ISRN Pharmacology

Antiurolithiatic Activity of Extract and Oleanolic Acid Isolated from the Roots of Lantana camara on Zinc Disc Implantation Induced Urolithiasis

Narendra Vyas and Ameeta Argal — Wed, 15 May 2013 08:02:17 +0000

The present study was done to evaluate the antiurolithiatic activity of ethanolic extract of roots (ELC 200 mg/kg) and oleanolic acid (OA 60 mg/kg, O.A. 80 mg/kg, O.A. 100 mg/kg) isolated from roots of Lantana camara in albino wistar male rats using zinc disc implantation induced urolithiatic model. The group in which only zinc disc was implanted without any treatment showed increase in calcium output ( mg/dL). Cystone receiving animals showed significant protection from such change (). Treatment with OA and ELC significantly reduced the calcium output at a dose of OA 60 mg/kg (), OA 80 mg/kg (), ELC 200 mg/kg (), and OA 100 mg/kg (), as compared with zinc disc implanted group. The average weight of zinc discs along with the deposited crystals in the only disc implanted group was found to be mg. Group that received Cystone 500 mg/kg showed significant reduction in the depositions (). Similarly, the rats which received OA and ELC showed reduced formation of depositions around the zinc disc (). The X-ray images of rats also showed significant effect of OA and ELC on urolitiasis. Thus, OA and ELC showed promising antiurolithiatic activity in dose dependant manner.

On the Performance of Trimetazidine and Vitamin E as Pharmacoprotection Agents in Cyclosporin A-Induced Toxicity

Thu, 11 Apr 2013 10:29:37 +0000

The immunosuppressant drug cyclosporin A (CyA) has been used in diseases with immunological basis and in transplant patients. Nephrotoxicity and hepatotoxicity are the main adverse effects of this drug. To find a protective drug against those effects we assayed the cardioprotector Trimetazidine (TMZ) and vitamin E, used as nutritional supplements to alleviate oxidative stress. Six groups of eight male Wistar rats each were prepared (groups A–F): A, control; B, vitamin E (10 mg/Kg/day); C, TMZ (20 mg/Kg/day); D, 25 mg/Kg/day CyA; E, CyA and vitamin E (25 mg/Kg/day CyA + 10 mg/Kg/day Vit E); F, TMZ for 20 days (20 mg/kg/day); and then CyA (25 mg/kg/day) and TMZ (20 mg/Kg/day). The experiment lasted 120 days. The exposure of rats to CyA promoted nephrotoxicity and hepatotoxicity with an increase in serum urea, creatinine, and glutamate dehydrogenase (GLDH). Structural and ultrastructural studies of liver and kidney were performed. Group D showed adverse effects induced by CyA since statistically significant differences were found with respect to the control group (A). Vitamin E (E) showed no protective effect. Pretreatment with TMZ (F) attenuated the adverse effects of CyA. We conclude that CyA-induced nephrotoxicity and hepatotoxicity are attenuated by the cytoprotective effect of TMZ. TMZ inhibits the reabsorption and, consequently, the accumulation of CyA in the cell. The antioxidant capacity of vitamin E did not improve the effect of CyA.

Pharmacokinetics of Caffeine following a Single Administration of Coffee Enema versus Oral Coffee Consumption in Healthy Male Subjects

Mon, 04 Mar 2013 07:19:27 +0000

The objective of this study was to determine the pharmacokinetics of caffeine after single administration of a coffee enema versus coffee consumed orally in healthy male subjects. The study design was an open-label, randomized two-phase crossover study. Eleven healthy subjects were randomly assigned either to receive 500 mL of coffee enema for 10 minutes or to consume 180 mL of ready-to-drink coffee beverage. After a washout period of at least 10 days, all the subjects were switched to receive the alternate coffee procedure. Blood samples were collected immediately before and at specific time points until 12 hours after coffee administration in each phase. The mean caffeine content in both the coffee solution prepared for the coffee enema and the ready-to-drink coffee beverage was not statistically different. The and AUC of caffeine obtained from the coffee enema were about 3.5 times significantly less than those of the coffee consumed orally, despite having slightly but statistically faster . The t1/2 of caffeine obtained following both coffee procedures did not statistically differ. In summary, the relative bioavailability of caffeine obtained from the coffee enema was about 3.5 times significantly less than those of the coffee consumed orally.

Scientific Challenges and Implementation Barriers to Translation of Pharmacogenomics in Clinical Practice

Y. W. Francis Lam — Thu, 28 Feb 2013 16:28:33 +0000

The mapping of the human genome and subsequent advancements in genetic technology had provided clinicians and scientists an understanding of the genetic basis of altered drug pharmacokinetics and pharmacodynamics, as well as some examples of applying genomic data in clinical practice. This has raised the public expectation that predicting patients’ responses to drug therapy is now possible in every therapeutic area, and personalized drug therapy would come sooner than later. However, debate continues among most stakeholders involved in drug development and clinical decision-making on whether pharmacogenomic biomarkers should be used in patient assessment, as well as when and in whom to use the biomarker-based diagnostic tests. Currently, most would agree that achieving the goal of personalized therapy remains years, if not decades, away. Realistic application of genomic findings and technologies in clinical practice and drug development require addressing multiple logistics and challenges that go beyond discovery of gene variants and/or completion of prospective controlled clinical trials. The goal of personalized medicine can only be achieved when all stakeholders in the field work together, with willingness to accept occasional paradigm change in their current approach.

Amelioration of Collagen-Induced Arthritis in Female Dark Agouti Rats by Glucosamine Treatment

Thu, 14 Feb 2013 11:57:16 +0000

The present study assessed the therapeutic efficacy of glucosamine hydrochloride against collagen-induced arthritis in female Dark Agouti rats (DA). Arthritis was induced by intradermaly injecting a collagen and complete Freund’s adjuvant suspension at multiple sites in the rat at a dose of 4 mg/kg of body weight and thereafter followed by two more boosters of the same dose, after the 1st week and 2nd week of primary immunization. After 21 days from the day of primary immunization, the arthritic group rats were given oral supplementation of glucosamine hydrochloride at a dose of 300 mg/kg of body weight until day 45. The arthritic group treated with glucosamine hydrochloride from day 21 to day 45 showed significant reduction in arthritic histopathological changes of the joints, reduction in paw thickness and also a significant decrease in C-reactive protein and TNF-alpha in the serum. Treatment with 300 mg/kg of glucosamine hydrochloride was able to reverse the arthritic changes, hence suggesting that glucosamine has a therapeutic effect against collagen-induced arthritis.

Comparative Cytochrome P450 In Vitro Inhibition by Atypical Antipsychotic Drugs

Guillermo Gervasini, Maria J. Caballero, Juan A. Carrillo, and Julio Benitez — Wed, 13 Feb 2013 10:11:05 +0000

The goal of this study was to assess in human liver microsomes the inhibitory capacity of commonly used antipsychotics on the most prominent CYP450 drug metabolizing enzymes (CYP1A2, CYP2C9, CYP2D6, and CYP3A). Chlorpromazine was the only antipsychotic that inhibited CYP1A2 activity ( μM), whilst levomepromazine, chlorpromazine, and thioridazine significantly decreased CYP2D6-mediated formation of -hydroxybufuralol (IC50 range, 3.5–25.5 μM). Olanzapine inhibited CYP3A-catalyzed production of , and -hydroxymidazolam ( and 42.20 μM, resp.). In contrast, risperidone ( μM) and levomepromazine ( μM) showed selectivity towards the inhibition of midazolam -hydroxylation reaction, and haloperidol did so towards -hydroxylation (IC50 of 2.76 μM). Thioridazine displayed a of 1.75 μM and an inhibitory potency of 1.57 on CYP2D6, suggesting a potential to induce in vivo interactions. However, with this exception, and given the observed values, the potential of the assayed antipsychotics to produce clinically significant inhibitions of CYP450 isoforms in vivo seems limited.

Comparison of Efficacy and Safety of Rosuvastatin, Atorvastatin and Pravastatin among Dyslipidemic Diabetic Patients

Lolwa Barakat, Amin Jayyousi, Abdulbari Bener, Bilal Zuby, and Mahmoud Zirie — Sun, 10 Feb 2013 14:51:15 +0000

Objectives. To investigate the efficacy and the safety of the three most commonly prescribed statins (rosuvastatin, atorvastatin, and pravastatin) for managing dyslipidemia among diabetic patients in Qatar. Subjects and Methods. This retrospective observational population-based study included 350 consecutive diabetes patients who were diagnosed with dyslipidemia and prescribed any of the indicated statins between September 2005 and September 2009. Data was collected by review of the Pharmacy Database, the Electronic Medical Records Database (EMR viewer), and the Patient's Medical Records. Comparisons of lipid profile measurements at baseline and at first- and second-year intervals were taken. Results. Rosuvastatin (10 mg) was the most effective at reducing LDL-C (29.03%). Atorvastatin reduced LDL-C the most at a dose of 40 mg (22.8%), and pravastatin reduced LDL-C the most at a dose of 20 mg (20.3%). All three statins were safe in relation to muscular and hepatic functions. In relation to renal function, atorvastatin was the safest statin as it resulted in the least number of patients at the end of 2 years of treatment with the new onset of microalbuminuria (10.9%) followed by rosuvastatin (14.3%) and then pravastatin (26.6%). Conclusion. In the Qatari context, the most effective statin at reducing LDL-C was rosuvastatin 10 mg. Atorvastatin was the safest statin in relation to renal function. Future large-scale prospective studies are needed to confirm these results.

Bioequivalence Study of Pantoprazole Sodium-HPBCD and Conventional Pantoprazole Sodium Enteric-Coated Tablet Formulations

Sandesh P. Kamdi and Prashant J. Palkar — Thu, 07 Feb 2013 16:06:15 +0000

The objective of this study was to investigate the bioequivalence of two formulations of 40 mg pantoprazole sodium enteric-coated tablets: Tripepsa as the test and Pantocid as the reference. The two products were administered as a single oral dose according to a randomized two-phase crossover with a 1-month washout period in 25 healthy Indian volunteers. After drug administration, serial blood samples were collected over a period of 30 hours. Plasma pantoprazole concentrations were measured by high-performance liquid chromatography with UV detection. Pharmacokinetic parameters were analyzed based on noncompartmental analysis. The logarithmically transformed data of and were analyzed for 90% confidence intervals (CI) using ANOVA. The mean (90% CI) values for the ratio of and values of the test product over those of the reference product were 90.21 (83.69–97.24) and 108.68 (100.21–117.86), respectively (within the bioequivalence range of 80–125%). On the basis of pharmacokinetic parameters including , , and values, both the formulations were bioequivalent.

Inhibitory Effect of Aqueous Extract of Stem Bark of Cissus populnea on Ferrous Sulphate- and Sodium Nitroprusside-Induced Oxidative Stress in Rat’s Testes In Vitro

Mon, 21 Jan 2013 15:13:59 +0000

Cissus populnea are plants associated with a myriad of medicinal uses in different parts of the world and are good sources of carotenoids, triterpenoids, and ascorbic acid. The antioxidant properties and inhibitory effect of water extractible phytochemicals from stem bark of C. populnea on FeSO4 and sodium nitroprusside- (SNP-) induced lipid peroxidation in rat testes were investigated in vitro. The results revealed that the extract was able to scavenge DPPH radical, chelate Fe2+ and also had a high reducing power. Furthermore, the incubation of the testes tissue homogenate in the presence of FeSO4 and SNP, respectively, caused a significant increase in the malondialdehyde (MDA) contents of the testes. However, the aqueous extract of the stem bark of C. populnea caused a significant decrease in the MDA contents of both Fe2+ (EC50 = 0.027 mg/mL) and SNP- (EC50 = 0.22 mg/mL) induced lipid peroxidation in the rat testes homogenates in a dose-dependent manner. The water extractible phytochemicals from C. populnea protect the testes from oxidative stress and this could be attributed to their high antioxidant activity: DPPH-scavenging ability, Fe2+-chelating and -reducing power. Therefore, oxidatively stress in testes could be potentially managed/prevented by this plant.

Examination of Haematotoxicity of Fixed-Dose Highly Active Antiretroviral Drug in Albino Wistar Rats

Thomas Nubila, Ernest O. Ukaejiofo, Nkoyo I. Nubila, and Godfrey I. Okorie — Sun, 30 Dec 2012 15:01:20 +0000

Highly active antiretroviral therapy (HAART) is considered toxic and has other life-threatening side effects. Our aim was to evaluate the haematotoxic effects of lamivudine, zidovudine, and nevirapine fixed-dose combinations in Albino Wistar rats. Fifty (50) three (3) months old male Albino Wistar rats weighing between 200 and 250 g were randomly assigned to five (5) groups (A, B, C, D, and E). Group A served as control. Two (2 mLs) of venous blood was aseptically collected on Days 5, 10, 15, 20, and 25 of treatment. Red blood cell (RBC) mean value recorded statistically significant increase () in groups B and C when compared with the control group on Day 5. However, there was a statistically significant decrease () in RBC, haemoglobin concentration (Hb), packed cell volume (PCV), and some red cell indices on Day 10. In addition there was no statistically significant difference () in all the parameters evaluated when the test group was compared with the control on Day 25. Furthermore, there was a time-related statistically significant increase () in the two major blood cells—RBC and platelet counts. From the result of this present study, it can be concluded that HAART when administered in fixed-dose combinations have no subacute haematotoxic effects.

Beneficial Effects of Pentanema vestitum Linn. Whole Plant on the Glucose and Other Biochemical Parameters of Alloxan Induced Diabetic Rabbits

Ikram Ilahi, Ali Asghar, Shujat Ali, Murad Khan, and Nasrullah Khan — Thu, 20 Dec 2012 15:20:30 +0000

The residents of Lower Dir and Malakand agency, Khyber Pakhtunkhwa, Pakistan, use the dry powder of whole plant of Pentanema vestitum for the treatment of asthma and diabetes. No documented reports are available about the therapeutic action of Pentanema vestitum. The present study was aimed to explore the antihyperglycemic effect of 70% methanol extract of Pentanema vestitum whole plant in glucose-induced nondiabetic hyperglycemic and alloxan-induced diabetic rabbits. During this study, the effects of plant extract on the serum lipid profile, GPT, ALP, bilirubin and creatinine of diabetic rabbits were also studied. The extract of Pentanema vestitum whole plant exhibited significant antihyperglycemic activity in glucose-induced hyperglycemic rabbits. Treatment of alloxan-induced diabetic rabbits with extract significantly reduced the elevated levels of serum glucose, GPT, ALP, bilirubin and creatinine. During the study of lipid profile, the extract proved to be antihyperlipidemic and HDL boosting in diabetic rabbit models. From the finding of the present research, it was concluded that the 70% methanol extract of Pentanema vestitum whole plant has beneficial effects on serum levels of glucose, lipid profile, GPT, ALP, bilirubin, and creatinine of diabetic rabbits.

Analgesic and Toxicity Studies of Aminoacetylenic Isoindoline-1,3-dione Derivatives

Raghad Shakir, Zuhair A. Muhi-eldeen, Khalid Z. Matalka, and Nidal A. Qinna — Thu, 20 Dec 2012 08:17:34 +0000

We have developed a series of aminoacetylenic isoindoline-1,3-dione compounds and showed their anti-inflammatory activities by reducing carrageenan-induced rat paw edema and modulating proinflammatory and anti-inflammatory cytokines. In the present study and due to efficacy reasons, we are exploring only two of these compounds, namely, ZM4 and ZM5, to reveal their analgesic activity and toxicity. Following oral administration, both compounds were effective in reducing significantly (–0.001) acetic acid-induced writhing behavior, hot plate latency test, and formalin-induced paw licking time as antinociceptive indicators in mice and rats, respectively. Regarding the toxicity, the acute (20, 50, and 150 mg/kg) and repeated oral administration (10, 20, and 50 mg/kg) of these compounds for ten days did not produce any mortality and the compounds were considered well tolerated. However, repeated oral administration of 50 mg/kg of both compounds induced erythropoiesis by means of increasing significantly red blood cells, hemoglobin, and packed cell volume. Moreover, these compounds did not induce gastric lesions in the stomach of experimental animals at the doses that exhibited analgesic and anti-inflammatory activity compared to indomethacin as a positive control. The results indicate that ZM4 and ZM5 possess potential analgesic activity while being preliminarily safe and have minimal ulcerogenic activity.

Pharmacokinetics and Biodistribution Study of 7A7 Anti-Mouse Epidermal Growth Factor Receptor Monoclonal Antibody and Its Fragment in an Immunocompetent Mouse Model

Wed, 21 Nov 2012 14:45:41 +0000

Immunocompetent mice, Fc receptor γ-chain deficient mice (), and molecular tools as F(ab′)2 bivalent fragments appear as the most suitable biological models to study the mechanisms of the action of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs). In vivo experiments contrasting antitumor effects of whole Abs and their bivalent fragments commonly involve a previous comparative pharmacokinetics study. In this paper, pharmacokinetics and biodistribution of an anti-mouse EGFR Ab were assessed using immunocompetent mice. 125I-labeled 7A7 mAb holds an elimination half-life () of 23.1 h in C57BL/6 mice. Accumulation of mAb was found in liver, spleen, kidneys, and mostly in lungs. We used an ELISA method to determine the of a 7A7 mAb using the same experimental setting. Results from this new analysis revealed a of 23.9 h, supporting this method as a safer and easier system to evaluate pharmacokinetics parameters of mAbs targeting mouse EGFR. Using this system we also studied pharmacokinetics of 7A7 F(ab′)2 fragment. A tenfold difference between the mAb and fragment was found. These data support the use of the 7A7 F(ab′)2 fragment in in vivo studies to explore the contribution of the EGFR signaling blockade and the Fc region to the antitumor effect of 7A7 mAb in this autologous scenario.

Clinical Pharmacology in Sleep Medicine

Ashley Proctor and Matt T. Bianchi — Wed, 14 Nov 2012 10:06:07 +0000

The basic treatment goals of pharmacological therapies in sleep medicine are to improve waking function by either improving sleep or by increasing energy during wakefulness. Stimulants to improve waking function include amphetamine derivatives, modafinil, and caffeine. Sleep aids encompass several classes, from benzodiazepine hypnotics to over-the-counter antihistamines. Other medications used in sleep medicine include those initially used in other disorders, such as epilepsy, Parkinson’s disease, and psychiatric disorders. As these medications are prescribed or encountered by providers in diverse fields of medicine, it is important to recognize the distribution of adverse effects, drug interaction profiles, metabolism, and cytochrome substrate activity. In this paper, we review the pharmacological armamentarium in the field of sleep medicine to provide a framework for risk-benefit considerations in clinical practice.

Bioequivalence Study of Donepezil Hydrochloride Tablets in Healthy Male Volunteers

Thu, 01 Nov 2012 16:33:00 +0000

The objective of this study was to investigate the bioequivalence of two formulations of 5 mg donepezil HCL tablets: Tonizep as the test and Aricept as the reference. The two products were administered as a single oral dose according to a randomized two-phase crossover with a 3-week washout period in 20 healthy Thai Male volunteers. After drug administration, serial blood samples were collected over a period of 216 hours. Plasma donepezil concentrations were measured by high performance liquid chromatography with UV detection. Pharmacokinetic parameters were analyzed based on noncompartmental analysis. The logarithmically transformed data of AUC0–∞ and were analyzed for 90% confidence intervals (CI) using ANOVA. The mean (90% CI) values for the ratio of AUC0–∞ and values of the test product over those of the reference product were 1.08 (1.02–1.14) and 1.08 (0.99–1.17), respectively (within the bioequivalence range of 0.8–1.25). The median for the test product was similar to that of the reference product (2.0 hr), and the 90% CI for the difference between the two preparations was –0.19 to 0.29 hr and within the bioequivalence range of ± 20% of the of the reference formulation. Our study demonstrated the bioequivalence of the two preparations.

Vitamins E and C Alleviate the Germ Cell Loss and Oxidative Stress in Cryptorchidism When Administered Separately but Not When Combined in Rats

Ayobami Oladele Afolabi, Olaolu Opeyemi Olotu, and Isiaka Abdullateef Alagbonsi — Tue, 30 Oct 2012 09:36:37 +0000

The antioxidant effects of vitamins C and E on cryptorchidism-induced oxidative stress were investigated in male Sprague-Dawley rats. Forty rats (200–250 g) were randomly divided in a blinded fashion into five groups (). Group 1 was sham operated and treated with vehicle (corn-oil, 10 mL/kg). Groups 2, 3, 4, and 5 were rendered unilaterally cryptorchid and treated with vehicle (10 mL/kg), vitamin E solution (75 mg/kg), vitamin C solution (1.25 g/kg), and combination of vitamin E (75 mg/kg) and vitamin C (1.25 g/kg) solutions, respectively. Germ cell count, superoxide dismutase (SOD), total protein (TP), and testicular weight (TW) were lower, but malondialdhyde (MDA) was higher in the cryptorchid rats than the sham-operated rats. When administered separately, vitamins C and E increased germ cell count, SOD, TP, and TW but did not reduce MDA in the cryptorchid rats when compared to the vehicle-treated cryptorchid rats. However, there was no significant difference in these parameters between vehicle-treated and combined vitamins C- and E-treated rats. This suggests that vitamins E and C alleviate the germ cell loss and oxidative stress in cryptorchidism when administered separately but not when combined in rats.

Erratum to “Bedtime Single-Dose Prednisolone in Clinically Stable Rheumatoid Arthritis Patients"

Mohammad Bagher Owlia, Golbarg Mehrpoor, and Moneyreh Modares Mosadegh — Sun, 23 Sep 2012 11:07:37 +0000

Bioequivalence Study of Modified-Release Gliclazide Tablets in Healthy Volunteers

Mon, 17 Sep 2012 10:30:17 +0000

This study was aimed to investigate bioequivalence of modified-release 30 mg gliclazide tablets in 18 healthy Thai volunteers. A test product, Glycon MR (Siam Bheasach, TH), was compared with a reference product, Diamicron MR (Servier, France). The study was performed under a single-dose, two-treatment, two-period, and two-sequence crossover design in fasted and fed conditions with a washout period of 2 weeks. Blood samples were collected for 72 h after drug administration. Drug plasma concentrations were determined by HPLC with a UV detector. Analysis of pharmacokinetic characteristics was based on a non-compartmental model. The logarithmically transformed data of Cmax and AUCs were analyzed for 90% confidence intervals using ANOVA. The test product gave slightly higher Cmax in both conditions and shorter Tmax in the fed condition. However, there is no significant difference in pharmacokinetic characteristics between both products under fasted and fed conditions. Effect of food was not significantly observed. The 90% confidence intervals were within the acceptance criteria of 0.80–1.25 regardless of the food effect, indicating bioequivalence between the two products on the rate and extent of gliclazide MR absorption without regard to meals.

Effects of Nigerian Piliostigma thonningii Species Leaf Extract on Lipid Profile in Wistar Rats

O. M. Ighodaro and J. O. Omole — Thu, 06 Sep 2012 09:20:04 +0000

Cardiovascular complications and associated conditions remain a major cause of death, globally. Piliostigma thonningii has been used for different and several medicinal purposes. On this background, the effect of aqueous leaf extract of the plant on the lipid profile of physiologically normal rats was examined. Graded doses of the extract, 0.0, 0.2, and 0.4 g/kg of body weight (bwt) were orally administered to rats for a period of 14 days. The effect of the extract was assessed on the basis of comparative determinations of the evaluated indices in treated rats vis-à-vis the nontreated group as well as in respect to the differences between the basal and final concentrations of the indices in each group. The extract, especially at 0.2 g per kg body weight caused a significant decrease in the total cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol in the treated rats when compared to the control group and basal concentrations. Though, the level of high-density lipoprotein (HDL) cholesterol increased in the treated rats, the increase was not significant when compared to the basal concentration. The LDL/HDL ratio in all the experimental groups was less than 0.9. The results obtained in this study suggest that P. thonningii aqueous leaf extract likely contains antilipidaemic and anticholesterolaemic substance(s), which may be useful in the prophylactic and curative management of lipid peroxidation, high blood pressure, and cardiovascular disorders.

The Effect of Tempol Administration on the Aortic Contractile Responses in Rat Preeclampsia Model

Mohammad Sharif Talebianpoor and Hossein Mirkhani — Mon, 03 Sep 2012 10:18:10 +0000

It is reported that reactive oxygen species production has a critical role in the manifestations and complications of preeclampsia. In the present study, the effect of tempol on the response changes of aortic rings of preeclamptic rats has been studied. Preeclamptic rats (induced by L-NAME) were treated with three different oral doses of tempol (20, 60 and 180 mg/kg/day) from the Day 10 of gestation. Systolic blood pressure, plasma malondialdehyde and 8-isoprostane and the vascular effects of phenylephrine, calcium, acetylcholine and diazoxide were the studied parameters. L-NAME administration resulted in hypertension, proteinuria, increased oxidative stress markers, increased vascular sensitivity to phenylephrine and decreased sensitivity to acetylcholine in pregnant rats. No significant changes in response to calcium and diazoxide were observed. Tempol at doses of 20 and 60 mg/kg/day significantly reversed these changes but at a high dose (180 mg/kg/day), it had no significant effect and in some cases intensified the effect. These results revealed that in the experimental preeclampsia, the sensitivity of rat aorta to alpha- adrenergic receptor agonists was increased and its endothelium-dependent relaxation was decreased. Tempol at lower used doses reduced the blood pressure and oxidative stress and restored the normal responsiveness of vascular tissue in preeclamptic rats.

Short-Term Therapy with Rosiglitazone, a PPAR-𝜸 Agonist, Improves Metabolic Profile and Vascular Function in Nonobese Lean Wistar Rats

Mohammad M. Naderali, Imose Itua, Abdul-Razak Abubakari, and Ebrahim K. Naderali — Tue, 21 Aug 2012 16:06:43 +0000

A number of preclinical and clinical studies have reported blood-pressure-lowering benefits of thiazolidinediones in diabetic subjects and animal models of diabetes. This study was designed to further elucidate vascular effects of rosiglitazone, on healthy nonobese, lean animals. Adult male Wistar rats were randomized and assigned to control and rosiglitazone-treated groups and were dosed daily with either vehicle or rosiglitazone (10 mg kg−1 day−1) by oral gavage for 5 days. Compared with control group, rosiglitazone treatment significantly reduced plasma levels of triglycerides (>240%) and nonesterified free fatty acids (>268%) (both, 𝑃<0.001). There were no changes in vascular contractility to KCl or noradrenaline between two groups. However, rosiglitazone therapy improved carbamylcholine-induced vasorelaxation (93±3 % versus control 78±2, 𝑃<0.01) an effect which was abolished by L-NAME. There was no difference in sodium nitroprusside-induced vasorelaxation between the control and rosiglitazone-treated animals. These results indicate that short-term rosiglitazone therapy improves both metabolic profile and vascular function in lean rats. The vascular effect of rosiglitazone appears to be mediated by alteration in NO production possibly by activation of endothelial PPARγ. This increased NO production together with improved lipid profile may explain mechanism(s) of blood-pressure-lowering effects of thiazolidinediones on both human and experimental animals.

Menadione : Sodium Orthovanadate Combination Eliminates and Inhibits Migration of Detached Cancer Cells

Zahid M. Delwar, Åke Siden, Mabel H. Cruz, and Juan S. Yakisich — Fri, 17 Aug 2012 13:24:31 +0000

Exposure of cancer cells to anticancer agents in cultures induces detachment of cells that are usually considered dead. These drug-induced detached cells (D-IDCs) may represent a clinical problem for chemotherapy since they may survive anoikis, enter the circulation, invade other tissues and resume proliferation, creating a metastasis, especially in tissues where the bioavailability of anticancer agents is not enough to eliminate all cancer cells. In this study we evaluated the antiproliferative effect of menadione : sodium orthovanadate (M : SO) combination on A549 lung cancer cells as well as the ability of M : SO to induce cell detachment. In addition, we followed the fate and chemosensitivity of M : SO-induced detached cells. Using transwell chambers, we found that a fraction of the M : SO-induced detached cells were viable and, furthermore, were able to migrate, re-attach, and resume proliferation when re-incubated in drug-free media. The total elimination of A549 detachment-resistant cells and M : SO-induced detached cells were successfully eliminated by equivalent M : SO concentration (17.5 μM : 17.5 μM). Thus, M : SO prevented cell migration. Similar results were obtained on DBTRG.05MG human glioma cells. Our data guarantee further studies to evaluate the in vivo occurrence of D-IDCs, their implications for invasiveness and metastasis and their sensitivity to anticancer drugs.

Pharmacological Evaluation and Docking Studies of 3-Thiadiazolyl- and Thioxo-1,2,4-triazolylcoumarin Derivatives as Cholinesterase Inhibitors

Thu, 16 Aug 2012 10:46:38 +0000

Inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is considered a promising strategy for the treatment of Alzheimer’s disease (AD). This research project aims to provide a comprehensive knowledge of newly synthesized coumarin analogues with anti-AD potential. In the present work a series of 3-thiadiazolyl- and thioxo-1,2,4-triazolylcoumarins derivatives were designed, synthesized, and tested as potent inhibitors of cholinesterases. These compounds were assayed against AChE from electrophorus electricus and rabbit; and BChE from horse serum and rabbit by Ellman’s method using neostigmine methylsulphate and donepezil as reference drugs. Some of the assayed compounds proved to be potent inhibitors of AChE and BChE with 𝐾𝑖 values in the micromolar range. 4b was found to be the most active compound with 𝐾𝑖 value 0.028±0.002 μM and higher selectivity for AChE/BChE. The ability of 4b to interact with AChE was further confirmed through computational studies, in which a primary binding was proved to occur at the active gorge site, and a secondary binding was revealed at the peripheral anionic site. Structure activity relationships of prepared compounds were also discussed.

Synthesis, Urease Inhibition, Antioxidant, Antibacterial, and Molecular Docking Studies of 1,3,4-Oxadiazole Derivatives

Mon, 13 Aug 2012 10:28:18 +0000

A series of eighteen 1,3,4-oxadiazole derivatives have been synthesized by treating aromatic acid hydrazides with carbon disulfide in ethanolic potassium hydroxide yielding potassium salts of 1,3,4-oxadiazoles. Upon neutralization with 1 N hydrochloric acid yielded crude crystals of 1,3,4-oxadiazoles, which were purified by recrystallization in boiling methanol. The synthesized 1,3,4-oxadiazoles derivatives were evaluated in vitro for their urease inhibitory activities, most of the investigated compounds were potent inhibitors of Jack bean urease. The molecular docking studies were performed by docking them into the crystal structure of Jack bean urease to observe the mode of interaction of synthesized compounds. The synthesized compounds were also tested for antibacterial and antioxidant activities and some derivatives exhibited very promising results.

Designing Paclitaxel Drug Delivery Systems Aimed at Improved Patient Outcomes: Current Status and Challenges

Madhu S. Surapaneni, Sudip K. Das, and Nandita G. Das — Sun, 12 Aug 2012 14:06:30 +0000

Paclitaxel is one of the most widely used and effective antineoplastic agents derived from natural sources. It has a wide spectrum of antitumor activity, particularly against ovarian cancer, breast cancer, nonsmall cell lung cancer, head and neck tumors, Kaposi's sarcoma, and urologic malignancies. It is a highly lipophilic compound with a log P value of 3.96 and very poor aqueous solubility of less than 0.01 mg/mL. In addition, the compound lacks functional groups that are ionizable which could potentially lead to an increase in its solubility with the alteration in pH. Therefore, the delivery of paclitaxel is associated with substantial challenges. Until the introduction of Abraxane, only commercial formulation was solution of paclitaxel in cremophor, which caused severe side effects. However, in recent years, a number of approaches have been reported to solubilize paclitaxel using cosolvents and inclusion complexes. In addition, innovative approaches have been reported for passive targeting of tumors using nanoparticles, nanosuspensions, liposomes, emulsions, micelles, implants, pastes and gels. All approaches for delivery of improved therapeutic outcome have been discussed in this paper.

Influence of Alternanthera brasiliana (L.) Kuntze on Altered Antioxidant Enzyme Profile during Cutaneous Wound Healing in Immunocompromised Rats

Thu, 09 Aug 2012 09:42:43 +0000

Alternanthera brasiliana (L.) Kuntze (Amaranthaceae) is a herbaceous plant used against inflammation, cough, and diarrhea in Brazilian popular medicine. In our preliminary study, promising wound healing activity of methanol extract of leaves of A. brasiliana (MEAB) was observed in normal excision and incision wound models. Therefore, the present study was designed to investigate the wound healing activity along with the antioxidant enzyme profile during cutaneous excision immunocompromised wound after topical application of 5% w/w ointment of MEAB in rats. Immunocompromised state was induced by pretreatment with hydrocortisone (HC) at 40 mg/kg body weight (i.m.) in male rats. Following one-week pretreatment with HC, wounds were created. The vehicle, 5% (w/w) ointment of MEAB, or standard drug (Himax) was applied topically twice daily. Healing potential was evaluated by the rate of wound contraction, estimation of enzymatic and nonenzymatic antioxidants like catalase, SOD, GSH, protein, vitamin C, and hydroxyproline content, which was supported by histopathological study on the 8th day following wounding. There was significant increase in the enzymatic and nonenzymatic antioxidant parameters in the extract-reated group as compared to control group. Histopathological study revealed collagen deposition, fibroblast proliferation, angiogenesis, and development of basement membrane in A. brasiliana group. The results of the present investigation revealed significant wound healing activity of MEAB.

A Review of the Ethnobotany and Pharmacological Importance of Alstonia boonei De Wild (Apocynaceae)

Mon, 30 Jul 2012 10:12:45 +0000

Alstonia boonei De Wild is a herbal medicinal plant of West African origin, popularly known as God's tree or “Onyame dua”. Within West Africa, it is considered as sacred in some forest communities; consequently the plant parts are not eaten. The plant parts have been traditionally used for its antimalarial, aphrodisiac, antidiabetic, antimicrobial, and antipyretic activities, which have also been proved scientifically. The plant parts are rich in various bioactive compounds such as echitamidine, Nα-formylechitamidine, boonein, loganin, lupeol, ursolic acid, and β-amyrin among which the alkaloids and triterpenoids form a major portion. The present paper aims at investigating the main research undertaken on the plant in order to provide sufficient baseline information for future work and for commercial exploitation.

Doripenem Dosing Recommendations for Critically Ill Patients Receiving Continuous Renal Replacement Therapy

Thu, 19 Jul 2012 15:13:02 +0000

Doripenem dosing regimens for patients receiving continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodiafiltration (CVVHDF) were devised based on an established efficacy criterion (free plasma doripenem concentrations above the minimum inhibitory concentration [𝑓T>MIC] of 1 mg/L for ≥35% of the dosing interval) while maintaining exposure below that with the highest studied dose of 1000 mg infused over 1 hour every 8 hours in healthy subjects. Simulations were utilized to assure ≥90% probability of achieving the efficacy criterion with the recommended doripenem regimens. Inflated intersubject variability of 40% (coefficient of variation) was used for pharmacokinetic parameters (representative of clinical variation) and nonrenal clearance was doubled to account for potential changes with acute renal insufficiency. Results indicate that a reduction in doripenem dose will be needed for critically ill patients receiving CVVH or CVVHDF. This work was conducted to fulfill a health authority request and resulted in the addition of dosing recommendations to the Doribax Summary of Product Characteristics.

Interaction of Herbs and Glibenclamide: A Review

Amita Rai, Cicy Eapen, and V. G. Prasanth — Sun, 15 Jul 2012 10:15:25 +0000

Herbs and herbal products are considered to be safer and people mix it often with the oral hypoglycemic agent in diabetes therapy. But numerous reports say that every combination of herbs and drugs is not safe. Some combinations may be beneficial and some may be harmful also. So before taking any herbal remedies with oral hypoglycemic agent, patient should consult physician. In this paper we are summarizing the reports available on the interaction of herbal remedies to one of the oral hypoglycemic agents (glibenclamide) and categorizing the effect of the combination is beneficial and harmful.

Antioxidant, Antimicrobial, and Free Radical Scavenging Potential of Aerial Parts of Periploca aphylla and Ricinus communis

Jamshed Iqbal, Sumera Zaib, Umar Farooq, Afsar Khan, Irum Bibi, and Saba Suleman — Wed, 11 Jul 2012 09:22:07 +0000

Context. Many diseases are associated with oxidative stress caused by free radicals. Objective. The present study evaluated the in vitro antioxidant and antibacterial activities of various extracts of aerial parts of Periploca aphylla and Ricinus communis. Materials and Methods. In vitro antioxidant activities of the plant extract were determined by DPPH and NO scavenging method. Superoxide anion radical activity was measured by the reduction of nitro blue tetrazolium as compared with standard antioxidants. Total phenolic contents and antibacterial activities of these plants were determined by gallic acid equivalent (GAE) and serial tube dilution method, respectively. Results. Plants showed significant radical scavenging activity. The results were expressed as IC50. n-Propyl gallate and 3-t-butyl-4-hydroxyanisole were used as standards for antioxidant assay. All the extracts of both plants showed comparable IC50 to those of standards. Plants extract exhibited high phenolic contents and antibacterial activities were comparable with standard drug, Ciprofloxacin. Discussion and Conclusion. The present study provides evidence that Periploca aphylla and Ricinus communis prove to be potent natural antioxidants and could replace synthetic antioxidants. Plants can also be used against pathogenic bacterial strains.