RESUMEN

ß-site amyloid precursor protein cleaving enzyme (BACE1) represents a key target for Alzheimer's disease (AD) therapy because it is essential for producing the toxic amyloid ß (Aß) peptide that plays a crucial role in the disease's development. BACE1 inhibitors are a promising approach to reducing Aß levels in the brain and preventing AD progression. However, systemic delivery of such inhibitors to the brain demonstrates limited efficacy because of the presence of the blood-brain barrier (BBB). Nose-to-brain (NtB) delivery has the potential to overcome this obstacle. Liposomal drug delivery systems offer several advantages over traditional methods for delivering drugs and nucleic acids from the nose to the brain. The current study aims to prepare, characterize, and evaluate in vitro liposomal forms of donepezil, memantine, BACE-1 siRNA, and their combination for possible treatment of AD via NtB delivery. All the liposomal formulations were prepared using the rotary evaporation method. Their cellular internalization, cytotoxicity, and the suppression of beta-amyloid plaque and other pro-inflammatory cytokine expressions were studied. The Calu-3 Transwell model was used as an in vitro system for mimicking the anatomical and physiological conditions of the nasal epithelium and studying the suitability of the proposed formulations for possible NtB delivery. The investigation results show that liposomes provided the effective intracellular delivery of therapeutics, the potential to overcome tight junctions in BBB, reduced beta-amyloid plaque accumulation and pro-inflammatory cytokine expression, supporting the therapeutic potential of our approach.

Asunto(s)

Administración Intranasal , Enfermedad de Alzheimer , Secretasas de la Proteína Precursora del Amiloide , Ácido Aspártico Endopeptidasas , Donepezilo , Liposomas , ARN Interferente Pequeño , Enfermedad de Alzheimer/tratamiento farmacológico , Humanos , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , ARN Interferente Pequeño/administración & dosificación , Donepezilo/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Piperidinas/farmacología , Mucosa Nasal/metabolismo , Mucosa Nasal/efectos de los fármacos , Indanos/administración & dosificación , Indanos/farmacocinética , Péptidos beta-Amiloides/metabolismo

Asunto(s)

Inhibidores de la Colinesterasa , Delirio , Donepezilo , Humanos , Donepezilo/efectos adversos , Donepezilo/administración & dosificación , Delirio/inducido químicamente , Delirio/tratamiento farmacológico , Inhibidores de la Colinesterasa/efectos adversos , Inhibidores de la Colinesterasa/administración & dosificación , Quimioterapia Combinada , Masculino , Anciano , Femenino , Piperidinas/efectos adversos , Piperidinas/administración & dosificación , Indanos/efectos adversos , Indanos/administración & dosificación

RESUMEN

The gut microbiota is a complex ecosystem, home to hundreds of bacterial species and a vast repository of enzymes capable of metabolising a wide range of pharmaceuticals. Several drugs have been shown to affect negatively the composition and function of the gut microbial ecosystem. Janus Kinase (JAK) inhibitors and Sphingosine-1-phosphate (S1P) receptor modulators are drugs recently approved for inflammatory bowel disease through an immediate release formulation and would potentially benefit from colonic targeted delivery to enhance the local drug concentration at the diseased site. However, their impact on the human gut microbiota and susceptibility to bacterial metabolism remain unexplored. With the use of calorimetric, optical density measurements, and metagenomics next-generation sequencing, we show that JAK inhibitors (tofacitinib citrate, baricitinib, filgotinib) have a minor impact on the composition of the human gut microbiota, while ozanimod exerts a significant antimicrobial effect, leading to a prevalence of the Enterococcus genus and a markedly different metabolic landscape when compared to the untreated microbiota. Moreover, ozanimod, unlike the JAK inhibitors, is the only drug subject to enzymatic degradation by the human gut microbiota sourced from six healthy donors. Overall, given the crucial role of the gut microbiome in health, screening assays to investigate the interaction of drugs with the microbiota should be encouraged for the pharmaceutical industry as a standard in the drug discovery and development process.

Asunto(s)

Microbioma Gastrointestinal , Enfermedades Inflamatorias del Intestino , Inhibidores de las Cinasas Janus , Moduladores de los Receptores de fosfatos y esfingosina 1 , Humanos , Microbioma Gastrointestinal/efectos de los fármacos , Inhibidores de las Cinasas Janus/farmacología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/microbiología , Enfermedades Inflamatorias del Intestino/metabolismo , Pirazoles/farmacología , Colon/microbiología , Colon/metabolismo , Colon/efectos de los fármacos , Sulfonamidas/farmacología , Sulfonamidas/administración & dosificación , Purinas , Azetidinas/farmacología , Azetidinas/administración & dosificación , Compuestos de Bencilo/farmacología , Compuestos de Bencilo/administración & dosificación , Piperidinas/farmacología , Piperidinas/administración & dosificación , Pirimidinas/farmacología , Pirimidinas/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Oxadiazoles/farmacología , Oxadiazoles/administración & dosificación , Receptores de Esfingosina-1-Fosfato/metabolismo , Receptores de Esfingosina-1-Fosfato/antagonistas & inhibidores , Pirroles/farmacología , Pirroles/administración & dosificación , Indanos/farmacología , Indanos/administración & dosificación , Piridinas , Triazoles

RESUMEN

BACKGROUND: Choline alfoscerate (alpha-glycerylphosphorylcholine) is a phospholipid that includes choline, which increases the release of acetylcholine. The ASCOMALVA trial, a combination of donepezil and choline alfoscerate, slowed cognitive decline in Alzheimer disease. This study aims to replicate the effect by combining donepezil with other nootropics currently used in South Korea. METHODS: The 119 patients with cognitive decline who were eligible to use donepezil, with an mini-mental state examination (MMSE) score of 26 or less, were assigned to: donepezil alone (DO); donepezil and choline alfoscerate (DN); donepezil and acetyl-l-carnitine (DA); or donepezil and ginkgo biloba extract (DG). Cognitive evaluations such as MMSE, clinical dementia rating, Alzheimer disease assessment scale-cognitive subscale (ADAS-Cog), and Alzheimer disease assessment scale-noncognitive subscale were performed at the 12th and 24th weeks from the baseline time point. RESULTS: At the 12th week, the MMSE score increased 3.52% in the DN group, whereas it increased by 1.36% in the DO group. In the DA + DG group, it decreased by 2.17%. At the 24th week, the MMSE score showed an increase of 1.07% in the DO group and 1.61% in the DN group, but decreased by 5.71% in the DA + DG group. ADAS-Cog decreased by 0.9% in the DO group, while it improved by 13.9% in the DN group at the 12th week. At the 24th week, ADAS-Cog showed improvement in the DN group by 18.5%, whereas it improved by 9.4% in the DO group. Alzheimer disease assessment scale-noncognitive subscale also revealed better performance in the DN group than in the DO group at the 12th and 24th weeks. CONCLUSION: Choline alfoscerate exhibits additional cognitive improvement in both cognitive and noncognitive domains, supporting the findings of the ASCOMALVA trial.

Asunto(s)

Donepezilo , Quimioterapia Combinada , Ginkgo biloba , Glicerilfosforilcolina , Indanos , Nootrópicos , Humanos , Donepezilo/uso terapéutico , Donepezilo/administración & dosificación , Masculino , Femenino , Anciano , Método Doble Ciego , Glicerilfosforilcolina/uso terapéutico , Glicerilfosforilcolina/administración & dosificación , Nootrópicos/administración & dosificación , Nootrópicos/uso terapéutico , Indanos/uso terapéutico , Indanos/administración & dosificación , Enfermedad de Alzheimer/tratamiento farmacológico , Piperidinas/uso terapéutico , Piperidinas/administración & dosificación , Extractos Vegetales/uso terapéutico , Extractos Vegetales/administración & dosificación , República de Corea , Acetilcarnitina/uso terapéutico , Acetilcarnitina/administración & dosificación , Disfunción Cognitiva/tratamiento farmacológico , Pruebas de Estado Mental y Demencia , Resultado del Tratamiento , Anciano de 80 o más Años , Cognición/efectos de los fármacos , Extracto de Ginkgo

RESUMEN

PURPOSE: To test efficacy of donepezil, a cognitive enhancer, to improve memory in breast cancer survivors who report cancer-related cognitive impairment 1-5 years postchemotherapy. PATIENTS AND METHODS: Adult female BCS exposed to ≥4 cycles of adjuvant chemotherapy 1-5 years before enrollment who reported cancer-related cognitive impairment were eligible. Participants, enrolled at sites affiliated with the Wake Forest NCI Community Oncology Research Program (NCORP) Research Base, were randomly assigned to receive 5 mg of donepezil once daily for 6 weeks titrated to 10 mg once daily for 18 weeks or placebo. Cognition and self-report cognitive functioning was assessed at baseline, 12, 24 (end of intervention), and 36 (washout) weeks postrandomization. Mixed-effects repeated measures analysis of covariance models were used to assess treatment differences in immediate recall (primary outcome) on the Hopkins Verbal Learning Test-Revised (HVLT-R) and other cognitive domains (secondary outcomes) with covariates of treatment, time, time by treatment interaction, baseline outcome level, age stratification, and an unstructured covariance matrix to account for within participant correlation over time. RESULTS: Two hundred seventy-six BCS from 87 NCORP practices (mean age, 57.1, standard deviation [SD], 10.5) who were at a mean of 29.6 months (SD, 14.2) postchemotherapy were randomly assigned to donepezil (n = 140) or placebo (n = 136). At 24 weeks, treatment groups did not differ on HVLT-R scores (donepezil mean = 25.98, placebo = 26.50, P = .32). There were no statistically significant differences between treatments at 12, 24, or 36 weeks for attention, executive function, verbal fluency, processing speed, or self-reported cognitive functioning. Endocrine therapy and menopausal status did not affect results. CONCLUSION: BCS 1-5 years after completing chemotherapy with documented memory problems, randomly assigned to 24 weeks of 5-10 mg of donepezil once daily, did not perform differently at the end of treatment on tests of memory, other cognitive functions, or subjective functioning than those randomly assigned to placebo.

Asunto(s)

Neoplasias de la Mama , Supervivientes de Cáncer , Disfunción Cognitiva , Donepezilo , Humanos , Donepezilo/uso terapéutico , Donepezilo/efectos adversos , Donepezilo/administración & dosificación , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/psicología , Persona de Mediana Edad , Quimioterapia Adyuvante/efectos adversos , Supervivientes de Cáncer/psicología , Anciano , Disfunción Cognitiva/etiología , Disfunción Cognitiva/tratamiento farmacológico , Piperidinas/uso terapéutico , Piperidinas/efectos adversos , Piperidinas/administración & dosificación , Método Doble Ciego , Adulto , Nootrópicos/uso terapéutico , Nootrópicos/efectos adversos , Nootrópicos/administración & dosificación , Indanos/uso terapéutico , Indanos/efectos adversos , Indanos/administración & dosificación , Cognición/efectos de los fármacos

RESUMEN

INTRODUCTION: One of the fundamental challenges of managing patients with severe asthma is treatment adherence, particularly with inhaled corticosteroids. Adherence is difficult to measure objectively and poor adherence is associated with worse outcomes. In this study, assess the ability of a 'smart' inhaler to record adherence in severe asthma patients and measure the impact of this on asthma control. METHODS: Consecutive consenting patients meeting criteria for biologics had their existing high-dose ICS/LABA//LAMA combination inhaler/s switched to mometasone/indacaterol/glycopyrronium (114/46/136). Routine clinical data, including blood eosinophils, FeNO, and ACQ-6 scores were collected at baseline and at 4 wk. Adherence was then checked on the Propeller Health app, and good adherence was defined as >80% of prescribed usage. Participants were then followed-up at 12 months to record the proportion of patients who were initiated on biologics. RESULTS: 77 patients (mean [SD] age = 50.4 [15.7] years, 67.5% female [n = 52]) participated. 71 participants were able to use the device and 65% (n = 46) of these attained good asthma control and were not initiated on biologics at 12-month follow-up. Both groups demonstrated a significant reduction in ACQ6 score at follow-up (2.81 vs. 1.92, p < 0.001 and 3.05 vs. 2.60, p < 0.001, respectively), but there was no statistically significant difference in improvement between groups. Patients with optimal adherence also demonstrated a significant reduction in median FeNO at follow-up (47 ppb vs. 40 ppb, p = 0.003). CONCLUSIONS: In severe asthma patients, 'smart' inhalers may represent an effective management tool to improve adherence and asthma control, therefore avoiding the need for patients to commence biological therapies.

Asunto(s)

Antiasmáticos , Asma , Cumplimiento de la Medicación , Humanos , Asma/tratamiento farmacológico , Femenino , Masculino , Persona de Mediana Edad , Adulto , Cumplimiento de la Medicación/estadística & datos numéricos , Administración por Inhalación , Antiasmáticos/administración & dosificación , Antiasmáticos/uso terapéutico , Quinolonas/administración & dosificación , Indanos/administración & dosificación , Glicopirrolato/administración & dosificación , Glicopirrolato/uso terapéutico , Nebulizadores y Vaporizadores , Índice de Severidad de la Enfermedad , Furoato de Mometasona/administración & dosificación , Furoato de Mometasona/uso terapéutico , Anciano , Combinación de Medicamentos , Corticoesteroides/administración & dosificación , Corticoesteroides/uso terapéutico

Asunto(s)

Enfermedad de Alzheimer , Donepezilo , Nootrópicos , Administración Cutánea , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/administración & dosificación , Inhibidores de la Colinesterasa/uso terapéutico , Donepezilo/administración & dosificación , Donepezilo/uso terapéutico , Humanos , Indanos/administración & dosificación , Indanos/uso terapéutico , Nootrópicos/administración & dosificación , Nootrópicos/uso terapéutico , Rivastigmina/administración & dosificación , Rivastigmina/uso terapéutico , Parche Transdérmico

RESUMEN

RATIONALE: The long-acting ß2-agonist/long-acting muscarinic antagonist combination indacaterol/glycopyrronium (IND/GLY) elicits bronchodilation, improves symptoms, and reduces exacerbations in COPD. Magnetic resonance imaging (MRI) of the lung with hyperpolarized gas and gadolinium contrast enhancement enables assessment of whole lung functional responses to IND/GLY. OBJECTIVES: The primary objective was assessment of effect of IND/GLY on global ventilated lung volume (%VV) versus placebo in COPD. Lung function, regional ventilation and perfusion in response to IND/GLY were also measured. METHODS: This double-blind, randomized, placebo-controlled, crossover study assessed %VV and pulmonary perfusion in patients with moderate-to-severe COPD after 8 days of once-daily IND/GLY treatment (110/50 µg) followed by 8 days of placebo, or vice versa, using inhaled hyperpolarized 3He gas and gadolinium contrast-enhanced MRI, respectively. Lung function measures including spirometry were performed for each treatment after 8 days. MEASUREMENTS AND MAIN RESULTS: Of 31 patients randomized, 29 completed both treatment periods. IND/GLY increased global %VV versus placebo (61.73% vs. 56.73%, respectively, least squares means treatment difference: 5.00% [90% CI 1.40 to 8.60]; P = 0.025). IND/GLY improved whole lung index of ventilation volume to perfusion volume (V/Q) ratio versus placebo; 94% (90% CI 83 to 105) versus 86% (90% CI 75 to 97; P = 0.047), respectively. IND/GLY showed a trend to improve diffusing capacity for carbon monoxide (DLCO) (+ 0.66 mL/min/mmHg; P = 0.082). By Day 8, forced expiratory volume in 1 s (FEV1) was increased by 0.32 L versus placebo (90% CI 0.26 to 0.38; P < 0.0001), substantiating earlier findings and providing evidence of assay sensitivity for this trial. CONCLUSIONS: IND/GLY improved lung ventilation assessed by 3He MRI after 1 week of treatment. This observation may provide mechanistic support for the symptomatic clinical benefit shown with IND/GLY in COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02634983).

Asunto(s)

Broncoconstricción/efectos de los fármacos , Volumen Espiratorio Forzado/efectos de los fármacos , Glicopirrolato/análogos & derivados , Indanos/administración & dosificación , Pulmón/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Quinolonas/administración & dosificación , Capacidad Vital/efectos de los fármacos , Anciano , Estudios Cruzados , Método Doble Ciego , Combinación de Medicamentos , Femenino , Estudios de Seguimiento , Glicopirrolato/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Pruebas de Función Respiratoria , Estudios Retrospectivos , Resultado del Tratamiento

Asunto(s)

Colitis Ulcerosa/tratamiento farmacológico , Fármacos Gastrointestinales/uso terapéutico , Indanos/uso terapéutico , Oxadiazoles/uso terapéutico , Método Doble Ciego , Aprobación de Drogas , Interacciones Farmacológicas , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/efectos adversos , Humanos , Indanos/administración & dosificación , Indanos/efectos adversos , Oxadiazoles/administración & dosificación , Oxadiazoles/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Índice de Severidad de la Enfermedad , Estados Unidos , United States Food and Drug Administration

RESUMEN

α2 -Adrenoceptor agonists such as clonidine and dexmedetomidine are used as adjuvants to local anesthetics in regional anesthesia. Fadolmidine is an α2 -adrenoceptor agonist developed especially as a spinal analgesic. The current studies investigate the effects of intrathecally administered fadolmidine with a local anesthetic, bupivacaine, on antinociception and motor block in conscious rats and dogs. The antinociceptive effects of intrathecal fadolmidine and bupivacaine alone or in combination were tested in the rat tail-flick and the dog's skin twitch models. The durations of motor block in rats and in dogs were also assessed. In addition, the effects on sedation, mean arterial blood pressure, heart rate, respiratory rate and body temperature were evaluated in telemetrized dogs. Concentrations of fadolmidine in plasma and spinal cord were determined after intrathecal and intravenous administration in rats. Co-administration of intrathecal fadolmidine with bupivacaine increased the magnitude and duration of the antinociceptive effects and prolonged motor block without hypotension. The interaction of the antinociceptive effect was synergistic in its nature in rats. Concentration of fadolmidine in plasma was very low after intrathecal dosing. Taken together, these studies show that fadolmidine as an adjuvant to intrathecal bupivacaine provides enhanced sensory-motor block and enables a reduction of the doses of both drugs. The results indicate that co-administration of fadolmidine with intrathecal bupivacaine was able to achieve an enhanced antinociceptive effect without hypotension and could thus represent a suitable combination for spinal anesthesia.

Asunto(s)

Adyuvantes Anestésicos/administración & dosificación , Agonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Analgésicos/administración & dosificación , Anestesia Raquidea , Anestésicos Locales , Bupivacaína , Imidazoles/administración & dosificación , Indanos/administración & dosificación , Adyuvantes Anestésicos/sangre , Adyuvantes Anestésicos/farmacocinética , Agonistas de Receptores Adrenérgicos alfa 2/sangre , Agonistas de Receptores Adrenérgicos alfa 2/farmacocinética , Analgésicos/sangre , Analgésicos/farmacocinética , Animales , Presión Arterial/efectos de los fármacos , Temperatura Corporal/efectos de los fármacos , Perros , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Imidazoles/sangre , Imidazoles/farmacocinética , Indanos/sangre , Indanos/farmacocinética , Masculino , Ratas Sprague-Dawley , Frecuencia Respiratoria/efectos de los fármacos , Prueba de Desempeño de Rotación con Aceleración Constante , Médula Espinal/metabolismo

RESUMEN

BACKGROUND AND OBJECTIVE: Clinical evidence suggests no clinically relevant pharmacokinetic interactions between indacaterol (IND), glycopyrronium (GLY) and mometasone furoate (MF). A population pharmacokinetic (popPK) analysis was conducted to identify structural models describing systemic pharmacokinetic profiles of IND, GLY and MF, and estimate the effect of covariates on their pharmacokinetics following inhalation as IND/GLY/MF. METHODS: Pharmacokinetic data from 698 patients with asthma were pooled from two Phase III studies that evaluated IND/MF medium- (150/160 µg) and high-dose (150/320 µg), IND/GLY/MF medium- (150/50/80 µg) and high-dose (150/50/160 µg), and a device bridging Phase II study with MF. One popPK model was developed each for IND, GLY and MF using a nonlinear mixed-effect modelling approach. Maximal and trough plasma concentrations were compared across formulations and studies, including data for IND/GLY from chronic obstructive pulmonary disease (COPD) patients. The effect of predefined covariates on the pharmacokinetics of components was evaluated using a full covariate modelling approach. RESULTS: The final pharmacokinetic models were two-compartment disposition models with first-order elimination and sequential zero-order/first-order absorption (IND), with bolus administration and first-order elimination (GLY), and with mixed zero-order/first-order absorption and first-order elimination (MF). All model parameters were estimated with good precision (% relative standard error: IND and MF ≤25%; GLY <10%). No clinically relevant covariate effect was observed on the pharmacokinetics of IND, GLY and MF. IND and GLY pharmacokinetic profiles were similar across different formulations. CONCLUSION: Two-compartment popPK models adequately described the pharmacokinetics of IND, GLY and MF. The effect of covariates was not clinically relevant. The pharmacokinetic profiles of MF were comparable for combination products at corresponding medium- or high-dose inhaled corticosteroids. On a population level, the pharmacokinetics of IND and GLY were comparable between patients with asthma and COPD.

Asunto(s)

Asma/tratamiento farmacológico , Glicopirrolato/análogos & derivados , Indanos/farmacocinética , Modelos Biológicos , Furoato de Mometasona/farmacocinética , Quinolonas/farmacocinética , Administración por Inhalación , Adolescente , Adulto , Anciano , Antiasmáticos/administración & dosificación , Antiasmáticos/farmacocinética , Niño , Ensayos Clínicos Fase III como Asunto , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Femenino , Glicopirrolato/administración & dosificación , Glicopirrolato/farmacocinética , Humanos , Indanos/administración & dosificación , Masculino , Persona de Mediana Edad , Furoato de Mometasona/administración & dosificación , Nebulizadores y Vaporizadores , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Quinolonas/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto Joven

RESUMEN

Rasagiline mesylate (RSM) is a selective and irreversible monoamine oxidase B inhibitor used for the treatment of Parkinson's disease (PD). However, its unfavorable biopharmaceutical properties, such as extensive degradation in the gastrointestinal tract and first-pass metabolism are responsible for its low oral bioavailability and suboptimal therapeutic efficacy. Here, we report the feasibility of delivering RSM via the transdermal route using RSM containing microemulsion-based gel (RSM-MEG) to achieve effective management of PD. Our in vitro skin permeation studies of RSM-MEG showed significantly higher (at least ~1.5-fold) permeation across rat skin compared to the conventional RSM hydrogel. Our skin irritation studies in rabbits showed that RSM-MEG is safe for transdermal application. Finally, using the rat model of rotenone-induced Parkinsonism, we demonstrated that the topical application of RSM-MEG was equally effective in reversing PD symptoms when compared to oral RSM therapy. Thus, our study confirmed the feasibility and potential of transdermal delivery of RSM via simple topical application of RSM-MEG, and this approach could be an alternative therapeutic intervention for the treatment of Parkinson's disease.

Asunto(s)

Indanos/administración & dosificación , Inhibidores de la Monoaminooxidasa/administración & dosificación , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Piel/metabolismo , Administración Cutánea , Administración Oral , Animales , Disponibilidad Biológica , Modelos Animales de Enfermedad , Emulsiones , Estudios de Factibilidad , Humanos , Hidrogeles/administración & dosificación , Hidrogeles/farmacocinética , Indanos/farmacocinética , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Inhibidores de la Monoaminooxidasa/farmacocinética , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/fisiopatología , Conejos , Ratas , Rotenona/administración & dosificación , Rotenona/toxicidad , Pruebas Cutáneas

RESUMEN

Multiple sclerosis (MS) is a complex disease of the central nervous system that can cause permanent disability in young adults. A large armamentarium is available for its management and is increasing over time. Ozanimod is an oral drug belonging to the sphingosine-1-phosphate receptor (S1PR) modulator family recently approved in different countries for MS with active disease. It selectively modulates S1PR1 and S1PR5 to prevent autoreactive lymphocytes from entering the central nervous system (CNS), where they can determine inflammation and neurodegeneration. Ozanimod was tested in one Phase II and two Phase III pivotal trials and was shown to be effective and well tolerated. Moreover, further investigations, including comparative trials with other S1P modulators and MS disease-modifying drugs, are needed to better define placement in MS treatment. Furthermore, ozanimod is currently under evaluation for inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, in international phase III studies. This article retraces the itinerary leading to the approval of ozanimod for MS treatment and its peculiarities and potentiality inside the S1PR modulator family.

Asunto(s)

Indanos/administración & dosificación , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Oxadiazoles/administración & dosificación , Moduladores de los Receptores de fosfatos y esfingosina 1/administración & dosificación , Administración Oral , Animales , Humanos , Indanos/efectos adversos , Indanos/farmacología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Oxadiazoles/efectos adversos , Oxadiazoles/farmacología , Moduladores de los Receptores de fosfatos y esfingosina 1/efectos adversos , Moduladores de los Receptores de fosfatos y esfingosina 1/farmacología

RESUMEN

α-Synuclein (α-Syn) protein is involved in the pathogenesis of Parkinson's disease (PD). Point mutations and multiplications of the α-Syn, which encodes the SNCA gene, are correlated with early-onset PD, therefore the reduction in a-Syn synthesis could be a potential therapy for PD if delivered to the key affected neurons. Several experimental strategies for PD have been developed in recent years using oligonucleotide therapeutics. However, some of them have failed or even caused neuronal toxicity. One limiting step in the success of oligonucleotide-based therapeutics is their delivery to the brain compartment, and once there, to selected neuronal populations. Previously, we developed an indatraline-conjugated antisense oligonucleotide (IND-1233-ASO), that selectively reduces α-Syn synthesis in midbrain monoamine neurons of mice, and nonhuman primates. Here, we extended these observations using a transgenic male mouse strain carrying both A30P and A53T mutant human α-Syn (A30P*A53T*α-Syn). We found that A30P*A53T*α-Syn mice at 4-5 months of age showed 3.5-fold increases in human α-Syn expression in dopamine (DA) and norepinephrine (NE) neurons of the substantia nigra pars compacta (SNc) and locus coeruleus (LC), respectively, compared with mouse α-Syn levels. In parallel, transgenic mice exhibited altered nigrostriatal DA neurotransmission, motor alterations, and an anxiety-like phenotype. Intracerebroventricular IND-1233-ASO administration (100 µg/day, 28 days) prevented the α-Syn synthesis and accumulation in the SNc and LC, and recovered DA neurotransmission, although it did not reverse the behavioral phenotype. Therefore, the present therapeutic strategy based on a conjugated ASO could be used for the selective inhibition of α-Syn expression in PD-vulnerable monoamine neurons, showing the benefit of the optimization of ASO molecules as a disease modifying therapy for PD and related α-synucleinopathies.

Asunto(s)

Glicoconjugados/genética , Oligonucleótidos Antisentido/administración & dosificación , Enfermedad de Parkinson/terapia , Mutación Puntual , alfa-Sinucleína/antagonistas & inhibidores , alfa-Sinucleína/genética , Sustitución de Aminoácidos , Animales , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Glicoconjugados/administración & dosificación , Glicoconjugados/metabolismo , Humanos , Indanos/administración & dosificación , Indanos/química , Indanos/metabolismo , Inyecciones Intraventriculares , Locus Coeruleus/metabolismo , Locus Coeruleus/patología , Masculino , Mesencéfalo/metabolismo , Mesencéfalo/patología , Metilaminas/administración & dosificación , Metilaminas/química , Metilaminas/metabolismo , Ratones , Ratones Transgénicos , Norepinefrina/metabolismo , Oligonucleótidos Antisentido/genética , Oligonucleótidos Antisentido/metabolismo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Porción Compacta de la Sustancia Negra/metabolismo , Porción Compacta de la Sustancia Negra/patología , Transmisión Sináptica , alfa-Sinucleína/metabolismo

RESUMEN

OBJECTIVE: To evaluate cardiovascular safety of two new inhaled fixed-dose combinations for treatment of asthma: (i) the inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) mometasone furoate/indacaterol acetate (MF/IND), (ii) the ICS/LABA/long-acting muscarinic antagonist (LAMA) MF/IND/glycopyrronium bromide (GLY). METHODS: Patient-level data were pooled from four randomized trials, including 52-week studies PALLADIUM (n = 2216) and IRIDIUM (n = 3092), 24-week study ARGON (n = 1426), and 12-week study QUARTZ (n = 802). Cardio-/cerebrovascular (CCV) event frequencies were examined in the following comparisons: (1) LABA effect: pooled-dose MF/IND vs. pooled-dose MF; (2) LAMA effect: pooled-dose MF/IND/GLY vs. pooled-dose MF/IND; (3) ICS-dose effects: (a) high-dose MF/IND vs. medium-dose MF/IND, (b) high-dose MF/IND/GLY vs. medium-dose MF/IND/GLY; (4) intra-class effects: (a) high-dose MF/IND vs. Fluticasone/Salmeterol (F/S), (b) high-dose MF/IND/GLY vs. F/S + Tiotropium (TIO). Risk estimates (percentage of patients with ≥1 CCV event) and risk differences (RDs) with 95% confidence intervals (CIs) were calculated for each comparison. RESULTS: The frequency of CCV events was low, without notable differences between comparison groups. Risk estimates and corresponding RDs (95% CIs) were as follows: (1) pooled-dose MF/IND = 2.35%, pooled-dose MF = 2.18%, RD = 0.17% (-1.00%, 1.34%); (2) pooled-dose MF/IND/GLY = 3.65%, pooled-dose MF/IND = 3.77%, RD = -0.12% (-1.63%, 1.39%); (3a) high-dose MF/IND = 3.69%, medium-dose MF/IND = 3.35%, RD = 0.34% (-1.25%, 1.94%); (3b) high-dose MF/IND/GLY = 2.84%, medium-dose MF/IND/GLY = 2.02%, RD = 0.82% (-0.49%, 2.13%); (4a) high-dose MF/IND = 3.69%, F/S = 2.82%, RD = 0.87% (-0.66%, 2.40%); (4b) high-dose MF/IND/GLY = 1.26%, F/S + TIO = 1.05%, RD = 0.21% (-1.26%, 1.68%). CONCLUSIONS: There was no evidence of increased cardiovascular risk attributable to the addition of IND to MF or addition of GLY to MF/IND. Similarly, no evidence of increased cardiovascular risk was observed with an increase in the ICS-dose or relative to F/S ± TIO.

Asunto(s)

Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Asma/tratamiento farmacológico , Glicopirrolato/administración & dosificación , Factores de Riesgo de Enfermedad Cardiaca , Indanos/administración & dosificación , Furoato de Mometasona/administración & dosificación , Quinolonas/administración & dosificación , Administración por Inhalación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Ensayos Clínicos Fase III como Asunto , Quimioterapia Combinada , Femenino , Glicopirrolato/efectos adversos , Humanos , Indanos/efectos adversos , Masculino , Persona de Mediana Edad , Furoato de Mometasona/efectos adversos , Quinolonas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Seguridad , Resultado del Tratamiento , Adulto Joven

RESUMEN

Ozanimod is approved for the treatment of relapsing forms of multiple sclerosis. Absorption, metabolism, and excretion of ozanimod were investigated after a single oral dose of 1.0 mg [14C]ozanimod hydrochloride to six healthy subjects. In vitro experiments were conducted to understand the metabolic pathways and enzymes involved in the metabolism of ozanimod and its active metabolites. The total mean recovery of the administered radioactivity was ∼63%, with ∼26% and ∼37% recovered from urine and feces, respectively. Based on exposure, the major circulating components were active metabolite CC112273 and inactive metabolite RP101124, which together accounted for 50% of the circulating total radioactivity exposure, whereas ozanimod accounted for 6.7% of the total radioactive exposure. Ozanimod was extensively metabolized, with 14 metabolites identified, including two major active metabolites (CC112273 and CC1084037) and one major inactive metabolite (RP101124) in circulation. Ozanimod is metabolized by three primary pathways, including aldehyde dehydrogenase and alcohol dehydrogenase, cytochrome P450 isoforms 3A4 and 1A1, and reductive metabolism by gut microflora. The primary metabolite RP101075 is further metabolized to form major active metabolite CC112273 by monoamine oxidase B, which further undergoes reduction by carbonyl reductases to form CC1084037 or CYP2C8-mediated oxidation to form RP101509. CC1084037 is oxidized rapidly to form CC112273 by aldo-keto reductase 1C1/1C2 and/or 3ß- and 11ß-hydroxysteroid dehydrogenase, and this reversible oxidoreduction between two active metabolites favors CC112273. The ozanimod example illustrates the need for conducting timely radiolabeled human absorption, distribution, metabolism, and excretion studies for characterization of disproportionate metabolites and assessment of exposure coverage during drug development. SIGNIFICANCE STATEMENT: Absorption, metabolism, and excretion of ozanimod were characterized in humans, and the enzymes involved in complex metabolism were elucidated. Disproportionate metabolites were identified, and the activity of these metabolites was determined.

Asunto(s)

Indanos/administración & dosificación , Indanos/metabolismo , Oxadiazoles/administración & dosificación , Oxadiazoles/metabolismo , Moduladores de los Receptores de fosfatos y esfingosina 1/administración & dosificación , Moduladores de los Receptores de fosfatos y esfingosina 1/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Administración Oral , Adulto , Animales , Células CHO , Cricetinae , Cricetulus , Humanos , Masculino , Persona de Mediana Edad

RESUMEN

BACKGROUND: A once-daily (o.d.) fixed-dose combination of indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF) delivered via the Breezhaler® device (IND/GLY/MF) is being developed for treatment of asthma. This study compared steady-state pharmacokinetics of IND, GLY and MF between Japanese and Caucasian male subjects after multiple inhalations of IND/GLY/MF o.d. METHODS: This was a single-center, open-label, 2-treatment crossover study with a 21-day washout period. Japanese and Caucasian subjects received IND/GLY/MF 150/50/80 µg (inhaled corticosteroid [ICS] medium-dose) or 150/50/160 µg o.d. (ICS high-dose) for 14 days in each period. Pharmacokinetics were characterized up to 24 h post-dose on Days 1 and 14. RESULTS: In total, 16 Japanese (median age 31 years [range 20-40 years], mean weight 68.3 kg) and 17 Caucasian subjects (median age 27 years [range 21-43 years], mean weight 75.0 kg) were randomized. Geometric mean ratios (Japanese/Caucasian) [90% confidence interval (CI)] for Cmax for IND, GLY and MF at the high ICS dose on Day 14 were 1.31 [1.13, 1.51] 1.38 [1.13, 1.69] and 1.07 [0.969, 1.18], respectively. Geometric mean ratios (Japanese/Caucasian) [90% CI] for AUC0-24h on Day 14 for IND, GLY and MF at the high ICS dose were 1.17 [1.01, 1.35], 1.05 [0.920, 1.20] and 1.15 [1.05, 1.27] respectively. Similar trends were noted for all components for the medium ICS dose treatment. IND/GLY/MF was safe and well tolerated; no AEs suspected to be study drug-related were observed. CONCLUSION: Pharmacokinetics of IND, GLY and MF (high and medium dose) when delivered as a fixed-dose combination were comparable between Japanese and Caucasian subjects. The IND/GLY/MF combination at the administrated doses was safe and well tolerated in both ethnic groups. TRIAL REGISTRATION: Japan Registry of Clinical Trial: jRCT2031200227, retrospectively registered on 04, December, 2020.

Asunto(s)

Antiasmáticos/farmacocinética , Glicopirrolato/farmacocinética , Indanos/farmacocinética , Furoato de Mometasona/farmacocinética , Quinolonas/farmacocinética , Administración por Inhalación , Adulto , Antiasmáticos/administración & dosificación , Pueblo Asiatico , Estudios Cruzados , Combinación de Medicamentos , Femenino , Glicopirrolato/administración & dosificación , Voluntarios Sanos , Humanos , Indanos/administración & dosificación , Masculino , Furoato de Mometasona/administración & dosificación , Quinolonas/administración & dosificación , Población Blanca , Adulto Joven

RESUMEN

Ozanimod, approved by regulatory agencies in multiple countries for the treatment of adults with relapsing multiple sclerosis, is a sphingosine 1-phosphate (S1P) receptor modulator, which binds with high affinity selectively to S1P receptor subtypes 1 and 5. The relationships between plasma concentrations of ozanimod and its major active metabolites, CC112273 and CC1084037, and the QTc interval (C-QTc) from a phase I multiple-dose study in healthy subjects were analyzed using nonlinear mixed effects modeling. QTc was modeled linearly as the sum of a sex-related fixed effect, baseline, and concentration-related random effects that incorporated interindividual and residual variability. Common linear, power, and maximum effect (Emax ) functions were assessed for characterizing the relationship of QTc with concentrations. Model goodness-of-fit and performance were evaluated by standard diagnostic tools, including a visual predictive check. The placebo-corrected change from baseline in QTc (ΔΔQTc) was estimated based on the developed C-QTc model using a nonparametric bootstrapping approach. QTc was better derived using a study-specific population formula (QTcP). Among the investigated functions, an Emax function most adequately described the relationship of QTcP with concentrations. Separate models for individual analytes characterized the C-QTcP relationship better than combined analytes models. Attributing QT prolongation independently to CC1084037 or CC112273, the upper bound of the 95% confidence interval of the predicted ΔΔQTcP was ~ 4 msec at the plateau of the Emax curves. Therefore, ΔΔQTcP is predicted to remain below 10 msec at the supratherapeutic concentrations of the major active metabolites.

Asunto(s)

Indanos/farmacocinética , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Oxadiazoles/farmacocinética , Moduladores de los Receptores de fosfatos y esfingosina 1/farmacocinética , Receptores de Esfingosina-1-Fosfato/metabolismo , Administración Oral , Adulto , Estudios de Casos y Controles , Método Doble Ciego , Electrocardiografía/efectos de los fármacos , Femenino , Voluntarios Sanos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Indanos/administración & dosificación , Indanos/efectos adversos , Síndrome de QT Prolongado , Masculino , Oxadiazoles/administración & dosificación , Oxadiazoles/efectos adversos , Placebos/administración & dosificación , Valor Predictivo de las Pruebas , Moduladores de los Receptores de fosfatos y esfingosina 1/administración & dosificación , Moduladores de los Receptores de fosfatos y esfingosina 1/efectos adversos

Asunto(s)

Indanos/administración & dosificación , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Oxadiazoles/administración & dosificación , Moduladores de los Receptores de fosfatos y esfingosina 1/administración & dosificación , Administración Oral , Ensayos Clínicos como Asunto/métodos , Humanos , Indanos/farmacocinética , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Oxadiazoles/farmacocinética , Moduladores de los Receptores de fosfatos y esfingosina 1/farmacocinética

RESUMEN

INTRODUCTION: Most guidelines recommend long-acting bronchodilators over short-acting bronchodilators for patients with chronic obstructive pulmonary disease (COPD). The available evidence for the guidelines was based on dry powder or pressurized metered dose inhalers, but not nebulizations. Nevertheless, there is considerable, poorly evidenced based, use of short acting nebulized bronchodilators. METHODS: This was an investigator initiated, randomized, active controlled, cross-over, double-blind and double-dummy single centre study in patients with stable COPD. The active comparators were indacaterol/glycopyrronium 110/50 µg as Ultibro® via Breezhaler® (IND/GLY) and salbutamol/ipratropium 2,5/0,5 mg via air driven nebulization (SAL/IPR), both given as a single dose on separate days. The primary end point was the area under the FEV1 curve from baseline till 6 h. Secondary end points included change in Borg dyspnoea score, adverse events and change in hyperinflation measured by the inspiratory capacity. RESULTS: A total of 33 COPD patients completed the trial and were evaluable, most of them were ex-smokers. The difference between the tested regimens for the primary endpoint, FEV1 AUC 0-6 h, 2965 ± 1544 mL (mean ± SD) for IND/GLY versus 3513 ± 1762 mL for SAL/IPR, was not significant (P = 0.08). The peak in FEV1 was higher and was reached faster with SAL/IPR compared to IND/GLY. No other significant differences were detected for the secondary endpoints including the Borg score, or adverse events. CONCLUSION: Among patients with stable COPD, dry powder long-acting single inhalation of a LABA and a LAMA (IND/GLY) was not superior compared to nebulized short-acting salbutamol plus ipratropium (SAL/IPR) in its bronchodilating effects over 6 h.The effects of the nebulization kicked in faster and peaked higher. The observed differences may be caused by the difference in dosing between the two regimens. The improvement in Borg dyspnoea score did not favour the nebulization. Long-term outcomes were not assessed in this study.

Asunto(s)

Albuterol/administración & dosificación , Broncodilatadores/administración & dosificación , Preparaciones de Acción Retardada/administración & dosificación , Glicopirrolato/análogos & derivados , Indanos/administración & dosificación , Ipratropio/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Quinolonas/administración & dosificación , Administración por Inhalación , Anciano , Estudios Cruzados , Método Doble Ciego , Combinación de Medicamentos , Quimioterapia Combinada , Femenino , Glicopirrolato/administración & dosificación , Humanos , Masculino , Inhaladores de Dosis Medida , Persona de Mediana Edad , Nebulizadores y Vaporizadores , Resultado del Tratamiento