ABSTRACT
Current pharmaceutical research directions tend to follow a systematic approach in the field of applied research and development. The concept of quality-by-design (QbD) has been the focus of the current progress of pharmaceutical sciences. It is based on, but not limited, to risk assessment, design of experiments and other computational methods and process analytical technology. These tools offer a well-organized methodology, both to identify and analyse the hazards that should be handled as critical, and are therefore applicable in the control strategy. Once implemented, the QbD approach will augment the comprehension of experts concerning the developed analytical technique or manufacturing process. The main activities are oriented towards the identification of the quality target product profiles, along with the critical quality attributes, the risk management of these and their analysis through in silico aided methods. This review aims to offer an overview of the current standpoints and general applications of QbD methods in pharmaceutical development.
ABSTRACT
Background and Objectives: The use of the dopamine-partial agonist subclass (also termed dopamine stabilizers) of atypical antipsychotics for the treatment of negative schizophrenia symptoms and some mood disorders has increased recently. Similar to other second-generation antipsychotics (SGAs), aripiprazole (ARI) and cariprazine (CAR) also influence food intake, but the peripheral effects of these drugs on adipose-tissue homeostasis, including adipokine secretion as well as lipo- and adipogenesis, are not fully elucidated. In this study, we explored the adipocyte-related mechanisms induced by second-generation antipsychotics (SGAs), leading to changes in peripheral signals involved in energy homeostasis. Materials and Methods: CAR, a new SGA, was compared with ARI and olanzapine (OLA), using cell cultures to study adipogenesis, and the expression levels of peroxisome proliferator-activated receptor-γ (PPAR-γ) was measured in adipocytes derived from mouse fibroblasts, by western blotting on days 7, 14, and 21 postinduction. The triglyceride (TG) content of the cells was also evaluated on day 15 using Oil Red O staining, and the adiponectin (AN) content in the cell culture supernatants was quantified on days 7 and 15 by enzyme-linked immunosorbent assay. Cells were treated with two concentrations of ARI (0.5 and 20 µg/mL), OLA (1 and 20 µg/mL), and CAR (0.1 and 2 µg/mL). Results: Both concentrations of ARI and OLA, as well as the lower concentration of CAR, significantly increased the TG contents. The AN levels in the supernatants were significantly increased by the higher concentration of ARI on days 7 and 15 (p < 0.05). Although PPAR-γ levels were not significantly affected by ARI and OLA, the lower concentration of CAR induced a significant time-dependent decrease in PPAR-γ expression (p < 0.05). Conclusions: The in vitro adipogenesis considered from TG accumulation, AN secretion, and PPAR-γ expression was differently influenced by ARI, CAR, and OLA. Understanding the adipocyte-related mechanisms of antipsychotics could contribute to understanding their weight-influencing effect.
Subject(s)
Aripiprazole/therapeutic use , Fibroblasts/drug effects , Olanzapine/therapeutic use , Piperazines/therapeutic use , Adiponectin/analysis , Adiponectin/blood , Animals , Aripiprazole/administration & dosage , Aripiprazole/pharmacology , Cell Differentiation/drug effects , Disease Models, Animal , Fibroblasts/pathology , Mice , Mood Disorders/drug therapy , Olanzapine/administration & dosage , Olanzapine/pharmacology , PPAR gamma/analysis , PPAR gamma/blood , Piperazines/administration & dosage , Piperazines/pharmacology , Triglycerides/analysis , Triglycerides/bloodABSTRACT
This study aims to investigate the effects of chronic fluoxetine (FLX) treatment on preadipocyte factor-1 (Pref-1) expression in subcutaneous, visceral and brown adipose tissues, and on the size of vacuoles in a dipocytes obtained from the perirenal regions in rats. Twenty-eight Wistar rats were treated with FLX at two different doses and fourteen animals received vehicle. After 40 days of treatment, the subcutaneous, perirenal and interscapular adipose tissues were collected. Pref-1 expression was examined using an immunohistochemical method and the vacuolar area was measured in stained sections. In the low dose FLX group, the size of vacuoles increased both in male and female animals. The high dose of FLX also induced a significant increase of vacuole size, but only in male animals. Neither of the two doses of FLX has significantly affected the Pref-1 expression in any type of adipose tissue.