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Drug Potency (drug + potency)
Selected AbstractsPharmacodynamic interactions between recombinant mouse interleukin-10 and prednisolone using a mouse endotoxemia modelJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 3 2005Abhijit Chakraborty Abstract The pharmacodynamic interactions between recombinant mouse interleukin-10 (IL-10) and prednisolone were examined in lipopolysaccharide (LPS)-induced experimental endotoxemia in Balb/c mice. Treatment phases consists of single doses of IL-10 (10 ,g/kg i.p.), prednisolone (25 (mg/kg i.p.), IL-10 (2.5 ,g/kg i.p.) with prednisolone (6.25 mg/kg i.p.), or placebo (saline). Measurements included plasma steroid kinetics and IL-10 concentrations and responses to LPS including proinflammatory cytokines (TNF-,, IFN-,) and circulatory NO measured as plasma nitrate/nitrite concentrations. The intraperitoneal dosing of LPS produced large and transient elevations of plasma TNF-,, IFN-,, and NO concentrations. Noncompartmental and model fitting using extended indirect response models based on drug inhibition of multiphase stimulation of biomarkers by LPS were used to describe the in vivo pharmacodynamics and drug interactions. Dosing with prednisolone, IL-10, or their combinations produced strong inhibition of cytokine and NO production. The IC50 values of prednisolone ranged from 54 to 171 ng/mL, and IC50 values for IL-10 ranged from 0.06 to 0.69 ng/mL. The production of NO was described as a cascading consequence of the TNF-, and IFN-, plasma concentrations. The joint dosing of IL-10 with prednisolone produces moderately synergistic immunosuppressive effects in this system. Both drugs were sufficiently protective in suppressing the inflammatory mediators when administered prior to the LPS trigger, while such effects were modest when administered after the inflammatory stimulus was provoked. The integrated and complex pharmacokinetic/pharmacodynamic models well capture the in vivo processes, drug potencies, and interactions of IL-10 and prednisolone. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:590,603, 2005 [source] Dose-response relationship of rocuronium: A comparison of electromyographic vs. acceleromyographic-derived valuesACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 3 2005A. F. Kopman Background: Acceleromyography (AMG) is being employed with increasing frequency as a research tool. However, there is almost no information available regarding the accuracy of values for drug potency obtained using AMG. This study was an attempt to determine if AMG-derived ED50/95 values are interchangeable with those measured with a more traditional neuromuscular monitor. Methods: Thirty adult patients were studied. Anesthesia was induced and maintained with N20, propofol, and supplementation opioid. Tracheal intubation was accomplished without muscle relaxants. Simultaneous ipsilateral AMG and EMG responses to 0.10 Hz stimulation was recorded. Following instrument calibrations, a single dose of rocuronium was administered. The first patient received a bolus of 0.17 mg kg,1 of rocuronium. Using the Hill equation with a postulated slope of 4.50, the ED50 was calculated. The second subject received a dose which approximated the calculated ED50 for patient no. 1. Successive subjects were given a dose based on the running average of the estimated ED50. Results: The AMG-derived ED50/95 values for rocuronium (0.163 ± 0.055 and 0.314 ± 0.105 mg mg,1) were virtually identical to those established using EMG (0.159 ± 0.043 and 0.306 ± 0.084 mg kg,1). While mean peak twitch depression (,T1) was the same in both groups for individual subjects ,T1 differed by ± 20% (95% confidence interval). Discussion: Acceleromyography-derived twitch heights for individual patients are not necessarily interchangeable with information obtained using electromyography. Nevertheless, acceleromyography appears to be a valid methodology for determining the drug potency when a population rather than an individual subject is being studied. [source] New guideline for tramadol usage following adverse drug reactions reported to the Iranian pharmacovigilance center,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 2 2007K. Gholami Pharm D Abstract Background Tramadol was introduced as injection and oral form to Iranian Pharmaceutical Market in 2002. Shortly after, the injection form of the drug was observed at the top of suspected drug list of Adverse Drug Reactions (ADRs) received monthly by Iranian Pharmacovigilance Center (IPC). Objectives To detect, assess and report total number of Tramadol-induced ADRs received by IPC. To assess the frequency of reported Tramadol-induced ADRs before and after interventions. To design a guideline for prevention of probable ADRs due to Tramadol injection. Methods A descriptive study was conducted on spontaneous reporting received by IPC from April 2002 to February 2005. All ADRs suspected to be induced by Tramadol registered in the database during mentioned period were analysed. To assess the effect of different interventions based on Spontaneous Reporting System, the trend of reporting frequency of Tramadol-induced ADRs was evaluated before and after interventions. Results There were 337 cases of Tramadol-induced ADRs describing 939 reactions, reported to IPC during the study period. Although causal relationship had not been established, three cases of deaths appeared among the reports. The severity of reactions led to implementation of limitations on injectable Tramadol distribution to community pharmacies and the restriction of its use to hospitals only. Since most adverse reactions were dose-dependent, the drug potency of injectable Tramadol available in the country changed from 100,mg to 50,mg. The assessment of ADR reports received by IPC showed that the frequency of adverse reactions registered in the centre was reduced considerably following these interventions. Conclusion Designing a detailed programme by Pharmacovigilance Centres and closely monitoring of newly marketed pharmaceutical products is highly recommended. Copyright © 2006 John Wiley & Sons, Ltd. [source] Influence of 1 and 25 Hz, 1.5 mT magnetic fields on antitumor drug potency in a human adenocarcinoma cell line,BIOELECTROMAGNETICS, Issue 8 2002M.J. Ruiz-Gómez Abstract The resistance of tumor cells to antineoplastic agents is a major obstacle during cancer chemotherapy. Many authors have observed that some exposure protocols to pulsed electromagnetic fields (PEMF) can alter the efficacy of anticancer drugs; nevertheless, the observations are not clear. We have evaluated whether a group of PEMF pulses (1.5 mT peak, repeated at 1 and 25 Hz) produces alterations of drug potency on a multidrug resistant human colon adenocarcinoma (HCA) cell line, HCA-2/1cch. The experiments were performed including (a) exposures to drug and PEMF exposure for 1 h at the same time, (b) drug exposure for 1 h, and then exposure to PEMF for the next 2 days (2 h/day). Drugs used were vincristine (VCR), mitomycin C (MMC), and cisplatin. Cell viability was measured by the neutral red stain cytotoxicity test. The results obtained were: (a) The 1 Hz PEMF increased VCR cytotoxicity (P,<,0.01), exhibiting 6.1% of survival at 47.5 ,g/ml, the highest dose for which sham exposed groups showed a 19.8% of survival. For MMC at 47.5 ,g/ml, the % of survival changed significantly from 19.2% in sham exposed groups to 5.3% using 25 Hz (P,<,0.001). Cisplatin showed a significant reduction in the % of survival (44.2,39.1%, P,<,0.05) at 25 Hz and 47.5 ,g/ml, and (b) Minor significant alterations were observed after nonsimultaneous exposure of cells to PEMF and drug. The data indicate that PEMF can induce modulation of cytostatic agents in HCA-2/1cch, with an increased effect when PEMF was applied at the same time as the drug. The type of drug, dose, frequency, and duration of PEMF exposure could influence this modulation. Bioelectromagnetics 23:578,585, 2002. © 2002 Wiley-Liss, Inc. [source] Differential inhibitory effects of drugs acting at the noradrenaline and 5-hydroxytryptamine transporters in rat and human neocortical synaptosomes,BRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2009M Mantovani Background and purpose:, Although the amino acid sequences of rat and human 5-hydroxytryptamine (5-HT) and noradrenaline (NA) transporters (i.e. SERT and NET) are highly homologous, species differences exist in the inhibitory effects of drugs acting at these transporters. Therefore, comparison of the potencies of drugs acting at SERT and NET in native human and rat neocortex may serve to more accurately predict their clinical profile. Experimental approach:, Synaptosomes prepared from fresh human and rat neocortical tissues were used for [3H]-5-HT and [3H]-NA saturation and competition uptake experiments. The drugs tested included NA reuptake inhibitors (desipramine, atomoxetine and (S,S)-reboxetine), 5-HT reuptake blockers (citalopram, fluoxetine and fluvoxamine) and dual 5-HT/NA reuptake inhibitors (duloxetine and milnacipran). Key results:, In saturation experiments on synaptosomal [3H]-5-HT and [3H]-NA uptake, the dissociation constants did not indicate species differences although a smaller density of both SERT and NET was observed in human tissues. In competition experiments with the various drugs, marked species differences in their potencies were observed, especially at SERT. The rank order of selectivity ratios (SERT/NET) in human neocortex was as follows: citalopram , duloxetine = fluvoxamine , fluoxetine > milnacipran > desipramine = atomoxetine > (S,S)-reboxetine. Significant species differences in these ratios were observed for duloxetine, atomoxetine and desipramine. Conclusions and implications:, This study provides the first compilation of drug potency at native human neocortical SERT and NET. The significant species differences (viz., human vs. rat) in drug potency suggest that the general use of rodent data should be limited to predict clinical efficacy or profile. [source] Increased rigidity of the chiral centre of tocainide favours stereoselectivity and use-dependent block of skeletal muscle Na+ channels enhancing the antimyotonic activity in vivoBRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2001Sophie Talon Searching for the structural requirements improving the potency and the stereoselectivity of Na+ channel blockers as antimyotonic agents, new derivatives of tocainide, in which the chiral carbon atom is constrained in a rigid ,-proline or pyrrolo-imidazolic cycle, were synthesized as pure enantiomers. Their ability to block Na+ currents, elicited from ,100 to ,20 mV at 0.3 Hz (tonic block) and 2 , 10 Hz (use-dependent block) frequencies, was investigated in vitro on single fibres of frog semitendinosus muscle using the vaseline-gap voltage-clamp method. The ,-proline derivative, To5, was 5 and 21 fold more potent than tocainide in producing tonic and 10 Hz-use-dependent block, respectively. Compared to To5, the presence of one methyl group on the aminic (To6) or amidic (To7) nitrogen atom decreased use-dependence by 2- and 6-times, respectively. When methylene moieties were present on both nitrogen atoms (To8), both tonic and use-dependent block were reduced. Contrarily to tocainide, all proline derivatives were stereoselective in relation to an increased rigidity. A further increase in the molecular rigidity as in pyrrolo-imidazolic derivatives markedly decreased the drug potency with respect to tocainide. Antimyotonic activity, evaluated as the shortening of the time of righting reflexes of myotonic adr/adr mice upon acute drug in vivo administration was 3 fold more effective for R-To5 than for R-Tocainide. Thus, constraining the chiral centre of tocainide in ,-proline cycle leads to more potent and stereoselective use-dependent Na+ channel blockers with improved therapeutic potential. British Journal of Pharmacology (2001) 134, 1523,1531; doi:10.1038/sj.bjp.0704366 [source] A mathematical model of the impact of infused targeted cytotoxic agents on brain tumours: implications for detection, design and deliveryCELL PROLIFERATION, Issue 6 2002Lawrence M. Wein Motivated by the recent development of highly specific agents for brain tumours, we develop a mathematical model of the spatio-temporal dynamics of a brain tumour that receives an infusion of a highly specific cytotoxic agent (e.g. IL-4-PE, a cytotoxin comprised of IL-4 and a mutated form of Pseudomonas exotoxin). We derive an approximate but accurate mathematical formula for the tumour cure probability in terms of the tumour characteristics (size at time of detection, proliferation rate, diffusion coefficient), drug design (killing rate, loss rate and convection constants for tumour and tissue), and drug delivery (infusion rate, infusion duration). Our results suggest that high specificity is necessary but not sufficient to cure malignant gliomas; a nondispersed spatial profile of pretreatment tumour cells and/or good drug penetration are also required. The most important levers to improve tumour cure appear to be earlier detection, higher infusion rate, lower drug clearance rate and better convection into tumour, but not tissue. In contrast, the tumour cure probability is less sensitive to a longer infusion duration and enhancements in drug potency and drug specificity. [source] | |||||||||||||