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Reference Drug (reference + drug)
Selected AbstractsPrescription Duration After Drug Copay Changes in Older People: Methodological AspectsJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 3 2002Sebastian Schneeweiss MD OBJECTIVES: Impact assessment of drug benefits policies is a growing field of research that is increasingly relevant to healthcare planning for older people. Some cost-containment policies are thought to increase noncompliance. This paper examines mechanisms that can produce spurious reductions in drug utilization measures after drug policy changes when relying on pharmacy dispensing data. Reference pricing, a copayment for expensive medications above a fixed limit, for angiotensin-converting enzyme (ACE) inhibitors in older British Columbia residents, is used as a case example. DESIGN: Time series of 36 months of individual claims data. Longitudinal data analysis, adjusting for autoregressive data. SETTING: Pharmacare, the drug benefits program covering all patients aged 65 and older in the province of British Columbia, Canada. PARTICIPANTS: All noninstitutionalized Pharmacare beneficiaries aged 65 and older who used ACE inhibitors between 1995 and 1997 (N = 119,074). INTERVENTION: The introduction of reference drug pricing for ACE inhibitors for patients aged 65 and older. MEASUREMENTS: Timing and quantity of drug use from a claims database. RESULTS: We observed a transitional sharp decline of 11%± a standard error of 3% (P = .02) in the overall utilization rate of all ACE inhibitors after the policy implementation; five months later, utilization rates had increased, but remained under the predicted prepolicy trend. Coinciding with the sharp decrease, we observed a reduction in prescription duration by 31% in patients switching to no-cost drugs. This reduction may be attributed to increased monitoring for intolerance or treatment failure in switchers, which in turn led to a spurious reduction in total drug utilization. We ruled out the extension of medication use over the prescribed duration through reduced daily doses (prescription stretching) by a quantity-adjusted analysis of prescription duration. CONCLUSION: The analysis of prescription duration after drug policy interventions may provide alternative explanations to apparent short-term reductions in drug utilization and adds important insights to time trend analyses of drug utilization data in the evaluation of drug benefit policy changes. J Am Geriatr Soc 50:521,525, 2002. [source] Modulatory effects of Aloe vera leaf gel extract on oxidative stress in rats treated with streptozotocinJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2005S. Rajasekaran Oxidative stress is currently suggested as a mechanism underlying diabetes and diabetic-related complications. Oxidative stress results from an imbalance between radical-generating and radical-scavenging systems. Many secondary plant metabolites have been reported to possess antioxidant activity. This study was designed to evaluate the potential antioxidative activity of the ethanolic extract from Aloe vera leaf gel in the plasma and pancreas of streptozotocin (STZ)-induced diabetic rats. Glibenclamide was used as a standard reference drug. Oral administration of ethanolic extract at a concentration of 300 mg kg,1 body weight for 21 days resulted in a significant reduction in fasting blood glucose, thiobarbituric acid reactive substances, hydroperoxides and alpha-tocopherol and significant improvement in ascorbic acid, reduced glutathione and insulin in the plasma of diabetic rats. Similarly, the treatment also resulted in a significant reduction in thiobarbituric acid reactive substances, hydroperoxides, superoxide dismutase, catalase and glutathione peroxidase and significant improvement in reduced glutathione in the pancreas of STZ-induced diabetic rats when compared with untreated diabetic rats. The ethanolic extract appeared to be more effective than glibenclamide in controlling oxidative stress. Thus, this study confirms the ethnopharmacological use of Aloe vera in ameliorating the oxidative stress found in diabetes. [source] Antifungal effects of aminosulphoxide and disulphide derivativesMYCOSES, Issue 3 2006Veerle Wittebolle Summary 2-Benzenesulphinyl-(1,4)-naphtoquinone and 14 derivatives were synthesised and were used to evaluate their cytotoxicity against a human myelomonocyte cell line and their antifungal activity against two yeast, i.e. Candida albicans and C. tropicalis and against two filamentous fungi such as Aspergillus niger and Fusarium oxysporum and against one dermatophyte, namely Trichophyton tonsurans. The cytotoxicity and antifungal activities were investigated in comparison with amphotericin B as reference drug. No compound was significantly more toxic than amphotericin B at 0.2 ,g ml,1. The best results of antifungal activity were obtained with GFL 10, GFL 13 and GFL 30 on C. tropicalis, F. oxysporum and T. tonsurans. For C. albicans and A. niger, there was no difference between amphotericin B and the other molecules. The sterol quantitation, the time-kill curves were carried out for these three compounds in order to confirm their action in ergosterol synthesis. Time-kill curves showed a fungistatic activity. For C. tropicalis GFL 10, GFL 13 and GFL 30 increased the growth delay better than amphotericin B, in contrast to F. oxysporum. As for T. tonsurans, GFL10 and GFL13 gave a delay, but the effect of GFL 30 was a bit less marked. [source] Biosimilars: pharmacovigilance and risk management,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 7 2010Leyre Zuñiga Ph.D. Abstract Biosimilars cannot be authorised based on the same requirements that apply to generic medicines. Despite the fact that the biosimilar and reference drug can show similar efficacy, the biosimilar may exhibit different safety profile in terms of nature, seriousness or incidence of adverse reactions. However, the data from pre-authorisation clinical studies normally are insufficient to identify all potential differences. Therefore, clinical safety of similar biological medicinal products must be monitored closely on an ongoing basis during the post-approval phase including continued risk,benefit assessment. The biosimilar applicant must provide the European Medicines Agency (EMEA) with a risk management plan (EU-RMP) and pharmacovigilance programme with its application, including a description of the potential safety issues associated with the similar biological medicinal product that may be a result of differences in the manufacturing process from the reference biologic. The most critical safety concern relating to biopharmaceuticals (including biosimilars) is immunogenicity. Risk management applies scientifically based methodologies to identify, assess, communicate and minimise risk throughout a drug's life cycle so as to establish and maintain a favourable benefit,risk profile in patients. The risk management plan for biosimilars should focus on heightens the pharmacovigilance measures, identify immunogenicity risk and implement special post-marketing surveillance. Although International Nonproprietary Names (INNs) served as a useful tool in worldwide pharmacovigilance, for biologicals they should not be relied upon as the only means of product identification. Biologicals should always be commercialised with a brand name or the INN plus the manufacturer's name. Copyright © 2010 John Wiley & Sons, Ltd. [source] The antidiarrhoeal activity of Alchornea cordifolia leaf extractPHYTOTHERAPY RESEARCH, Issue 11 2004Gabriel A. Agbor Abstract Diarrhoea is a public health problem in developing countries. It is therefore important and useful to identify plants with antidiarrhoeal activity. Alchornea cordifolia is quoted by many traditional healers as a plant with this activity. The antidiarrhoeal activity of its leaf extract was investigated against castor oil induced diarrhoea in mice, using morphine as the standard reference drug. A signi,cant (p < 0.01) dose related (100 mg/kg, 200 mg/kg, 400 mg/kg, 800 mg/kg) antidiarrhoeal activity of A. cordifolia leaf ethanol extract was observed with 800 mg/kg extract being the most effective. It delayed mouse intestinal transit accelerated by castor oil, inhibited the production of diarrhoeal faeces and modi,ed the ,uid and electrolyte transport across the colonic mucosa when administered intraluminally. Phytochemical screening revealed the presence of tannins and ,avonoids which may account for the increased colonic water and electrolyte reabsorption, a mechanism suggested for the antidiarrhoeal activity of A. cordifolia. Copyright © 2004 John Wiley & Sons, Ltd. [source] Design and Synthesis of 2-Phenoxynicotinic Acid Hydrazides as Anti-inflammatory and Analgesic AgentsARCHIV DER PHARMAZIE, Issue 9 2010Alireza Moradi Abstract A series of 2-phenoxynicotinic acid hydrazides were synthesized and evaluated for their analgesic and anti-inflammatory activities. Several compounds having an unsubstituted phenyl/4-pyridyl or C-4 methoxy substituent on the terminal phenyl ring showed moderate to high analgesic or anti-inflammatory activity in comparison to mefenamic acid as the reference drug. The compounds with highest anti-inflammatory activity were subjected to in vitro COX-1/COX-2 inhibition assays and showed moderate to good COX-1 and weak COX-2 inhibition activities. [source] Synthesis and Structure-Activity Relationship Studies of Pyrazole-based Heterocycles as Antitumor AgentsARCHIV DER PHARMAZIE, Issue 7 2010Ahmad M. Farag Abstract Several 4-cyano-1,5-diphenylpyrazoles attached to different heterocyclic ring systems at position 3 were synthesized starting from ethyl 4-cyano-1,5-diphenyl-1H -pyrazole-3-carboxylate 1. The newly synthesized compounds were tested in vivo for their anti-estrogenic effects and evaluated in vitro for their cytotoxic properties against estrogen-dependent tumors. 3-(5-Mercapto-1,3,4-oxadiazole-2-yl)-1,5-diphenyl-1H -pyrazole-4-carbonitrile 13 revealed the highest cytotoxic activity with a GI50 value equal to 40 nM against the IGROVI ovarian tumor cell line. It also showed an anti-estrogen activity 1.6 more effective than the reference drug, in addition to a high tolerable dose. 3-(5-(Methylthio)-4-phenyl-4H -1,2,4-triazol-3-yl)-1,5-diphenyl-1H -pyrazole-4-carbonitrile 7 was found to have the highest anti-estrogenic activity, while 1,5-diphenyl-3-[5-(phenylamino)-1,3,4-thiadiazol-2-yl]-1H -pyrazole-4-carbonitrile 11 showed the lowest activity. The oral LD50 values revealed that most of the tested compounds are relatively nontoxic. [source] Comparison of IY81149 with omeprazole in rat reflux oesophagitisAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 5-6 2000B. J. Kil 1 This study was aimed at evaluating the effects of IY81149{2-[[(4methoxy-3-methyl)-2-pyridinyl]methylsulfinyl]-5-(1H-pyrrol-1-yl)-1H-benzimidazole}, a new proton pump inhibitor, on the development of the surgically induced reflux oesophagitis, on gastric secretion and on lipid peroxidation which is a marker of oxidative stress. Omeprazole was used as a reference drug. We furthermore investigated the influence of quercetin and desferrioxamine (DFO) on the development of the surgically induced reflux oesophagitis in rats on gastric secretion and on lipid peroxidation. 2 IY81149 and omeprazole significantly prevented the development of reflux oesophagitis and gastric secretion in a dose-dependent manner. The ED50 values of IY81149 for inhibition of oesophagitis and volume of gastric secretion were lower than of omeprazole (5.7 vs. 14.2 ,mol, 15.3 vs. 24.0 ,mol, respectively). IY81149 was also more potent in the acid output inhibition with an ED50 of 6.8 ,mol compared with 20.8 ,mol of omeprazole. 3 Malonyldialdehyde (MDA) content, the end product of lipid peroxidation, increased significantly in the oesophageal mucosa after the induction of reflux oesophagitis. IY81149 and omeprazole significantly and dose-dependently prevented lipid peroxidation. Quercetin (200 mg kg,1, p.o.) and DFO (800 mg kg,1, i.d.) significantly prevented the development of reflux oesophagitis and inhibited the lipid peroxidation independent of their actions on gastric secretion. 4 This result suggests that IY81149 is comparable with omeprazole in the treatment of reflux oesophagitis. [source] Anti-Inflammatory and Analgesic Activities of the Aqueous Extract of Acacia karroo Stem Bark in Experimental AnimalsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 5 2008Adeolu A. Adedapo The extract at 100 and 200 mg/kg reduced significantly the formation of oedema induced by carrageenan and histamine. In the acetic acid-induced writhing model, the extract showed a good analgesic effect characterized by a significant reduction in the number of writhes with two doses (100 and 200 mg/kg) used when compared to the untreated control group. In the tail immersion test, the extract at the doses used (100 and 200 mg/kg) increased reaction time to pain after 30 min. of oral administration of the extract. Indomethacin at 10 mg/kg served as reference drug in all these tests. The results gave a scientific basis to the traditional uses of Acacia karroo mainly for wound poultices, eye treatments and cold remedies. [source] Bioanalytical LC-MS/MS method validation for plasma determination of topiramate in healthy Indian volunteersBIOMEDICAL CHROMATOGRAPHY, Issue 11 2009Dipanjan Goswami Abstract A LC-MS/MS method for plasma topiramate analysis is delineated involving least number of healthy volunteers. Topiramate and amlodipine internal standard (IS) were extracted by simple centrifuge-coupled solid-phase extraction and reverse-phase chromatographic separation was performed on an Ascentis C18 column. Turbo-spray negative-ion mode multiple-reaction monitoring was selected for mass pair detection at m/z 338.3 , 78.0 and m/z 407.3 , 295.5 for analyte and IS respectively. The method showed a dynamic linearity range from 10.4 to 2045.0 ng/mL, lower limit of quantitation achieved at 10.4 ng/mL and finally a mass spectrometric total run time of within 2.5 min for human sample analysis. Bioequivalence was assessed successfully using this fully validated method on 16 fasted Indian male subjects with 25 mg topiramate tablet administration. An appropriate study design describes plasma samples collection up to 216 h post dose in two periods, separated by a 28 day washout period. The challenge of half-life matching for test and reference drug was achieved with 73.43 ± 9.68 and 73.06 ± 14.03 h, respectively, and intra-subject coefficient of variation achieved within 11% for AUCs and Cmax evaluated by non-compartmental pharmacokinetic analysis. The results of LCMS topiramate complete method validation supported by pharmacokinetic study have not been published before, and are presented and discussed for the first time in this article. Copyright © 2009 John Wiley & Sons, Ltd. [source] Pharmacokinetics of nifedipine in TaiwaneseBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2004Shu-Chen Chien Abstract To elucidate the pharmacokinetics of nifedipine in Taiwanese, a retrospective review of nifedipine bioequivalence studies completed in Taiwan in the past 5 years was conducted. A total of 198 healthy male volunteers were given a single dose of a 10 mg Adalat® capsule as a reference drug after overnight fasting. Pharmacokinetic parameters derived from Adalat® administration were calculated by non-compartmental analysis with the WinNonlin program. After oral administration of an immediate-release dosage form of a 10 mg nifedipine capsule to Taiwan residents, a skewed distribution with no clear evidence of bimodality of pharmacokinetic parameters was observed. The mean Cmax was 143.12±53.48 ng/ml, the mean AUC was 293.77±115.62 ng·h/ml, the mean T1/2 was 3.08±1.61 h, and the median value of Tmax was 0.61 h. Compared with other published studies, the Cmax and AUC of nifedipine after 10 mg administration were significantly higher in Taiwanese than in British and American subjects. However, the Cmax and AUC were similar to those of Indian and Mexican subjects. According to the antimode of AUC distribution of 22.5 ng·h/ml/mg proposed by Kleinbloesem, 69.7% of Taiwanese can be categorized as slow metabolizers. Based on the results in this study, the majority of Taiwanese show lower activity of nifedipine metabolism. Copyright © 2004 John Wiley & Sons, Ltd. [source] Distinct effects of atypical 1,4-dihydropyridines on 1-methyl-4-phenylpyridinium-induced toxicityCELL BIOCHEMISTRY AND FUNCTION, Issue 1 2007Linda Klimaviciusa Abstract Our previous data obtained from in vivo experiments demonstrated high neuroprotective effects of three novel atypical neuronal non-calcium antagonistic 1,4-dihydropyridine (DHP) derivatives cerebrocrast, glutapyrone and tauropyrone. The present studies were carried out in vitro to clarify, at least in part, their mechanism of action in primary culture of cerebellar granule cells by use of 1-methyl-4-phenylpyridinium (MPP+) as a neurotoxic agent which causes dramatic oxidative stress. Cerebrocrast (highly lipophilic, with a classical two-ring structure) dose-dependently (0.01,10.0,µM, EC50,=,13,nM) reduced MPP+ -induced cell death. At the same time, the calcium antagonist nimodipine (reference drug) protected cell death at much higher concentrations (EC50,=,12.4,µM). Cerebrocrast decreased also the generation of reactive oxygen species and loss of mitochondrial membrane potential. In contrast, low lipophilic amino acid-containing DHPs glutapyrone and tauropyrone (glutamate- and taurine-containing, correspondingly) were without significant effects indicating their distinct mode of action in comparison to cerebrocrast. We have demonstrated for the first time an ability of atypical non-calcium antagonistic DHP cerebrocrast (which has classical DHP structure elements and high lipophilicity) to protect MPP+ -induced deterioration of mitochondrial bioenergetics. One may suggest mitochondria as an essential intracellular target for the neuroprotective action of cerebrocrast and indicate its usefulness in the treatment of Parkinson's disease. Copyright © 2006 John Wiley & Sons, Ltd. [source] Anti-allergic properties of Mangifera indica L. extract (Vimang) and contribution of its glucosylxanthone mangiferinJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2006Dagmar García Rivera Vimang is the brand name of formulations containing an extract of Mangifera indica L., ethnopharmacologically used in Cuba for the treatment of some immunopathological disorders, including bronchial asthma, atopic dermatitis and other allergic diseases. However, the effects of Vimang on allergic response have not been reported until now. In this study, the effects of Vimang and mangiferin, a C-glucosylxanthone isolated from the extract, on different parameters of allergic response are reported. Vimang and mangiferin showed a significant dose-dependent inhibition of IgE production in mice and anaphylaxis reaction in rats, histamine-induced vascular permeability and the histamine release induced by compound 48/80 from rat mast cells, and of lymphocyte proliferative response as evidence of the reduction of the amount of B and T lymphocytes able to contribute to allergic response. In these experiments, ketotifen, promethazine and disodium cromoglicate were used as reference drugs. Furthermore, we demonstrated that Vimang had an effect on an in-vivo model of inflammatory allergy mediated by mast cells. These results constitute the first report of the anti-allergic properties of Vimang on allergic models, as well as suggesting that this natural extract could be successfully used in the treatment of allergic disorders. Mangiferin, the major compound of Vimang, contributes to the anti-allergic effects of the extract. [source] Effects of furocoumarins from Cachrys trifida on some macrophage functionsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2001M. J. Abad Phytochemical and biological studies aimed at the discovery and development of novel antiinflammatory agents from natural sources have been conducted in our laboratory for a number of years. In this communication, three naturally occurring furocoumarins (imperatorin, isoimperatorin and prantschimgin) were evaluated as potential inhibitors of some macrophage functions involved in the inflammatory process. These furocoumarins have been tested in two experimental systems: ionophore-stimulated mouse peritoneal macrophages serve as a source of cyclooxygenase-1 and 5-lipoxygenase, and mouse peritoneal macrophages stimulated with E. coli lipopolysaccharide are the means of testing for anti-cyclooxygenase-2 and nitric-oxide-synthase activity. All above-mentioned furocoumarins showed significant effect on 5-lipoxygenase (leukotriene C4) with IC50 values of < 15 ,M. Imperatorin and isoimperatorin exhibited strong-to-medium inhibition on cyclooxygenase-1- and cyclooxygenase-2-catalysed prostaglandin E2 release, with inhibition percentages similar to those of the reference drugs, indometacin and nimesulide, respectively. Of the three furocoumarins, only imperatorin caused a significant reduction of nitric oxide generation. Imperatorin and isoimperatorin can be classified as dual inhibitors, since it was evident that both cyclooxygenase and lipoxygenase pathways of arachidonate metabolism were inhibited by these compounds. However, selective inhibition of the 5-lipoxygenase pathway is suggested to be the primary target of action of prantschimgin. [source] Isotopic pattern and accurate mass determination in urine drug screening by liquid chromatography/time-of-flight mass spectrometryRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 7 2006Suvi Ojanperä An efficient method was developed for toxicological drug screening in urine by liquid chromatography coupled with electrospray ionization time-of-flight mass spectrometry. The method relies on a large target database of exact monoisotopic masses representing the elemental formulae of reference drugs and their metabolites. Mass spectral identification is based on matching measured accurate mass and isotopic pattern (SigmaFitÔ) of a sample component with those in the database. Data post-processing software was developed for automated reporting of findings in an easily interpretable form. The mean and median of SigmaFitÔ for true-positive findings were 0.0066 and 0.0051, respectively. The mean and median of mass error absolute values for true-positive findings were 2.51 and 2.17,ppm, respectively, corresponding to 0.65 and 0.60,mTh. For routine screening practice, a SigmaFitÔ tolerance of 0.03 and a mass tolerance of 10,ppm were chosen. Ion abundance differences from urine extracts did not affect the accuracy of the automatically acquired SigmaFitÔ or mass values. The results show that isotopic pattern matching by SigmaFitÔ is a powerful means of identification in addition to accurate mass measurement. Copyright © 2006 John Wiley & Sons, Ltd. [source] Conformationally Constrained Analogs of N -Substituted Piperazinylquinolones: Synthesis and Antibacterial Activity of N -(2,3-Dihydro-4-hydroxyimino-4H -1-benzopyran-3-yl)-piperazinylquinolonesARCHIV DER PHARMAZIE, Issue 7 2009Saeed Emami Abstract A series of novel quinolone agents bearing a particular bulky and conformationally constrained bicyclic substituent (2,3-dihydro-4-hydroxyimino-4H -1-benzopyran-3-yl- moiety) on the piperazine ring of 7-piperazinyl quinolones (norfloxacin, enoxacin, ciprofloxacin, and levofloxacin) were synthesized and evaluated against a panel of Gram-positive and Gram-negative bacteria. Among these derivatives, ciprofloxacin counterpart 9c, highly inhibited the tested Gram-positive bacteria, superior to that of the reference drugs, and displayed antibacterial activity at non-cytotoxic concentrations. [source] Antinociceptive effect of a ruthenium complex in miceAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 4 2008M. P. Cristiano Summary 1,The ruthenium complexes are important tools in inorganic chemistry. Different biological properties are found in the presence of distinct coordinate ligands, which offer a variety of potential clinical and pharmacological uses. 2,The aim of this work was to evaluate the antinociceptive and behavioural effects of the ruthenium complex, trans -[RuCl2(i-dinic)4]Cl, in mice. 3,The potential analgesic activity was tested using the formalin and hot plate tests and the behavioural effect was evaluated using the rotarod and spontaneous locomotor tests. The complex was administered at concentrations of 1.3, 4.5 and 18.0 ,mol kg,1 i.p. Morphine (6.0 mg kg,1, i.p.) and diclofenac sodium (20.0 mg kg,1, i.p.) were used as reference drugs. 4,The compound had no sedative activity on motor ataxia in the behavioural and analgesic tests. No significant effect was observed in the first phase of the formalin test, however, an effect was observed in the second phase. 5,The complex studied was probably more powerful than the reference drugs as an antinociceptive agent, as this mechanism also involved the nitric oxide (NO) pathway. From this perspective, further experimental studies will be useful to understand the effect of these compounds on NO and the relationship between prostaglandin and NO biosynthesis. [source] Antinociceptive Activity of a New Benzofuranone Derived from a ChalconeBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2009Pâmela Padaratz The aim of this work was the synthesis of a new benzofuranone compound and evaluation of its antinociceptive potential in mice. The new benzofuranone 4 was synthesized from chalcone 3. The antinociceptive activity of 4 was determined by writhing, formalin, capsaicin, and glutamate and hot-plate tests. Compound 4 caused potent and dose-related inhibition against the writhing test with ID50 6.1 (5.1,7.6) ,mol/kg, i.p., being about 15 times more active than the reference drugs, acetyl salicylic acid and acetaminophen. It was also effective in a dose-dependent manner in significantly reducing the painful stimulus in both phases of formalin, in the capsaicin and in the glutamate test with ID50 values of 27.3 (24.5,30.6) and 18.9 (18.5,19.4) ,mol/kg (first and second phase), 12.6 (9.8,16.2) and 24.5 (20.4,29.6) ,mol/kg respectively. The results showed that the studied compound exhibits both central and peripheral antinociceptive activities and might be further used as a model to obtain new and more potent analgesic drugs. [source] Dog left ventricular midmyocardial myocytes for assessment of drug-induced delayed repolarization: short-term variability and proarrhythmic potentialBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2010Najah Abi-Gerges Background and purpose:, Evaluation of the potential for delayed ventricular repolarization and proarrhythmia by new drugs is essential. We investigated if dog left ventricular midmyocardial myocytes (LVMMs) that can be used as a preclinical model to assess drug effects on action potential duration (APD) and whether in these cells, short-term variability (STV) or triangulation could predict proarrhythmic potential. Experimental approach:, Beagle LVMMs and Purkinje fibres (PFs) were used to record APs. Effects of six reference drugs were assessed on APD at 50% (APD50) and 90% (APD90) of repolarization, STV(APD), triangulation (ratio APD90/APD50) and incidence of early afterdepolarizations (EADs) at 1 and 0.5 Hz. Key results:, LVMMs provided stable recordings of AP, which were not affected by four sequential additions of dimethyl sulphoxide. Effects of dofetilide, d-sotalol, cisapride, pinacidil and diltiazem, but not of terfenadine, on APD in LVMMs were found to be comparable with those recorded in PFs. LVMMs, but not PFs, exhibited a proarrhythmic response to IKr blockers. Incidence of EADs was not related to differences in AP prolongation or triangulation, but corresponded to beat-to-beat variability of repolarization, here quantified as STV of APD. Conclusions and implications:, LVMMs provide a suitable preclinical model to assess the effects of new drugs on APD and also yield additional information about putative indicators of proarrhythmia that add value to an integrated QT/TdP risk assessment. Our findings support the concept that increased STV(APD) may predict drug-induced proarrhythmia. This article is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010 [source] Synthesis, Cruzain Docking, and in,vitro Studies of Aryl-4-Oxothiazolylhydrazones Against Trypanosoma cruziCHEMMEDCHEM, Issue 9 2007Cristina, Lima Leite Prof. Abstract Research in recent years has demonstrated that the Trypanosoma cruzi cysteine protease cruzain (TCC) is a valid chemotherapeutic target. Herein we describe a small library of aryl-4-oxothiazolylhydrazones that have been tested in assays against T.,cruzi cell cultures. The docking studies carried out suggest that these compounds are potential ligands for the TCC enzyme. The most promising compound of this series, N -(4-oxo-5-ethyl-2,-thiazolin-2-yl)- N,-phenylthio-(Z)-ethylidenehydrazone (6,f), was shown to be very active at non-cytotoxic concentrations in in,vitro assays with mammalian cells and has a potency comparable with reference drugs such as nifurtimox (Nfx) and benznidazole (Bdz). [source] | |||||||||||||