (FQ) resistance (aOR 2.7, 95% CI 1.8-4.2) and female sex (aOR 1.5, 95% CI 1.1-2.0) were also associated with mortality. When restricted to 2012-2019, use of LZD/BDQ/DLM was associated with lower mortality (aOR 0.58, 95% CI 0.39-0.87).CONCLUSIONS: While LZD/BDQ/DLM reduced 6-month mortality between 2012 and 2019, there was no significant effect overall. These findings may be due to initially restricted LZD/BDQ/DLM use for those with high-level resistance or treatment failure. Additional contributors include increased treatment initiation among individuals who would have otherwise died before treatment due to universal drug susceptibility testing from 2012, an effect that also likely contributed to higher mortality among females (survival through to care-seeking).
Asunto(s)
Mycobacterium tuberculosis , Tuberculosis Resistente a Múltiples Medicamentos , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Diarilquinolinas/uso terapéutico , Femenino , Humanos , Pruebas de Sensibilidad Microbiana , Estudios Retrospectivos , Rifampin/farmacología , Rifampin/uso terapéutico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológicoRESUMEN
Premature ovarian insufficiency (POI) - the loss of ovarian function before the age of 40 years, a decade before natural menopause - is a life-changing diagnosis for women. POI causes significant short-term and long-term morbidity related to estrogen deficiency. The condition is managed by providing exogenous estrogen replacement, usually as the oral contraceptive pill or hormone therapy. These preparations have different estrogen formulations and may have differing benefits and risks. At present, there are no robust data to inform clinical recommendations and women's decision-making about treatment that they may be taking for many years. The POISE study (Premature Ovarian Insufficiency Study of Effectiveness of hormonal therapy) has been designed to determine whether hormone therapy is superior to combined oral contraceptives on important clinical outcomes and patient-reported symptoms, based on the hypothesis that hormone therapy provides more physiological continuous hormone supplementation with natural estrogens. The study is an open and pragmatic, parallel, randomized controlled trial. The primary outcome is absolute bone mineral density assessed by dual-energy X-ray absorptiometry of the lumbar spine after 2 years of treatment. The study will also investigate cardiovascular markers, symptom relief and acceptability of treatment, and will continue to collect long-term data on fractures and cardiovascular events. Results will inform future guidance on management of POI.
Asunto(s)
Terapia de Reemplazo de Estrógeno , Menopausia Prematura , Insuficiencia Ovárica Primaria , Adulto , Anticonceptivos Orales Combinados , Terapia de Reemplazo de Estrógeno/efectos adversos , Estrógenos , Femenino , Humanos , Menopausia , Insuficiencia Ovárica Primaria/tratamiento farmacológicoRESUMEN
The treatment of pulmonary carcinoid has changed over the last decades. Although surgical resection is still the gold standard, minimally invasive endobronchial procedures have emerged as a parenchyma sparing alternative for tumors located in the central airways. This review was performed to identify the optimal treatment strategy for pulmonary carcinoid, with a particular focus on the feasibility and outcome of parenchyma sparing techniques versus surgical resection. A systematic review of the literature was carried out using MEDLINE, Embase and the Cochrane databases, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement. Two separate searches of publications in endobronchial and surgical treatment in patients with pulmonary carcinoid, were performed. Outcomes were overall survival, disease free survival, recurrence rate, complications, quality of life, and healthcare costs. Combining the two main searches for endobronchial therapy and surgical therapy yielded 3111 records. Finally, 43 studies concerning surgical treatment and 9 studies related to endobronchial treatment for pulmonary carcinoid were included. Assessment of included studies showed that lymph node involvement, histological grade, tumor location and tumor diameter were identified as poor prognostic factors and seem to be important for patients with pulmonary carcinoid. For patients with a more favorable prognosis, tumor location and tumor diameter are important factors that can help decide on the optimal treatment strategy. Centrally located small intraluminal pulmonary carcinoids, without signs of metastasis can be treated with minimally invasive alternatives such as endobronchial treatment or parenchyma sparing surgical resection. Patients with parenchyma sparing resections should be followed with long term follow up to exclude recurrence of disease. In a multidisciplinary setting, it should be determined whether individual patients are eligible for parenchyma sparing procedures or anatomical resection. Overall evidence is of low quality and future studies should focus on prospective trials in the treatment of pulmonary carcinoid.
Asunto(s)
Broncoscopía , Tumor Carcinoide/cirugía , Neoplasias Pulmonares/cirugía , Neumonectomía , Broncoscopía/métodos , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/mortalidad , Costos de la Atención en Salud , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidad , Tratamientos Conservadores del Órgano/métodos , Neumonectomía/métodos , Complicaciones Posoperatorias , Pronóstico , Calidad de Vida , Recurrencia , Resultado del TratamientoRESUMEN
BACKGROUND: 2-Hydroxybenzylamine (2-HOBA) is a selective scavenger of dicarbonyl electrophiles that protects proteins and lipids from being modified by these electrophiles. It is currently being developed for use as a nutritional supplement to help maintain good health and protect against the development of conditions associated with dicarbonyl electrophile formation, such as the cognitive decline associated with Mild Cognitive Impairment and Alzheimer's disease. METHODS: In this first-in-human study, the safety, tolerability, and pharmacokinetics of six ascending single oral doses of 2-HOBA acetate were tested in eighteen healthy human volunteers. RESULTS: Reported adverse events were mild and considered unlikely to be related to 2-HOBA. There were no clinically significant changes in vital signs, ECG recordings, or clinical laboratory parameters. 2-HOBA was fairly rapidly absorbed, with a tmax of 1-2 h, and eliminated, with a t1/2 of approximately 2 h. Both tmax and t1/2 were independent of dose level, while Cmax and AUC increased proportionally with dose level. CONCLUSIONS: 2-HOBA acetate was safe and well-tolerated at doses up to 825 mg in healthy human volunteers, positioning it as a good candidate for continued development as a nutritional supplement. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT03176940).
Asunto(s)
Acetatos/farmacocinética , Bencilaminas/farmacocinética , Suplementos Dietéticos , Fármacos Neuroprotectores/farmacocinética , Acetatos/sangre , Administración Oral , Adulto , Área Bajo la Curva , Bencilaminas/sangre , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Masculino , Fármacos Neuroprotectores/sangre , Adulto JovenRESUMEN
2-hydroxybenzylamine (2-HOBA), a compound found in buckwheat, is a potent scavenger of reactive γ-ketoaldehydes, which are increased in diseases associated with inflammation and oxidative stress. While the potential of 2-HOBA is promising, studies were needed to characterize the safety of the compound before clinical trials. In a series of experiments, the risks of 2-HOBA-mediated mutagenicity and cardio-toxicity were assessed in vitro. The effects of 2-HOBA on the mRNA expression of select cytochrome P450 (CYP) enzymes were also assessed in cryopreserved human hepatocytes. Further, the distribution and metabolism of 2-HOBA in blood were determined. Our results indicate that 2-HOBA is not cytotoxic or mutagenic in vitro and does not induce the expression of CYP1A2, CYP2B6, or CYP3A4 in human hepatocytes. The results of the hERG testing showed a low risk of cardiac QT wave prolongation. Plasma protein binding and red blood cell distribution characteristics indicate low protein binding and no preferential distribution into erythrocytes. The major metabolites identified were salicylic acid and the glycoside conjugate of 2-HOBA. Together, these findings support development of 2-HOBA as a nutritional supplement and provide important information for the design of further preclinical safety studies in animals as well as for human clinical trials with 2-HOBA.
Asunto(s)
Bencilaminas/farmacología , Adulto , Proteínas Sanguíneas , Sistema Enzimático del Citocromo P-450/metabolismo , Canal de Potasio ERG1/genética , Canal de Potasio ERG1/metabolismo , Eritrocitos/metabolismo , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Humanos , Masculino , Persona de Mediana Edad , Pruebas de Mutagenicidad , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genéticaRESUMEN
Based on a hypothesis that an intramolecular hydrogen bond was present in our lead series of picolinamide mGlu5 NAMs, we reasoned that an inactive nicotinamide series could be modified through introduction of a fused heterocyclic core to generate potent mGlu5 NAMs. In this Letter, we describe the synthesis and evaluation of compounds that demonstrate the viability of that approach. Selected analogs were profiled in a variety of in vitro assays, and two compounds were evaluated in rat pharmacokinetic studies and a mouse model of obsessive-compulsive disorder. Ancillary pharmacology screening revealed that members of this series exhibited moderate inhibition of the dopamine transporter (DAT), and SAR was developed that expanded the selectivity for mGlu5 versus DAT.
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Amidas/química , Receptor del Glutamato Metabotropico 5/metabolismo , Regulación Alostérica , Amidas/farmacocinética , Amidas/farmacología , Animales , Permeabilidad de la Membrana Celular/efectos de los fármacos , Perros , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Concentración 50 Inhibidora , Células de Riñón Canino Madin Darby , Ratones , Microsomas Hepáticos/metabolismo , Piridinas/química , Ratas , Receptor del Glutamato Metabotropico 5/química , Relación Estructura-Actividad , Triazoles/químicaRESUMEN
There are multiple treatment options for depression, anxiety, psychosis, and other psychiatric disorders, and psychiatry patients are often comorbid with complex, polypharmacy treatment regimens. Unlike cardiovascular disease and diabetes, there are no readily available biomarkers to gauge treatment success with psychotropic medications, often resulting in subjective determination of medication therapy effectiveness. The physiochemical properties of psychiatric medications in general lend themselves to quantitative measurement in blood, offering an avenue to optimize treatment for each patient. Herein, we describe a novel application that employs comprehensive therapeutic drug monitoring of both psychiatric and nonpsychiatric medications to holistically personalize therapy for complex psychiatry patients.
Asunto(s)
Monitoreo de Drogas , Trastornos Mentales/tratamiento farmacológico , Psicotrópicos/uso terapéutico , Monitoreo de Drogas/métodos , Humanos , Medicina de PrecisiónRESUMEN
Preclinical evidence in support of the potential utility of mGlu5 NAMs for the treatment of a variety of psychiatric and neurodegenerative disorders is extensive, and multiple such molecules have entered clinical trials. Despite some promising results from clinical studies, no small molecule mGlu5 NAM has yet to reach market. Here we present the discovery and evaluation of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (27, VU0424238), a compound selected for clinical evaluation. Compound 27 is more than 900-fold selective for mGlu5 versus the other mGlu receptors, and binding studies established a Ki value of 4.4 nM at a known allosteric binding site. Compound 27 had a clearance of 19.3 and 15.5 mL/min/kg in rats and cynomolgus monkeys, respectively. Imaging studies using a known mGlu5 PET ligand demonstrated 50% receptor occupancy at an oral dose of 0.8 mg/kg in rats and an intravenous dose of 0.06 mg/kg in baboons.
Asunto(s)
Aminopiridinas/farmacología , Evaluación Preclínica de Medicamentos/métodos , Ácidos Picolínicos/farmacología , Receptor del Glutamato Metabotropico 5/metabolismo , Relación Estructura-Actividad , Regulación Alostérica , Aminopiridinas/síntesis química , Animales , Técnicas de Química Sintética , Células HEK293 , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Macaca fascicularis , Masculino , Ratones Endogámicos , Ácidos Picolínicos/síntesis química , Ratas Sprague-Dawley , Receptor del Glutamato Metabotropico 5/agonistas , Distribución TisularRESUMEN
The use of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in neuroscience has rapidly expanded in rodent studies but has lagged behind in nonhuman primate (NHP) experiments, slowing the development of this method for therapeutic use in humans. One reason for the slow adoption of DREADD technology in primates is that the pharmacokinetic properties and bioavailability of clozapine-n-oxide (CNO), the most commonly used ligand for human muscarinic (hM) DREADDs, are not fully described in primates. We report an extensive pharmacokinetic study using subcutaneous (SC) administration of CNO in five adult rhesus monkeys. CNO reached maximal plasma and cerebrospinal fluid (CSF) concentrations within 2 h after injection, with an observed dose-dependent increase in levels following a 3 and 10 mg/kg SC dose. Since CSF concentrations were below values predicted from unbound plasma concentrations, we investigated whether CNO was restricted from the CNS through active transport at the blood-brain barrier. In vitro assessment demonstrated that CNO is a substrate for P-glycoprotein (Pgp; efflux ratio, 20), thus providing a likely mechanism limiting CNO levels in the CNS. Furthermore, CNO is metabolized to the psychoactive compounds clozapine and n-desmethylclozapine in monkeys. The concentrations of clozapine detected in the CSF are sufficient to activate several types of receptor (including the hM-DREADDs). Our results suggest that CNO metabolism and distribution may interfere with reproducibility and interpretation of DREADD-related experiments in NHPs and calls for a re-evaluation of the use of CNO in DREADD-related experiments in NHPs along with the need to test alternative compounds.
Asunto(s)
Antipsicóticos/farmacocinética , Clozapina/análogos & derivados , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Animales , Antipsicóticos/sangre , Antipsicóticos/líquido cefalorraquídeo , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Permeabilidad Capilar/efectos de los fármacos , Clozapina/sangre , Clozapina/líquido cefalorraquídeo , Clozapina/farmacocinética , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Macaca mulatta , Células de Riñón Canino Madin Darby , Masculino , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , TransfecciónRESUMEN
Dopaminergic medications ameliorate many of the motor impairments of Parkinson's disease (PD). However, parkinsonism is often only partially reversed by these drugs, and they can have significant side effects. Therefore, a need remains for novel treatments of parkinsonism. Studies in rodents and preliminary clinical evidence have shown that T-type calcium channel (TTCC) antagonists have antiparkinsonian effects. However, most of the available studies utilized nonselective agents. We now evaluated whether systemic injections of the specific TTCC blocker ML218 have antiparkinsonian effects in MPTP-treated parkinsonian Rhesus monkeys. The animals were treated chronically with MPTP until they reached stable parkinsonism. In pharmacokinetic studies, we found that ML218 reaches a peak CSF concentration 1-2 h after s.c. administration. In electrocardiographic studies, we found no effects of ML218 on cardiac rhythmicity. As expected, systemic injections of the dopamine precursor L-DOPA dose-dependently increased the movements in our parkinsonian animals. We then tested the behavioral effects of systemic injections of ML218 (1, 10, or 30 mg/kg) or its vehicle, but did not detect specific antiparkinsonian effects. ML218 (3 or 10 mg/kg) was also not synergistic with L-DOPA. Using recordings of electrocorticogram signals (in one animal), we found that ML218 increased sleep. We conclude that ML218 does not have antiparkinsonian effects in MPTP-treated parkinsonian monkeys, due at least in part, to the agent's sedative effects.
Asunto(s)
Compuestos de Azabiciclo/farmacología , Benzamidas/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Intoxicación por MPTP/tratamiento farmacológico , Animales , Antiparkinsonianos/sangre , Antiparkinsonianos/líquido cefalorraquídeo , Antiparkinsonianos/farmacología , Nivel de Alerta/efectos de los fármacos , Compuestos de Azabiciclo/sangre , Compuestos de Azabiciclo/líquido cefalorraquídeo , Benzamidas/sangre , Benzamidas/líquido cefalorraquídeo , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/fisiopatología , Bloqueadores de los Canales de Calcio/sangre , Bloqueadores de los Canales de Calcio/líquido cefalorraquídeo , Canales de Calcio Tipo T/metabolismo , Cromatografía Liquida , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Electrocardiografía , Electrocorticografía , Femenino , Corazón/efectos de los fármacos , Levodopa/farmacología , Intoxicación por MPTP/patología , Intoxicación por MPTP/fisiopatología , Macaca mulatta , Masculino , Espectrometría de Masas , Actividad Motora/efectos de los fármacos , Insuficiencia del TratamientoRESUMEN
Once thought to be an artifact of microsomal systems, atypical kinetics with cytochrome P450 (CYP) enzymes have been extensively investigated in vitro and found to be substrate and species dependent. Building upon increasing reports of heterotropic CYP activation and inhibition in clinical settings, we screened a compound library of clinically approved drugs and various probe compounds to identify the frequency of heterotropism observed with different drug classes and the associated CYP enzymes thereof (1A2, 2C9, 2D6, and 3A4/5). Results of this screen revealed that the prescribed androgen receptor antagonist flutamide activated the intrinsic midazolam hydroxylase activity of CYP3A in human hepatic microsomes (66%), rat and human hepatocytes (36 and 160%, respectively), and in vivo in male Sprague-Dawley rats (>2-fold, combined area under the curve of primary rat in vivo midazolam metabolites). In addition, a screen of the pharmacologically active metabolite 2-hydroxy-flutamide revealed that this principle metabolite increased CYP3A metabolism of midazolam in human microsomes (30%) and hepatocytes (110%). Importantly, both flutamide and 2-hydroxy-flutamide demonstrated a pronounced increase in the CYP3A-mediated metabolism of commonly paired medications, nifedipine (antihypertensive) and amiodarone (antiarrhythmic), in multispecies hepatocytes (100% over baseline). These data serve to highlight the importance of an appropriate substrate and in vitro system selection in the pharmacokinetic modeling of atypical enzyme kinetics. In addition, the results of our investigation have illuminated a previously undiscovered class of heterotropic CYP3A activators and have demonstrated the importance of selecting commonly paired therapeutics in the in vitro and in vivo modeling of projected clinical outcomes.
Asunto(s)
Antagonistas de Receptores Androgénicos/metabolismo , Citocromo P-450 CYP3A/metabolismo , Activadores de Enzimas/metabolismo , Flutamida/metabolismo , Antagonistas de Receptores Androgénicos/farmacología , Animales , Evaluación Preclínica de Medicamentos/métodos , Activadores de Enzimas/farmacología , Femenino , Flutamida/farmacología , Cobayas , Humanos , Masculino , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Ratas , Ratas Sprague-Dawley , Porcinos , Porcinos EnanosRESUMEN
We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound 4a as a mGlu5 PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation.
Asunto(s)
Antipsicóticos/química , Compuestos Heterocíclicos con 2 Anillos/química , Imidazoles/química , Pirimidinonas/química , Receptor del Glutamato Metabotropico 5/química , Regulación Alostérica , Animales , Antipsicóticos/síntesis química , Antipsicóticos/farmacocinética , Encéfalo/metabolismo , Evaluación Preclínica de Medicamentos , Semivida , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Humanos , Imidazoles/síntesis química , Imidazoles/farmacocinética , Locomoción/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Unión Proteica , Pirimidinonas/síntesis química , Pirimidinonas/farmacocinética , Ratas , Receptor del Glutamato Metabotropico 5/metabolismo , Relación Estructura-ActividadRESUMEN
A functional high throughput screen identified a novel chemotype for the positive allosteric modulation (PAM) of the muscarinic acetylcholine receptor (mAChR) subtype 5 (M5). Application of rapid analog, iterative parallel synthesis efficiently optimized M5 potency to arrive at the most potent M5 PAMs prepared to date and provided tool compound 8n (ML380) demonstrating modest CNS penetration (human M5 EC50 = 190 nM, rat M5 EC50 = 610 nM, brain to plasma ratio (Kp) of 0.36).
Asunto(s)
Sistema Nervioso Central/metabolismo , Descubrimiento de Drogas , Indazoles/metabolismo , Indazoles/farmacología , Piperidinas/metabolismo , Piperidinas/farmacología , Receptor Muscarínico M5/química , Receptor Muscarínico M5/metabolismo , Sulfonamidas/metabolismo , Sulfonamidas/farmacología , Regulación Alostérica/efectos de los fármacos , Animales , Evaluación Preclínica de Medicamentos , Ensayos Analíticos de Alto Rendimiento , Humanos , Indazoles/química , Indazoles/farmacocinética , Masculino , Piperidinas/química , Piperidinas/farmacocinética , Ratas , Especificidad por Sustrato , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMEN
Of the five G-protein-coupled muscarinic acetylcholine receptors (mAChRs; M1-M5), M5 is the least explored and understood due to a lack of mAChR subtype-selective ligands. We recently performed a high-throughput functional screen and identified a number of weak antagonist hits that are selective for the M5 receptor. Here, we report an iterative parallel synthesis and detailed molecular pharmacologic profiling effort that led to the discovery of the first highly selective, central nervous system (CNS)-penetrant M5-orthosteric antagonist, with sub-micromolar potency (hM5 IC50=450â nM, hM5 Ki=340â nM, M1-M4 IC50>30â µM), enantiospecific inhibition, and an acceptable drug metabolism and pharmacokinetics (DMPK) profile for in vitro and electrophysiology studies. This compound will be a powerful tool and molecular probe for the further investigation into the role of M5 in addiction and other diseases.
Asunto(s)
Acetofenonas/química , Isoxazoles/química , Sondas Moleculares/química , Antagonistas Muscarínicos/química , Receptor Muscarínico M5/antagonistas & inhibidores , Acetofenonas/metabolismo , Acetofenonas/farmacocinética , Animales , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Isoxazoles/metabolismo , Isoxazoles/farmacocinética , Sondas Moleculares/metabolismo , Sondas Moleculares/farmacocinética , Antagonistas Muscarínicos/metabolismo , Antagonistas Muscarínicos/farmacocinética , Unión Proteica , Ratas , Receptor Muscarínico M5/metabolismoRESUMEN
A functional high throughput screen and subsequent multidimensional, iterative parallel synthesis effort identified the first muscarinic acetylcholine receptor (mAChR) negative allosteric modulator (NAM) selective for the M5 subtype. ML375 is a highly selective M5 NAM with submicromolar potency (human M5 IC50 = 300 nM, rat M5 IC50 = 790 nM, M1-M4 IC50 > 30 µM), excellent multispecies PK, high CNS penetration, and enantiospecific inhibition.
Asunto(s)
Encéfalo/metabolismo , Descubrimiento de Drogas , Imidazoles/química , Imidazoles/farmacología , Indoles/química , Indoles/farmacología , Receptor Muscarínico M5/metabolismo , Regulación Alostérica/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Células CHO , Cricetinae , Cricetulus , Evaluación Preclínica de Medicamentos , Humanos , Imidazoles/metabolismo , Imidazoles/farmacocinética , Indoles/metabolismo , Indoles/farmacocinética , Masculino , Ratas , Receptor Muscarínico M5/química , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
The G-protein activated, inward-rectifying potassium (K(+)) channels, "GIRKs", are a family of ion channels (Kir3.1-Kir3.4) that has been the focus of intense research interest for nearly two decades. GIRKs are comprised of various homo- and heterotetrameric combinations of four different subunits. These subunits are expressed in different combinations in a variety of regions throughout the central nervous system and in the periphery. The body of GIRK research implicates GIRK in processes as diverse as controlling heart rhythm, to effects on reward/addiction, to modulation of response to analgesics. Despite years of GIRK research, very few tools exist to selectively modulate GIRK channels' activity and until now no tools existed that potently and selectively activated GIRKs. Here we report the development and characterization of the first truly potent, effective, and selective GIRK activator, ML297 (VU0456810). We further demonstrate that ML297 is active in two in vivo models of epilepsy, a disease where up to 40% of patients remain with symptoms refractory to present treatments. The development of ML297 represents a truly significant advancement in our ability to selectively probe GIRK's role in physiology as well as providing the first tool for beginning to understand GIRK's potential as a target for a diversity of therapeutic indications.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/agonistas , Compuestos de Fenilurea/uso terapéutico , Pirazoles/uso terapéutico , Convulsiones/tratamiento farmacológico , Animales , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Señalización del Calcio/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Electrochoque/efectos adversos , Células HEK293 , Ensayos Analíticos de Alto Rendimiento , Humanos , Inyecciones Intraperitoneales , Ratones , Microsomas Hepáticos/metabolismo , Estructura Molecular , Técnicas de Placa-Clamp , Pentilenotetrazol/toxicidad , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Pirazoles/administración & dosificación , Pirazoles/química , Pirazoles/farmacología , Ratas , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Proteínas Recombinantes/efectos de los fármacos , Convulsiones/etiología , Ácido Valproico/uso terapéuticoRESUMEN
Herein we report a next generation muscarinic receptor 4 (M(4)) positive allosteric modulator (PAM), ML253 which exhibits nanomolar activity at both the human (EC(50)=56 nM) and rat (EC(50)=176 nM) receptors and excellent efficacy by the left-ward shift of the ACh concentration response curve (fold shift, human=106; rat=50). In addition, ML253 is selective against the four other muscarinic subtypes, displays excellent CNS exposure and is active in an amphetamine-induced hyperlocomotion assay.
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Amidas/química , Encéfalo/metabolismo , Piridinas/química , Receptor Muscarínico M4/metabolismo , Tiofenos/química , Regulación Alostérica , Amidas/farmacocinética , Amidas/uso terapéutico , Animales , Encéfalo/efectos de los fármacos , Colinérgicos/química , Colinérgicos/farmacocinética , Colinérgicos/uso terapéutico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Unión Proteica , Piridinas/farmacocinética , Piridinas/uso terapéutico , Ratas , Receptor Muscarínico M4/química , Esquizofrenia/tratamiento farmacológico , Relación Estructura-Actividad , Tiofenos/farmacocinética , Tiofenos/uso terapéuticoRESUMEN
Herein we describe the discovery and development of a novel class of M(4) positive allosteric modulators, culminating in the discovery of ML293. ML293 exhibited modest potency at the human M4 receptor (EC(50)=1.3 µM) and excellent efficacy as noted by the 14.6-fold leftward shift of the agonist concentration-response curve. ML293 was also selective versus the other muscarinic subtypes and displayed excellent in vivo PK properties in rat with low IV clearance (11.6 mL/min/kg) and excellent brain exposure (PO PBL, 10 mg/kg at 1h, [Brain]=10.3 µM, B:P=0.85).
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Encéfalo/metabolismo , Niacinamida/análogos & derivados , Receptor Muscarínico M4/química , Regulación Alostérica , Amidas/química , Animales , Células CHO , Cricetinae , Cricetulus , Evaluación Preclínica de Medicamentos , Humanos , Niacinamida/química , Niacinamida/farmacocinética , Ratas , Receptor Muscarínico M4/metabolismo , Relación Estructura-ActividadRESUMEN
BACKGROUND: Uncomplicated urinary tract infections (UTI) in dogs usually are treated with antimicrobial drugs for 10-14 days. Shorter duration antimicrobial regimens have been evaluated in human patients. HYPOTHESIS: A high dose short duration (HDSD) enrofloxacin protocol administered to dogs with uncomplicated UTI will not be inferior to a 14-day treatment regimen with amoxicillin-clavulanic acid. ANIMALS: Client-owned adult, otherwise healthy dogs with aerobic bacterial urine culture yielding ≥ 10(3) CFU/mL of bacteria after cystocentesis. METHODS: Prospective, multicenter, controlled, randomized blinded clinical trial. Enrolled dogs were randomized to group 1 (enrofloxacin 18-20 mg/kg PO q24h for 3 days) or group 2 (amoxicillin-clavulanic acid 13.75-25 mg/kg PO q12h for 14 days). Urine cultures were obtained at days 0, 10, and 21. Microbiologic and clinical cure rates were evaluated 7 days after antimicrobial treatment was discontinued. Lower urinary tract signs and adverse events also were recorded. RESULTS: There were 35 dogs in group 1 and 33 in group 2. The microbiologic cure rate was 77.1 and 81.2% for groups 1 and 2, respectively. The clinical cure rate was 88.6 and 87.9% for groups 1 and 2, respectively. Cure rates between groups did not differ according to the selected margin of noninferiority. CONCLUSIONS AND CLINICAL IMPORTANCE: HDSD enrofloxacin treatment was not inferior to a conventional amoxicillin-clavulanic acid protocol for the treatment of uncomplicated bacterial UTI in dogs. Further research is warranted to determine if this protocol will positively impact owner compliance and decrease the emergence of antimicrobial resistance.
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Antibacterianos/administración & dosificación , Enfermedades de los Perros/tratamiento farmacológico , Fluoroquinolonas/administración & dosificación , Infecciones Urinarias/veterinaria , Animales , Recuento de Colonia Microbiana/veterinaria , Enfermedades de los Perros/microbiología , Enfermedades de los Perros/orina , Perros , Método Doble Ciego , Enrofloxacina , Femenino , Masculino , Estudios Prospectivos , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/microbiología , Infecciones Urinarias/orinaRESUMEN
OBJECTIVE: To determine the relative effectiveness of second generation ablation techniques in the treatment of heavy menstrual bleeding. DESIGN: Network meta-analysis on the primary outcome measures of amenorrhoea, heavy bleeding, and patients' dissatisfaction with treatment. DATA SOURCES: Nineteen randomised controlled trials (involving 3287 women) were identified through electronic searches of the Cochrane Library, Medline, Embase and PsycINFO databases from inception to April 2011. The reference lists of known relevant articles were searched for further articles. Two reviewers independently selected articles without language restrictions. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials involving second generation endometrial destruction techniques for women with heavy menstrual bleeding unresponsive to medical treatment. RESULTS: Of the three most commonly used techniques, network meta-analysis showed that bipolar radiofrequency and microwave ablation resulted in higher rates of amenorrhoea than thermal balloon ablation at around 12 months (odds ratio 2.51, 95% confidence interval 1.53 to 4.12, P<0.001; and 1.66, 1.01 to 2.71, P=0.05, respectively), but there was no evidence of a convincing difference between the three techniques in the number of women dissatisfied with treatment or still experiencing heavy bleeding. Compared with bipolar radio frequency and microwave devices, an increased number of women still experienced heavy bleeding after free fluid ablation (2.19, 1.07 to 4.50, P=0.03; and 2.91, 1.23 to 6.88, P=0.02, respectively). Compared with radio frequency ablation, free fluid ablation was associated with reduced rates of amenorrhoea (0.36, 0.19 to 0.67, P=0.004) and increased rates of dissatisfaction (4.79, 1.07 to 21.5, P=0.04). Of the less commonly used devices, endometrial laser intrauterine thermotherapy was associated with increased rates of amenorrhoea compared with all the other devices, while cryoablation led to a reduced rate compared with bipolar radio frequency and microwave. CONCLUSIONS: Bipolar radio frequency and microwave ablative devices are more effective than thermal balloon and free fluid ablation in the treatment of heavy menstrual bleeding with second generation endometrial ablation devices.