Search

A rapid UPLC-MS-MS method was developed and validated for determination of losartan in rabbit plasma. Protonated adducts of losartan and eprosartan (IS) were monitored in multiple reaction monitoring mode. Molecular masses of daughter species of losartan were m/z 423.19 > 207 and m/z 423.19 > 180; and of eprosartan were m/z 425.11 > 135 and m/z 425.11 > 107. Losartan from plasma samples was extracted by protein precipitation method. The mobile phase comprising water (0.1% formic acid) (A) and acetonitrile (0.1% formic acid) (B) was used in gradient mode. Analytes were eluted on Acquity UPLC®BEH C18 1.7 μm, 2.1 × 50 mm column. Sample run time was 3.0 min. The validation parameters: accuracy, precision and recovery were within recommended limits. Losartan as well as internal standard remains stable in benchtop stability study as well as in post-preparative stability study. Pharmacokinetic parameters such as Cmax (182.79 ± 23.80 ng/mL), Tmax (1.16 ± 0.28 h), AUC0-t (1188.57 ± 404.60 ng h/mL) and Kel (0.0954 ± 0.0140 h-1) of losartan were measured. Method was successfully applied for pharmacokinetic investigation in rabbits and can be used for losartan determination in plasma sample obtained from other animals.

The present research has been investigated to study the protective outcomes of sinapic acid (SA) against methotrexate (MTX) encouraged liver damage in rats by modulating the Nrf2/HO-1 and NF-κB signaling pathways. The animals were arbitrarily allocated into four groups: group I rats administered a 0.5% carboxymethyl cellulose (CMC) vehicle orally for 15 consecutive days with a single intravenous standard saline injection (0.9% NaCl) on day seven. Groups II, III, and IV were injected intraperitoneally with 20 mg MTX/kg on 7th day. Animals in group III and IV were treated orally for 14 days with 20 mg of SA/kg dissolved daily in 0.5% CMC respectively. In all experimental groups, liver function, biochemical, histopathological and molecular changes were evaluated. MTX-induced changes in liver function indices like ALT, AST, and ALP are substantially restored with SA pretreatment. Moreover, antioxidant defense mechanisms (GSH, SOD, and CAT) and oxidative/nitrostative stress (MDA and NO) and inflammatory cytokine (TNF-α, IL-β and MPO) were also substantially restored. Furthermore, the conclusions indicate that SA prevents the hepatic damage caused by MTX through apoptosis inhibition and stimulation of Nrf2/HO-1-medial antioxidant enzymes by NF-κB inhibition. Histological findings have shown that SA therapy has greatly protected liver damage caused by MTX.

Background: In the current study, we evaluated the therapeutic potential of sinapic acid (SA) in terms of the mechanism underlying its gastroprotective action against ethanol-induced gastric ulcers in rats.Methods: These effects were examined through gross macroscopic evaluation of the stomach cavity [gastric ulcer index (GUI)], alteration in pH, gastric juice volume, free acidity, total acidity, total gastric wall mucus, and changes in PGE2. In addition, we evaluated lipid peroxidation (malondialdehyde), antioxidant systems (catalase and glutathione), inflammatory markers [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and myeloperoxidase (MPO)], apoptotic markers (caspase-3, Bax, and Bcl-2), nuclear factor-κB [NF-κB (p65)], NO levels, and histopathological staining (H and E and PAS).Results: In rats with ethanol-induced ulcers, pre-treatment with SA (40 mg/kg p. o.) decreased the sternness of ethanol-induced gastric mucosal injuries by decreasing the GUI, gastric juice volume, free acidity, and total acidity. In addition, the pH and total gastric mucosa were increased, together with histopathological alteration, neutrophil incursion, and increases in PGE2 and NO2. These effects were similar to those observed for omeprazole, a standard anti-ulcer drug. SA was shown to suppress gastric inflammation through decreasing TNF-α, IL-6, and MPO, as well as curbing gastric oxidative stress through the inhibition of lipid peroxidation (MDA) and restoration of depleted glutathione and catalase activity. SA inhibited Bcl-2-associated X (Bax) and caspase-3 activity, and restored the antiapoptotic protein Bcl-2; these findings indicate the antiapoptotic potential of SA, leading to enhanced cell survival. SA also repressed NF-κB signaling and increased IκBα. Moreover, SA upregulated the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), thereby restoring depleted antioxidant defense enzymes and implicating the NRF2/HO-1 signaling pathways.Conclusion: These results suggest that the prophylactic administration of SA (40 mg/kg) can ameliorate ethanol-induced gastric ulcers in rats primarily via the modulation of Nrf2/HO-1 and NF-κB signaling and subsequent enhancement of cell viability.

Objectives To study the effect of Zingiber officinale and Hibiscus sabdariffa on pharmacokinetics and pharmacodynamics of amlodipine. Methods Hypertension was induced in rats (SBP 173.2 ± 1.7 mmHg, mean, 1–24 h). Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP) and heart rate (HR) of group-I (amlodipine treated), group-II (Z. officinale, and Z. officinale + amlodipine) and group-III (H. sabdariffa, and H. sabdariffa + amlodipine) animals were measured by “tail-cuff system”. Pharmacokinetics of amlodipine with and without herbs (Z. officinale or H. sabdariffa) was also investigated. Results Z. officinale as well as H. sabdariffa decreased the SBP, DBP and MBP. Concurrent treatment with Z. officinale + amlodipine (SBP 129.4 ± 4.5) or H. sabdariffa + amlodipine (SBP 130.4 ± 3.9) showed higher decrease in BP (mean, 1–24h), than individually administered amlodipine (SBP 149.5 ± 2.4) or Z. officinale (SBP 150.2 ± 3.1) or H. sabdariffa (SBP 139.1 ± 1.2). These herbs also influenced the Cmax, AUC0-t, and Tmax of amlodipine. H. sabdariffa increased AUC0-t of amlodipine from 81.8 ± 14.7 to 125.0 ± 10.6 (ng h/mL). Conclusion Simultaneous administration of Z. officinale or H. sabdariffa with amlodipine, improves its pharmacodynamic response.

The aim of this study was to formulate and evaluate SR matrix pellets containing losartan potassium (LP) solid dispersion using extrusion-spheronization technique to minimize the fluctuation of its plasma concentration. LP solid dispersions were prepared by using different hydrophobic polymers at different weight ratios (0.5, 1, 2, and 5%). LP-Eudragit RS solid dispersion at 1:5 ratio resulted in slower drug release (only 20% of LP was released in about 8 h). Different concentrations of hydrophilic polymer, PEG 6000, were mixed with Avicel

Erlotinib (OSI-774), marketed by Genentech as Tarceva®, is anticancer drug approved by US-FDA for the treatment of Non-Small Cell Lung Cancer (NSCLC) and Pancreatic Cancer. Erlotinib inhibited epidermal growth factor receptor (EGFR) that blocks tumor cell division, produces cell cycle arrest, and initiates programmed cell death in EGFR-overexpressing human tumor cells. This study presents a comprehensive profile of erlotinib, including detailed nomenclature, formula, elemental analysis, methods of preparation, physico-chemical characteristics, and methods of analysis (including spectroscopic, electrochemical, and chromatographic methods of analysis). Spectroscopic and spectrometric analyses include UV/vis spectroscopy, vibrational spectroscopy, nuclear magnetic resonance spectrometry ((1)H and (13)C NMR), and mass spectrometry. Chromatographic methods of analyses include thin layer chromatography, and high-performance liquid chromatography. Pharmacology of erlotinib including pharmacodynamics, mechanism of action, pharmacokinetics and drug-drug interactions were also presented. An appropriate table and figures were attached to each of the above mentioned sections along with total of 48 references.

The present study aimed to determine the effect of

In the present study, we explored SA’s activity against DOX-induced cardiotoxicity and revealed its underlying mechanisms. Male Wistar rats (weight, 190-210g;n=6) were randomly divided into four groups: group I, normal control; group II, DOX 15 mg/kg via intraperitoneal (ip) route; group III, administered DOX+SA 20 mg/kg; and group IV, administered DOX+captopril (CAP 30 mg/kg). SA and CAP were administered orally for seven days, and DOX (15 mg/kg) was injected intraperitoneally an hour before SA treatment on the fifth day. Forty-eight hours after DOX administration, animals were anesthetized and sacrificed for molecular and histology experiments. SA significantly mitigated the myocardial effects of DOX, and following daily administration, it reduced serum levels of lactate dehydrogenase (LDH) and creatine kinase isoenzyme-MB to near normal values. Levels of oxidative stress markers, glutathione-peroxidase, superoxide dismutase, and catalase, in the cardiac tissue were significantly increased, whereas malondialdehyde levels decreased after SA treatment in DOX-administered rats. Furthermore, DOX caused an inflammatory reaction by elevating the levels of proinflammatory cytokines, tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), and endothelin- (ET-) 1, as well as nuclear factor kappa-B (NF-κB) expression. Daily administration of SA significantly repressed TNF-α, IL-1β, ET-1, and NF-κB levels. caspase-3 and Bax expression, bcl-2-like protein and caspase-3 activities and levels. Overall, we found that SA could inhibit DOX-induced cardiotoxicity by inhibiting oxidative stress, inflammation, and apoptotic damage.

The aim of the present study was to investigate the potential effect of thymoquinone (TQ) on the metabolic activity of four major drug metabolizing enzymes in human liver microsomes, namely cytochrome P450 (CYP) 1A2, CYP2C9, CYP2D6 and CYP3A4. The inhibition of CYP enzymatic activities by TQ was evaluated by incubating typical substrates (phenacetin for CYP1A2, tolbutamide for CYP2C9, dextromethorphan for CYP2D6, and testosterone for CYP3A4) with human liver microsomes and NADPH in the absence or presence of TQ (1, 10 and 100 µM). The respective metabolite of the substrate that was formed was measured by HPLC. Results of the presented study presented that the metabolic activities of all the investigated CYP enzymes, viz. CYP1A2, CYP2C9, CYP2D6 and CYP3A4, were inhibited by TQ. At 1 µM TQ, CYP2C9 enzyme activity was maximally inhibited by 46.35%, followed by CYP2D6 (20.26%) > CYP1A2 (13.52%) > CYP3A4 (12.82%). However, at 10 µM TQ, CYP2C9 enzyme activity was maximally inhibited by 69.69%, followed by CYP3A4 (23.59%) > CYP1A2 (23.51%) > CYP2D6 (11.42%). At 100 µM TQ, CYP1A2 enzyme activity was maximally inhibited by 81.92%, followed by CYP3A4 (79.24%) > CYP2C9 (69.22%) > CYP2D6 (28.18%). The IC50 (mean ± SE) values for CYP1A2, CYP2C9, CYP2D6 and CYP3A4 inhibition were 26.5 ± 2.9 µM, 0.5 ± 0.4 µM, >500 µM and 25.2 ± 3.1 µM, respectively. These findings suggest that there is a high probability of drug interactions resulting from the co-administration of TQ or herbs containing TQ with drugs that are metabolized by the CYP enzymes, particularly CYP2C9. Keywords: Thymoquinone, Cytochrome P450, Metabolism, Human liver microsomes

Cytochrome P450 (CYP) 1A2, 2C9, 2D6, and 3A4 are the most important phase I drug-metabolizing enzymes in the liver, but there is a dearth of literature available on the effects of naltrexone hydrochloride on these major enzymes present in the human liver. Thus, in the present study, the effect of naltrexone hydrochloride on the activity of CYP1A2, 2C9, 2D6, and 3A4 using human liver microsomes (HLM) was investigated. A selective probe for CYP1A2, 2C9, 2D6, and 3A4 was incubated with HLM with or without naltrexone hydrochloride. Phenacetin O-deethylation, tolbutamide 4-hydroxylation, dextromethorphan O-demethylation, and testosterone 6β-hydroxylation reactions were monitored for enzyme activity. The activity of all the studied CYP enzymes except 1A2 was significantly inhibited by naltrexone hydrochloride 1 µM. Furthermore, 1 µM naltrexone hydrochloride inhibited CYP3A4 enzyme activity, the most by 37.9% followed by CYP2C9 (36.5%) and CYP2D6 (31.8%). The CYP2C9 and CYP2D6 metabolic activities were greatly affected by naltrexone hydrochloride, which even at the lowest concentration of naltrexone hydrochloride (0.01 µM) significantly decreased the metabolic activity by 34.9 and 16.0%, respectively. The half maximal inhibition concentration (IC50) values for CYP2C9 and CYP2D6 inhibition were 3.40 ± 1.78 and 5.92 ± 1.58 µM, respectively. These outcomes advocate that there is a great possibility of drug interactions resulting from the concurrent administration of naltrexone hydrochloride with actives that are metabolized by these CYP enzymes, particularly CYP2C9 and CYP2D6. Nevertheless, further clarification is needed through detailed in vivo pharmacokinetic studies.

Thymoquinone (TQ) is a poorly water soluble bioactive compound which shows poor oral bioavailability upon oral administration. Due to poor aqueous solubility and bioavailability of TQ, various self-nanoemulsifying drug delivery systems (SNEDDS) of TQ were developed and evaluated for enhancement of its hepatoprotective effects and oral bioavailability. Hepatoprotective and pharmacokinetic studies of TQ suspension and TQ-SNEDDS were carried out in rat models. Different SNEDDS formulations of TQ were developed and thermodynamically stable TQ-SNEDDS were characterized for physicochemical parameters and evaluated for drug release studies via dialysis membrane. Optimized SNEDDS formulation of TQ was selected for further evaluation of in vivo evaluation. In vivo hepatoprotective investigations showed significant hepatoprotective effects for optimized TQ-SNEDDS in comparison with TQ suspension. The oral administration of optimized SNEDDS showed significant improvement in in vivo absorption of TQ in comparison with TQ suspension. The relatively bioavailability of TQ was enhanced 3.87-fold by optimized SNEDDS in comparison with TQ suspension. The results of this research work indicated the potential of SNEDDS in enhancing relative bioavailability and therapeutic effects of natural bioactive compounds such as TQ.

The objective of the current study was to formulate the eprosartan mesylate loaded transfersomes using different proportions of Phospholipon® 90 G and Tween® 80 (95–75:5–25% w/w). The prepared tran...

The objective of present study was to prepare eprosartan mesylate (EM)-loaded transfersomes Carbopol® gel and characterized for various parameters, including in vitro skin permeation, in vivo antihypertensive study, skin irritation, and histological study. Furthermore, effect of transfersomes gel on angiotensin II type-1 receptor (AT1R) mRNA and protein expressions on smooth vascular muscles of aorta was determined by real-time polymerase chain reaction (RT-PCR) and western blot analysis. The physical evaluation parameters were detected to be in correspondence with reference marketed gel formulation. The transdermal flux, permeability coefficient, and Tlag of EM from transfersomes gel were found to be 26.76 ± 1.66μg/cm2/h, 8.93 ± 0.55 ×10-3 cm/h, and 2.17 ± 0.29h, respectively, across rat skin pretreated with microneedle (Dermaroller®). Pharmacodynamic study showed prolonged and better management of hypertension after the application of transfersomes gel in experimentally induced hypertensive Wistar rats as compared with oral control formulation. The in vivo angiotensin II type-1 blocking efficacy of prepared transfersomes gel and control formulation was also supported with RT-PCR and western blot analysis of AT1R mRNA and protein expressions on smooth vascular muscles of aorta. Skin irritation and skin histological assessment showed that the prepared transfersomes Carbopol® gel was safe to be used for transdermal route. It is concluded that the incorporation of transfersomes into gel formulation offered enhanced skin contact, ease of application, and found to be a suitable drug reservoir for the transdermal delivery of EM for the management of hypertension in Wistar rats.

Sorafenib, a tyrosine kinase inhibitor that is used in the treatment of hepatocellular and renal cell carcinoma, was reported to induce cardiotoxicity. This study aimed to investigate the potential cardioprotective effect of losartan against sorafenib-induced cardiotoxicity in rat. Sorafenib significantly reduced the left ventricular pressure, heart rate dp/dt max & dp/dt min (indexes of myocardial contractility and relaxation; respectively), and prolonged both the systolic and diastolic periods. Coadminstration of losartan significantly reversed the effects of sorafenib on heart rate, dp/dt max and dp/dt min. In addition, there was a tendency for losartan to reverse sorafenib reduction in left ventricular pressure and perfusion pressure but it did not reach statistical significance. A GC-MS non-targeted based metabolites profiling of rat plasma revealed elevated metaboites, including urea and fatty acids levels, associated with sorafenib induced cardiotoxicity. However, only glycine and lactic acid were statistically significant. Interestingly, losartan co-administration with sorafenib restored these changes, and resulted in a significantly reduced glycine, urea and some fatty acids levels namely; Cis-vaccenic acid, oleic acid, stearic acid and undecanoic acid. In addition, based on histology results, losartan coadminitration almost obviated sorafenib-induced changes in cardiac tissues. The study suggests that losartan has the potential to exert a protective effect against sorafenib-induced cardiotoxicity.

In the present study, we explored SA's activity against DOX-induced cardiotoxicity and revealed its underlying mechanisms. Male Wistar rats (weight, 190-210g; n = 6) were randomly divided into four groups: group I, normal control; group II, DOX 15 mg/kg via intraperitoneal (ip) route; group III, administered DOX+SA 20 mg/kg; and group IV, administered DOX+captopril (CAP 30 mg/kg). SA and CAP were administered orally for seven days, and DOX (15 mg/kg) was injected intraperitoneally an hour before SA treatment on the fifth day. Forty-eight hours after DOX administration, animals were anesthetized and sacrificed for molecular and histology experiments. SA significantly mitigated the myocardial effects of DOX, and following daily administration, it reduced serum levels of lactate dehydrogenase (LDH) and creatine kinase isoenzyme-MB to near normal values. Levels of oxidative stress markers, glutathione-peroxidase, superoxide dismutase, and catalase, in the cardiac tissue were significantly increased, whereas malondialdehyde levels decreased after SA treatment in DOX-administered rats. Furthermore, DOX caused an inflammatory reaction by elevating the levels of proinflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and endothelin- (ET-) 1, as well as nuclear factor kappa-B (NF-κB) expression. Daily administration of SA significantly repressed TNF-α, IL-1β, ET-1, and NF-κB levels. caspase-3 and Bax expression, bcl-2-like protein and caspase-3 activities and levels. Overall, we found that SA could inhibit DOX-induced cardiotoxicity by inhibiting oxidative stress, inflammation, and apoptotic damage.

Sorafenib (BAY-43-9006), marketed by Bayer as Nexavar® (USA), is anticancer drug approved by US-FDA for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma. Sorafenib inhibited tumor growth and angiogenesis through targeting both the RAF/MEK/ERK pathway and receptor tyrosine kinases. This study presents a comprehensive profile of sorafenib, including detailed nomenclature, formula, elemental analysis, methods of preparation, physico-chemical characteristics, and methods of analysis (including spectroscopic, electrochemical, and chromatographic methods of analysis). Spectroscopic and spectrometric analyses include UV/vis spectroscopy, vibrational spectroscopy, nuclear magnetic resonance spectrometry ((1)H and (13)C NMR), and mass spectrometry. Chromatographic methods of analyses include thin layer chromatography and high-performance liquid chromatography. Only few stability indicating methods were found for quantification of sorafenib after exposing tablet dosage form to various stress conditions such as hydrolysis, oxidation, thermal stress, photo and UV light. However, none of these described methods were made to separate and quantify the degradation products. Pharmacology studies including pharmacodynamics, mechanism of action, pharmacokinetics and drug-drug interactions were also presented. An appropriate table and figures were attached to each of the above mentioned sections along with total of 55 references.

Diabetic nephropathy (DN) has become a primary cause of end-stage kidney disease. Several complex dynamics converge together to accelerate the advancement of DN. The present investigation was postulated to explore the mechanism of reno-protective nature of Momordica Charantia polysaccharides (MCP) by evaluating the anti-hyperglycemic, anti-lipidemic as well as markers for oxidative stress and antioxidant proficiency in streptozotocin (STZ)-induced diabetic rats. The oral administration of MCP showed a significant normalization in the levels of kidney function test in the STZ-induced diabetic rats. The levels of blood urea nitrogen (BUN), urea protein and creatinine increased by 316.58%, 195.14% and 800.97% respectively, in STZ-induced diabetic rats when compared with normal rats. MCP treatment also illustrated a significant improvement in glutathione peroxidase, superoxide dismutase and catalase levels, with a significant decline in MDA in diabetic kidneys. Immunoblots of heme-oxygenase 1 (HO-1) and Nrf2 of MCP treated diabetic rats showed a significant up-regulation of HO-1 and Nrf2 protein. Histological and ultra-structural observations also reveal that MCP efficiently protects the kidneys from hyperglycemia-mediated oxidative damage. These findings illustrate that the reno-protective nature of MCP mitigates the progression of STZ induced DN in rats by suppression of oxidative stress and amelioration of the HO-1/Nrf2 pathway.

The intention of the present research work was to investigate the antioxidant activity and trace element analysis of Ood-saleeb, a known herbal medicine. Preliminary screening of phytochemicals showed that the extract of Ood-saleeb had flavonoids and phenolics. The significant activities in all antioxidant assays were observed in the extract of Ood-saleeb in comparison with the standard antioxidant with respect to dose of Ood-saleeb. Incredible activities to scavenge reactive oxygen species were also observed by the extract of Ood-saleeb. The IC50 values of all factors were determined using ascorbic acid as a standard. The inductive coupled plasma-mass spectroscopy (ICP-MS) was employed for the estimation of trace elements in Ood-saleeb extract. The concentrations of up to 18 elements were detected successfully. Silicon was found in high concentration (85.3 μg/g) while lithium was in low concentration (3 ng/g). The trace elements in the sample were found at different percentage levels which play a key role in the treatment of diseases.

Background Pulmonary fibrosis is a multifaceted disease with high mortality and morbidity, and it is commonly nonresponsive to conventional therapy. Purpose We explore the possible discourse of sinapic acid (SA) against the prevention of bleomycin (BLM)-instigated lung fibrosis in rats through modulation of Nrf2/HO-1 and NF-κB signaling pathways. Design/Methods Lung fibrosis was persuaded in Sprague-Dawley rats by a single intratracheal BLM (6.5 U/kg) injection. Then, these rats were treated with SA (10 and 20 mg/kg, p.o.) for 28 days. The normal control rats provided saline as a substitute of BLM. The lung function and biochemical, histopathological, and molecular alterations were studied in serum, bronchoalveolar lavage fluid (BALF), and the lungs tissues. Results SA treatment significantly restored BLM-induced alterations in body weight index and serum biomarkers [lactate dehydrogenase (LDH) and alkaline phosphatase (ALP)]. SA (10 and 20 mg/kg) treatment appeared to show a pneumoprotective effect through upregulation of antioxidant status, downregulation of inflammatory cytokines and MMP-7 expression, and reduction of collagen accumulation (hydroxyproline). Nrf2, HO-1, and TGF-β expression was downregulated in BLM-induced fibrosis model, while the reduced expression levels were significantly and dose-dependently upregulated by SA (10 and 20 mg/kg) treatment. We demonstrated that SA ameliorates BLM-induced lung injuries through inhibition of apoptosis and induction of Nrf2/HO-1-mediated antioxidant enzymes via NF-κB inhibition. The histopathological findings also revealed that SA treatment (10 and 20 mg/kg) significantly ameliorated BLM-induced lung injury. Conclusion The present results showed the ability of SA to restore the antioxidant system and to inhibit oxidative stress, proinflammatory cytokines, extracellular matrix, and TGF-β. This is first report demonstrating that SA amoleriates BLM induced lung injuries through inhibition of apoptosis and induction of Nrf2 and HO-1 mediated antioxidant enzyme via NF-κB inhibition. The histopathological finding reveals that SA treatment (10 and 20 mg/kg) significantly ameliorates BLM induced lung injuries.

The aim of present study was to develop and evaluate vesicles containing bile salt formulation of telmisartan for the treatment of diabetic nephropathy. Different vesicles containing bile salt formulations were developed by varying ratios of soybean phosphatidylcholine and sodium deoxycholate. Prepared formulations were characterized for their size, polydispersity index, zeta potential, morphology and entrapment efficiency. Further, the renoprotective outcome of optimized formulation was studied in streptozotocin-induced diabetic nephropathy rat model. Results of the present study demonstrated that the average vesicles size, polydispersity index, zeta potential and entrapment efficiency were found to be in the range of 64.98 ± 1.40 to 167.60 ± 6.46 nm, 0.02 ± 0.04 to 0.31 ± 0.01, -24.30 ± 1.39 to -42.60 ± 6.67 mV and 29.68 ± 1.08% to 77.21 ± 0.52%, respectively. Further, the best chosen formulation F4 presented vesicles size, polydispersity index, zeta potential and entrapment efficiency of 64.98 ± 1.40 nm, 0.24 ± 0.02, -35.40 ± 1.48 mV and 77.21 ± 0.52%, respectively. In addition, formulation F4 improved the biological indices in streptozotocin-induced diabetic nephropathy in rats. It was concluded that prepared formulation exerts a valuable results on diabetic nephropathy and it may be a potential pharmaceutical dosage form for the treatment of diabetic nephropathy.

Quick and specific bioanalytical methods are required for analyzing drugs in biological samples. A simple, quick, sensitive, and specific UPLC-MS/MS method was developed and validated for glibenclamide determination in plasma samples. The plasma samples were processed by protein precipitation technique. Glimepiride was used as internal standard (IS). Glibenclamide and glimepiride were eluted on C18 column (Acquity UPLC®BEH). Mobile phase consisting of acetonitrile (0.1% formic acid) and water (0.1% formic acid) was pumped in binary gradient mode at flow rate of 150 μL/min. Glibenclamide and IS elution time was about 1.0 min, and total run time was 2.0 min. The mass spectrometer (triple-quadrupole) was operated in positive electrospray ionization mode. Sodium adducts [M + Na]+ of glibenclamide and IS were monitored in MRM mode. A linear calibration curve was obtained in the range of 10-1280 ng/mL, with regression equation Y = 0.0076 X – 0.0165 and linear regression coefficient r2 = 0.999. Lower limit of quantitation was 10 ng/mL. Accuracy of the method at LQC, MQC, and HQC was 109.7% (± 6.7), 93.6% (± 0.4), and 99.3% (± 1.9), respectively. The coefficient of variation for precision at all QC concentrations was less than 6%. Recovery at LLQC, MQC, and HQC was 104.2% (± 4.9), 100.6% (± 0.9), and 102.9% (± 5.8), respectively. The method was successfully implemented for pharmacokinetic investigations (in-house data).

Hypertension is the most common cardiovascular disease worldwide. Moreover, management of hypertension requires long-term treatment that may result in poor patient compliance with conventional dosage forms due to greater frequency of drug administration. Although there is availability of a plethora of therapeutically effective antihypertensive molecules, inadequate patient welfare is observed; this arguably presents an opportunity to deliver antihypertensive agents through a different route. Ever since the transdermal drug delivery came into existence, it has offered great advantages including non-invasiveness, prolonged therapeutic effect, reduced side effects, improved bioavailability, better patient compliance and easy termination of drug therapy. Attempts were made to develop the transdermal therapeutic system for various antihypertensive agents, including β-blockers, an important antihypertensive class. β-blockers are potent, highly effective in the management of hypertension and other heart ailments by blocking the effects of normal amounts of adrenaline in the heart and blood vessels. The shortcomings associated with β-blockers such as more frequent dose administration, extensive first pass metabolism and variable bioavailability, make them an ideal candidate for transdermal therapeutic systems. The present article gives a brief view of different β-blockers formulated as transdermal therapeutic system in detail to enhance the bioavailability as well as to improve patient compliance. Constant improvement in this field holds promise for the long-term success in technologically advanced transdermal dosage forms being commercialized sooner rather than later.

A simple, precise and accurate high-performance liquid chromatography-ultraviolet method was developed and validated for the quantification of theophylline in rabbit plasma using hydroxyethyl theophylline as an internal standard. Separation was performed on Waters(®) C18 column (µBondapak™ 5 µm, 150 × 3.9 mm) using a mobile phase consisting of water-acetonitrile (96:4 v/v) at a flow rate of 1 mL/min. Validation of the method was performed in order to demonstrate its selectivity, linearity, precision, accuracy and stability. The calibration curves of theophylline were linear over a concentration range of 0.1-25 µg/mL. The within- and between-day coefficient of variation (CV) were

Commiphora myrrha (Burseraceae), a shrub resembling a small tree, has been used for several centuries for the treatment of various diseases.This study investigates the hepatoprotective activity of C. myrrha ethanol extract against d-galactosamine/lipopolysaccharide (d-GalN/LPS)-induced acute hepatic injury in an animal model.Rats were pretreated with ethanolic extract C. myrrha (250 and 500 mg/kg; p.o.) for 7 d prior to the induction of an acute phase response by d-GalN/LPS. Animals were sacrificed 24 h after d-GalN/LPS (800 mg/kg and 50 µg/kg i.p.) administration for the biochemical and histological analyses.The administration of d-GalN/LPS increased plasma aminotransferases (174.47 ± 4.5761 and 260.96 ± 1.9839 µkat/l) and total bilirubin levels (1.012 ± 0.0288 mg/dl), which were attenuated by C. myrrha treatment. Hepatic lipid peroxidation activity and nitric oxide content also increased, while the antioxidant activity measured by GSH (0.76 nmol/g protein), SOD (81.91 U/mg protein), and CAT (15.78 U/mg protein) was reduced. Commiphora myrrha provided significant restoration of GSH (0.815 nmol/gm protein), SOD (140.57 U/mg protein), and CAT (27.02 U/mg protein) levels. Furthermore, the acute phase response elicited by d-GalN/LPS administration enhanced mRNA expressions of TNF-α, IL-6, IL-10, iNOS-2, and HO-1, which were ameliorated by C. myrrha treatment.These findings indicate that C. myrrha considerably reduces the oxidative stress of d-GalN/LPS-induced hepatic injury via multiple pathways including adown regulation of inflammatory mediators and cytokines. Such a property might be sufficient to combat cellular damage caused by various conditions that resemble fulminant hepatitis and could be of a potential clinical application.

Background: The present study investigated the effect of fenugreek seeds powder and its alcoholic extract on metabolic activity of drug-metabolizing enzymes CYP2D6 and CYP3A4. Materials and Methods: Dextromethorphan (DEX) was used as a probe for measuring metabolic activity, based on its CYP2D6- and CYP3A4-mediated metabolism to dextrorphan (DOR) and 3-methoxymorphinan (3-MM), respectively. For the in vitro investigations, DEX (25µM) was incubated with human liver microsomes and NADPH and tested with and without the fenugreek extract. For the in vivo study, phase I, 6 subjects received a single dose of DEX (30 mg); in phase II, after washout period, the fenugreek seeds powder was administered for 1 week and DEX was administered with its last dose. Results: In vitro, fenugreek extract inhibits CYP2D6-mediated O-demethylation of DEX. Higher concentrations (50 and 100µg/ml) of extract inhibit CYP2D6 and CYP3A4 activity. In vivo results indicated that fenugreek does not significantly inhibit CYP2D6 and CYP3A4 metabolic activity. There was no significant change in the levels of DEX metabolites (DOR 12% and 3-MM 9%) excreted in urine and their urine metabolic ratios (P values: 0.257 and 0.333 DEX/DOR and DEX/3-MM, respectively). Conclusion: In vitro and in vivo observations suggested that fenugreek may not have substantial effect on the metabolic activity of CYP2D6 and CYP3A4.

Present study investigated the potential effects of Ferula asafetida resin on metabolic activities of human drug metabolizing enzymes: CYP2D6 and CYP3A4. Dextromethorphan (DEX) was used as a marker to assess metabolic activities of these enzymes, based on its CYP2D6 and CYP3A4 mediated metabolism to dextrorphan (DOR) and 3-methoxymorphinan (3-MM), respectively. In vitro study was conducted by incubating DEX with human liver microsomes and NADPH in the presence or absence of Asafetida alcoholic extract. For clinical study, healthy human volunteers received a single dose of DEX alone (phase-I) and repeated the same dose after a washout period and four-day Asafetida treatment (phase-II). Asafetida showed a concentration dependent inhibition on DOR formation (in vitro) and a 33% increase in DEX/DOR urinary metabolic ratio in clinical study. For CYP3A4, formation of 3-MM in microsomes was increased at low Asafetida concentrations (10, 25 and 50μg/ml) but slightly inhibited at the concentration of 100μg/ml. On the other hand, in vivo observations revealed that Asafetida significantly increased DEX/3-MM urinary metabolic ratio. The findings of this study suggest that Asafetida may have a significant effect on CYP3A4 metabolic activity. Therefore, using Ferula asafetida with CYP3A4 drug substrates should be cautioned especially those with narrow therapeutic index such as cyclosporine, tacrolimus and carbamazepine.

This study investigated the therapeutic role of polysaccharides from M. charantia and their mechanism of action against ethanol-induced gastric ulcers in rats. Their effects were determined through macroscopic evaluation of the gastric cavity (gastric ulcer index [GUI]), changes in PGE2, lipid peroxidation (malondialdehyde), antioxidant systems (catalase and reduced glutathione), inflammatory markers (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and myeloperoxidase [MPO]), apoptotic markers (caspase 3, Bax, and Bcl-2), nuclear factor-κB (NF-κB [p65]), and histopathological staining (H&E and PAS). Pretreatment with MCP (300mg/kg p.o.) attenuated the severity of ethanol-induced gastric mucosal damage, reductions in GUI, histopathologic aberrations, and neutrophil invasion, and PGE2 upregulation. These actions were similar to those of omeprazole, a reference anti-ulcer drug. MCP repressed gastric inflammation through the reduction of MPO, TNF-α, and IL-6, and prevented gastric oxidative stress through the inhibition of lipid peroxides with the concomitant enhancement of glutathione and catalase activity. Apoptotic markers indicated that MCP suppressed Bax and caspase-3 activity and enhanced the anti-apoptotic protein Bcl-2, which favored cell survival. MCP downregulated NF-κB and upregulated IκBα. Our study results suggested that the prophylactic administration of MCP reduced ethanol-induced gastric injury in rats through the suppression of gastric inflammation and oxidative stress, predominantly via NF-κB inhibition.

The objective of the present study was to formulate eprosartan mesylate loaded nano-bilosomes and investigates its potential for controlling streptozotocin induced diabetes nephropathy in Wistar rats. The eprosartan mesylate loaded nano-bilosomes comprising of various ratios of soybean phosphatidylcholine/sodium deoxycholate were prepared by thin film hydration technique. The prepared formulations were evaluated for vesicles size, polydispersity index, zeta potential and entrapment efficiency. Further the optimized formulation was characterized for vesicles morphology, and its efficacy for the management of diabetic nephropathy in Wistar rats. The optimized eprosartan mesylate loaded nano-bilosomes exhibited vesicles size, polydispersity index, zeta potential and entrapment efficiency of 63.88±3.46nm, 0.172±0.026, -30.40±2.75mV and 61.19±0.88% respectively. In vivo activity demonstrated that the prepared eprosartan mesylate loaded nano-bilosomes formulation demonstrated a nephro-protecting outcome as shown by the substantial decrease in serum creatinine, urea, lactate dehydrogenase, total albumin, and malondialdehyde. Additionally, an oral administration of eprosartan mesylate loaded nano-bilosomes decreases the raised expressions of Angiotensin II type 1 receptor, inducible nitric oxide synthase, and transforming growth factor-β1 in Wistar rats. Further, histopathological examination established the nephro-protective effect of prepared formulation. In conclusion, the research work in the paper suggests that the prepared eprosartan mesylate loaded nano-bilosomes could serve as a practical oral formulation for diabetic nephropathy in future therapy and may offer potential benefits in cases with hypertension and renal disease.

Herbal medicines, dietary supplements, and other foods may pharmacokinetically and/or pharmacodynamically interact with carbamazepine (CBZ), which could lead to potential clinical consequences. Paeonia emodi (PE) is one of the herbs used as complementary therapy in the treatment of epileptic patients in some cultures, and may also be co-administered with CBZ. This study evaluates the effects of PE on the pharmacokinetics of CBZ and determines a possible mechanism of interaction. Rats were administered vehicle saline or PE (200mg/kg, p.o. daily for 7days), then administered a single CBZ dose (80mg/kg, p.o.) on day 7. Plasma samples were analyzed for CBZ concentrations using a sensitive reversed-phase high-performance liquid chromatography (RP-HPLC) assay. Pharmacokinetic parameters were calculated using non-compartmental analysis. The co-administration of PE with CBZ resulted in increased plasma maximum concentration (Cmax), area under the curve (AUC0-∞), and half-life (T½), by 14.61%, 48.12%, and 43.72%, respectively. The calculated oral clearance (CL/F) was reduced by 33.54%, while the volume of distribution (Vss) was unaffected. The PE extract also showed a significant potential to reduce CYP3A and CYP2C protein expression by approximately 50%. Therefore, a reduction in the metabolic capacity responsible for CBZ clearance appears to be the mechanism behind this herb-drug interaction. Consequently, the concomitant administration of PE and CBZ should be viewed cautiously. Further studies are needed to determine the clinical relevance of these observations.

The objective of the present work was to formulate, optimize and evaluate the potential of novel soft nanovesicles i.e. nano-transfersomes, containing eprosartan mesylate (EM) for transdermal delivery. Nano-transfersomes of EM were developed using Phospholipon 90G, Span 80 (SP) and sodium deoxycholate (SDC) and characterized for vesicle size, shape, entrapment efficiency, in vitro skin permeation study and confocal laser scanning microscopy. The optimized nano-transfersomes formulation showed vesicles size of 108.53 ± 0.06 nm and entrapment efficiency of 63.00 ± 2.76%. The optimized nano-transfersomes provided an improved transdermal flux of 27.22 ± 0.29 µg/cm2/h with an enhancement ratio of 16.80 over traditional liposomes through Wistar rat skin. Confocal laser microscopy of rat skin treated with the optimized formulation showed that the formulation was eventually distributed and permeated deep into the rat skin. The present investigation has shown that the nature and concentration of surfactants (edge activators) influence immense control on the characteristics of nano-transfersomes. It was concluded that the developed nano-transfersomes surmount the limitation of low penetration ability of the traditional liposomes across the rat skin. Improved drug delivery presented by nano-transfersomes establishes this system as an encouraging dosage form for the delivery of EM via skin route.

The aim of the present study was to ascertain the solubility of nitrendipine (NP), an antihypertensive drug in six different pure solvents such as water, ethyl acetate (EA), ethanol, isopropyl alcohol (IPA), polyethylene glycol-400 (PEG-400), and Transcutol at temperature from 298.15 to 318.15 K under atmospheric pressure (p) of 0.1 MPa. Experimental solubility data of NP was fitted with Apelblat and ideal models. The mole fraction solubility of NP was found maximum in PEG-400 (6.85 × 10−2 at 318.15 K) followed by Transcutol (4.65 × 10−2 at 318.15 K), EA (1.68 × 10−2 at 318.15 K), ethanol (2.83 × 10−3 at 318.15 K), IPA (2.69 × 10−3 at 318.15 K), and water (1.29 × 10−7 at 318.15 K). The dissolution activity of NP was observed as an endothermic, spontaneous, and an entropy-driven in most of studied pure solvents. The solubility data of NP obtained in the present study could be useful in purification, recrystallization, and dosage forms design of NP.

Aim: Combined use of herbs and drugs may result in clinically important herb-drug interactions. The majorities of these interactions are thought to be metabolism-based and involve induction or inhibition of cytochrome P450 (CYP). The current study was designed to investigate the effect of some commonly used herbs on rat CYP2C11 gene expression and metabolic activity. Methods: Wistar rats were treated for 7 days with increasing doses of 3 herbs; Nigella sativa, Trigonella foenum-graecum, and Ferula asafoetida . Thereafter, CYP2C11 mRNA and protein levels were determined by real-time polymerase chain reaction (RT-PCR) and western blot analyses, respectively. In vitro metabolic activity of CYP2C11 was performed on rat hepatic microsomes using tolbutamide as specific substrate. Results: Our results showed that all the 3 herbs significantly inhibited the mRNA and protein expression levels of CYP2C11 in a dose-dependent manner. Furthermore, the in vitro enzyme metabolic activity study showed a significant decrease in the formation of 4-hyroxy-tolbutamide, a tolbutamide metabolite, at the higher doses. The inhibitory effects of the investigated herbs on rat CYP2C11 was in the order: Nigella Sativa > Trigonella foenum-graecum > Ferula asafoetida . Conclusions: The 3 herbs are strong inhibitor of CYP2C11 expression, which can lead to an undesirable pharmacological effect of clinically used CYP2C11 substrate drugs with a low therapeutic index.

A new UPLC-MS-MS method was developed and validated for quantification of diclofenac sodium in rabbit plasma. Acetonitrile-based protein precipitation method was used to extract the drug from plasma samples. Chromatographic separation was carried out on Acquity UPLC(®)BEH phenyl C18 1.7 µm, 2.1 × 50 mm column. Drug elution was facilitated by using mobile phase containing acetonitrile (0.1% glacial acetic) and water (pH 3.5), in a ratio of 75 : 25, flowing at 0.2 mL/min. Molecular ions were generated by using the positive electrospray ionization mode (ESI(+)) and analyzed on a triple-quadrupole mass spectrometer. The ionic transitions of diclofenac (m/z 296 > 214 and 249.9) and flufenamic acid (internal standard) (m/z 282.1 > 166.9 and 244) were measured in multiple reaction modes. Developed method is simple, quick, precise and accurate over a linearity range of 80-4,000 ng/mL. The lower limit of quantification (LLOQ) for diclofenac was 80 ng/mL. The percentage recoveries of diclofenac at three quality control samples were 54 ± 6.1, 67.1 ± 5.4 and 62.3 ± 1.4%. Precision and accuracy of the assay at LLOQ, middle limit of quantitation and higher limit of quantitation were 100 ± 7.0, 100 ± 1.0 and 100 ± 2.0% and 81.8 ± 4.6, 106.6 ± 3.1 and 103.3 ± 4.0%, respectively.

Present investigation evaluated permeability enhancing potential of pharmaceutical excipients (HPMC, PVP, Tween-80, Cremophor EL, Cremophor RH40, Transcutol, Labrasol and pluronics F-68) on the intestinal permeability of a P-glycoprotein substrate (domperidone). Everted and non-everted rat gut sacs were used for permeability studies. The investigation revealed that serosal to mucosal (S-M) transport of domperidone was greater than the mucosal to serosal (M-S) transport, which indicates that net movement of domperidone was towards lumen. Further, it was observed that S-M flux of domperidone was reduced by surfactant such as Tween-80, Cremophor EL, Cremophor RH40, Transcutol, Labrasol and pluronics F-68. Pluronics F-68 showed inhibitory effect at higher concentration (0.8 % w/v), but no significant inhibition was observed at lower concentrations. Polymers like HPMC and PVP did not produce any remarkable effect on the permeability of domperidone. The findings suggested that some of the excipients may be used to increase the permeability and absorption of P-gp substrates. However, their role should be confirmed at molecular level and clinical relevance of these findings should be evaluated.

The objective of present study was to prepare eprosartan mesylate (EM)-loaded transfersomes Carbopol

Background Fulminant hepatic failure (FHF) is clinical syndrome with very poor prognosis and high mortality there is urgent need for the development of safe and non-toxic hepatoprotective agents for the adequate management of hepatitis. Hepatoprotective effect of the Lepidium sativum ethanolic extract (LSEE) was assessed by D-galactosamine-induced/lipopolysaccharide (400 mg/kg and 30 μg/kg) liver damage model in rats. Methods Hepatoprotective activity of LSEE (150 and 300 mg/kg) and silymarin on D-GalN/LPS induced FHF in rat was assessed using several liver function enzyme parameters. Antioxidant properties as antioxidant stress enzymes were assessed in hepatic Liver as well as mRNA expression of cytokines genes such as TNF-α, IL-6, and IL-10 and stress related genes iNOS and HO-1 were determined by RT-PCR. Protein expression of apoptotic genes were evaluated through western blot. MPO and NF-κB DNA-binding activity was analyzed by ELISA. The magnitude of hepatic impairment was investigated through histopathological evaluation. Results Marked amelioration of hepatic injuries by attenuation of serum and lipid peroxidation has been observed as comparable with silymarin (25 mg/kg p.o). D-GalN/LPS induced significant decrease in oxidative stress markers protein level, and albumin. LSEE significantly down-regulated the D-GalN/LPS induced pro-inflammatory cytokines TNFα and IL-6 mRNA expression in dose dependent fashion about 0.47 and 0.26 fold and up-regulates the IL-10 by 1.9 and 2.8 fold, respectively. While encourages hepatoprotective activity by down-regulating mRNA expression of iNOS and HO-1. MPO activity and NF-κB DNA-binding effect significantly increased and was mitigated by LSEE in a dose-dependent style as paralleled with silymarin. Conclusion Our data suggests that pretreatment of LSEE down regulates the caspase 3 and up-regulates the BCl2 protein expression. The above findings revealed that Lepidium sativum has significant hepatoprotective activity. Electronic supplementary material The online version of this article (doi:10.1186/s12906-016-1483-4) contains supplementary material, which is available to authorized users.

The main objective of this study was to evaluate CYP2D6 genetic polymorphism in a Saudi Arabian population by determining the frequencies of CYP2D6*41, CYP2D6*29, CYP2D6*3, CYP2D6*6 and CYP2D6*14 alleles. Genomic DNA was isolated from 192 healthy Saudis representing different geographical regions, and genotyping of the selected CYP2D6 variants was carried out by direct sequencing. The allelic frequency of CYP2D6*41 was found to be 18.4%, and that of CYP2D6*29 to be 2.9%. The other investigated alleles were either not detected or rarely present in the study population. In addition, two commonly shared single nucleotide polymorphisms (SNPs) and two very rare SNPs among CYP2D6 alleles were detected. Further studies are therefore, required to evaluate the metabolic and clinical relevance of CYP2D6*41 in Saudi Arabians.

In this review, we discuss the methodologies and platform technologies for enhancing the oral bioavailability of poorly soluble drugs. We also highlight the mechanisms of formulation technologies for improving desired physicochemical attributes of active substances. We focus on various commercial technologies, along with marketed products, and identify proprietary technologies protected by patents. We also discuss nonpropriety technologies, such as mesoporous silica, cyclodextrin complexation and solid dispersions. In addition, we highlight the factors affecting drug absorption and/or bioavailability, the methodologies available to prepare bioavailability-enhanced products, stability issues and examples of technology implementation.

The present study investigated the effect of fenugreek seed powder on disposition of CYP3A substrates, cyclosporine and carbamazepine. Rabbits were treated with fenugreek seed powder (300 mg/kg p.o.) for 8 days and on 8th day the single dose of cyclosporine (30 mg/kg, p.o.) and carbamazepine (40 mg/kg, p.o.) were administered to the corresponding group after 1 h of fenugreek administration. Blood samples were drawn at several time points and analyzed by using UPLC-MS (cyclosporine) and HPLC (carbamazepine). Pharmacokinetic parameters were calculated by using PK Solver. The present investigation reveals that there was no statistically significant difference between pre- and post-treated pharmacokinetic parameters such as AUC(o-t), AUC(o-∞), C(max), T(max), T(1/2), K(el), MRT(o-∞) , V(z/F), and Cl/F for cyclosporine and carbamazepine. Two tailed "P" values for all these pharmacokinetic parameters were more than 0.05, indicating insignificant impact of fenugreek treatment on the disposition of cyclosporine and carbamazepine. Further, fenugreek may also not have any significant effect on the functionality of P-glycoprotein as cyclosporine is a substrate to P-glycoprotein. The outcomes of present study suggested that fenugreek may not likely to interfere cyclosporine and carbamazepine pharmacokinetics, when co-administered with these drugs.

Introduction Glucuronidation is an important phase II pathway responsible for the metabolism of many endogenous substances and drugs to less toxic metabolites, which undergo renal excretion. The aim of the current work was to evaluate genotype and allele frequencies of certain UDP-glucuronosyltransferase 1A1 (UGT1A1) variants in an Arab population. Material and methods Genomic DNA was isolated from 192 healthy unrelated Saudi males of various geographic regions and genotyping of UGT1A1*6, *27, *36, *28, *37, and *60 was carried out using polymerase chain reaction (PCR) amplification followed by direct sequencing. Results The most common allele for (TA) repeats was the wild type (TA)6 with a frequency of 74.3% followed by the mutant (TA)7 (i.e., UGT1A1*28) with a frequency of 25.7%. The distribution of UGT1A1*60 allele was 62.4% among subjects with the homozygous mutant genotype of 35.4%, while the wild type variant represents 10.6% only. Both UGT1A1*6 and *27 were not detected as all screened subjects showed a homozygous wild type pattern. Similarly, UGT1A1*36* and *37 were either not present or rarely found, respectively. In comparison to other populations, the frequency of UGT1A1*60 and *28 in the studied population was less than that of African Americans but higher than Asians. The geographical origin of the study subjects also implied some differences in genotype distribution of (TA) repeats and UGT1A1*60. Conclusions Our data indicate that Saudis harbor some important UGT1A1 mutations known to affect enzyme activity. Additional studies are warranted to assess the clinical implications of these gene polymorphisms in this ethnic group.

Polymorphisms in the PXR gene play important roles in influencing the efficacy and toxicity of a large number of endogenous and exogenous substrates. Because of ethnic specificity, several studies have been directed toward the determination of PXR polymorphisms in various populations. In the current study, we determined the genotype and allele frequencies of 19 coding and regulatory polymorphisms in the PXR gene in Saudi Arabians by direct sequencing. Our results show that the frequencies of the regulatory PXR SNPs in Saudi Arabians differ from those in other ethnic groups, and the results endorse the commonly seen ethnic pattern of a paucity of the PXR coding SNPs.

The present work was designed to evaluate the effect of some commonly used herbs viz. garden cress (Lepidium sativum), black seed (Nigella sativa) and fenugreek (Trigonella foenum-graceum) on the disposition of phenytoin after oral administration in a dog model. Phenytoin was given orally at a dose of 50 mg, and blood samples were obtained for the determination of drug's pharmacokinetic parameters. After a suitable washout period, animals were commenced on a specific herb treatment for one week. Garden cress treatment caused a modest increase in maximum observed concentration (Cmax) and terminal half-life (T1/2λ) of phenytoin with a reduction in clearance by 33%. The effect of black seed therapy was more drastic on drug elimination and to a lesser extent on its volume of distribution at steady state (Vss) with a consequent reduction in systemic exposure measured by area under the curve (AUC0-∞) by about 87%. The effect of fenugreek therapy resembled, albeit to a lesser extent, that of black seed with a significant reduction in AUC0-∞ by ~72%. In addition, there was a 73% increase in Vss. Our findings suggest that the phenytoin disposition can be significantly altered by the concurrent consumption of tested herbal products. Copyright © 2013 John Wiley & Sons, Ltd.

Background: Niosomes are non-ionic surfactant vesicles used as drug carriers for encapsulating both hydrophobic and hydrophilic drugs. The aim of the present study was to prepare and characterize niosomes formulations for oral delivery of telmisartan and evaluated for its antihypertensive activity. Method: Telmisartan loaded niosomes were prepared using thin film hydration method by varying the Span 60 and cholesterol at several molar ratios and characterized for vesicles size, polydispersity index, zeta potential, entrapment efficiency. The in vivo antihypertensive study of optimized formulation and molecular impact of angiotensin II type-1 receptor (AT1R) messenger Ribonucleic acid (mRNA) and protein expression on smooth vascular muscles of aorta was determined by real-time polymerase chain reaction (RT-PCR) and western blot analysis in Wistar albino rats. Results: The optimized niosomes formulation NS6 presented vesicles size of 618.47 nm, polydispersity index of 0.86, with entrapment efficiency of 83.83% and possesses negative charge. In vivo study showed that the optimized formulation could reduce the systolic blood pressure in methyl prednisolone acetate induced hypertensive rats in close proximity to normal range of systolic blood pressure and maintain it over an extended period. In addition, telmisartan loaded niosomes treatment to hypertensive rats significantly attenuates the raised mRNA level and protein level of AT1R gene in comparison to hypertensive rats. Conclusion: Results of present study confer the potential of developed niosomes as suitable carriers for improved oral delivery of telmisartan.