Formulation development, characterization, and evaluation of sorafenib-loaded PLGA-chitosan nanoparticles.

The basic purpose of this work was to develop environmentally friendly, biodegradable, and biocompatible polymeric nanoparticles of sorafenib that can effectively release the desired drug in a customized and controlled manner for targeting hepatocellular carcinoma. The solvent evaporation technique was employed for the synthesis of sorafenib-loaded PLGA-chitosan nanoparticles, followed by various experimental specifications and compatibility studies using poloxamer 407 as the stabilizer. The best nanoparticles thus synthesized were selected to be used for cytotoxicity investigations through in vitro and in vivo assessments. For the in vitro drug release tests, the dialysis bag diffusion technique was used. For both chitosan nanoparticles and PLGA loaded with sorafenib, a biphasic release pattern was found, exhibiting a protracted release lasting 10 days after a 24-h burst release. As experimental animals, rabbits were utilized to evaluate different in vivo pharmacokinetic properties of the selected formulations. Plasma samples were extracted with acetonitrile and analyzed through the developed HPLC method. Pharmacokinetic parameters such as AUC0-t, Cmax MRT, Vd, and half-life (t1/2) were enhanced significantly (p ≤ 0.001), while clearance was considerably decreased (p ≤ 0.001) for the chosen synthesized nanoparticles in contrast to the commercially accessible sorafenib formulation (Nexavar®). The cytotoxicity of the reference drug and sorafenib-loaded PLGA and chitosan nanoparticles was calculated by performing an MTT assay against HepG2 cell lines. The developed polymeric sorafenib nanoformulations possess the appropriate physicochemical properties, better targeting, surface morphology, and prolonged release kinetics. The pharmacokinetic parameters were improved significantly when the results were compared with commercially available sorafenib formulations.

Synthesis of novel hydrazide Schiff bases with anti-diabetic and anti-hyperlipidemic effects: in-vitro, in-vivo and in-silico approaches.

The increasing global incidence of non-insulin-dependent diabetes mellitus (NIDDM) necessitates innovative therapeutic solutions. This study focuses on the design, synthesis and biological evaluation of Schiff base derivatives from 2-bromo-2-(2-chlorophenyl) acetic acid, particularly hydrazone compounds 4a and 4b. Both in-vitro and in-vivo assays demonstrate these derivatives' strong antidiabetic and anti-hyperlipidemic properties. In a 15-d experiment, we administered 4a and 4b at doses of 2.5 and 5 mg/kg body weight, which effectively improved symptoms of alloxan-induced diabetes in mice. These symptoms included weight loss, increased water consumption and high blood glucose levels. The compounds also normalized abnormal levels of total cholesterol (TC), triacylglycerol (TG) and low-density lipoprotein cholesterol (LDL-C), while raising the levels of high-density lipoprotein cholesterol (HDLC). Computational analysis showed that these compounds effectively inhibited the α-glucosidase enzyme by interacting with key catalytic residues, specifically Asp214 and Asp349. These computational results were confirmed through in-vitro tests, where 4a and 4b showed strong α-glucosidase inhibitory activity, with IC50 values of 0.70 ± 0.11 and 10.29 ± 0.30 µM, respectively. These compounds were more effective than the standard drug, acarbose, which had an IC50 value of 873.34 ± 1.67 µM. Mechanistic studies further indicated competitive inhibition, reinforcing the therapeutic potential of 4a and 4b for NIDDM treatment.Communicated by Ramaswamy H. Sarma.

Quantification of toxic heavy metals, trace elements and essential minerals contents in traditional herbal medicines commonly utilized in Khyber Pakhtunkhwa, Pakistan.

Traditional herbal medicines and health supplements have been empirically used to treat various disorders but most of them are not standardized and have not been experimentally validated for safety and efficacy. In the present study, various dosage forms of traditional herbal medicines prescribed for specific diseases were collected from local practitioners at different districts of Khyber Pakhtunkhwa, Pakistan. The collected samples were analyzed for heavy metal, trace elements, and minerals using atomic absorption spectroscopy. All the tested samples contained heavy metals, trace elements and minerals in different concentrations. All the samples were tested positive for the presence of toxic heavy metals such as arsenic (As), cadmium (Cd) and lead (Pb). The trace elements like cobalt (Co), iron (Fe), zinc (Zn) and chromium (Cr) were also detected in acceptable range. Similarly, the samples analyzed were rich in some of the essential minerals such as sodium (Na), magnesium (Mg) and calcium (Ca) which are necessary for the proper functioning of the body. The hazard quotient (HQ) values were measured for toxic heavy metals to determine their safe ranges for human body. The HQ values were above the permissible range for arsenic (As) in all detected samples while for cadmium (Cd) and lead (Pb), the values ware above in 50 % of the analyzed samples. The detection of toxic metals and their HQ values beyond the permissible limits in different dosage forms raised questions about their quality. This study suggests that evaluation of traditional herbal remedies for the metals contents and their standardization are strongly recommended for quality assurance and protection of public health.

In vivo analgesic, anti-inflammatory and molecular docking studies of S-naproxen derivatives.

In the current studies two naproxen derivatives (NPD) were evaluated for analgesic and anti-inflammatory properties. The acetic acid and hot plate animal models were used to screen the compounds for analgesic potential. While the anti-inflammatory potential was evaluated through animal paw edema, induced by several inflammatory mediators (carrageenan, bradykinin, and prostaglandin E2), the xylene-induced ear edema was also used as an inflammatory model. Both NPDs showed significant (p < 0.001) antinociceptive effects in the acetic acid-induced writhing paradigm. In the case of the hot plate, the NPD 1 at the tested dose of 5 mg/kg enhanced the latency time after 60 min of injection, which remained significant (p < 0.001) up to the end of the experiment duration. The maximum percent inhibition of NPD 1 was 87.53. The naloxone injection significantly lowered the latency time of NPD 1 as compared to NPD 2. Regarding the anti-inflammatory effect, both of the tested NPDs demonstrated a significant reduction in paw edema against various inflammatory mediators, as mentioned above; however, the anti-inflammatory effect of NPD 1 was better. The maximal percent inhibition by NPD 1 and 2 was 43.24 (after 60 min) and 45.93 (after 90 min). A considerable effect also resulted from xylene-induced ere edema. Further, a molecular docking study was carried out to investigate the binding modes of the NPD. The docking analysis revealed that the NPD significantly interacted with the COX2 enzyme. Furthermore, molecular dynamics simulation was carried out for the docked complexes. The MD simulation analysis revealed the high stability of the two naproxen derivatives.

Effect of polymeric stabilizers on the size and stability of PLGA paclitaxel nanoparticles.

The aim of this study is to formulate polymeric paclitaxel nanoparticles with various stabilizers to improve solubility, enhance stability, maximize therapeutic efficacy and minimize detrimental toxicities of paclitaxel. In this study, trastuzumab-guided poly lactic-co-glycolic acid (PLGA)-loaded paclitaxel nanoparticles were formulated with pluronic F-127, polyvinyl alcohol (PVA), poloxamer 407, Tween-80, span 20, sodium dodecyl sulfate (SDS), and sodium lauryl sulfate (SLS) at different concentrations (0.5, 1, 1.5 and 2%) using the solvent evaporation method. The nanoparticles were evaluated for physicochemical characteristics and short and long-term stability. The optimum particle size (190 nm ± 12.42 to 350 nm ± 11.1), PDI (0.13 ± 0.02 to 0.2 ± 0.01), surface charge (-19.1mv ± 1.5 to -40.4mv ± 1.6), drug loading (2.43 to 9.5 %) and encapsulation efficiency (greater than 80 %) were obtained with these stabilizers while keeping the polymer concentration, temperature, probe size, amplitude and sonication time constant. The nanoformulations were stably stored at 4 °C. The nanoformulations of paclitaxel with pluronic F-127, polyvinyl alcohol (PVA), and poloxamer 407 were found to be more soluble, stable, uniform in physicochemical properties, and efficient in drug loading and encapsulation for improved therapeutic effects.

Multiple design and modelling approaches for the optimisation of carbon felt electro-Fenton treatment of dye laden wastewater.

This study utilizes artificial intelligence and statistical modelling to optimize the operating parameters of a carbon-based electro-Fenton process for purifying model dye (RB19)-contaminated wastewater. Multilevel experimental Box-Behnken and uniform deisgns (BBD, UD) with four variables were analysed using polynomial regression analysis (PRA) and artificial neural networks (ANN), while the process optimisation was done using desirability function. For the given testing range but different design matrices and runs, both designs predicted a maximum RB19 removal (RB19-RR) of 90 ± 2.1% at lowest energy consumption (EC) of 0.44 ± 2.5 Wh, when voltage, Na2SO4, FeSO4, and time were maintained as follows: 4-5.3 V, 7-11 mM, 0.4-0.6 mM, and 35-40 min, respectively. All the design-model combinations portrayed the similar senitivity analyses, revealing that RB19 degradation and EC are primarily influenced by electrolysis time and voltage. The performance assessment demonstrated that all the design-model combinations also excellently predicted for unseen conditions as the maximum root mean squared error (RMSE) value for RB19-RR was 4.07, while it was 0.072 for EC, however, BBD-ANN performance proved to be slightly better than others. Having ∼57% less experimentation, UD based models managed to accurately predict the results for unseen conditions as the statistical errors were quite insignificant, even in some cases, RMSE found to be less for UD compared to BBD, elucidating the potential of uniform design as an alternative of conventional factorial designs. Nevertheless, the prediction accuracy is also dependent on modelling approach, as in some cases ANN failed to predict the response precisely specially when dealing with small data. Furthermore, techno-economic evaluation results spell out the efficacy of carbon felt based enhanced electro-Fenton process as promising environmental remediation technology and highlight its practical implication from view of operational cost.

Design and Characterization of Paclitaxel-Loaded Polymeric Nanoparticles Decorated With Trastuzumab for the Effective Treatment of Breast Cancer.

The aim of the study was to design and formulate an antibody-mediated targeted, biodegradable polymeric drug delivery system releasing drug in a controlled manner to achieve a therapeutic goal for the effective treatment of breast cancer. Antibody-mediated paclitaxel-loaded PLGA polymeric nanoformulations were prepared by the solvent evaporation method using different experimental parameters and compatibility studies. The optimized formulations were selected for in vitro and in vivo evaluation and cytotoxicity studies. The in vitro drug release studies show a biphasic release pattern for the paclitaxel-loaded PLGA nanoparticles showing a burst release for 24 h followed by an extended release for 14 days; however, a more controlled and sustained release was observed for antibody-conjugated polymeric nanoparticles. The cytotoxicity of reference drug and paclitaxel-loaded PLGA nanoparticles with and without antibody was determined by performing MTT assay against MCF-7 cells. Rabbits were used as experimental animals for the assessment of various in vivo pharmacokinetic parameters of selected formulations. The pharmacokinetic parameters such as Cmax (1.18-1.33 folds), AUC0-t (39.38-46.55 folds), MRT (10.04-12.79 folds), t1/2 (3.06-4.6 folds), and Vd (6.96-8.38 folds) have been increased significantly while clearance (4.34-4.61 folds) has been decreased significantly for the selected nanoformulations as compared to commercially available paclitaxel formulation (Paclixil®). The surface conjugation of nanoparticles with trastuzumab resulted in an increase in in vitro cytotoxicity as compared to plain nanoformulations and commercially available conventional brand (Paclixil®). The developed PLGA-paclitaxel nanoformulations conjugated with trastuzumab have the desired physiochemical characteristics, surface morphology, sustained release kinetics, and enhanced targeting.

Safety and efficacy of ARNI (valsartan/sacubitril) vs ACEI (enalapril) in acute heart failure - A prospective observational study.

OBJECTIVE: To compare the safety and efficacy of valsartan/sacubitril (angiotensin receptor neprilysin inhibitor [ARNI]) against enalapril (angiotensin-converting enzyme inhibitor [ACEI]) in patients with acute heart failure at 6-month follow-up. METHODS: In this prospective, single centre, and observational study conducted between September 2017 and February 2020 in India, patients with acute decompensated heart failure with reduced ejection fraction (<40%) were included. Patients were divided in two groups: valsartan/sacubitril (ARNI) group and enalapril (ACEI). Patients were followed up for at least 6 months after administration of first dose and were evaluated for safety, efficacy, and tolerability of target drug. Student's independent t-test was employed for comparing continuous variables. Chi-square test or Fisher's exact test, whichever appropriate, was applied for comparing categorical variables. RESULTS: A total of 200 patients were included in the present study, 100 each in ARNI and ACEI group. The mean age of the population was 61.2 ± 8.4 years and 62.6 ± 8.6 years in ARNI group and ACEI group, respectively. The mean maximum tolerated dose by population in ARNI group was 203.6 mg and 8.9 mg in ACEI group. Readmission for heart failure were seen significantly higher in ACEI group than ARNI group (p value = 0.001). Parameters like ejection fraction, left ventricular end diastolic and systolic dimensions, 6 min walk test and Kansas City Cardiomyopathy Questionnaires (KCCQ) showed p values < 0.05 between the groups. CONCLUSION: The ARNI study group showed better safety and efficacy outcomes at the end of 6 months follow-up compared to ACEI group.

Association of XPD Lys751Gln gene polymorphism with susceptibility and clinical outcome of colorectal cancer in Pakistani population: a case-control pharmacogenetic study.

BACKGROUND: XPD Lys751Gln polymorphism may modulate inter-individual variation in repair capacity of DNA, which may enhance a person's susceptibility to develop colorectal cancer (CRC). The analysis of XPD Lys751Gln polymorphism may provide important information for identifying high-risk individuals and for selecting the most appropriate treatment for poor prognostic CRC patients. OBJECTIVE: The overall objective was to find out the association of XPD Lys751Gln gene polymorphism with the risk of having a colorectal cancer and the ultimate clinical outcomes. In this study a total of 300 subjects (CRC and Controls), were genotyped for XPD Lys751Gln. METHODS: Using PCR-RFLP methods, the association of XPD Lys751Gln gene polymorphism with the risk of having a colorectal cancer was studied. In addition to overall risk assessment, genotyping results were also investigated with respect to the lifestyle risk factors, patients treated with oxaliplatin-based chemotherapy and clinicopathological characteristics. RESULTS: The overall correlation between the XPD Lys751Gln genetic variation and the CRC risk was observed to be significant with both the homozygous variant genotype Gln/Gln as well as heterozygous genotype Lys/Gln being associated with the increased risk of CRC. Additional stratified analyses revealed that XPD Lys751Gln variants remarkably increased risk of CRC in males and younger individuals (≤ 50 years), Naswar users (8.09-fold) and high intake of red meat. CONCLUSIONS: Our findings suggest that the relationship between the XPD Lys751Gln variants and lifestyle factors modulates the risk for CRC in Pakistani population.

Rosuvastatin pharmacokinetics in Pakistani healthy volunteers in comparison with other population.

In current study, the pharmacokinetics (PK) of rosuvastatin were evaluated in Pakistani healthy volunteers and compared with those reported in other population. This was a randomized and open labeled clinical trial in which a single oral dose of 40 mg rosuvastatin was administered to the overnight fasted healthy volunteers. Plasma concentrations of rosuvastatin were quantified by a validated liquid chromatography-tandem mass spectrometry method. The PK parameters of rosuvastatin and its metabolite N-desmethyl-rosuvastatin were determined by PK specific software i.e., PK-Summit® (PK-Solutions). A total of 20 healthy volunteers having BMI in the normal ranges were included in this study. All PK parameters were represented as mean ± SD and 95% confidence intervals of the means have been calculated. The Cmax (29.07 ± 6.88 ng/mL), [AUC]xo (206.65 ± 55.27 ng/hr/mL) and CL/F (3275.26 ± 1072.87 mL/hr) were slightly higher in our study, whereas the values of Vd (19377.23 ± 9114.29 mL) and tmax (3.0 ± 0.46 hr) were comparatively smaller. Overall, the PK parameters of rosuvastatin determined in our study were in compliance with other reported. Therefore, no adjustments in the dosing schedule or dose are warranted.

Comparative pharmacokinetics of Omeprazole and its metabolites in poor and extensive metabolizer Pakistani healthy volunteers and a review of different studies.

This study was designed to evaluate a comparative single dose (40mg) pharmacokinetics (PK) of Omeprazole (OMP) and its two metabolites, 5-hydroxy Omeprazole (5-OH-OMP) and Omeprazole sulphone (OMP-S) in poor (PM) and extensive (EM) metabolizer Pakistani healthy adult volunteers. The frequency of CYP2C19 and CYP3A4 varies widely in different populations. The present study was conducted to evaluate the PK of OMP and its two metabolites in Pakistani population and to review different studies conducted after administration of single dose of OMP. Twenty two subjects were enrolled in this study and divided into two groups. The CYP2C19 phenotyping was evaluated by the metabolic ratio of OMP to 5-OH-OMP. It was a single dose, open label study and the blood samples from subjects were collected at different time intervals until 24 hours. The PK parameters were calculated using the PK-summit software. The metabolic ratio of area under the plasma concentration-time curve AUCOMP/5-OH-OMP was 1.86 ± 0.572 and13.84 ± 2.504 for EM and PM, respectively; maximum plasma concentration (Cmax) of OMP was increased by two folds for PM while the AUC∞ was increased by 3 folds; the Cmax and AUC∞ of 5-OH-OMP decreased for PM by 2 folds while there was 3 fold increase observed in the Cmax and AUC∞ of OMP-S. The PK of OMP and its metabolites in different populations were also discussed, and issues regarding CYP2C19 and CYP3A4 genotyping were also extensively reviewed. In EM of CYP2C19 the concentration of 5-OH-OMP is higher while that of OMP-S is lower. This study as well as reported studies reveals that in PM of CYP2C19 more drugs are available for CYP3A4 to be metabolized. A correlation between CYP2C19 EM and PM activity with CYP3A4 needs to be established.

A clinical study showing altered antioxidants profile in patients with hypertension.

We compared the plasma antioxidants level of normal control group with that of hypertensive patients in order to test the hypothesis "that antioxidants level has been diminished in hypertensive patients and that antioxidants are interconnected with each other making a network. The plasma and red blood cells antioxidants level of newly diagnosed hypertensive patients [(n=30), (mean age 53 years), (mean systolic BP 158 mmHg, mean diastolic BP 100 mmHg)] were compared to those of the control subjects [(n=30), (mean age 50 years), (mean systolic BP 126 mmHg, mean diastolic BP 90 mmHg)] using liquid chromatography linked with electrochemical detector (HPLC-ECD). The data was analyzed by Minitab software at a 95% confidence interval (p<0.05) as significant. The comparison between the two groups was made applying 2-sample and paired t-test. The individual concentration of antioxidants in both plasma and red blood cells of hypertensive patients was lower in comparison with that of control group while the oxidized/reduced ratios of these antioxidants were higher in hypertensive patients in comparison with that of control group. It is concluded that antioxidants level had been diminished in the hypertensive patients when compared with control group. The overall concentration of all antioxidants has been diminished in the oxidative stress induced pathological conditions which confirm that the studied antioxidants are working in a network. This study may be helpful for the recommendation of antioxidants intervention.

Evaluation of Serum Copper Level in Naswar (Smokeless Tobacco) Addicts Using Flame Atomic Absorption Spectroscopy.

BACKGROUND: Substance abuse and its consequences are a matter of great concern in South-East Asian countries, especially Pakistan and Afghanistan. Due to contamination of Naswar with copper, or by any other physiological mechanism, there is a great chance of copper poisoning in addicts. Keeping in view the literature, there is no comparative study on serum copper levels (SCuL) in Naswar addicts. Therefore, it is very important to evaluate SCuL in this population. METHODS: The current study was performed in September 2016 where a total of 75 volunteers (selected from villages near the University of Peshawar, Pakistan) were grouped as Naswar addicts (n = 45) and the control group (n = 30). The addicts were compared to controls for age, weight, BMI, FBS and creatinine clearance. For serum analysis, about 3mL of blood was collected from which the serum was separated, digested, and then evaluated for SCuL using  flame atomic absorption spectroscopy at the Department of Pharmacy and Centralized Resource Laboratory of University of Peshawar. RESULTS: The SCuL in addicts had a range of 2.6 to 11.1 µg/dL with a mean of 5.1 ± 2.4 µg/dL. In the healthy control group, SCuL was between 1.7 to 3.9 µg/dL with a mean of 2.6 ±0.1 µg/dL. The mean difference between the two study groups was statistically significant (P = 0.005); the duration of addiction and quantity of drug consumptions per day correlated positively with SCuL. CONCLUSION: Serum level of copper in Naswar addicts is elevated compared to the Control group. The exact cause of SCuL elevations and the mechanisms involved must be studied in large group samples.

Correlation of the plasma sphingoid base profile with results from oral glucose tolerance tests in gestational diabetes mellitus.

Oral glucose tolerance test (OGTT) is usually insufficient to accurately predict the risk for type 2 diabetes mellitus (T2DM), it is therefore necessary to identify an additional biomarker that would most likely improve the accuracy of OGTT. The current OGTT was performed in 53 volunteers after ingestion of 75 g glucose in 250 ml water to each volunteer. Similarly the sphingoid base profile of these volunteers was explored using liquid-chromatography linked with mass spectrometer (LC-MS) and correlated with the different time-points glucose values of OGTT as well as with total area under the curve (tAUC), incremental area under the curve (iAUC), and positive incremental area under the curve (pAUC). The findings showed that 1-deoxysphinganine (1-deoxySA) was significantly positively correlated with the 1-hour, 2-hour, and 3-hour plasma glucose level as well as with total, incremental, and positive incremental AUC while 1-deoxysphingosine (1-deoxySO) was correlated only with 1-hour, 2-hour glucose levels and tAUC of OGTT. The C18SAdiene was negatively correlated with all-time points glucose values and AUCs followed by negative correlation of C18SO, C16SO and C17SO with 2-hour glucose and tAUC of OGTT. The ratios of 1-deoxySA and 1-deoxySO with respect to C18SAdiene have shown significant correlation with 2-hour and AUCs. These ratios were higher in subjects with gestational diabetes in comparison with normal subjects. These findings underlined that 1-deoxysphingolipids (1-deoxySLs) and their ratios with C18SAdiene could be significantly correlated with the glucose load of OGTT and might be used as predictive biomarkers along with OGTT for the risk assessment of diabetes.

Nephroprotective property of Cinnamomum zeylanicum and its antibacterial activity in combination with gantamicin.

Cinnamomum zeylanicum has strong antioxidant properties and has been presented to have nephroprotective effects. Present work was aimed to study the nephroprotective property of the plant extract through urinary enzymes excretion, to confirm its protective effects and to observe the antibacterial activities of gentamicin in combination with the plant extract. 200mg/kg/day of the plant extracts were administered alone and as co-therapy with gentamicin. Urinary lactate dehydrogenase (LDH) and Urinary alkaline phospatase (ALP) excretions were observed through reagents kits with the help of Power-Lab 300. Antibacterial activities were assessed for gentamicin alone and in combination with the extract. Present study showed that the plant extract have excess quantity of flavonoids, which may responsible for attenuating the excessive excretion of urinary LDH. However, Urinary ALP excretion was found remained same throughout the study period in all experimental groups; might be detected in acute damage. Further, the plant also proved to have no decreasing impact on the antibacterial activities of gentamicin.

Effect of clopidogrel on the hydroxylation and sulfoxidation of omeprazole: A single dose study in healthy human volunteers.

Based upon the known potential interaction between omeprazole (OMP) and clopidogrel (CLOP), the current study was designed to evaluate the effect of CLOP on disposition of OMP and its two major metabolites, 5-hydroxyomeprazole (5-OH-OMP) and omeprazole sulfone (OMP-S) in healthy clinical subjects. A randomized, open label, 2-period, crossover study was designed. Twelve volunteers were selected, of whom eight were extensive metabolizers (EM) of CYP2C19 and 4 were poor metabolizers (PM). They received single dose of OMP either alone or in combination with CLOP (single dose) and samples were collected periodically to calculate various pharmacokinetic parameters. Changes in most of the pharmacokinetic parameters of OMP, 5-OH-OMP and OMP-S were insignificant (P ˃ 0.05) both in EM and PM except for the maximum concentration (Cmax) of 5-OH-OMP and OMP-S in EM. The OMP Cmax and AUC0-∞ was increased both in EM and PM after concomitant administration of OMP with CLOP. The 5-OH-OMP Cmax was decreased in both EM and PM, demonstrating that CLOP inhibits hydroxylation of OMP. The OMP-S Cmax and AUC0-∞ were increased both in EM and PM showing that CLOP may induce sulfoxidation of OMP. It was concluded that CLOP may inhibit hydroxylation of OMP to a greater extent in EM than in PM, leading to higher OMP Cmax and AUC0-∞. Furthermore, the sulfoxidation of OMP may also be induced by CLOP. So, it is suggested that both these drugs should be carefully prescribed together to avoid any harm to the patients. (Application number13/EC/Pharm. Ref number 12/Pharm).

A simple, rapid and sensitive RP-HPLC-UV method for the simultaneous determination of sorafenib & paclitaxel in plasma and pharmaceutical dosage forms: Application to pharmacokinetic study.

A simple, economical, fast, and sensitive RP-HPLC-UV method has been developed for the simultaneous quantification of Sorafenib and paclitaxel in biological samples and formulations using piroxicam as an internal standard. The experimental conditions were optimized and method was validated according to the standard guidelines. The separation of both the analytes and internal standard was achieved on Discovery HS C18 column (250mm×4.6mm, 5µm) using Acetonitrile and TFA (0.025%) in the ratio of (65:35V/V) as the mobile phase in isocratic mode at a flow rate of 1ml/min, with a wavelength of 245nm and at a column oven temperature of 25°Cin a short run time of 12min. The limits of detection (LLOD) were 5 and 10ng/ml while the limits of quantification (LLOQ) were 10 and 15ng/ml for sorafenib and paclitaxel, respectively. Sorafenib, paclitaxel and piroxicam (IS) were extracted from biological samples by applying acetonitrile as a precipitating and extraction solvent. The method is linear in the range of 15-20,000ng/ml for paclitaxel and 10-5000ng/ml for sorafenib, respectively. The method is sensitive and reliable by considering both of its intra-day and inter-day co-efficient of variance. The method was successfully applied for the quantification of the above mentioned drugs in plasma. The developed method will be applied towards sorafenib and paclitaxel pharmacokinetics studies in animal models.

Simultaneous determination of domperidone and Itopride in pharmaceuticals and human plasma using RP-HPLC/UV detection: Method development, validation and application of the method in in-vivo evaluation of fast dispersible tablets.

Domperidone and Itopride are pro-kinetic agents, regulating the gastric motility and are commonly prescribed as anti emetic drugs. In the present study a simple, rapid and sensitive RP-HPLC/UV method was developed for simultaneous determination of Domperidone and Itopride in pharmaceutical samples and human plasma, using Tenofavir as internal standard. Experimental conditions were optimized and method was validated according to the standard guidelines. Combination of water (pH 3.0) and acetonitrile (65:35 v/v) was used as mobile phase, pumped at the flow rate of 1.5 ml/min. Detector wavelength was set at 210 nm and column oven temperature was 40oC. Unlike conventional liquid-liquid extraction, simple precipitation technique was applied for drug extraction from human plasma using acetonitrile for deprotienation. The method showed adequate separation of both the analytes and best resolution was achieved using Hypersil BDS C8 column (150 mm × 4.6 mm, 5 µm). The method was quite linear in the range of 20-600 ng/ml. Recovery of the method was 92.31% and 89.82% for Domperidone and Itopride, respectively. Retention time of both the analytes and internal standard was below 15 min. The lower limit of detection (LLOD) and lower limit of quantification (LLOQ) for Domperidone were 5 and 10 ng/ml while for Itopride was 12 and 15 ng/ml, respectively. The developed method was successfully applied for in-vivo analysis of fast dispersible tablets of Domperidone in healthy human volunteer. The proposed method was a part of formulation development study and was efficiently applied for determination of the two drugs in various pharmaceutical products and human plasma.

Effect of Omeprazole on the Pharmacokinetics of Rosuvastatin in Healthy Male Volunteers.

The current study aimed at the evaluation of, in vivo, the effect of omeprazole on the pharmacokinetics of rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Omeprazole is an acid suppressant and CYP2C9, CYP3A4, and CYP2C19 substrate and inhibitor, as well as inhibitor of transporters (like P-gp). This was a randomized, open-label, 2-period, crossover study. Healthy male volunteers (N = 20), divided into 2 groups, were given single oral doses of rosuvastatin 40 mg either alone (treatment period I) or concomitantly with omeprazole 40-mg capsule (treatment period II). Plasma concentrations of rosuvastatin (rosuva) and its metabolite N-desmethyl rosuvastatin (NDM-rosuva) were quantified by a validated liquid chromatography-tandem mass spectrometry method developed in our laboratory. An insignificant decrease (P > 0.05) has been observed in the values of maximum plasma concentrations, clearance, and half-life of rosuva, whereas an insignificant increase (P > 0.05) has been observed in the area under the plasma concentration-time curves from zero time to the last measurable concentration(Equation is included in full-text article.), that extrapolated to infinity (Equation is included in full-text article.), and mean residence time values after concomitant administration with omeprazole. Although omeprazole concomitant administration altered the pharmacokinetics of NDM-rosuva metabolite significantly, rosuva's very little metabolism (10%) suggests that these changes are of no clinical significance. Concomitant administration of omeprazole with rosuva did not alter the pharmacokinetics of rosuva in healthy volunteers. These data are consistent with other reported studies, indicating that rosuva is not a good candidate for metabolism-based drug-drug interactions. Therefore, rosuva can be administered safely along with omeprazole.