RESUMEN
In 2012, AstraZeneca entered into a strategic relationship with Charles River Laboratories whereby preclinical safety packages comprising safety pharmacology, toxicology, formulation analysis, in vivo ADME, bioanalysis and pharmacokinetics studies are outsourced. New processes were put in place to ensure seamless workflows with the aim of accelerating the delivery of new medicines to patients. Here, we describe in more detail the AstraZeneca preclinical safety outsourcing model and the way in which a collaborative tool has helped to translate the processes in AstraZeneca and Charles River Laboratories into simpler integrated workflows that are efficient and visible across the two companies.
Asunto(s)
Evaluación Preclínica de Medicamentos , Industria Farmacéutica/organización & administración , Laboratorios/organización & administración , Servicios Externos , Conducta Cooperativa , Eficiencia Organizacional , Modelos OrganizacionalesRESUMEN
Hydroxypropyl-ß-cyclodextrin (HPßCD) is a complexation agent used to enhance drug solubilization and formulation stability. Although its toxicity is well characterized, its cardiovascular effects are less known. To investigate them, HPßCD was infused intravenously over 10 min in anesthetized dogs (10-40% (w/v, i.e. 200-800 mg/kg) in non-denervated animals and at 40% in denervated animals). HPßCD increased renal arteriolar resistance and decreased renal blood flow at all doses, almost immediately after infusion start, more drastically in females. A less pronounced increase in total peripheral resistance occurred in females only due to sex difference in sympathetic tone. Pulmonary hemodynamic parameters remained unaffected, suggesting that the renal effect was rather selective. As a consequence of the increased systemic blood pressure, heart rate decreased in normal animals without direct effect on cardiac conductance. This effect was abolished in denervated animals. This suggests that autonomous nervous feedback loops are functional in normal animals and that HPßCD has no direct chronotropic effect. In conclusion, systemic and renal hemodynamic changes should be considered as potential background effects at 200-400 mg/kg. At higher doses (800 mg/kg), changes are more pronounced and could mask/exacerbate hemodynamic response of drug candidate; such doses should be avoided in nonclinical safety studies.
Asunto(s)
Anestesia , Excipientes/efectos adversos , Hemodinámica/efectos de los fármacos , Riñón/efectos de los fármacos , beta-Ciclodextrinas/efectos adversos , 2-Hidroxipropil-beta-Ciclodextrina , Animales , Presión Sanguínea/efectos de los fármacos , Desnervación , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Excipientes/administración & dosificación , Femenino , Sistema de Conducción Cardíaco/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Infusiones Intravenosas , Riñón/irrigación sanguínea , Riñón/inervación , Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Pulmón/inervación , Masculino , Caracteres Sexuales , beta-Ciclodextrinas/administración & dosificación , beta-Ciclodextrinas/sangreRESUMEN
RATIONALE: Asenapine, a novel psychopharmacologic agent in the development for schizophrenia and bipolar disorder, has high affinity for serotonergic, alpha-adrenergic, and dopaminergic receptors, suggesting potential for antipsychotic and cognitive-enhancing properties. OBJECTIVES: The effects of asenapine in rat models of antipsychotic efficacy and cognition were examined and compared with those of olanzapine and risperidone. MATERIALS AND METHODS: Amphetamine-stimulated locomotor activity (Amp-LMA; 1.0 or 3.0 mg/kg s.c.) and apomorphine-disrupted prepulse inhibition (Apo-PPI; 0.5 mg/kg s.c.) were used as tests for antipsychotic activity. Delayed non-match to place (DNMTP) and five-choice serial reaction (5-CSR) tasks were used to assess short-term spatial memory and attention, respectively. Asenapine doses varied across tasks: Amp-LMA (0.01-0.3 mg/kg s.c.), Apo-PPI (0.001-0.3 mg/kg s.c.), DNMTP (0.01-0.1 mg/kg s.c.), and 5-CSR (0.003-0.3 mg/kg s.c.). RESULTS: Asenapine was highly potent (active at 0.03 mg/kg) in the Amp-LMA and Apo-PPI assays. DNMTP or 5-CSR performance was not improved by asenapine, olanzapine, or risperidone. All agents (P < 0.01) reduced DNMTP accuracy at short delays; post hoc analyses revealed that only 0.1 mg/kg asenapine and 0.3 mg/kg risperidone differed from vehicle. All active agents (asenapine, 0.3 mg/kg; olanzapine, 0.03-0.3 mg/kg; and risperidone, 0.01-0.1 mg/kg) significantly impaired 5-CSR accuracy (P < 0.05). CONCLUSIONS: Asenapine has potent antidopaminergic properties that are predictive of antipsychotic efficacy. Asenapine, like risperidone and olanzapine, did not improve cognition in normal rats. Rather, at doses greater than those required for antipsychotic activity, asenapine impaired cognitive performance due to disturbance of motor function, an effect also observed with olanzapine and risperidone.