New regimens based on 2 or more novel agents are sought to shorten or to simplify treatment of tuberculosis (TB), including drug-resistant forms. Prior studies showed that the novel combinations of bedaquiline (BDQ) plus pretomanid (PMD) plus pyrazinamide (PZA) and PMD plus moxifloxacin (MXF) plus PZA shortened the treatment duration necessary to prevent relapse by 2 to 3 months and 1 to 2 months, respectively, compared with the current first-line regimen, in a murine TB model. These 3-drug combinations are now being studied in clinical trials. Here, the 4-drug combination of BDQ+PMD+MXF+PZA was compared to its 3-drug component regimens and different treatment durations of PZA and MXF were explored, to identify the optimal regimens and treatment times and to estimate the likelihood of success against drug-resistant strains. BDQ+PMD+MXF+PZA rendered all mice relapse-free after 2 months of treatment. PZA administration could be discontinued after the first month of treatment without worsening outcomes, whereas the absence of MXF, PZA, or BDQ administration from the beginning necessitated approximately 0.5, 1, or 2 months, respectively, of additional treatment to attain the same outcome.

Intranasal drug delivery is known to overcome the blood-brain barrier (BBB) for delivery of drugs to brain. The objective of this study was to prepare risperidone (RSP)-loaded solid lipid nanoparticles (RSLNs) and explore the possibility of brain targeting by nose-to-brain delivery. RSLNs were prepared by solvent emulsification-solvent evaporation method and characterized for drug content, particle size and size distribution, zeta potential, and in vitro drug-release study. The pharmacodynamic study of RSLNs, which was performed by paw test using Perspex platform, showed higher hindlimb retraction time (HRT) values as compared with RSP solution (RS) indicating the superiority of RSLNs over the RS for brain targeting. The pharmacokinetics and biodistribution studies in mice showed that brain/blood ratio 1 h post-administration of RSLNs (i.n.) was found to be 1.36 ± 0.06 (nearly 10- and 5-fold higher) as compared with 0.17 ± 0.05 for RS (i.v.) and 0.78 ± 0.07 for RSLNs (i.v.), respectively. Gamma scintigraphy imaging of mice brain following intravenous and intranasal administration confirmed the localization of drug in brain. This finding substantiates the existence of direct nose-to-brain delivery route for nanoparticles administered to the nasal cavity.

Objective:To evaluate the antimicrobial efficacy and compressive strength of conventional glass ionomer cement (GIC) containing chlorhexidine and antibiotics at varying concentrations.Materials and Methods:Chlorhexidine diacetate and antibiotics (ciprofloxacin, metronidazole, and minocycline) were incorporated into GIC Fuji IX at 1.5% and 3% w/w ratio to form the experimental groups. The experimental GIC specimens were placed on brain heart infusion agar plates inoculated with Streptococcus mutans, and the area of inhibition was measured after 48 h. The 24-h compressive strength of the set specimens was evaluated using a Universal Testing Machine.Results:The control group demonstrated no zone of inhibition. All experimental groups showed inhibition against S. mutans (P < 0.05), with larger zones of inhibition found in the higher concentration groups. Compressive strength at the end of 24 h decreased in the experimental groups as compared to the control group (P < 0.05), but no difference was found between the experimental groups (P > 0.05).Conclusion:The present study demonstrated that experimental GICs containing chlorhexidine diacetate and antibiotics were effective in inhibiting S. mutans, and incorporation of 1.5% ABX was optimal to give the appropriate antibacterial and physical properties.

INTRODUCTIONThe objective of this research was to optimize the processing parameters for poly(D,L-lactide-coglycolide) (PLGA) microspheres of 5-fluorouracil (5-FU) and to mathematically relate the process parameters and properties of microspheres. Microspheres were prepared by a water-in-oil-in-water emulsion solvent evaporation technique. A 3 2 factorial design was employed to study the effect of the volume of the internal phase of the primary emulsion and the volume of the external phase of the secondary emulsion on yield, particle size, and encapsulation efficiency of microspheres. An increase in the volume of the internal phase of the primary emulsion resulted in a decrease in yield and encapsulation efficiency and an increase in particle size of microspheres. When the volume of the external phase of the secondary emulsion was increased, a decrease in yield, particle size, and encapsulation efficiency was observed. Microspheres with good batch-to-batch reproducibility could be produced. Scanning electron microscopic study indicated that microspheres existed as aggregates.Poly(D,L-lactide-co-glycolide) (PLGA) is a biocompatible, bioabsorbable, and biodegradable polymer that is used to formulate many types of implantable and injectable drug delivery systems for humans and other animals. PLGA microspheres have been reported as carriers for site-specific delivery of various drugs like adapalene 1 and tetracycline. 2In the present study, an attempt was made to prepare PLGA microspheres of 5-fluorouracil (5-FU) for sitespecific delivery of 5-FU through passive targeting. The pyrimidine analogue 5-FU is an antimetabolite and immunosuppressive agent. It is used in the treatment of breast, colon, stomach, pancreas, ovary, head and neck, urinary bladder and lung cancer. 3 It has a rapid plasma clearance and a short half-life (t 1/2 :10-20 minutes). The drug can be encapsulated in microspheres to prolong its residence time and thereby its action.The 5-FU is water soluble. Several reports are available for encapsulation of hydrophilic drugs into PLGA microspheres by a water-in-oil-in-water (w/o/w) emulsification solvent evaporation technique.4,5 Hence, we prepared PLGA microspheres containing 5-FU by this technique. We could prepare microspheres with good batch to batch reproducibility. KEYWORDS: 5-fluorouracil, microspheres, PLGA microspheres, optimizationSeveral researchers have tried to study the effect of process parameters on properties of microspheres and to derive mathematical models that can be used to predict process kinetics. Sato et al 6 reported that the sphericity, size, and yield of microspheres were influenced by the preparation procedure, surfactant type and concentration, temperature of the continuous phase, polymer concentration in the dispersed phase, and ratio of marker to polymer. Jeyanthi et al 2 have shown the effect of the solvent removal technique, the dispersed phase composition, and the ratio of dispersed to continuous phase volume (D/C ratio) on matrix character-

Tuberculosis (TB) drug, regimen, and vaccine development rely heavily on preclinical animal experiments, and quantification of bacterial and immune response dynamics is essential for understanding drug and vaccine efficacy. A mechanism-based model was built to describe Mycobacterium tuberculosis H37Rv infection over time in BALB/c and athymic nude mice, which consisted of bacterial replication, bacterial death, and adaptive immune effects. The adaptive immune effect was best described by a sigmoidal function on both bacterial load and incubation time. Applications to demonstrate the utility of this baseline model showed (i) the important influence of the adaptive immune response on pyrazinamide (PZA) drug efficacy, (ii) a persistent adaptive immune effect in mice relapsing after chemotherapy cessation, and (iii) the protective effect of vaccines after M. tuberculosis challenge. These findings demonstrate the utility of our model for describing M. tuberculosis infection and corresponding adaptive immune dynamics for evaluating the efficacy of TB drugs, regimens, and vaccines.