The in vitro metabolism and in vivo pharmacokinetic (PK) properties of DNDI-VL-2098, a potential oral agent for Visceral Leishmaniasis (VL) were studied and used to predict its human pharmacokinetics. DNDI-VL-2098 showed a low solubility (10μM) and was highly permeable (>200nm/s) in the Caco-2 model. It was stable in vitro in liver microsomes and hepatocytes and no metabolite was detectable in circulating plasma from dosed animals suggesting very slow, if any, metabolism of the compound. DNDI-VL-2098 was moderate to highly bound to plasma proteins across the species tested (94-98%). DNDI-VL-2098 showed satisfactory PK properties in mouse, hamster, rat and dog with a low blood clearance (<15% of hepatic blood flow except hamster), a volume of distribution of about 3 times total body water, acceptable half-life (1-6h across the species) and good oral bioavailability (37-100%). Allometric scaling of the preclinical PK data to human gave a blood half-life of approximately 20h suggesting that the compound could be a once-a-day drug. Based on the above assumptions, the minimum efficacious dose predicted for a 50kg human was 150mg and 300mg, using efficacy results in the mouse and hamster, respectively.

This paper describes a convenient method for the separation and simultaneous determination of six anti-diabetic drugs viz., glibenclamide (GLB), gliclazide (GLC), glipizide (GLZ), pioglitazone (PGL), repaglinide (RPG) and rosiglitazone (RGL) in pharmaceutical formulations. Also, the assay has been shown applied to support quantification of the six anti-diabetic drugs in human plasma. The analytes were either injected directly onto the column after suitable dilution (pharmaceutical formulation analysis) or a simple extraction procedure, using acetonitrile, from human plasma spiked with anti-diabetic drugs and internal standard (IS). Ternary gradient elution at a flow rate of 1 mL/min was employed on an Intertisl ODS 3V column (4.6 x 250 mm, 5 microm) at ambient temperature. The mobile phase consisted of 0.01 m formic acid (pH 3.0), acetonitrile, Milli Q water and methanol. Celecoxib was used as an IS. The six anti-diabetic drugs were monitored at a wavelength of 260 nm. The nominal retention times of RGL, PGL, GLZ, GLC, GLB, IS and RGL were 11.4, 13.3, 14.8, 17.6, 20.78, 22.1 and 25.4 min, respectively. The assay developed for formulation analysis was found to be accurate and precise. The calibration curves ranged from 0.1 to 100 microg/mL for all analytes with the exception of GLB, where the range was 0.3-100 microg/mL. The plasma assay was validated for parameters such as specificity, accuracy and extraction recovery. The proposed method is simple, selective and can be extended for routine analysis of anti-diabetics in pharmaceutical preparations and in biological matrices.

Sparingly water-soluble drugs such as candesartan cilexetil offer challenges in developing a drug product with adequate bioavailability. The objective of the present study was to develop a tablet dosage form of candesartan cilexetil incorporating drug nanoparticles to increase its saturation solubility and dissolution rate for enhancing bioavailability while reducing variability in systemic exposure. The bioavailability of candesartan cilexetil is dissolution limited following oral administration. To enhance bioavailability and overcome variability in systemic exposure, a nanoparticle formulation of candesartan cilexetil was developed. Candesartan cilexetil nanoparticles were prepared using a wet bead milling technique. The milled nanosuspension was converted into solid intermediate using a spray drying process. The nanosuspensions were characterized for particle size before and after spray drying. The spray dried nanoparticles were blended with excipients for tableting. The saturation solubility and dissolution characteristics of the nanoparticle formulation were investigated and compared with commercial candesartan cilexetil formulation. The drug nanoparticles were evaluated for solid-state transitions before and after milling. This study demonstrated that tablet formulation incorporating drug nanoparticles showed significantly faster rate of drug dissolution in a discriminating dissolution medium as compared to commercially available tablet formulation. Systemic exposure studies in rats indicated a significant increase in the rate and extent of drug absorption.

A uranyl nitrate-induced model of acute renal failure (UN-ARF) for various time periods was used to study its effect on the disposition of several drugs like chlorzoxazone, clarithromycin, vancomycin, methotrexate etc. An attempt to optimize the duration of UN dosing with respect to the pharmacokinetics of etoposide in rats was carried out after intravenous (i.v.) dosing of UN at 5 mg/kg for 1, 3, 5 and 7 days. Irrespective of the duration of UN dosing apart from day 1, ARF was observed, with significantly increased serum levels of creatinine (0.36 +/- 0.11 for controls vs 2.44 +/- 0.72 [day 7] for UN-ARF rats) and urea (33.71 +/- 9.46 for controls vs. 169.2 +/- 9.71 [day 5] for UN-ARF rats) in all the UN-treated groups. It has been reported that ARF may alter the pharmacokinetics (PK) and the exposure of renally eliminated drugs. Further, as exposure to etoposide has a correlation with toxicity, the need to investigate the possible alterations in etoposide pharmacokinetics in the UN-ARF model could be of significance. The PK of etoposide was therefore investigated in control and UN-ARF rats after a single i.v. dose of 25 mg/kg. The concentrations of etoposide in the plasma were determined by high- performance liquid chromatography (HPLC) method with fluorescence detector set at excitation and emission wavelengths of 380 and 520 nm respectively. The metabolic stability of etoposide was investigated in rat liver microsomes prepared from control and UN-ARF treated rats. The PK results showed increased plasma levels and systemic exposure to etoposide (19.97 +/- 2.12 for control vs 29.03 +/- 2.32, 34.45 +/- 3.37, 34.19 +/- 2.98 for 3, 5 and 7day UN-treated groups respectively), i.e. for all UN-ARF groups except for 1-day UN-ARF rats (20.06 +/- 1.53). Incubation with liver microsomes from UN-ARF rats treated for up to 5 days and control rats showed no significant difference in etoposide metabolism suggesting that the CYP3A4 isoenzyme responsible for the metabolism of etoposide was not considerably expressed thereby leading to the conclusion that 3 days UN dosing was sufficient to induce ARF in rats, and that the dose of etoposide required needs to be monitored due to altered PK.

This report addresses the study on nucleating effects of DI – water based phase change material by adding salt hydrate like a Sodium chloride, Magnesium chloride and Calcium chloride. DI-water is selected as base PCM in which nucleating agents are added in concentration of 0.3, 0.6 and 0.9 Wt.% to study the solidification characteristics of the PCM. The samples are prepared with the help of magnetic stirring and ultra-sonification process which ensures that the nucleating agents are completely dissolved in the base PCM. An experimental trail is carried out with surrounding heat transfer fluid temperature of -7°C and the solidification history is generated for all PCM samples. From the observation it can be concluded that NaCl 0.9 Wt.%, MgCl2 0.6 Wt.% and CaCl2 0.6 Wt.% shows a significant reduction of supercooling degree. Only NaCl of 0.9 Wt.% shows a reduction of 91.32% in supercooling degree with least increase of 6.73% in solidification time. Thus, Phase change materials proves to be effective in eliminating the discrepancy between demand and supply during peak hour by storing energy during non-peak hours and retrieving when demanded. Thus, it can be used to reduce power consumption during peak hour’s demand and reduce the effects on environment.