Phytochemical and toxicological evaluation of Zephyranthes citrina.

Drugs obtained from medicinal plants have always played a pivotal role in the field of medicine and to identify novel compounds. Safety profiling of plant extracts is of utmost importance during the discovery of new biologically active compounds and the determination of their efficacy. It is imperative to conduct toxicity studies before exploring the pharmacological properties and perspectives of any plant. The present work aims to provide a detailed insight into the phytochemical and toxicological profiling of methanolic extract of Zephyranthes citrina (MEZ). Guidelines to perform subacute toxicity study (407) and acute toxicity study (425) provided by the organization of economic cooperation and development (OECD) were followed. A single orally administered dose of 2000 mg/kg to albino mice was used for acute oral toxicity testing. In the subacute toxicity study, MEZ in doses of 100, 200, and 400 mg/kg was administered orally, consecutive for 28 days. Results of each parameter were compared to the control group. In both studies, the weight of animals and their selected organs showed consistency with that of the control group. No major toxicity or organ damage was recorded except for some minor alterations in a few parameters such as in the acute study, leukocyte count was increased and decreased platelet count, while in the subacute study platelet count increased in all doses. In the acute toxicity profile liver enzymes Alanine aminotransferase (ALT), as well as, aspartate aminotransferase (AST) were found to be slightly raised while alkaline phosphatase (ALP) was decreased. In subacute toxicity profiling, AST and ALT were not affected by any dose while ALP was decreased only at doses of 200 and 400 mg/kg. Uric acid was raised at a dose of 100 mg/kg. In acute toxicity, at 2000 mg/kg, creatinine and uric acid increased while urea levels decreased. Therefore, it is concluded that the LD50 of MEZ is more than 2000 mg/kg and the toxicity profile of MEZ was generally found to be safe.

Prediction of CYP-mediated silybin A-losartan pharmacokinetic interactions using physiological based pharmacokinetic modeling.

The concomitant use of herbal products and synthetic drugs necessitates the assessment of their interaction potentials. The herbal hepatoprotective medicine, silybin A inhibits cytochrome P450 (CYP) 2C9 and 3A4 enzymes, thus, may interact with the drugs that are substrates of CYP2C9 and 3A4, such as losartan. The three most prominent genotypes, expressed by CYP2C9 are the CYP2C9*1/*1, CYP2C9*1/*2 and CYP2C9*1/*3. This study aimed to assess silybin A-losartan interaction in different CYP2C9 genotypes using physiological-based pharmacokinetic (PBPK) model approach. The individual PBPK models for silybin A and losartan were developed using PK-Sim®. Losartan pharmacokinetics was predicted with or without co-administration of silybin A in individuals of different CYP2C9 genotypes to find herbal-drug interaction. The predicted drug plasma curves and pharmacokinetic parameters were optimized using parameter identification tool and were compared with reported pharmacokinetic parameters from the published clinical studies for model validation. The silybin-losartan interactions were predicted by change in area under the curve (AUC) and peak systemic concentration (Cmax). The co-treatment of silybin A, 420 mg/24 h (140 mg/8 h) with losartan 50 mg/24 h, exhibited a genotype-dependent change in the losartan's AUC and Cmax. In CYP 2C9*1/*1 genotype, AUC and Cmax of losartan were increased 1.16 and 1.37 folds, respectively falling in a range stipulated for negligible interaction. Increase in AUC and Cmax by 0.873 and 0.294 folds, respectively in CYP2C9*1/*3 after co-administration of silybin A exhibited a minor interaction with losartan. However, in individuals with CYP2C9*1/*2 genotype, the losartan's AUC and Cmax were decreased by 0.01 folds, manifesting a moderate interaction. Hence, in CYP2C9*1/*1 and CYP2C9*1/*3 genotypes, silybin A is a weak CYP inhibitor for losartan while in CYP2C9*1/*2 genotype, the co-administration of silybin consequents into a moderate pharmacokinetic interaction with losartan.

Precise and Sensitive Ambient Temperature Based Analytical Colorimetric Method for Pregabalin

Abstract Pregabalin, a GABA analogue is used to treat epilepsy and neuropathic pain. The drug poses problems in analytical quantification when estimated at a shorter UV wavelength. The expensive and non-repetitive reported analytical methods necessitate the utility and development of an accurate, precise, repetitive, simple and highly sensitive colorimetric method for pregabalin in solution as well as sustained release mini matrices. Pregabalin (having primary amino group) was derivatized at alkaline pH of mixture with optimized ninhydrin solution at ambient temperature (25oC). The ninhydrin-pregabalin derivatized complex (Ruhemann's Purple) was analyzed for drug concentration at absorption maximum (λmax) of 570nm. The linearity was observed in the concentration range of 5-150 µg/mL with coefficient of correlation, 0.998. The developed analytical method was validated according to ICH guidelines and proved to be highly sensitive (LOD 0.917µg/mL, LOQ 3.055µg/mL), with good inter-day as well as intra-day accuracy and precision as 4.65% and 3.75%, respectively. The proposed method was proved to be a simple, sensitive, precise and accurate for the estimation of the minute concentrations of pregabalin in pure form and the developed formulations. Results verified that the proposed method could determine pregabalin at the ambient temperature without requiring high temperatures used in the existing methods. It was concluded that developed method was easier and more suitable for analysis of pregabalin in quality control of commercial preparations

Preparation and Characterization of pH-Independent Sustained-Release Tablets Containing Hot Melt Extruded Solid Dispersions of Clarithromycin : Tablets Containing Solid Dispersions of Clarithromycin.

The limited solubility of clarithromycin (CAM), coupled with low bioavailability and rapid elimination, are major shortcomings, needed to be addressed to achieve optimum therapeutic goals. Therefore, sustained-release (SR) tablets containing solid dispersion (SD) granules of CAM were prepared in this study. Initially, SD granules of CAM were prepared by hot melt extrusion (HME) technique using Kollidon VA64 as a hydrophilic carrier. The saturation solubility of SD showed almost 4.5-fold increase as compared to pure CAM in pH 6.8 medium. In vitro drug dissolution data indicated a substantial increase in the dissolution of SD as compared to that of pure CAM. The thermal stability of drug, carrier, and SD at elevated HME temperatures was evident from the results of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Powder X-ray diffraction (PXRD) data and scanning electron microscope (SEM) images revealed a decrease in the crystallinity and the uniform dispersion of drug, respectively. Moreover, Fourier transformed infrared spectroscopy (FT-IR) data confirmed the formation of hydrogen bond between the carbonyl group of drug and the hydroxyl group of carrier. SD loaded sustained-release (SD-SR) matrix tablets were prepared with hydrophobic polymers (Eudragit RS100 and Eudragit RL100). The pH-independent swelling and permeability of both polymers were responsible for the sustained drug release from SD-SR tablets. Pharmacokinetic (PK) studies suggested a 3.4-fold increase in the relative bioavailability of SD-SR tablets as compared to that of pure CAM.

Prediction of lisinopril pediatric dose from the reference adult dose by employing a physiologically based pharmacokinetic model.

BACKGROUND: This study aimed to assess the pediatric lisinopril doses using an adult physiological based pharmacokinetic (PBPK) model. As the empirical rules of dose calculation cannot calculate gender-specific pediatric doses and ignores the age-related physiological differences. METHODS: A PBPK model of lisinopril for the healthy adult population was developed for oral (fed and fasting) and IV administration using PK-Sim MoBI® and was scaled down to a virtual pediatric population for prediction of lisinopril doses in neonates to infants, infants to toddler, children at pre-school age, children at school age and the adolescents. The pharmacokinetic parameters were predicted for the above groups at decremental doses of 20 mg, 10 mg, 5 mg, 2.5 mg, and 1.5 mg in order to accomplish doses producing the pharmacokinetic parameters, similar (or comparable) to that of the adult population. The above simulated pediatric doses were compared to the doses computed using the conventional four methods, such as Young's rule, Clark's rule, and weight-based and body surface area-based equations and the dose reported in different studies. RESULTS: Though the doses predicted for all subpopulations of children were comparable to those calculated by Young's rule, yet the conventional methods overestimated the pediatric doses when compared to the respective PBPK-predicted doses. The findings of previous real time pharmacokinetic studies in pediatric patients supported the present simulated dose. CONCLUSION: Thus, PBPK seems to have predictability potential for pediatric dose since it takes into consideration the physiological changes related to age and gender.