Understanding the Influence of Nanocarrier-Mediated Brain Delivery on Therapeutic Performance Through Pharmacokinetic-Pharmacodynamic Modeling

This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation.     

Docosahexaenoic acid supplementation during pregnancy as phospholipids did not improve the incorporation of this fatty acid into rat fetal brain compared with the triglyceride form

Prenatal docosahexaenoic acid (DHA) supply is important to ensure an adequate infant neurodevelopment. Several fat supplements with DHA under different chemical structures are available. There is an increased placental phospholipase activity at the end of pregnancy. The hypothesis of this study was to discern whether DHA consumption during pregnancy as phospholipids (PLs) could be more available for placental DHA uptake and fetal accretion than triglycerides (TGs) form. We aimed to evaluate maternofetal DHA status in pregnant rats fed with DHA as PL from egg yolk or TG from algae oil to determine which source might be most effective during pregnancy. Three experimental diets were tested: 2.5% DHA-TG (n = 10), 2.5% DHA-PL (n = 9), and 9% DHA-PL (n = 9). The total PL content of these diets was 2%, 12%, and 38%, respectively. We determined dietary fat absorption and quantified fatty acids by gas chromatography in maternal and fetal tissues. Dietary PL enhanced significantly dietary fat absorption. However, animals fed the highest PL-content diet (38% PL and 9% DHA-PL) stored most of the absorbed fat in maternal liver, promoting hepatic steatosis, which was not observed in the lower PL-content diets (12% and 2%). Despite higher fat absorption of PL-containing diets, maternal and fetal tissues (including fetal brain) did not show major differences in DHA content between the 2.5% DHA-PL and 2.5% DHA-TG–fed groups. We conclude that the chemical form of DHA consumed by the rat during gestation (PL or TG) does not differentially affect DHA accretion into fetal brain, and both lipid sources can be equally used for maternal DHA supplementation during pregnancy.     

High Prevelance of Rifampin-Monoresistant Tuberculosis: A Retrospective Analysis among Iranian Pulmonary Tuberculosis Patients

We determined the prevalence of rifampin-monoresistant tuberculosis (RMR-TB) in Iran. Because development of RMR-TB is not common, we also identified the major risk factors associated with RMR-TB reported from different provinces of Iran. Data for 3,020 TB patients who remained or became smear positive after two, four, six, and nine months of standard first-line chemotherapy were retrospectively analyzed. Of 3,020 patients, 1,242 patients (41.1%) were culture and DNA positive for Mycobacterium tuberculosis. Of these patients, 73 (7.4%) patients had monoresistant isolates to rifampin, which was significantly higher than that for multidrug-resistant TB (5.8%). The average rate of RMR-TB in the studied population ranged from 5% to 10%. Classical investigation showed that 33.6% of patients had either a previous or family history of TB. Molecular epidemiology methods (i.e., spoligotyping and Mycobacterium intespersed repetitive unit–variable number tandem repeat), defined transmission link in three clusters (13%). These results outline the urgent need for a comprehensive plan for detection and treatment of RMR-TB cases.