Pharmacokinetics and Pharmacodynamics of Cenerimod, A Selective S1P1 R Modulator, Are Not Affected by Ethnicity in Healthy Asian and White Subjects.

Cenerimod is a sphingosine-1-phosphate 1 receptor (S1P1 R) modulator in phase II development for treatment of systemic lupus erythematosus. Its pharmacokinetics (PKs), pharmacodynamics (PDs), as well as safety and tolerability were investigated in white and Asian subjects to allow for recruitment of Asian patients in future studies. A randomized, double-blind, placebo-controlled parallel-group study was performed in 20 healthy male subjects (n = 10 per ethnicity). A single, oral dose of 4 mg cenerimod or placebo (ratio 8:2) was administered under fasted conditions. The PKs of cenerimod were similar in white and Asian subjects indicated by geometric mean ratios (90% confidence interval) of 0.99 (0.80-1.21) for maximum plasma concentration, 0.96 (0.75-1.24) for area under the plasma concentration-time curve from 0 to infinity, and 1.04 (0.86-1.25) for terminal half-life. Accordingly, the extent and time course of reduction in lymphocyte count (as PD biomarker) were also similar in white and Asian subjects as compared with placebo. As observed for other S1PR modulators, a transient mean (SD) heart rate reduction in white (15.1 (14.8) bpm) and Asian (11.8 (6.16) bpm) subjects was observed following administration of cenerimod. The drug was safe and well-tolerated indicated by occurrence of a single adverse event of chemical conjunctivitis in a white subject that was not suspected as study drug related. In conclusion, the determined absence of any relevant PK or PD differences supports using the same doses of cenerimod in white and Asian patients in upcoming late-phase studies.

Opicapone and Levodopa-Carbidopa Intestinal Gel Infusion: The Way Forward Towards Cost Savings for Healthcare Systems?

Combined catechol-O-methyl-transferase-inhibition and Levodopa-Carbidopa intestinal gel (LCIG) infusion has the potential to reduce LCIG daily dose and the costs of this therapy. In this retrospective analysis, we report on Parkinson's disease (PD) patients on LCIG with concomitant Opicapone. In 11 patients, the introduction of Opicapone led to LCIG daily dose being reduced by 24.8% (p = 0.05) without any significant worsening of dyskinesia. Three patients withdrew from Opicapone due to side effects or inefficacy. LCIG daily dose reduction could lead to cost savings of £142,820.63/year in the United Kingdom while maintaining clinical care.

Novel hybrids of benzothiazole-1,3,4-oxadiazole-4-thiazolidinone: Synthesis, in silico ADME study, molecular docking and in vivo anti-diabetic assessment.

A series of new benzothiazole-1,3,4-oxadiazole-4-thiazolidinone hybrid analogs (Tz1-Tz28) were synthesized in search of potential anti-diabetic agents. Molecular docking study was conducted with binding pocket of peroxisome proliferator activated receptor-gamma to elucidate the binding interactions of newly synthesized targets. Seven selected compounds with best docking scores were further screened for in vivo anti-hyperglycemic efficacy by oral glucose tolerance test in non-diabetic rats and on streptozotocin induced diabetic rat models. All the tested compounds demonstrated excellent to moderate reduction in blood glucose levels. Three of the compounds (Tz21, Tz7 and Tz10) showed excellent anti-diabetic effect by reducing concentration of glucose to 157.15 ±â€¯1.79 mg/dL, 154.39 ±â€¯1.71 mg/dL, 167.36 ±â€¯2.45 mg/dL, respectively better than the standard drug, pioglitazone, 178.32 ±â€¯1.88 mg/dL. Moreover, three derivatives Tz21, Tz4 and Tz24 with IC50 values of 0.21 ±â€¯0.01 µM, 9.03 ±â€¯0.12 µM and 11.96 ±â€¯0.40 µM respectively also showed better inhibitory activities on alpha-glucosidase even more than the standard acarbose (IC50 = 18.5 ±â€¯0.20 µM), indicating Tz21 has the highest inhibitory effect among the seven tested derivatives. Prediction of Drug like properties using molinspiration online software suggests that all the synthesized compounds have potential of becoming the orally active molecules. Thus, these novel hybrids could serve as potential candidates to become leads for the development of new drugs eliciting anti-hyperglycemic effect orally.

In vitro and in vivo assessment of newer quinoxaline-oxadiazole hybrids as antimicrobial and antiprotozoal agents.

A new series of N-(substituted-phenyl)-2-[5-(quinoxalin-2-yloxymethyl)-[1,3,4] oxadiazol-2-ylsulfanyl]-acetamides (5a-o) was designed and synthesised from the parent compound 2-hydroxy quinoxaline (1) through a multistep reaction sequence and was characterised by spectral and elemental analyses. All of the compounds synthesised were evaluated for their antimicrobial and antiprotozoal activities. The results revealed that quinoxaline-based 1,3,4-oxadiazoles displayed promising antibacterial, antifungal and anti-Trypanosoma cruzi activities compared with reference drugs, particularly the lead compound 5l in a short-term in vivo model in T. cruzi.

Seguridad y eficacia de ataluren en pacientes con diagnóstico de distrofia muscular de duchenne portadores de una mutación sin sentido en el gen de distrofina / Safety and efficacy of ataluren in patients diagnosed with duchenne muscular dystrophy who carry a nonsense mutation in the dystrophin gene

INTRODUCCIÓN: Antecedentes: El Instituto de Evaluación de Tecnologías en Salud e Investigación ha recibido la solicitud de evaluar el uso de Ataluren para su uso en Pacientes ambulantes mayores de 5 años con diagnóstico de distrofia muscular de Duchenne debida a una mutación sin sentido en el gen de la distrofina dentro del sistema de EsSalud, indicación actualmente no contemplada en el petitorio de medicamentos. Esta acción sigue lo estipulado en la Directiva N° 002-IETSI-ESSALUD-2015 y el objetivo final es determinar el estado del arte sobre la eficacia y seguridad de ataluren. Tecnología Sanitaria de Interés: Ataluren: La PTC124 (3-(5-(2-fluorofeni)-1, 2,4-oxadiazol-3-y1)-ácido benzoico), también conocida como Ataluren (TranslarnaTM) es una molécula pequeña de oxadiazol cuyo mecanismo de acción consiste en cominuar la traducción de ARNm sobre los codones de terminación prematuros causados por la mutación sin sentido, permitiendo la síntesis de distrofina completa y funcional. METODOLOGIA: Estrategia de Busqueda: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de Ataluren para el tratamiento de la DMD en las bases de datos de MEDLINE, EMBASE, CENTRAL, DARE y TRIPDATABASE. Se hizo una búsqueda adicional en www.clinicaltrials.gov, para poder identificar ensayos clínicos aún en elaboración o que no hayan sido publicados. Adicionalmente, se hizo una búsqueda dentro de la información generada por las principales instituciones internacionales oncológicas y agencias de tecnologías sanitarias que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC). RESULTADOS:Sinopses de la Evidencia: Se realizó la búsqueda bibliográfica y de evidencia científica que sustente el uso de ataluren en DMD según la pregunta PICO establecida. Para el presente documento se seleccionó el siguiente cuerpo de evidencia que es resumido a continuación: Guías Clínicas: Se identificó una única guía práctica realizada en Colombia que hizo mención a este tratamiento. Evaluaciones de tecnología sanitaria: Se identificó una ETS del Reino Unido. Revisiones sistemáticas: No se identificaron revisiones sistemáticas. Estudios de calidad de vida: No se identificaron estudios que evaluaran calidad de vida. Ensayos clínicos: Se identificaron dos ECAs correspondientes a las fases 2a y fase 2 b. Ensayos clínicos en curso: se identificó el registro correspondiente a un estudio de fase III pendiente de publicar sus resultados. CONCLUSIONES: se evidencia que ataluren es un medicamento aún en estudio que no ha demostrado al momento ser diferente a placebo en el tratamiento de la DMD con mutación sin sentido. De hecho, la evidencia disponible que el ataluren no es mejor que el placebo en mejorar indicadores clínicos importantes en el manejo de esta enfermedad, como la DC6M, considerada como desenlace principal en enfermedades raras con compromiso neuromuscular. Ataluren tampoco mostró ser diferente al placebo en mejorar la calidad de vida de los pacientes, ni disminuye los tiempos para realizar tareas motoras como subir o bajar escalones, correr o caminar 10 metros y levantarse desde la posición supina. El Instituto de Evaluación de Tecnología en Salud e investigación ­ IETSI, no aprueba el uso de ataluren para el tratamiento de la DMD con mutación sin sentido del gen de la distrofina.

In vivo electrophysiological assessment of the putative antidepressant Wf-516 in the rat raphe dorsalis, locus coeruleus and hippocampus.

Wf-516 is a potential novel antidepressant. It has high affinity for serotonin (5-hydroxytryptamine; 5-HT) transporters, 5-HT(1A) and 5-HT(2A) receptors. In the present study, the pharmacologic properties of Wf-516 were thus assessed using in vivo electrophysiology in the rat dorsal raphe nucleus (DRN), locus coeruleus (LC) and hippocampus. Glass microelectrodes were lowered into the DRN, LC or hippocampus, and neurons were recorded and tested using systemic or microiontophoretic injections of drugs. In the DRN, cumulative doses of 0.5 mg/kg of Wf-516 were injected intravenously and total inhibition of 5-HT neurons firing was obtained with 2.8 +/- 0.3 mg/kg. The administration of 1 mg/kg of Wf-516, which by itself did not induce a change in the firing of 5-HT neurons, markedly attenuated the inhibitory effect of the 5-HT(1A) autoreceptor agonist LSD, indicating that Wf-516 is a 5-HT(1A) autoreceptor antagonist. In the LC, 1 mg/kg of Wf-516 dampened the inhibitory effect of the preferential 5-HT(2A) agonist DOI on norepinephrine (NE) neurons, indicating that Wf-516 is also a 5-HT(2A) receptor antagonist. In the hippocampus, cumulative intravenous doses of Wf-516 significantly increased the recovery time of firing activity of CA(3) pyramidal neurons after 5-HT applications, indicating an inhibitory effect on 5-HT reuptake. Unlike the 5-HT(1A) antagonist WAY100635, Wf-516 did not block the inhibitory effect of microiontophoretic application of 5-HT, indicating that this drug is devoid of 5-HT(1A) receptor antagonistic activity in this postsynaptic structure. These properties of WF-516 define the transporter/receptorial profile of an antidepressant with superior effectiveness.