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International Science Index

Commenced in January 1999 Frequency: Monthly Edition: International Abstract Count: 40418

Pharmacological and Pharmaceutical Sciences

In silico and Toxicity Study of the Combination of Roselle (Hibiscus sabdariffa L.) and Garlic (Allium sativum L.) as Antihypertensive Herbs
Hypertension is a disease with a high prevalence in Indonesia. The prevalence of hypertension in Indonesia is based on the Basic Health Research (Riskesdas) in 2013 which amounted to 25.8%. Medicinal plants have been widely used to treat hypertension including roselle (Hibiscus sabdariffa L.) and garlic (Allium sativum L.) by a mechanism as angiotensin converting enzyme (ACE) inhibitor. The purpose of this research is to analyze the in silico (molecular studies) of pharmacological effects and toxicity of roselle (Hibiscus sabdariffa L.) and garlic (Allium sativum L.) as well as a combination of both are used as antihypertensive herbs. The results of study showed that roselle (Hibiscus sabdariffa L.) and garlic (Allium sativum L.) have great potential as antihypertensive herbs based on the affinity and stability of active substances to specific receptor with a much better value than a of antihypertensive drugs (lisinopril). Toxicity values determined by the method of AST, ALT and ALP in which the three values obtained indicate the presence of acute toxic effects that need to be considered in determining the dose of the extract of roselle and garlic as antihypertensives.
Aframomum melegueta Improves Antioxidant Status of Type 2 Diabetes Rats Model
Aframomum melegueta K.Schum commonly known as Grains of Paradise has been a popularly used spice in most of the African food preparation. Available data have shown that ethyl acetate fraction from crude ethanolic extract exhibited α-amylase and α-glucosidase inhibitory actions, improved pancreatic β-cell damage and ameliorated insulin resistance in diabetic rats. Additionally, 6-gingerol, 6-shogaol, 6-paradol and oleanolic acid are shown to be the compounds responsible for the antidiabetic action of A. melegueta. However, detail antioxidant potential of this spice in a diabetic animal model has not yet been reported. Thus, the present study investigates the effect of oral consumption of A. melegueta fruit on the in vivo antioxidant status of type 2 diabetes (T2D) model of rats. T2D was induced in rats by feeding a 10% fructose solution ad libitum for two weeks followed by a single intraperitoneal injection of streptozotocin (40 mg/kg body weight (bw)). The animals were orally administered with 150 (DAML) or 300 mg/kg bw (DAMH) of the fraction once daily for four weeks. Data were analyzed by using a statistical software package (SPSS for Windows, version 22, IBM Corporation, NY, USA) using Tukey’s-HSD multiple range post-hoc test. Values were considered significantly different at p < 0.05. According to the data, after four weeks of intervention, diabetic untreated animals showed significantly (p < 0.05) elevation of blood glucose levels. The levels of thiobarbituric acid reactive substances (TBARS) were observed to increase with concomitant reduction of reduced glutathione (GSH) levels in the serum and organs (liver, kidney, heart and pancreas) of diabetic untreated animals. The activities of endogenous antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, and reductase) were greatly reduced in the serum and organs of diabetic untreated animals compared to the normal animals. These alterations were reverted to near-normal after the treatment of A. melegueta fruit in the treated groups (DAML & DAMH) within the study period, especially at the dose of 300 mg/kg bw. This potent antioxidant action may partly be attributed to the presence of the 6-Gingerol, 6-shogaol and 6-paradol are known to possess antioxidant action. The results of our study showed that A. melegueta intake improved the antioxidant status of T2D rats and therefore could be used to ameliorate the diabetes-induced oxidative damage.
Quantification of Plasma Angiotensinogen Redox Forms in a Case-Control Study of Pre-Eclampsia Using Targeted LC-MS/MS
Angiotensinogen (AGT) is a critical protein in the renin-angiotensin system and has an important role in the pathogenesis of pre-eclampsia. The disulphide linkage between cysteine (Cys) 18 and 138 has a key role in the redox switch of AGT that modulates the release of angiotensin I, and hence production of angiotensin II, with consequential effects on blood pressure. An increased percentage of the oxidised form of AGT is present in the plasma of preeclamptic women. Currently, there is no quantitative targeted Liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach to detect and quantify the sulphydryl-bridged (oxidised) and the free thiol (reduced) forms of AGT in human plasma. The aim of the study was to quantify the level of total AGT and the percentage of AGT oxidation in the plasma of pre-eclamptic women (n=17), normotensive matched pregnant controls (n=17), and healthy non-pregnant women (n=10) using a differential alkylation approach coupled with the targeted LC-MS/MS method. Plasma glycoproteins were enriched via ConA Sepharose followed by fractionation by reversed-phase solid phase extraction (RP-SPE). The dried, collected fraction, containing the highest % of AGT, was deglycosylated with PNGase F followed by alkylation of the protein reduced form with iodoacetamide. The oxidised form of the protein was reduced first; then the free thiol was blocked with ¹³C₂, D₂-iodoacetamide and digestion was carried out using chymotrypsin. Targeted LC-MS/MS method was used to quantify the total and the oxidation plasma levels of AGT-based on the quantification of the marker AGT and Cys18 peptides respectively. The study revealed a significant increase in the level of AGT (~3.5 fold) in the maternal circulation compared to non-pregnant women and showed that patients with pre-eclampsia had significantly higher plasma level of oxidised AGT (70 ± 4.8) compared to matched normotensive pregnant controls (65.3 ± 3.6, P=0.008), whilst maintaining a similar total AGT level in the plasma. This provides further evidence that the conversion of the reduced form to its more active oxidised form might be a contributing factor to the hypertension characteristic of pre-eclampsia. The findings of this study confirm the previous two reports that linked the AGT redox switch with the pathogenesis of pre-eclampsia and provide an extra line of evidence linking the oxidative state and the generation of reactive oxygen species in the placenta with hypertension in pregnancy that leads on to the development of pre-eclampsia.
Branched Chain Amino Acid Kinesio PVP Gel Tape from Extract of Pea (Pisum sativum L.) Based on Ultrasound-Assisted Extraction Technology
Modern sports competition as a consequence of the increase in the value of the business and entertainment in the field of sport has been demanding athletes to always have excellent physical endurance performance. Physical exercise is done in a long time, and intensive may pose a risk of muscle tissue damage caused by the increase of the enzyme creatine kinase. Branched Chain Amino Acids (BCAA) is an essential amino acid that is composed of leucine, isoleucine, and valine which serves to maintain muscle tissue, keeping the immune system, and prevent further loss of coordination and muscle pain. Pea (Pisum sativum L.) is a kind of leguminous plants that are rich in Branched Chain Amino Acids (BCAA) where every one gram of protein pea contains 82.7 mg of leucine; 56.3 mg isoleucine; and 56.0 mg of valine. This research aims to develop Branched Chain Amino Acids (BCAA) from pea extract is applied in dosage forms Gel PVP Kinesio Tape technology using Ultrasound-assisted Extraction. The method used in the writing of this paper is the Cochrane Collaboration Review that includes literature studies, testing the quality of the study, the characteristics of the data collection, analysis, interpretation of results, and clinical trials as well as recommendations for further research. Extraction of BCAA in pea done using ultrasound-assisted extraction technology with optimization variables includes the type of solvent extraction (NaOH 0.1%), temperature (20-250C), time (15-30 minutes) power (80 watt) and ultrasonic frequency (35 KHz). The advantages of this extraction method are the level of penetration of the solvent into the membrane of the cell is high and can increase the transfer period so that the BCAA substance separation process more efficient. BCAA extraction results are then applied to the polymer PVP (Polyvinylpyrrolidone) Gel powder composed of PVP K30 and K100 HPMC dissolved in 10 mL of water-methanol (1: 1) v / v. Preparations Kinesio Tape Gel PVP is the BCAA in the gel are absorbed into the muscle tissue, and joints through tensile force then provides stimulation to the muscle circulation with variable pressure so that the muscle can increase the biomechanical movement and prevent damage to the muscle enzyme creatine kinase. Analysis and evaluation of test preparation include interaction, thickness, weight uniformity, humidity, water vapor permeability, the levels of the active substance, content uniformity, percentage elongation, stability testing, release profile, permeation in vitro and in vivo skin irritation testing.
An in vivo Study on the Sensitivity Pattern of Plasmodium bergei to Stem Bark Extract of Echinaceae angustifolia DC
The methanol extract of E. angustifolia DC was screened for the presence of secondary metabolites and was earlier tested for the median lethal dose LD50 using Swiss albino mice to ascertain the in vivo acute toxicity and hence the practically safe dose to be used in a three model antimalarial investigation. The result of the phytochemical screening indicated the presence of alkaloids, terpenes, tannins, flavonoids, saponins and anthraquinones. The extract was found to be very toxic to the mice, which guided our choice for practically safe dose in the three models of the antimalarial evaluations. The result of the suppressive test showed a significant % suppression compared to the control with values of 57.92%, 66.62%, and 75.62% for the doses 100mg/kg, 150mg/kg, and 250mg/kg respectively. The result of the prophylactic (residual malaria infection) tests showed a significant level of inhibition compared to the control for the three doses. The curative (established malaria infection) tests also showed a significant level of parasite suppression compared to the control with % parasitemia of 0.13 ± 0.07, 0.12 ± 0.06, and 0.07 ± 0.04 for the doses 100, 150, and 250mg/kg respectively. The result justified the use of E. angustifolia DC as remedy to malaria infection by the traditional medicine practitioners in North-Eastern Nigeria.
Silymarin Loaded Mesoporous Silica Nanoparticles: Preparation, Optimization, Pharmacodynamic And Oral Multi-dose Safety Assessment
The present work aimed to prepare Silymarin loaded MCM-41 type mesoporous silica nanoparticles (MSNs) and to assess the system’s solubility enhancement ability on the pharmacodynamic performance of Silymarin as a hepatoprotective agent. MSNs prepared by soft-templating technique, were loaded with Silymarin, characterized for particle size, zeta potential, surface properties, DSC and XRPD. DSC and specific surface area data confirmed deposition of Silymarin in an amorphous state in MSNs’ pores. In-vitro drug dissolution testing displayed enhanced dissolution rate of Silymarin upon loading on MSNs. High dose Acetaminophen was then used to inflict hepatic injury upon albino male Wistar rats simultaneously receiving either free Silymarin, Silymarin loaded MSNs or blank MSNs. Plasma AST, ALT, albumin and total protein and liver homogenate content of TBARs or LDH as measures of antioxidant drug action were assessed for all animal groups. Results showed a significant superiority of Silymarin loaded MSNs to free drug in almost all parameters. Meanwhile prolonged administration of blank MSNs had no evident toxicity on rats.
Anti-Inflammatory Effect of Carvedilol 1% Ointment in Topical Application to the Animal Model
Inflammation is the body's response to impaired homeostasis caused by infection, injury or trauma resulting in systemic and local effects. Inflammation causes the body's response to injury and is characterized by a series of events including inflammatory response, response to pain receptors and the recovery process. Inflammation can be acute and chronic. The inflammatory response is described in three different phases. Free radical is an atom or molecule that has the unpaired electron and is therefore generally very reactive chemical species. Biologically important example of reaction with free radicals is called Lipid peroxidation (LP). Lipid peroxidation reactions occur in biological membranes, and if at the outset is not stopped with the action of antioxidants, it will bring damage to the membrane, which results in partial or complete loss of their physiological functions. Calcium antagonists and beta-adrenergic receptor antagonists are known drugs, and for many years and widely used in the treatment of cardiovascular diseases. Some of these compounds also show antioxidant activity. The mechanism of antioxidant activities of calcium antagonists and beta-blockers is unknown, since their structure varies widely. This research investigated the possible local anti-inflammatory activity of ointments containing 1% carvedilol in the white petrolatum USP. Ear inflammation was induced by 3% croton oil acetone solution, in quantity of 10 µl on both mouse ears. Albino Swiss mouse (n = 8) are treated with 2.5 mg/ear ointment, and control group was treated on the same way as previous with hydrocortisone 1% ointment (2.5 mg/ear). The other ear of the same animal was used as control one. Ointments were administered once per day, on the left ear. After treatment, ears were observed for three days. After three days, we measured mass (mg) of 6 mm ear punch of treated and controlled ears. The results of testing anti-inflammatory effects of ointments with carvedilol in the mouse ear model show stronger observed effect than ointment with 1% hydrocortisone in the same basis. Identical results were confirmed by the difference between the mass of 6 mm ears punch. The results were also confirmed by histological examination. Ointments with carvedilol showed significant reduction of the inflammation process caused by croton oil on the mouse inflammation model.
Synthesis and Antimicrobial Activity of Tolyloxy Derived Oxadiazoles
m-Cresol and oxadiazoles are the potent antimicrobial moieties. 2-(m-Tolyloxy)acetohydrazide (1) on cyclization with aromatic acids yielded 2-(aryl)-5-(m-tolyloxymethyl)-1,3,4-oxadiazole (1A-E). The structures of newer oxadiazoles were confirmed by elemental and spectral analysis. The newer compounds were evaluated for their antimicrobial potential. The compound 1E containing strong electron withdrawing group showed maximum antimicrobial potential. Other compounds also displayed antimicrobial potential to certain extent. The SAR of newer oxadiazoles indicated that substitution of strong electronegative group in the tolyloxy derived oxadiazoles enhanced their antimicrobial potential.
Discerning of Antimicrobial Potential of Phenylpropanoic Acid Derived Oxadiazoles
2-Phenyl propionic acid and oxadiazoles possess antimicrobial potential. 2-Phenyl propane hydrazide (1), on cyclization with aromatic acids offered 2-aryl-5-(1-phenylethyl)-1,3,4-oxadiazole derivatives (1A-E). The PPA derived oxadiazoles were characterized by elemental analysis and spectral studies. The compounds were screened for antimicrobial potential. The compound 1D bearing strong electron withdrawing group showed maximum antimicrobial potential. Other compounds also displayed antimicrobial potential to a certain extent. The SAR of newer oxadiazoles indicated that substitution of strong electronegative group in the PPA derived oxadiazoles enhanced their antimicrobial potential.
Comparison of the Isolation Rates and Characteristics of Salmonella Isolated from Antibiotic-Free and Conventional Chicken Meat Samples
Salmonella contamination in chicken samples can cause major health problems in humans. However, not only the effects of antibiotic treatment during growth but also the impacts of poultry slaughter line on the prevalence of Salmonella in final chicken meat sold to consumers are unknown. In this study, we compared the isolation rates and antimicrobial resistance of Salmonella between antibiotic-free, conventional, conventional Korean native retail chicken meat samples and clonal divergence of Salmonella isolates by multilocus sequence typing. In addition, the distribution of extended-spectrum β-lactamase (ESBL) genes in ESBL-producing Salmonella isolates was analyzed. A total of 72 retail chicken meat samples (n = 24 antibiotic-free broiler [AFB] chickens, n = 24 conventional broiler [CB] chickens, and n = 24 conventional Korean native [CK] chickens) were collected from local retail markets in Seoul, South Korea. The isolation rates of Salmonella were 66.6% in AFB chickens, 45.8% in CB chickens, and 25% in CK chickens. By analyzing the minimum inhibitory concentrations of β -lactam antibiotics with the disc-diffusion test, we found that 81.2% of Salmonella isolates from AFB chickens, 63.6% of isolates from CB chickens, and 50% of isolates from CK chickens were ESBL producers; all ESBL-positive isolates had the CTX-M-15 genotype. Interestingly, all ESBL-producing Salmonella were revealed as ST16 by multilocus sequence typing. In addition, all CTX-M-15-positive isolates had the genetic platform of blaCTX-M gene (IS26-ISEcp1-blaCTX-M-15-IS903), to the best of our knowledge, this is the first report in Salmonella around the world. The Salmonella ST33 strain (S. Hadar) isolated in this study has never been reported in South Korea. In conclusion, our findings showed that antibiotic-free retail chicken meat products were also largely contaminated with ESBL-producing Salmonella and that their ESBL genes and genetic platforms were the same as those isolated from conventional retail chicken meat products.
Stenotrophomonas maltophilia: The Major Carbapenem Resistance Bacteria from Waste Water Treatment Plant of Pig Farm
Stenotrophomonas maltophilia is one of the emerging opportunistic pathogens, and also known to have extensive drug resistance intrinsically including carbepenems which is last resort for most serious infections. One possible way for S. maltophilia to infect human is via wastewater treatment plant (WWTP). In the period between October 2016 and February 2017, effluent samples of WWTP from 3 different pig farms were collected once a month and screened for isolation of S. maltophilia. Total 16 strains of S. maltophilia were isolated and, the antibiotic susceptibility phenotypes were determined by Vitek 2 system for 16 antibiotics, ampicillin (AMP), amoxicillin/clavulanic acid (AMC), piperacillin/tazobactam (TZP), cefazolin (CZ), cefoxitin (FOX), cefotaxime (CTX), ceftazidime (CAZ), cefepime (FEP), aztreonam (AZT), ertapenem (ETP), imipenem (IMP), amikacin (AK), gentamicin (GN), ciprofloxacin (CIP), tigecycline (TGC) and trimethoprim/sulfamethoxazole (SXT). All isolates showed high resistance to AMP (100%), CZ (100%), FOX (100%), CTX (100%), CAZ (100%), FEP (94%), AZT (100%), ETP (100%), IMP (100%), AK (100%), GN (100%) whereas were susceptible to CIP (0%), TGC (0%), SXT (6%). All strains harbored at least one of the antibiotic resistance determinant such as spgM, rmlA, and rpfF. Some isolates had similar MLST (multilocus sequence typing) types with clinical isolates, suggesting WWTP could have potential role in the transmission of S. maltophilia to aquatic environment and, possibly, to humans.
Development and Validation Method for Quantitative Determination of Rifampicin in Human Plasma and Its Application in Bioequivalence Test
Rifampicin is a semisynthetic antibiotic derivative of rifamycin B produced by Streptomyces mediterranei. RIF has been used worldwide as first line drug-prescribed throughout tuberculosis therapy. This study aims to develop and to validate an HPLC method couple with a UV detection for determination of rifampicin in spiked human plasma and its application for bioequivalence study. The chromatographic separation was achieved on an RP-C18 column (LachromHitachi, 250 x 4.6 mm., 5μm), utilizing a mobile phase of phosphate buffer/acetonitrile (55:45, v/v, pH 6.8 ± 0.1) at a flow of 1.5 mL/min. Detection was carried out at 337 nm by using spectrophotometer. The developed method was statistically validated for the linearity, accuracy, limit of detection, limit of quantitation, precise and specifity. The specifity of the method was ascertained by comparing chromatograms of blank plasma and plasma containing rifampicin; the matrix and rifampicin were well separated. The limit of detection and limit of quantification were 0.7 µg/mL and 2.3 µg/mL, respectively. The regression curve of standard was linear (r > 0.999) over a range concentration of 20.0 – 100.0 µg/mL. The mean recovery of the method was 96.68 ± 8.06 %. Both intraday and interday precision data showed reproducibility (R.S.D. 2.98% and 1.13 %, respectively). Therefore, the method can be used for routine analysis of rifampicin in human plasma and in bioequivalence study. The validated method was successfully applied in pharmacokinetic and bioequivalence study of rifampicin tablet in a limited number of subjects (under an Ethical Clearance No. KE/FK/6201/EC/2015). The mean values of Cmax, Tmax, AUC(0-24) and AUC(o-∞) for the test formulation of rifampicin were 5.81 ± 0.88 µg/mL, 1.25 hour, 29.16 ± 4.05 µg/mL. h. and 29.41 ± 4.07 µg/mL. h., respectively. Meanwhile for the reference formulation, the values were 5.04 ± 0.54 µg/mL, 1.31 hour, 27.20 ± 3.98 µg/mL.h. and 27.49 ± 4.01 µg/mL.h. From bioequivalence study, the 90% CIs for the test formulation/reference formulation ratio for the logarithmic transformations of Cmax and AUC(0-24) were 97.96-129.48% and 99.13-120.02%, respectively. According to the bioequivamence test guidelines of the European Commission-European Medicines Agency, it can be concluded that the test formulation of rifampicin is bioequivalence with the reference formulation.
The Influence of Polysaccharide Isolated from Morinda Citrifolia Fruit to the Growth of Vero, He-La and T47D Cell Lines against Doxorubicin in vitro
Background: Doxorubicin is widely used as a chemotherapeutic drug despite having many side effects. It may cause macrophage dysfunction and decreasing proliferation of lymphocyte. Noni (Morinda citrifolia) fruit which has rich of polysaccharide content has potential as antitumor and immunostimulant effect. The isolation of polysaccharide from Noni fruit has been optimized according to four different methods based on macrophage and lymphocyte activities. We found the highest polysaccharide content from one of the four methods isolation. A method of polysaccharide isolation which has the highest immunostimulant effect was used for further observation as co-chemotherapy. The aim of the study: was to evaluate the isolated polysaccharide from the method of choice as co-chemotherapy of doxorubicin for the growth of Vero, He-La, and T47D cell lines in vitro. The method: in vitro growth assay of Vero, He-La, and T47D cell lines was done using MTT-reduction method, and apoptosis test was done by double staining method to evaluate the induction apoptotic effect of the combination. Every group was treated with doxorubicin and isolated polysaccharide from method of choice with 4 variances of concentrations (25 µg/ml, 50 µg/ml, 100 µg/ml and 200 µg/ml) a long with negative control (doxorubicin only) and normal control (without doxorubicin or polysaccharide administration). Results: The combination of polysaccharide fraction in the concentration of 100μg/ml with 2μmol of doxorubicin against He-La and T47D cell lines influenced the highest cytotoxic effect by suppressing cell viability comparing with doxorubicin only. The combination of polysaccharide fraction in the concentration of 100μg/ml with 2μmol of doxorubicin-induced apoptotic effect the He-La cell line comparing with doxorubicin only. The result of the study: it can be concluded that the combination of polysaccharide fraction and doxorubicin effect more selective toward He-La and T47D cell lines than to Vero cell line. It can be suggested isolated polysaccharide from the method of choice has co-chemotherapy activity against doxorubicin.
Effect of Honey on Rate of Healing of Socket after Tooth Extraction in Rabbits
Background: Honey is the worlds’ oldest known wound dressing. Its wound healing properties are not fully established till today. Concerns about antibiotic resistance, and a renewed interest in natural remedies have prompted the resurgence in the antimicrobial and wound healing properties of Honey. Evidence from animal studies and some trials has suggested that honey may accelerate wound healing in burns, infected wounds and open wounds. None of these reports have documented the effect of honey on the healing of socket after tooth extraction. Therefore, the present experimental study was planned to evaluate the efficacy of honey on the healing of socket after tooth extraction in rabbits. Materials and Methods: An experimental study was conducted in six New Zealand White rabbits. Extraction of first premolar tooth on both sides of the lower jaw was done under anesthesia produced by Ketamine and Xylazine followed by application of honey on one socket (test group) and normal saline (control group) in the opposite socket. The intervention was continued for two more days. On the 7th day, the biopsy was taken from the extraction site, and histopathological examination was done. Student’s t-test was used for comparison between the groups and differences were considered to be statistically significant at p-value less than 0.05. Results: There was a significant difference between control group and test group in terms of fibroblast proliferation (p = 0.0019) and bony trabeculae formation (p=0.0003). Inflammatory cells were also observed in both groups, and it was not significant (p=1.0). Overlying epithelium was hyperplastic in both the groups. Conclusion: The study showed that local application of honey promoted the rapid healing process particularly by increasing fibroblast proliferation and bony trabeculae.
Pharmacokinetic Modeling of Valsartan in Dog following a Single Oral Administration
Valsartan is a potent and highly selective antagonist of the angiotensin II type 1 receptor, and is widely used for the treatment of hypertension. The aim of this study was to investigate the pharmacokinetic properties of the valsartan in dogs following oral administration of a single dose using quantitative modeling approaches. Forty beagle dogs were randomly divided into two group. Group A (n=20) was administered a single oral dose of valsartan 80 mg (Diovan® 80 mg), and group B (n=20) was administered a single oral dose of valsartan 160 mg (Diovan® 160 mg) in the morning after an overnight fast. Blood samples were collected into heparinized tubes before and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 and 24 h following oral administration. The plasma concentrations of the valsartan were determined using LC-MS/MS. Non-compartmental pharmacokinetic analyses were performed using WinNonlin Standard Edition software, and modeling approaches were performed using maximum-likelihood estimation via the expectation maximization (MLEM) algorithm with sampling using ADAPT 5 software. After a single dose of valsartan 80 mg, the mean value of maximum concentration (Cmax) was 2.68 ± 1.17 μg/mL at 1.83 ± 1.27 h. The area under the plasma concentration-versus-time curve from time zero to the last measurable concentration (AUC24h) value was 13.21 ± 6.88 μg·h/mL. After dosing with valsartan 160 mg, the mean Cmax was 4.13 ± 1.49 μg/mL at 1.80 ± 1.53 h, the AUC24h was 26.02 ± 12.07 μg·h/mL. The Cmax and AUC values increased in proportion to the increment in valsartan dose, while the pharmacokinetic parameters of elimination rate constant, half-life, apparent of total clearance, and apparent of volume of distribution were not significantly different between the doses. Valsartan pharmacokinetic analysis fits a one-compartment model with first-order absorption and elimination following a single dose of valsartan 80 mg and 160 mg. In addition, high inter-individual variability was identified in the absorption rate constant. In conclusion, valsartan displays the dose-dependent pharmacokinetics in dogs, and Subsequent quantitative modeling approaches provided detailed pharmacokinetic information of valsartan. The current findings provide useful information in dogs that will aid future development of improved formulations or fixed-dose combinations.
Ph-Triggered Cationic Solid Lipid Nanoparticles Mitigated Colitis in Mice
In this study, we hypothesized that prolonged gastrointestinal transit at the inflamed colon conferred by a pH-triggered mucoadhesive smart nanoparticulate drug delivery system aids in achieving selective and sustained levels of the drug within the inflamed colon for the treatment of ulcerative colitis. We developed budesonide-loaded pH-sensitive charge-reversal solid lipid nanoparticles (SLNs) using a hot homogenization method. Polyetylenimine (PEI) was used to render SLNs cationic (PEI-SLNs). Eudragit S100 (ES) was coated on PEI-SLNs for pH-trigger charge-reversal SLNs (ES-PEI-SLNs). Therapeutic potential of the prepared SNLs formulation was evaluated in ulcerative colitis in mice. The transmission electron microscopy, zeta size and zeta potential data showed the successful formation of SLNs formulations. SLNs and PEI-SLNs showed burst drug release in acidic pH condition mimicking stomach and early small intestine environment which limiting their application as oral delivery systems. However, ES-PEI-SLNs prevented a burst drug release in acidic pH conditions and showed sustained release at a colonic pH. Most importantly, the surface charge of ES-PEI-SLNs switched from negative to positive in colonic conditions by pH-triggered removal of ES coating and accumulated selectively in inflamed colon. Furthermore, a charge reversal ES-PEI-SLNs showed a superior mitigation of dextran sulfate sodium (DSS)-induced acute colitis in mice as compared to SLNs and PEI-SLNs treated groups. Moreover, histopathological analysis of distal colon sections stained with hematoxylin/eosin and E-cadherin immunostaining revealed attenuated inflammation in an ES-PEI-SLNs-treated group. We also found that ES-PEI-SLNs markedly reduced the myeloperoxidase level and expression of TNF-alpha in colon tissue. Our results suggest that the pH-triggered charge reversal SLNs presented in this study would be a promising approach for ulcerative colitis therapy.
Establishment of an Information Platform Increases Spontaneous Reporting of Adverse Drug Reactions
Introduction: The pharmacist is responsible for encouraging adverse drug reaction (ADR) reporting. In a local center in Northern Taiwan, promotion and rewarding of ADR reporting have continued for over six years but failed to bring significant changes. This study aims to find a solution to increase ADR reporting. Research question or hypothesis: We hypothesized that under-reporting is due to the inconvenience of the reporting system. Reports were made conventionally through printed sheets. We proposed that reports made per month will increase if they were computerized. Study design: An ADR reporting platform was established in April 2015, before which was defined as the first stage of this study (January-March, 2015) and after which the second stage. The third stage commenced in November, 2015, after adding a reporting module to physicians prescription system. ADRs could be reported simultaneously when documenting drug allergies. Methods: ADR report rates during the three stages of the study were compared. Effects of the information platform on reporting were also analyzed. Results: During the first stage, the number of ADR reports averaged 6 per month. In the second stage, the number of reports per month averaged 1.86. Introducing the information platform had little effect on the monthly number of ADR reports. The average number of reports each month during the third stage of the study was 11±3.06, with 70.43% made electronically. Reports per month increased significantly after installing the reporting module in November, 2015 (P< 0.001, t-test). In the first two stages, 29.03% of ADR reports were made by physicians, as compared to 70.42% of cases in the third stage of the study. Increased physician reporting possibly account for these differences. Conclusion: Adding a reporting module to the prescription system significantly increased ADR reporting. Improved accessibility is likely the cause. The addition of similar modules to computer systems of other healthcare professions may be considered to encourage spontaneous ADR reporting.
Synthesis and Biological Evaluation of Some Benzoxazole Derivatives as Inhibitors of Acetylcholinesterase / Butyrylcholinesterase and Tyrosinase
Alzheimer’s disease (AD), a neurodegenerative disorder characterized by a progressive deterioration of memory and cognition, occurs more frequently in elderly people. Current treatment approaches in this disease with the major therapeutic strategy are based on the AChE and BChE inhibition. On the other hand, tyrosinase inhibition has become a target for the treatment of Parkinson’s disease (PD) since this enzyme may play a role in neuromelanin formation in the human brain and could be critical in the formation of dopamine neurotoxicity associated with neurodegeneration linked to PD. Also benzoxazoles are structural isosteres of natural nucleotides that can interact with biopolymers so that benzoxazoles showed a lot of different biological activities. In this study, a series of 2,5-disubstituted-benzoxazole derivatives were synthesized and were evaluated as possible inhibitors of acetylcholinesterase (AChE) / butyrylcholinesterase (BChE) and tyrosinase. The results demonstrated that the compounds exhibited a weak spectrum of AChE / BChE inhibitory activity ranging between 3.92% - 54.32% except compound 8 which showed no activity against AChE and compound 4 which showed no activity against BChE at the specified molar concentrations. Also, the compounds indicated lower than tyrosinase inhibitory activity of ranging between 8.14% - 22.90% to that of reference (kojic acid).
Optimation of Ethanol Extract of Gotu Kola and Majapahit Composition as Natural Antioxidant Source
The development of natural antioxidants in the Centella asiatica and Majapahit is a great potential. This research has been optimizing the composition of ethanol extract of Centella asiatica and leaves Majapahit as an antioxidants source using measure the free radical scavenging activity of DPPH. The results of the research showed that both the ethanol extract of Centella asiatica and leaves Majapahit has a total content of phenol. It is shown with the ability to reduce reagent Folin Ciocalteu become blue colour. The composition optimization of extract Centella asiatica leaves Majapahit = 30:70 has free radical scavenging activity of DPPH most well compared ethanol extract of Centella asiatica and leaves Majapahit. IC50 values for the composition of ethanol extract of Centella asiatica : leaves Majapahit = 30:70 is 0,103 mg/mL.
Formulation of Sun Screen Cream and Sun Protecting Factor Activity from Standardized–Partition Compound of Mahkota Dewa Leaf, (Phaleria macrocarpa (Scheff.) Boerl.)
Mahkota Dewa contains phalerin which has activity as sun screen. In this study, 13 formulations of cream oil in water (o/w) were prepared and tested for their physical characteristics. The physical characteristics were then used for determining the optimum formula. This study aimed to explore the physical stability of optimized formulation of cream, its sun protecting factor (SPF) values using in vitro and in vivo tests. The optimum formula of o/w cream were prepared based on Simplex Lattice Design (LSD) method using software Design Expert®. The formulation of o/w cream were varied based on the proportion of cetyl alcohol, mineral oil and tween 80. The difference of physical characteristic of optimum and predicted formula was tested using t-test with significant level of 95%. The optimum formula of o/w cream was the formula which consists of cetyl alcohol 9.71%, mineral oil, 29%, and tween 80 3.29. Based on t-test, there was no significant difference of physical characteristics of optimum and predicted formulation. Viscosity, spread power, adhesive power, and separation volume ratio of o/w at week 0-4 were relatively stable. The o/w creams were relatively stable at extreme temperature. The o/w creams from mahkota dewa, phalerin, and benzophenone have SPF values of 21.32, 33.12, and 42.49, respectively. The formulas did not irritate the skin based on in vivo test.
Hepatoprotective Assessment of L-Ascorbate 1-(2-Hydroxyethyl)-4,6-Dimethyl-1, 2-Dihydropyrimidine-2-On Exposure to Carbon Tetrachloride
Among hepatic pyrimidine used as a means of stimulating protein synthesis and recovery of liver cells in her damaged toxic and infectious etiology. When an experimental toxic hepatitis hepatoprotective activity detected some pyrimidine derivatives. There are literature data on oksimetiluratcila hepatoprotective effect. For analogs of pyrimidine nucleobases - drugs Methyluracilum pentoxy and hepatoprotective effect of weakly expressed. According to the American scientists broad spectrum of biological activity, including hepatoprotective properties, have a 2,4-dioxo-5-arilidenimino uracils. Influenced Xymedon medicinal preparation (1- (beta-hydroxyethyl) -4,6-dimethyl-1,2-dihydro-2-oksopirimidin) developed as a means of stimulating the regeneration of tissue revealed increased activity of microsomal oxidases human liver. In studies on the model of toxic liver damage in rats have shown hepatoprotective effect xymedon and stimulating its impact on the recovery of the liver tissue. Hepatoprotective properties of the new compound in the series of pyrimidine derivatives L-ascorbate 1-(2-hydroxyethyl)-4,6-dimethyl-1,2-dihydropirimidine-2-one synthesized on the basis Xymedon preparation were firstly investigated on rats under the carbon tetrachloride action. It was shown the differences of biochemical parameters from the reference value and severity of structural-morphological liver violations decreased in comparison with control group under the influence of the compound injected before exposure carbon tetrachloride. Hepatoprotective properties of the investigated compound were more pronounced in comparison with Xymedon.
Study of Actoprotective Properties of Xymedon and Its Analogs
The effects of the drug xymedon and its six new analogues containing xymedon fragments and biogenic acids, on the physical performance of rats in the test "Swimming to the full". It has been shown that single and multiple doses (21 days) of the studied compounds does not cause a statistically significant effect in this test. In 11-day conditions intraperitoneal administration of pyrimidine derivatives among the studied most pronounced effect aktoprotektornyh has L-ascorbate compound is 1- (2-hydroxyethyl) -4,6-dimethyl-1,2-dihydropyrimidine-2-one, the introduction of which 20 mg/kg caused a statistically significant increase in the duration of swimming of rats on the 14th day of the experiment at 440% compared to the control group. The compound is a conjugate comprising moieties xymedon and ascorbic acid. The introduction of the compound for 11 days under conditions of physical activity does not affect the leucopoiesis but stimulates erythropoiesis, resulting in the increase in the number of erythrocytes and hemoglobin level. The introduction of the substance in a mixed character debilitating stress prevents the reduction of glucose levels, increased levels of urea and lactic acid, which indicates an improvement loads of animals and tolerability of anti-catabolic effect of the compound. The absence of hepato and cardiotoxic effects of the substance.
Design of Experiment for Optimization of Lercanidipine Nanocrystals
Lercanidipine hydrochloride is a calcium channel blockers used for treating angina pectoris and hypertension. Lercanidipine is poorly water soluble drug having BCS Class II. Absolute bioavailability of Lercanidipine is very low and the main reason ascribed for this is poor aqueous solubility of the drug. Design and formulatation of nanocrystals by media milling method was the main focus of this study. In this present study preliminary optimization was carried out with one factor at a time (OFAT) approach. For this, different parameters like size of milling beads, amount of zirconium beads, types of stabilizer, concentrations of stabilizer, concentrations of the drug, stirring speeds and milling time were optimized on the basis of particle size, polydispersity index and zeta potential. From the OFAT model different levels for above parameters selected for Plackett - Burman Design (PBD). Plackett - Burman design having 18 runs involving 6 independent variables was carried out at higher and lower level. Based on statistical analysis of PBD it was found that concentration of stabilizer, concentration of drug and stirring speed have significant impact on particle size, PDI, zeta potential value and saturation solubility. These experimental designs for preparation of nanocrystals were applied successfully which shows an increase in aqueous solubility and dissolution rate of Lercanidipine hydrochloride.
Comparative Therapeutic Effect of Acalypha Indica Linn. Extract and Gemfibrozil on High Fructose and Cholesterol Diet Induced Pancreas Steatosis in Sprague-Dawley Mice
Sedentary lifestyle and imbalance consumption pattern has made metabolic syndrome as the global time bomb phenomenon in the world. The increasing tendency of people in consuming high amount of fructose and cholesterol food has worsened this issue in the society. Pancreas steatosis become one of the most comorbid when early diagnosis and prompt treatment has not been applied on hyperglycemic and hyperlipidemic condition in metabolic syndrome patient. Gemfibrozil become the drug of choice to prevent this issue, yet the efficacy of this regiment was still questionable. Acalypha indica Linn. is the herb that has protective effect on hyperlipidemic and hyperglycemic condition. This study was aimed to compare therapeutic effect of gemfibrozil (G) and Acalypha indica Linn. (AI) on high fructose and cholesterol diet-induced pancreas steatosis in Sprague-Dawley mice. The post induction mice were divided into four groups: control, gemfibrozil, AI extract, and G+AI combination regiment. Each group received four weeks intervention. The result of statistical analysis using the One-Way ANOVA test and Tukey Post Hoc test showed significant decrease in pancreatic steatosis between the control group and administered Acalypha indica group (p = 0.004, 95% CI: 0.170-0.959) and the group administered with a combination of Gemfibrozil-Acalypha indica (p = 0.023, 95% CI: 0.537-0.813). The protective effect of Acalypha indica Linn. shows that this plant has the potential as therapeutic option in overcoming the condition of pancreas steatosis in metabolic syndrome.
Patient Support Program in Pharmacovigilance: Foster Patient Confidence and Compliance
The Pharmaceutical companies are getting more inclined towards Patient support programmes (PSPs), which assists patients and /or Healthcare professionals (HCPs) in more desirable disease management and cost-effective treatment. The utmost objective of these programmes is patient care. The PSPs may include financial assistance to patients, medicine compliance programmes, access to HCPs via phone or online chat centers etc. The PSP has a crucial role in terms of customer acquisition and retention strategies. During the conduct of these programmes, Marketing Authorisation Holder (MAH) may receive information related to concerned medicinal products, which is usually reported by patients or involved HCPs. This information may include suspected adverse reaction(s) while/after administration of medicinal products. Hence, the MAH should design PSP to comply with regulatory reporting requirements and avoid non-compliance during PV inspection. The emergence of wireless health devices is lowering the burden on patients to manually incorporate safety data, and building a significant option for patients to observe major swings in reference to drug safety. Therefore, to enhance the adoption of these programmes, MAH not only needs to aware patients about advantages of the program, but also recognizes the importance of time of patients and commitments made in a constructive manner. It is indispensable that strengthening the public health is considered as the topmost priority in such programmes and the MAH is compliant to Pharmacovigilance (PV) requirements along with regulatory obligations.
Psychometric Properties of the Eq-5d-3l and Eq-5d-5l Instruments for Health Related Quality of Life Measurement in Indonesian Population
Cost utility analysis is the most recommended pharmacoeconomic method since it allows widely comparison of cost-effectiveness results from different interventions. The method uses outcome of quality-adjusted life year (QALY) or disability-adjusted life year (DALY). Measurement of QALY requires the data of utility dan life years gained. Utility is measured with the instrument for quality of life measurement such as EQ-5D. Recently, the EQ-5D is available in two versions which are EQ-5D-3L and EQ-5D-5L. This study aimed to compare the EQ-5D-3L and EQ-5D-5L to examine the most suitable version for Indonesian population. This study was an observational study employing cross sectional approach. Data of quality of life measured with EQ-5D-3L and EQ-5D-5L were collected from several groups of population which were respondent with chronic diseases, respondent with acute diseases, and respondent from general population (without illness) in Yogyakarta Municipality, Indonesia. Convenience samples of hypertension patients (83), diabetes mellitus patients (80), and osteoarthritis patients (47), acute respiratory tract infection (81), cephalgia (43), dyspepsia (42), and respondent from general population (293) were recruited in this study. Responses on the 3L and 5L versions of EQ-5D were compared by examining the psychometric properties including agreement, internal consistency, ceiling effect, and convergent validity. Based on psychometric properties tests of EQ-5D-3L dan EQ-5D-5L, EQ-5D-5L tended to have better psychometric properties compared to EQ-5D-3L. Future studies for health related quality of life (HRQOL) measurements for pharmacoeconomic studies in Indonesia should apply EQ-5D-5L.
Cedrela Toona Roxb.: An Exploratory Study Describing Its Antidiabetic Property
Diabetes mellitus is considered to be a serious endocrine syndrome. Synthetic hypoglycemic agents can produce serious side effects including hematological effects, coma, and disturbances of the liver and kidney. In addition, they are not suitable for use during pregnancy. In recent years, there have been relatively few reports of short-term side effects or toxicity due to sulphonylureas. Published figures and frequency of side effects in large series of patient range from about 1 to 5%, with symptoms severe enough to lead to the withdrawal of the drug in less than 1 to 2%. Adverse effects, in general, have been of the following type: allergic skin reactions, gastrointestinal disturbances, blood dyscrasias, hepatic dysfunction, and hypoglycemia. The associated disadvantages with insulin and oral hypoglycemic agents have led to stimulation in the research for locating natural resources showing antidiabetic activity and to explore the possibilities of using traditional medicines with proper chemical and pharmacological profiles. Literature survey reveals that the inhabitants of Abbottabad district of Pakistan use the dried leaf powder along with table salt and water orally for treating diabetes, skin allergy, wounds and as a blood purifier, where they pronounced the plant locally as ‘Nem.' The detailed phytochemical investigation of the Cedrela toona Roxb. leaves for antidiabetic activity has not been documented. Hence, there is a need for phytochemical investigation of the leaves for antidiabetic activity. The collection of fresh leaves and authentification followed by successive extraction, phytochemical screening, and testing of antidiabetic activity. The blood glucose level was reduced maximum in ethanol extract at 5th and 7th h after treatment. Blood glucose was depressed by 8.2% and 10.06% in alloxan – induced diabetic rats after treatment which was comparable to the standard drug, Glibenclamide. This may be due to the activation of the existing pancreatic cells in diabetic rats by the ethanolic extract.
Short-Term versus Long-Term Effect of Waterpipe Smoking Exposure on Cardiovascular Biomarkers in Mice
Introduction: Tobacco use is one of the main risk factors to cardiovascular diseases (CVD) and atherosclerosis in particular. WPS contains several toxic materials such as: nicotine, carcinogens, tar, carbon monoxide and heavy metals. Thus, WPS is considered to be as one of the toxic environmental factors that should be investigated intensively. Therefore, the aim of this study is to investigate the effect of WPS on several cardiovascular biological markers that may cause atherosclerosis in mice. The study also conducted to study the temporal effects of WPS on the atherosclerotic biomarkers upon short (2 weeks) and long-term (8 weeks) exposures. Methods: mice were exposed to WPS and heart homogenates were analyzed to elucidate the effects of WPS on matrix metalloproteinase (MMPs), endothelin-1 (ET-1) and, myeloperoxidase (MPO). Following protein estimation, enzyme-linked immunosorbent assays were done to measure the levels of MMPs (isoforms 1, 3, and 9), MPO, and ET-1 protein expressions. Results: our data showed that acute exposure to WPS significantly enhances the levels of MMP-3, MMP- 9, and MPO expressions (p < 0.05) compared to their corresponding control. However, the body was capable to normalize the level of expressions for such parameters following continuous exposure for 8 weeks (p > 0.05). Additionally, we showed that the level of ET-1 expression was significantly higher upon chronic exposure to WPS compared to both control and acute exposure groups (p < 0.05). Conclusion: Waterpipe exposure has a significant negative effect on atherosclerosis and the enhancement of the atherosclerotic biomarkers expression (MMP-3 and 9, MPO, and ET-1) might represent an early scavenger of compensatory efforts to maintain cardiac function after WP exposure.
Cycas beddomei Dyer: An Endemic and Endangered Indian Medicinal Plant
Herbal medicines are gaining importance due to holistic nature and lesser side effects. Cycas beddomei Dyer is one of the highly exploited medicinal plants in India. Due to over-exploitation of male and female cones, young leaves and starch-bearing pithy stems for edible, medicinal and socio-cultural practices by the locals, tribals and traders, the plant population has drastically declined in its natural habitats. Cycas beddomei is an endemic to India. The current IUCN status of this plant species in the wild is endangered. Perhaps, it is the only species of Cycas enlisted in Appendix I of CITES (Convention on International Trade in Endangered Species of wild fauna and flora). Endorsing the CITES decisions, the Government of India has placed C. beddomei in the “Negative List of Exports” during 1998. Though this plant has been banned legally, but illegally, it is highly exploited by different means. Therefore, conservation of this species is an urgent need of the hour. The present paper highlights unique morphological and anatomical characters of C. beddomei, along with its present status, major threats and conservation measures. Cycas beddomei can easily be identified by some of the distinguishing morphological and anatomical characters, viz., 2–4 mm wide leaflets with revolute margins; the apices of microsporophylls from the middle to apex of the pollen cones turn downwards on maturity; mucilage canal cells are seen in the midrib region of the leaflets; stomatal frequency is about 18 numbers at 250x; pollen grains are monocolpate and their diameter ranging from 22.5 to 30 µm.
Aqueous Extract of Picrorrhiza kurroa Royle ex Benth: A Potent Inhibitor of Human Topoisomerases
Topoisomerase I and II α plays a crucial role in the DNA-maintenance in all living cells, and for this reason, inhibitors of this enzyme have been much studied. In this paper, we have described the inhibitory effect of the aqueous extract of Picrorrhiza kurroa on human topoisomerases by measuring the relaxation of superhelical plasmid pBR322 DNA. The aqueous extract inhibited topoisomerase I and II α in a concentration-dependent manner (Inhibitory concentration (IC) ≈ 25 and 50 µg, respectively). By stabilization studies of topoisomerase I-DNA complex and preincubation studies of topoisomerase I and II α with the extract; we conclude that the possible mechanism of inhibition is both; 1) stabilization of covalent complex of topo I-DNA complex and 2) direct inhibition of the enzyme topoisomerases. These findings might explain the antineoplastic activity of Picrorrhiza kurroa and encourage new studies to elucidate the usefulness of the extract as a potent antineoplastic agent.