paliperidone-palmitate and Inflammation

The present study aims at elucidating the intricate nature of the drug release and absorption following intramuscular (i.m.) injection of sustained-release prodrug nanocrystals/microcrystals. A paliperidone palmitate (PPP) long-acting suspension was characterized with regard to particle size (Dv,50 = 1.09 μm) and morphology prior to i.m. injection in rats. The local disposition was rigorously investigated by means of (immuno)histochemistry and transmission electron microscopy while the concurrent multiphasic pharmacokinetics was linked to the microanatomy. A transient (24 h) trauma-induced inflammation promptly evolved into a subclinical but chronic granulomatous inflammatory reaction initiated by the presence of solid material. The dense inflammatory envelope (CD68(+) macrophages) led to particle agglomeration with subsequent drop in dissolution rate beyond 24 h postinjection. This was associated with a decrease in apparent paliperidone (PP) absorption (near-zero order) until 96 h and a delayed time of occurrence of observed maximum drug plasma concentration (168 h). The infiltrating macrophages phagocytosed large fractions of the depot, thereby influencing the (pro)drug release. Radial angiogenesis (CD31(+)) was observed throughout the inflammatory rim from 72 h onwards and presumably contributed to the sustained systemic PP concentrations by maintaining a sufficient absorptive capacity. No solid-state transitions of the retrieved formulation were recorded with X-ray diffraction analysis. In summary, the initial formulation-driven prodrug (PPP) dissolution and drug (PP) absorption were followed by a complex phase determined by the relative contribution of formulation factors and dynamic physiological variables.

Topics: Animals; Delayed-Action Preparations; Immunohistochemistry; Inflammation; Injections, Intramuscular; Isoxazoles; Male; Microscopy, Electron, Transmission; Models, Biological; Muscle, Skeletal; Nanoparticles; Paliperidone Palmitate; Palmitates; Particle Size; Prodrugs; Rats, Wistar; Surface Properties; Suspensions; Tissue Distribution

Metabolic syndrome and antipsychotic medications are associated with inflammation. This study investigated the relationship between inflammation and metabolic syndrome in patients with schizophrenia. It also examined the effects of paliperidone extended release (ER) treatment on metabolic parameters.. Data were analyzed from schizophrenic patients who participated in a multi-center, open-label, non-comparative clinical trial. Anthropomorphic measurements (i.e., weight, waist circumference, and blood pressure) were assessed along with fasting laboratory values, including white blood cell (WBC) count, glucose, high-density lipoprotein, and triglycerides.. Among the 225 patients at baseline, the group with the highest WBC count displayed a 5.9-fold risk for metabolic syndrome compared with that of the lowest group. An increase of 10(3)WBCs/μL was associated with a 1.4-fold increased risk for metabolic syndrome. After 24weeks of treatment with paliperidone ER, significant increases were observed in waist circumference and body weight. Changes in WBC count were positively correlated with changes in waist circumference.. Schizophrenic patients with high levels of inflammation should be carefully monitored for metabolic syndrome. Moreover, strategies to reduce inflammation and obesity may prevent metabolic syndrome in patients with schizophrenia who take atypical antipsychotic medication.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Delayed-Action Preparations; Female; Humans; Inflammation; Isoxazoles; Leukocyte Count; Male; Metabolic Syndrome; Middle Aged; Paliperidone Palmitate; Pyrimidines; Schizophrenia