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Pharmacokinetic Profile (pharmacokinetic + profile)
Selected AbstractsPharmacokinetic profile of immediate-release omeprazole in patients with gastro-oesophageal reflux associated with gastroparesisALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 4 2010J. M. WO Aliment Pharmacol Ther,31, 516,522 Summary Background, Immediate-release omeprazole has a more rapid absorption compared with delayed-release omeprazole in asymptomatic volunteers. However, effects of delayed gastric emptying on omeprazole absorption remain unknown. Aim, To compare pharmacokinetics between immediate and delayed-release omeprazole in patients with GERD associated with gastroparesis. Methods, Open-label, randomized, cross-over study was performed. Antireflux and prokinetic medications were discontinued. Subjects were randomized into: (i) Immediate-release omeprazole 40 mg suspension o.m. for 7 days, wash-out for 10,14 days, followed by delayed-release omeprazole 40 mg capsule o.m. for 7 days, or (ii) the same schedule in reverse order. On day 7, omeprazole concentrations were obtained before and up to 5 h after taking the study drug. Patient Assessment of GI Disorders,Symptom Severity Index was obtained. Results, A total of 12 women (mean age 51 years) completed the protocol. Time to maximal omeprazole concentration was significantly shorter for omeprazole. Maximal concentration was significantly greater for omeprazole, but total area under concentration,time curves was similar. Pharmacokinetic profile was less variable for immediate compared with delayed-release omeprazole. Conclusions, Immediate-release omeprazole was associated with a more rapid absorption and less variable pharmacokinetic profile compared with delayed-release omeprazole in reflux patients associated with gastroparesis. [source] Pharmacokinetic profile and behavioral effects of gabapentin in the horseJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2010R. L. TERRY Terry, R. L., McDonnell, S. M., van Eps, A. W., Soma, L. R., Liu, Y., Uboh, C. E., Moate, P. J., Driessen, B. Pharmacokinetic profile and behavioral effects of gabapentin in the horse. J. vet. Pharmacol. Therap. 33, 485,494. Gabapentin is being used in horses although its pharmacokinetic (PK) profile, pharmacodynamic (PD) effects and safety in the equine are not fully investigated. Therefore, we characterized PKs and cardiovascular and behavioral effects of gabapentin in horses. Gabapentin (20 mg/kg) was administered i.v. or p.o. to six horses using a randomized crossover design. Plasma gabapentin concentrations were measured in samples collected 0,48 h postadministration employing liquid chromatography-tandem mass spectrometry. Blood pressures, ECG, and sedation scores were recorded before and for 12 h after gabapentin dosage. Nineteen quantitative measures of behaviors were evaluated. After i.v. gabapentin, the decline in plasma drug concentration over time was best described by a 3-compartment mammillary model. Terminal elimination half-life (t1/2,) was 8.5 (7.1,13.3) h. After p.o. gabapentin terminal elimination half-life () was 7.7 (6.7,11.9) h. The mean oral bioavailability of gabapentin (±SD) was 16.2 ± 2.8% indicating relatively poor absorption of gabapentin following oral administration in horses. Gabapentin caused a significant increase in sedation scores for 1 h after i.v. dose only (P < 0.05). Among behaviors, drinking frequency was greater and standing rest duration was lower with i.v. gabapentin (P < 0.05). Horses tolerated both i.v. and p.o. gabapentin doses well. There were no significant differences in and . Oral administration yielded much lower plasma concentrations because of low bioavailability. [source] Pharmacokinetic profile of a modified release formulation of trimetazidine (TMZ MR 35 mg) in the elderly and patients with renal failureBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2003J. Barré Abstract Objectives , To study the effect of age and renal function on the pharmacokinetic profile of a modified release tablet of trimetazidine (TMZ MR 35 mg) administered twice daily. Methods, Study 1: Twelve healthy elderly subjects (CLcreat 72±8 ml/min, 72±4 years mean±SD) and eight young volunteers (CLcreat 134±18 ml/min, 25±8 years) received TMZ MR 35 mg b.i.d. (eight doses). Study 2: eight patients with severe renal failure (CLcreat. 17±5 ml/min, 54±10 years), five patients with moderate renal failure (CLcreat. 39±6 ml/min, 54±15 years) and eight volunteers (CLcreat. 104±17 ml/min, 53±9 years) received TMZ MR 35 mg b.i.d. (patients: ten doses, volunteers: eight doses). Serial blood and urine samples were obtained following administration of the last dose in each study. TMZ plasma and urine concentrations were determined by gas chromatography (NPD-detector). The resulting data were analysed using standard non-compartmental pharmacokinetic methods. Results, Study 1: Elimination half-life of TMZ was significantly longer and renal clearance significantly lower in the elderly subjects. Study 2: In patients with either moderate or severe renal failure, exposure (AUC0,24) was significantly increased and renal clearance (CLR) was significantly decreased. Significant correlations were observed between CLcreat and CLR (r=0.94) and between CLcreat and AUC0,24 (r=,0.94). Conclusion , With repeated administration of TMZ MR 35 mg b.i.d., a decrease in CLcreat is directly related to a decrease in CLR and results in an increase in exposure to TMZ. Copyright © 2003 John Wiley & Sons, Ltd. [source] Accelerating botulism therapeutic product development in the Department of Defense,DRUG DEVELOPMENT RESEARCH, Issue 4 2009Andrea M. Stahl Abstract Coordinated small-molecule drug discovery research efforts for the treatment of botulism by the public sector, especially the U.S. Department of Defense (DoD) and Department of Health and Human Services (DHHS), began in the 1990s and represent a significant resource investment. Organization of an effective botulism therapeutic drug program, however, presents formidable technical and logistical challenges. Seven distinct BoNT serotypes are known, each representing a different target. Moreover, BoNT exerts its action inside peripheral cholinergic neurons, and some serotypes may persist functionally within nerve cells for weeks or months. Clinical botulism occurs infrequently, and the effectiveness of prolonged mechanical ventilation to treat poisoning further limits experimental drug testing. The efficacy of experimental compounds must be extrapolated from disparate cell- or tissue-based or rodent models. Numerous compounds with moderate efficacy in experimental laboratory assays have been reported, but may not possess the necessary safety, efficacy, and pharmacokinetic profile to support therapeutic development. To mitigate these challenges, we propose product development tools to assist in management of the BoNT portfolio and to clearly define the desired therapeutic product. Establishing a target product profile (TPP) is proposed to guide public sector managers toward critical aspects of the desired therapeutic product. Additional product development tools to assist in shaping research portfolios and to inform decisions regarding lead candidates to pursue are also discussed. Product development tools that facilitate the characterization of the ideal therapeutic product, and assist in the maintenance of a robust portfolio, will ameliorate the inherent financial risk in drug development for treating BoNT intoxication. Drug Dev Res 70:303,326, 2009. Published 2009 Wiley-Liss, Inc. [source] Anticonvulsant profile and teratogenicity of 3,3-dimethylbutanoylurea: A potential for a second generation drug to valproic acidEPILEPSIA, Issue 7 2008Jakob Avi Shimshoni Summary Purpose: The purpose of this study was to evaluate the anticonvulsant activity and teratogenic potential of branched aliphatic acylureas represented by isovaleroylurea (IVU), pivaloylurea (PVU) and 3,3-dimethylbutanoylurea (DBU), as potential second-generation drugs to valproic acid (VPA). Methods: The anticonvulsant activity of IVU, PVU, and DBU was determined in mice and rats utilizing the maximal electroshock seizure (MES) and the pentylenetetrazole (scMet) tests. The ability of DBU to block electrical-, or chemical-induced seizures was further examined in three acute seizure models: the psychomotor 6 Hz model, the bicuculline and picrotoxin models and one model of chronic epilepsy (i.e., the hippocampal kindled rat model). The induction of neural tube defects (NTDs) by IVU, PVU, and DBU was evaluated after i.p. administration at day 8.5 of gestation to a mouse strain highly susceptible to VPA-induced teratogenicity. The pharmacokinetics of DBU was studied following i.v. administration to rats. Results: DBU emerged as the most potent compound having an MES-ED50of 186 mg/kg (mice) and 64 mg/kg (rats) and an scMet-ED50of 66 mg/kg (mice) and 26 mg/kg (rats). DBU underwent further evaluation in the hippocampal kindled rat (ED50= 35 mg/kg), the psychomotor 6 Hz mouse model (ED50= 80 mg/kg at 32 mA and ED50= 133 mg/kg at 44 mA), the bicuculline- and picrotoxin-induced seizure mouse model (ED50= 205 mg/kg and 167 mg/kg, respectively). In contrast to VPA, DBU, IVU, and PVU did not induce a significant increase in NTDs as compared to control. DBU was eliminated by metabolism with a half-life of 4.5 h. Conclusions: DBU's broad spectrum and potent anticonvulsant activity, along with its high safety margin and favorable pharmacokinetic profile, make it an attractive candidate to become a new, potent, and safe AED. [source] From heparins to factor Xa inhibitors and beyondEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2005S. Alban Abstract Despite some disadvantages, unfractionated heparin (UFH) and oral anticoagulants have been the only anticoagulants for prophylaxis and therapy of thromboembolic disorders for several decades. Based on the increasing knowledge of the structure and pharmacology of heparin, low molecular weight heparins (LMWH) have been developed in the 1980s. Compared to UFH, their advantages are mainly based on their reduced nonspecific binding to proteins and cells resulting in improved pharmacokinetics. In 1991, LMWH were declared as the most efficient prophylaxis in high-risk patients. Although the use of LMWH is increasing and they are today also applied for therapy and in other indications like acute coronary syndrome, they are considered not optimal concerning efficacy and safety. With the approval of fondaparinux for the prevention of venous thromboembolic disease in high-risk orthopedic patients, there might be a paradigm shift in the field of anticoagulants. Fondaparinux, a synthetic, chemically defined pentasaccharide, is the first selective inhibitor of factor Xa. By its highly specific binding to antithrombin, it selectively inhibits factor Xa and consequently prevents thrombin generation. In contrast to UFH and LMWH, it does not bind to any other cells and other proteins than antithrombin. This leads to a favourable linear pharmacokinetic profile, allowing once-daily subcutaneous application of a fixed dose without monitoring in thromboembolism prophylaxis. In addition to the evaluation of fondaparinux for further indications, chemical modifications of this pentasaccharide such as the long-acting idraparinux are currently under investigation. [source] Treatment of congestive heart failure , current status of use of digitoxinEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue S2 2001G. G. Belz Digitalis glycosides exert a positive inotropic effect, i.e. an increase in myocardial contractility associated with a prolongation of relaxation period, and glycosides lower the heart rate (negative chronotropic), impede stimulus conduction (negative dromotropic) and promote myocardial excitability (positive bathmotropic). They seem to influence the activities of both the vagal and the sympathetic systems. Digitalis glycosides that belong to different substance classes are closely comparable concerning pharmacodynamics but differ substantially in regard to pharmacokinetics. Digoxin and its derivatives are less lipophilic, show lower protein binding and shorter half-life, are mainly eliminated via the kidney and accumulate rather rapidly in cases of insufficient kidney function. Digitoxin is highly lipophilic and extensively bound to plasma proteins, has a longer half-life, is mainly eliminated in the metabolized state via urine and faeces and does not accumulate in kidney dysfunction. As a result of a more stable pharmacokinetic profile, the incidence of toxic side effects seems to be lower with digitoxin than with digoxin. Since the beginning of the 1990s, the antagonists of the RAAS qualified as the standard treatment for congestive heart failure, often in combination with diuretics, vasodilators or ,-antagonists. However, the important role of digitalis glycosides as therapeutic comedication or alternative was never denied, especially in atrial fibrillation with tachycardia. The PROVED and RADIANCE trials proved a detrimental effect of the withdrawal of digoxin therapy on exercise capacity, left-ventricular ejection fraction and clinical symptoms. The DIG trial revealed that digoxin comedication in sinus rhythm patients with congestive heart failure was associated with a lower morbidity (as taken from death or hospitalization because of worsening heart failure) and an unchanged overall mortality , being a unique feature among the available inotropic drugs. Comparable studies for digitoxin have not yet been performed but, because of its higher pharmacological stability, it might well be associated with even more advantages in this regard than digoxin. [source] Pre-clinical studies of pramipexole: clinical relevanceEUROPEAN JOURNAL OF NEUROLOGY, Issue 2000J. P. Hubble This paper reviews the preclinical study of the novel dopamine agonist pramipexole and its use in early Parkinson's disease (PD). Emphasis will be given to those properties distinguishing this drug from other dopamine agonists, the relevance of the preclinical data to clinical trial results in early PD, and the putative neuroprotective properties of the compound. The conventional dopamine agonists are ergot-derived compounds that are most widely used as adjunctive therapies in advancing Parkinson's disease (PD). Examples of conventional agonists are bromocriptine and pergolide. Pramipexole is an aminobenzothiazole compound, recently introduced for the treatment of both early and advanced PD. Its nonergot structure may reduce the risk of side-effects, considered unique to ergot drugs, such as membranous fibrosis. Pramipexole is a full dopamine agonist with high selectivity for the D2 dopamine receptor family. This family includes the D2, D3 and D4 receptor subtypes. Pramipexole has a 5- to 7-fold greater affinity for the D3 receptor subtype with lower affinities for the D2 and D4 receptor subtypes. The drug has only minimal ,2 -adrenoceptor activity and virtually no other receptor agonism or antagonism. The optimal dopamine receptor activation for the safe and effective treatment of PD is not known. Findings in animal models and clinical studies indicate that activation of the postsynaptic D2 receptor subtype provides the most robust symptomatic improvement in PD. Given its pharmacological profile, it is not surprising that pramipexole was found to be effective in ameliorating parkinsonian signs in animal models. This therapeutic effect has been confirmed in clinical trials in both early and advanced PD. In early disease, it provides a clear reduction in the chief motor manifestations of PD and improved activities of daily living. Perhaps most striking is the large number of clinical trial patients who have remained on pramipexole monotherapy for many months. The majority of these subjects have been maintained on pramipexole for an excess of 24 months without requiring additional symptomatic treatment with levodopa. This is in contrast to the general clinical experience with older conventional agonists. Pramipexole also has a favourable pharmacokinetic profile. It is rapidly absorbed with peak levels appearing in the bloodstream within 2 h of oral dosing. It has a high absolute bioavailability of > 90% and can be administered without regard to meals. It has no significant effects on other antiparkinson drugs such as levodopa or selegiline. Its excretion is primarily renal and, thus, has little or no impact on hepatic cytochrome P450 enzymes or other related metabolic pathways. Pramipexole has also been theorized to have ,neuroprotectant' properties. Oxyradical generation is posited as a cause or accelerant of brain nigral cell death in PD. Pramipexole stimulates brain dopamine autoreceptors and reduces dopamine synthesis and turnover which may minimize oxidative stress due to dopamine metabolism. Furthermore, the compound has a low oxidation potential that may serve as an oxyradical scavenger in the PD brain. In summary, pramipexole is a new antiparkinson medication found to have unique dopamine agonist characteristics and putative neuroprotective properties. [source] Influence of administration vehicles and drug formulations on the pharmacokinetic profile of lamotrigine in ratsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2002M. M. Castel-Branco Abstract Given that administration vehicles and drug formulations can affect drug bioavailability, their influence on the pharmacokinetic profile of lamotrigine (LTG), a new-generation anti-epileptic drug, was studied in rats. Three different formulations administered intraperitoneally at a dose of 10 mg/kg were used: (1) LTG suspended in a 0.25% methylcelulose solution, (2) LTG dissolved in a 50% propylene glycol solution, and (3) LTG isethionate dissolved in distilled water. Plasma and brain homogenate levels were determined in order to evaluate vehicle-dependent drug absorption. The results demonstrated rapid absorption of LTG when it was administered as an aqueous solution, in contrast to a slower and more erratic absorption after the injection of either the lipophilic solution or the suspension. A plasma peak was achieved 15 min post-dose with the aqueous solution, with a brain peak being achieved 15 min later, while with the other formulations both plasma and brain homogenate peaks were reached 2 h after LTG administration. This study suggests that LTG isethionate dissolved in distilled water is the most suitable formulation for successful LTG pharmacokinetic studies in rats. [source] Efficacy and safety of a factor VIII,von Willebrand factor concentrate 8Y: stability, bacteriological safety, pharmacokinetic analysis and clinical experienceHAEMOPHILIA, Issue 5 2002A. Lubetsky Summary., The present study was undertaken to evaluate stability, pharmacokinetic profile and efficacy of continuous infusion of 8Y in patients with different types of von Willebrand disease (vWD). Following reconstitution, 8Y levels of von Willebrand factor ristocetin cofactor (vWF:Rco), vWF antigen and factor VIII coagulant activity (FVIII:C) decreased to about 80% of the baseline levels; addition of low molecular weight heparin decreased the level of FVIII:C even further. Reconstituted 8Y was found to be sterile for up to 6 days postreconstitution. Ten vWD patients (four with type 2A, three with type 3, two with type 1 and one with 2N) underwent pharmacokinetic analysis. The recovery of vWF: RCo was significantly lower in patients with type 3 vWD (1.4 ± 0.05% U,1 kg,1) compared withthat of the patients with types 1 (2.3 ± 0.52% U,1 kg,1) or 2A (2.0 ± 0.06% U,1 kg,1) vWD (P = 0.015). Type 3 vWD patients exhibited significantly higher vWF:RCo clearance (5.1 ± 1.1 mL kg,1 h,1) compared with that of patients with type 2A (2.8 ± 0.7 mL kg,1 h,1) and type 1 (2.6 ± 1.0 mL kg,1 h,1) vWD (P = 0.028). Accordingly, terminal half-life was lower in patients with type 3 vWD (8.0 ± 0.6 h,1) compared with type 2A (12.7 ± 5.9 h,1) or type 1 (14 ± 1.2 h,1) vWD patients. Multimeric pattern of vWF from patients' plasma was similar to that of 8Y. In two patients treated with 8Y by continuous infusion for prevention or treatment of bleeding haemostasis was achieved. Thus, 8Y is suitable and haemostatically effective for continuous infusion treatment in patients with vWD. [source] Clinical Pharmacokinetics of FrovatriptanHEADACHE, Issue 2002P. Buchan PhD Objective.,To review available data on the clinical pharmacokinetics of frovatriptan. Background.,Preclinical data suggest that the pharmacokinetic profile of frovatriptan may differ from that of the currently available triptans. Methods.,Studies of healthy volunteers, subjects with renal or hepatic impairment, elderly subjects, and patients with migraine during and between attacks were reviewed. Results.,Oral bioavailability of frovatriptan is 22% to 30%, and although the time to maximum concentration is typically 2 to 3 hours, approximately 60% to 70% of plasma maximum concentration is achieved within 1 hour of dosing. Frovatriptan distributes into erythrocytes, with binding reversible and time dependent. The relatively long terminal elimination half-life (about 26 hours) confers good systemic exposure and may produce a long duration of therapeutic action, thus reducing migraine recurrence and the need for redosing. Systemic exposure to frovatriptan generally correlates with dose between 1 and 100 mg. Blood and plasma frovatriptan concentrations are consistently higher in females, but there is no need to adjust dose according to gender. Pharmacokinetics are essentially unaffected by food and were predictable after repeat dosing; steady state is approached in about 4 to 5 days. Pharmacokinetics were changed only slightly in subjects with renal impairment or mild-to-moderate hepatic impairment, elderly individuals, and during migraine attacks. Frovatriptan is principally metabolized by the CYP1A2 isoenzyme of cytochrome P-450 and is cleared by the kidney and liver, each having sufficient capacity to compensate for impairment of the other. Conclusions.,Frovatriptan can be taken without regard for food intake, and because of the large therapeutic margin and shallow dose-response curve, there is no need for dosage adjustment in the elderly, in women taking a combined oral contraceptive, in patients with mild-to-severe renal impairment, mild-to-moderate hepatic impairment, or according to gender. The long duration of exposure may reduce the likelihood of early migraine recurrence. [source] Pharmacokinetics of mesalazine pellets in children with inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 5 2004Heleen Wiersma MD Abstract Mesalazine is a first-line drug in pediatric inflammatory bowel disease (IBD), and is customarily used to induce and maintain remission in mild to moderate disease. In children, pharmacokinetic data are scarce, and dosage recommendations are largely extrapolated from studies in adults. Aim of the study was to obtain the pharmacokinetic profile of a new mesalazine pellet formulation in children with ulcerative colitis and Crohn's colitis. A single oral dose of 20 mg/kg mesalazine was administered to 13 patients (age 6,16 years). Serial blood and urine sampling for determination of mesalazine and acetylmesalazine was performed before and during 24 hours following ingestion. Maximum plasma concentration of mesalazine (Cmax) was 1332 ng/mL (geometric mean, geometric coefficient of variation [CV]: 0.57), obtained 3.7 hours (tmax; CV: 0.31) after drug administration. Systemic exposure as determined by area under the plasma concentration-time curve (AUC0,, ) was 8712 ng/ml*h (CV: 0.44). Terminal half-life of elimination of mesalazine was 3.5 hours (t1/2; CV: 1.43). This study presents extensive pharmacokinetic data on mesalazine in children with mild-moderately active ulcerative colitis and Crohn's colitis. In comparison with previous experience in adults, pharmacokinetics of mesalazine administered as pellets appear to be similar in both populations. [source] Efficacy, Safety, and Pharmacokinetics of Candesartan Cilexetil in Hypertensive Children Aged 6 to 17 YearsJOURNAL OF CLINICAL HYPERTENSION, Issue 10 2008Howard Trachtman MD This 4-week randomized, double blind, placebo-controlled study (N=240), 1-year open label trial (N=233), and single-dose pharmacokinetic study (N=22) evaluated candesartan cilexetil (3 doses) in hypertensive children aged 6 to 17 years. Seventy-one percent were 12 years of age or older, 71% were male, and 47% were black. Systolic (SBP)/diastolic (DBP) blood pressure declined 8.6/4.8,11.2/8.0 mm Hg with candesartan and 3.7/1.8 mm Hg with placebo (P<.01 compared to placebo for SBP and for the mid and high doses for DBP; placebo-corrected 4.9/3.0,7.5/6.2 mm Hg). The slopes for dose were not, however, different from zero (P>.05). The response rate (SBP and DBP <95th percentile) after 1 year was 53%. The pharmacokinetic profiles in 6- to 12- and 12- to 17-year-olds were similar and were comparable to adults. Eight candesartan patients discontinued treatment because of an adverse event. Candesartan is an effective, well-tolerated antihypertensive agent for children aged 6 to 17 years and has a pharmacokinetic profile that is similar to that in adults. [source] Determination of glycyrrhetic acid in human plasma by HPLC-MS method and investigation of its pharmacokineticsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2008W.-J. Zhao PhD Summary Objective:, To develop a high performance liquid chromatography mass spectrometry (HPLC-MS) method for the determination of the glycyrrhetic acid (GA) in human plasma and for the investigation of its pharmacokinetics after the oral administration of 150 mg diammonium glycyrrhizinate test and reference capsule formulations. Methods:, The GA in plasma was extracted with ethyl acetate, separated on a C18 column with a mobile phase of methanol (5 mmol/L ammonium acetate),water (85 : 15, V/V) and analysed using a MS detector. Ursolic acid (UA) was used as internal standard. The target ions were m/z 469·5 for GA and m/z 455·6 for UA, the fragment voltages were 200 V and 100 V for GA and UA respectively. Results:, The calibration curve was linear over the range of 0·5,200 ng/mL (r = 0·9974). The limit of quantification for GA in plasma was 0·5 ng/mL, the recovery was 76·0,80·0%, and the inter- and intra-day relative standard deviations (RSD) were <12%. The pharmacokinetic parameters of GA after a single dose of 150 mg diammonium glycyrrhizinate test and reference were as follows: the half life (t1/2) 9·65 ± 3·54 h and 9·46 ± 2·85 h, the time to peak concentration (Tmax) 10·95 ± 1·32 h and 11·00 ± 1·30 h, the peak concentration (Cmax) 95·57 ± 43·06 ng/mL and 103·89 ± 49·24 ng/mL; the area under time-concentration curve (AUC0,48 and AUC0,,) 1281·84 ± 527·11 ng·h/mL and 1367·74 ± 563·27 ng·h/mL, 1314·32 ± 566·40 ng·h/mL and 1396·97 ± 630·06 ng·h/mL. The relative bioavailability of diammonium glycyrrhizinate capsule was 98·88 ± 12·98%. Conclusion:, The assay was sensitive, accurate and convenient, and can be used for the determination of GA in human plasma. Comparison of the bioavailability and pharmacokinetic profile of GA indicated that the test and reference capsules were bioequivalent. [source] Methods of estimation of IC50 and SC50 parameters for indirect response models from single dose dataJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2003Elzbieta Wyska Abstract The basic indirect response models are described by several pharmacodynamic parameters of which IC50 (drug concentration eliciting 50% of the maximum inhibition) and SC50 (drug concentration eliciting 50% of the maximum stimulation) are not readily derived from the response versus time or response versus concentration plots. We discuss limitations of existing methods of IC50 and SC50 estimation from single dose data. A novel approach to such estimations based on the area between the baseline and effect curve is introduced. The effects of pharmacokinetic profile, dose, data variability, and number of data on the parameter estimation are analyzed for the new and one of the previously described methods. Our analysis is based on reconstruction of true IC50 and SC50 values from rich and sparse computer-generated data sets modified by two noise levels. Extensions of these methods to two dose data sets are presented. Both methods yielded IC50 and SC50 close to the known true values. Depending on the factors mentioned above, these methods exhibited different levels of accuracy. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1438,1454, 2003 [source] Formulation and evaluation of nimodipine-loaded lipid microspheresJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2006Jia Yu The purpose of this study was to develop an alternative, improved and better tolerated formulation and investigate the pharmacokinetic profile of the new formulation of nimodipine (NM) compared with nimodipine ethanol solutions. Lipid microspheres (LMs) prepared using lecithin and vegetable oils have attracted a lot of interest owing to their versatile properties, such as non-immunogenicity, being easily biodegradable and exhibiting high entrapment efficiency. NM incorporated in LMs could reduce irritation by avoiding the use of ethanol as a solubilizer. The solubility of NM was also increased by dissolving it in the oil phase. The particle size distribution, zeta potential, entrapment efficacy and assay of the NM-loaded LMs were found to be 188.2 ± 5.4 nm, ,31.6 mV, 94.2% and 1.04 mg mL,1, respectively. The preparation was stable for 1 year at 4,10°C. The formulation and some physicochemical properties of NM-loaded LMs were investigated. The pharmacokinetic and biodistribution studies were performed in rats at a dose of 1.2 mg kg,1. From the observed data, there is no obvious retention of NM-loaded LMs in plasma. Moreover, incorporation of NM in LMs did not alter the tissue distribution significantly except for the relatively greater drug accumulation in the liver and spleen. The stimulation studies demonstrate that LMs of NM reduce irritation markedly compared with NM solutions. These results suggest that the LM system is a promising option to replace NM ethanol solutions as an intravenous treatment. [source] Biostability and pharmacokinetics of LJP 920, an octameric Gal (,1,3) Gal conjugate for the inhibition of xenotransplantation rejectionJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2001Lee Jia Antibodies to an ,-galactosyl saccharide structure present in human serum are associated with hyperacute rejection and delayed xenograft rejection after pig-to-primate xenotransplantation. To overcome this major barrier to the xenotransplantation, LJP 920, a galactosyl ,1,3 galactose (Gal (,1,3) Gal) coupled to a non-immunogenic platform at a valency of eight Gal (,1,3) Gal molecules/platform, was synthesized to clear circulating antibodies and to inhibit their production by B cells that produce these antibodies. Herein we report on the stability of LJP 920 in biological media and its pharmacokinetic profile. Incubation of LJP 920 with mouse serum or liver microsomes at 37°C for 2 days showed no indication of degradation of the conjugate as detected by a reversed-phase HPLC method, indicating that the conjugate is not subject to enzymatic metabolism. After intravenous administration of LJP 920 to mice at the doses of 20 and 100 mg kg,1, LJP 920 serum concentration decreased rapidly, showing a biphasic pattern, with a distribution half-life of 3 min and an elimination half-life of more than 30 min, respectively. The serum-to-erythrocyte concentration ratio of LJP 920 was 33- and 36-fold excess at 0.5 and 5 min, respectively, after intravenous administration (100 mg kg,1). Both Cmax and AUC values increased in a dose-proportional manner. LJP 920 displayed a great distribution to well-perfused tissues. It was eliminated mainly through renal excretion in the unchanged form, which accounted for 23% of the total amount within 8 h of dosing. [source] The Effect of Different Dosing Schedules of UCN-01 on its Pharmacokinetics and Cardiohaemodynamics in DogsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2000N. KURATA 7-Hydroxy-staurosporine (UCN-01) is now under development as a novel anticancer drug. In clinical studies, different infusion schedules are being investigated in the USA and Japan. To examine the effect of different infusion schedules on the pharmacokinetics and cardiohaemodynamics of UCN-01, dogs were treated with UCN-01 as either a 3-h or a 24-h constant intravenous infusion. Blood pressure and heart rate, together with UCN-01 concentrations during and after infusion, were monitored. To analyse the relationship between the pharmacokinetics and cardiohaemodynamics of UCN-01, the plasma concentration of UCN-01 at the end of infusion (Cend), the area under the plasma concentration versus time curves (AUC0-,) and the mean residence time (MRT) were used. As indices of cardiohaemodynamic changes, the area under decreasing systolic blood pressure and increasing heart rate versus time curves (dAUCpressure and AUCheart rate) were calculated by the trapezoidal method. For the 3-h (0.22 and 0.65 mgkg,1) and 24-h infusion (0.81 to 6.48 mgkg,1), systolic and diastolic blood pressures fell after or during infusions, accompanied by a dose-dependent increase in heart rate for both infusions. During both infusion schedules, the plasma concentrations of UCN-01 gradually increased and Cend showed a dose-proportional increase. After that, UCN-01 was eliminated bi-exponentially with an elimination half-life of 5.14 ± 1.12 to 8.32 ± 1.80 h. The total clearance (CLtotal) ranged from 0.383 to 0.666 ± 0.149L h,1kg,1. There was no significant difference in these parameters among the doses in each infusion schedule, indicating that UCN-01 has a linear pharmacokinetic profile over the dose range examined for each infusion, and there were also no significant differences between the 3-h and 24-h infusion except for MRT. The pharmacokinetic parameters of Cend, AUC0-, and slope0-3h exhibited a degree of correlation with the AUCheart rate in the 3-h infusion and correlated significantly with the dAUCpressure in the 24-h infusion. The MRT did not correlate with cardiohaemodynamic changes during either infusion. In conclusion, the pharmacokinetic profile of UCN-01 after the shorter infusion is similar to that after the longer one. However, a longer dosing period of UCN-01 increased the residence time in comparison with the shorter infusion. This may be due to the effect on the circulatory function in dogs. [source] The pharmacokinetics of idraparinux, a long-acting indirect factor Xa inhibitor: population pharmacokinetic analysis from Phase III clinical trialsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2009C. VEYRAT-FOLLET Summary.,Background: Idraparinux, a long-acting synthetic pentasaccharide, is a specific antithrombin-dependent inhibitor of activated factor X that has been investigated in the treatment and prevention of thromboembolic events. Objectives: To characterize the population pharmacokinetic profile of idraparinux in patients enrolled in van Gogh and Amadeus Phase III clinical trials. Patients and methods: Idraparinux was administered once-weekly subcutaneously at a dose of 2.5 mg, or 2.5 mg (first dose) and then 1.5 mg for patients with severe renal insufficiency (creatinine clearance <30 mL min,1). A population pharmacokinetic model was developed using data from 704 patients with acute deep-vein thrombosis or pulmonary embolism, 1310 patients suffering from atrial fibrillation, and 40 healthy subjects. Potential covariates analyzed included demographics (age, sex, weight and ethnicity), and serum creatinine and creatinine clearance determinations. Results: A three-compartment model best described idraparinux pharmacokinetics, with interindividual variability on clearance, central volume of distribution, and absorption rate constant; residual variability was low. Typical clearance, central volume of distribution, absorption rate constant and volume of distribution at steady-state were 0.0255 L h,1, 3.36 L, 1.37 h and 30.8 L, respectively. Peak concentration was reached at 2.5 h. The terminal half-life was 66.3 days and time to steady-state was 35 weeks. At steady-state, exposures were similar for patients without and with severe renal impairment receiving adjusted-dose. Creatinine clearance was the most important covariate affecting idraparinux clearance. The particular characteristics of idraparinux , rapid onset of action and long-acting anticoagulant effect , offer interesting clinical perspectives currently under investigation with idrabiotaparinux, the reversible biotinylated form of idraparinux. [source] Kinetics and residues after intraperitoneal procaine penicillin G administration in lactating dairy cowsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2009A. L. CHICOINE This paper describes the pharmacokinetic profile of procaine penicillin G after intraperitoneal (IP) administration in eight lactating dairy cows. Procaine pencillin G (PPG, 21 000 IU/kg) was deposited into the abdominal cavity of each cow following an incision in the right paralumbar fossa. Blood and milk samples were taken over the following 10 days, at which point the cows were euthanized. Plasma, milk, muscle, liver, and kidney penicillin concentrations were determined by HPLC, with a limit of quantification of 5 ng/mL for plasma and milk and 40 ng/g for tissue samples. A noncompartmental method was used to analyze plasma kinetics. The mean pharmacokinetic parameters (±SD) were: Cmax, 5.5 ± 2.6 ,g/mL; Tmax, 0.75 ± 0.27 h; AUC0-,, 10.8 ± 4.9 ,g·h/mL; MRT, 2.2 ± 0.9 h. All milk from treated cows contained detectable penicillin residues for a minimum of three milkings (31 h) and maximum of five milkings (52 h) after administration. Concentrations of penicillin in all muscle, liver, and kidney samples taken 10 days postadministration were below the limit of quantification. Necropsy examinations revealed foci of hemorrhage on the rumenal omentum of most cows but peritonitis was not observed. Systemic inflammation as determined by change in leukogram or plasma fibrinogen was noted in one cow. The results of this study demonstrate that IP PPG is absorbed and eliminated rapidly in lactating dairy cows. [source] Pharmacokinetic,pharmacodynamic integration of orbifloxacin in rabbits after intravenous, subcutaneous and intramuscular administrationJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2008P. MARÍN The single-dose disposition kinetics of orbifloxacin were determined in clinically normal rabbits (n = 6) after intravenous (i.v.), subcutaneous (s.c.) and intramuscular (i.m.) administration of 5 mg/kg bodyweight. Orbifloxacin concentrations were determined by high performance liquid chromatography with fluorescence detection. Minimal inhibitory concentrations (MICs) assay of orbifloxacin against 30 strains of Staphylococcus aureus from several European countries was performed in order to compute pharmacodynamic surrogate markers. The concentration,time data were analysed by compartmental and noncompartmental kinetic methods. Steady-state volume of distribution (Vss) and total body clearance (Cl) of orbifloxacin after i.v. administration were estimated to be 1.71 ± 0.38 L/kg and 0.91 ± 0.20 L/h·kg, respectively. Following s.c. and i.m. administration orbifloxacin achieved maximum plasma concentrations of 2.95 ± 0.82 and 3.24 ± 1.33 mg/L at 0.67 ± 0.20 and 0.65 ± 0.12 h, respectively. The absolute bio-availabilities after s.c. and i.m. routes were 110.67 ± 11.02% and 109.87 ± 8.36%, respectively. Orbifloxacin showed a favourable pharmacokinetic profile in rabbits. However, on account of the low AUC/MIC and Cmax/MIC indices obtained, its use by i.m. and s.c. routes against the S. aureus strains assayed in this study cannot be recommended given the risk of selection of resistant populations. [source] Role of drug metabolism in drug discovery and developmentMEDICINAL RESEARCH REVIEWS, Issue 5 2001Gondi N. Kumar Abstract Metabolism by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. High metabolic lability usually leads to poor bioavailability and high clearance. Formation of active or toxic metabolites will have an impact on the pharmacological and toxicological outcomes. There is also potential for drug,drug interactions with coadministered drugs due to inhibition and/or induction of drug metabolism pathways. Hence, optimization of the metabolic liability and drug,drug interaction potential of the new chemical entities are some of the most important steps during the drug discovery process. The rate and site(s) of metabolism of new chemical entities by drug metabolizing enzymes are amenable to modulation by appropriate structural changes. Similarly, the potential for drug,drug interactions can also be minimized by appropriate structural modifications to the drug candidate. However, the optimization of the metabolic stability and drug,drug interaction potential during drug discovery stage has been largely by empirical methods and by trial and error. Recently, a lot of effort has been applied to develop predictive methods to aid the optimization process during drug discovery and development. This article reviews the role of drug metabolism in drug discovery and development. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 5, 397,411, 2001 [source] Efficacy and safety of conversion of mycophenolate mofetil to enteric-coated mycophenolate sodium in Mexican renal transplant childrenPEDIATRIC TRANSPLANTATION, Issue 6 2010H. Reyes Reyes H, Hernández AM, Valverde S, Cataneo A, Mendoza A, Barrera I, Ortíz L, García-Roca P, Lopéz-Martínez B, Castañeda-Hernández G, Medeiros M. Efficacy and safety of conversion of mycophenolate mofetil to enteric-coated mycophenolate sodium in Mexican renal transplant children. Pediatr Transplantation 2010: 14:746,752. © 2010 John Wiley & Sons A/S. Abstract:, The aim of the study was to evaluate the efficacy and safety of the conversion of MMF to EC-MPS in pediatric renal transplant recipients. We included 12 patients with stable graft function who were receiving MMF treatment. In the first visit, a complete medical examination was performed, which included a GSRS, a nine-point pharmacokinetic profile, samples for renal, liver and hematological tests and evaluation of IMPDH2 gene expression. The patients were transferred to an equimolar dose of EC-MPS. Two wk later, a clinical evaluation and blood collection, as in the first visit were performed. There was no change in serum creatinine, leukocyte count, serum albumin, or transaminase levels, but we found a statistically significant reduction of hemoglobin after conversion (13.2 ± 1.6 g/dL with MMF vs. 12.5 ± 1.3 g/dL when receiving EC-MPS). The GSRS total mean score was 16 ± 12 with MMF vs. 8 ± 5 with EC-MPA (p < 0.05). There was no statistically significant difference between formulations in the gene expression of IMPDH 2, in the AUC0-12h or in Cmax. However, peak concentration occurred later with EC-MPS. [source] Characterization of sirolimus metabolites in pediatric solid organ transplant recipientsPEDIATRIC TRANSPLANTATION, Issue 1 2009Guido Filler Abstract:, Potential age-dependent changes of sirolimus metabolite patterns in pediatric renal transplant recipients remain elusive. Thirteen pediatric solid organ transplant recipients (10 kidney, one combined liver,kidney, two liver, mean age 8.0 ± 5.0 yr) underwent a sirolimus pharmacokinetic profile in steady-state with 10 samples drawn over 12 h post-intake to calculate the AUC0,12 h. Concentrations of sirolimus and metabolite were quantified using a validated LC-MS/MS assay and metabolite structures were identified directly in blood extracts using LC-MS/iontrap. Average sirolimus AUC0,12 h was 64.9 ± 29.7 ng h/mL. Median (range) AUC0,12 h for each metabolite (ng h/mL) was: 12-hydroxy-sirolimus 7.6 (0.2,18.8), 46-hydroxy sirolimus 3.1 (0.0,12.4), 24-hydroxy sirolimus 4.3 (0.0,12.6), piperidine-hydroxy sirolimus 3.5 (0.0,8.3), 39- O -desmethyl sirolimus 3.6 (0.0,11.3), 16- O -desmethyl sirolimus 5.0 (0.1,9.9), and di-hydroxy sirolimus 4.3 (0.0,32.5). The metabolites reached a median total AUC0,12 h of 60% of that of sirolimus. The range was 2.6,136%, indicating significant variability. In all, 77.5% of the metabolites were hydroxylated, while 39- O -desmethyl sirolimus accounted for only 8.4% of the AUC0,12 h. This is clinically relevant as 39- O -desmethyl sirolimus shows 86,127% cross-reactivity with the antibody of the widely used Abbott sirolimus immunoassay. The metabolism of sirolimus in the children included in our study differed from that reported in adults, which should be considered when monitoring sirolimus exposure immunologically. [source] Frequency of high-risk use of QT-prolonging medications,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 6 2006Nancy M. Allen LaPointe PharmD Abstract Purpose Prolongation of the QT interval has been associated with increased risk of torsades de pointes and death. Concurrent use of more than one QT-prolonging drug or a QT-prolonging drug with a drug that alters its pharmacokinetic profile is an important risk factor for adverse outcomes. Methods Using a representative sample of 2 million health plan members from 10 health maintenance organizations with pharmacy benefits between January 1999 and July 2001, we identified potential drug interactions involving QT-prolonging medications. Prescription claims overlapping by at least 7 days for either 2 or more QT-prolonging drugs or a QT-prolonging drug with a drug that alters its clearance were considered potential drug interactions. We determined the number of drug interactions overall and the number of these interactions involving patients with other risk factors for torsades de pointes. Results A total of 48,465 potential drug interactions were identified in 10,415 (4.6%) of the 228,550 patients with at least one prescription for a QT-prolonging drug. Amitriptyline was involved in 37,859 (78.1%) of the drug interactions. Of all potential drug interactions, 43,689 (90.1%) occurred in patients with at least one other risk factor for torsades de pointes, and 1053 (2.2%) were listed as a contraindicated combination in product labeling. Conclusion Potential drug interactions involving currently marketed QT-prolonging drugs occurred in 4.6% of patients who had a prescription for a QT-prolonging medication. The findings suggest several areas for targeted interventions to decrease the potential risk from QT-prolonging medications. Copyright © 2005 John Wiley & Sons, Ltd. [source] Remifentanil in paediatric anaesthetic practiceANAESTHESIA, Issue 3 2009D. F. Marsh Summary Remifentanil is a synthetic opioid, first introduced into clinical practice in 1996. Its unique pharmacokinetic profile has resulted in a gradual increase in its popularity in paediatric anaesthesia. It is an opioid of high potency and rapid clearance, consequently lacking problems of accumulation. These characteristics give it a high degree of predictability and it has become an attractive choice for a wide variety of anaesthetic challenges, from premature neonates to the elderly. Neonates and infants have a higher clearance than older children and, as a result, remifentanil has additional benefits in this group. Remifentanil can be described as the only consistently predictable opioid in paediatric practice. [source] Pharmacokinetic profile of a modified release formulation of trimetazidine (TMZ MR 35 mg) in the elderly and patients with renal failureBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2003J. Barré Abstract Objectives , To study the effect of age and renal function on the pharmacokinetic profile of a modified release tablet of trimetazidine (TMZ MR 35 mg) administered twice daily. Methods, Study 1: Twelve healthy elderly subjects (CLcreat 72±8 ml/min, 72±4 years mean±SD) and eight young volunteers (CLcreat 134±18 ml/min, 25±8 years) received TMZ MR 35 mg b.i.d. (eight doses). Study 2: eight patients with severe renal failure (CLcreat. 17±5 ml/min, 54±10 years), five patients with moderate renal failure (CLcreat. 39±6 ml/min, 54±15 years) and eight volunteers (CLcreat. 104±17 ml/min, 53±9 years) received TMZ MR 35 mg b.i.d. (patients: ten doses, volunteers: eight doses). Serial blood and urine samples were obtained following administration of the last dose in each study. TMZ plasma and urine concentrations were determined by gas chromatography (NPD-detector). The resulting data were analysed using standard non-compartmental pharmacokinetic methods. Results, Study 1: Elimination half-life of TMZ was significantly longer and renal clearance significantly lower in the elderly subjects. Study 2: In patients with either moderate or severe renal failure, exposure (AUC0,24) was significantly increased and renal clearance (CLR) was significantly decreased. Significant correlations were observed between CLcreat and CLR (r=0.94) and between CLcreat and AUC0,24 (r=,0.94). Conclusion , With repeated administration of TMZ MR 35 mg b.i.d., a decrease in CLcreat is directly related to a decrease in CLR and results in an increase in exposure to TMZ. Copyright © 2003 John Wiley & Sons, Ltd. [source] Vancomycin dosing assessment in intensive care unit patients based on a population pharmacokinetic/pharmacodynamic simulationBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2010Natalia Revilla WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Despite the frequent use of vancomycin in intensive care unit (ICU) patients, few studies aimed at characterizing vancomycin population pharmacokinetics have been performed in this critical population. , Population pharmacokinetics coupled with pharmacodynamic analysis, in order to optimize drug exposure and hence antibacterial effectiveness, has been little applied in these specific patients. WHAT THIS STUDY ADDS , Our population model characterized the pharmacokinetic profile of vancomycin in adult ICU patients, higher distribution volume values (V) being observed when the patient's serum creatinine (CrSe) was greater than 1 mg dl,1. , Age and creatinine clearance (CLcr) were identified as the main covariates explaining the pharmacokinetic variability in vancomycin CL. , Our pharmacokinetic/pharmacodynamic (PK/PD) simulation should aid clinicians to select initial vancomycin doses that will maximize the rate of response in the ICU setting, taking into account the patient's age and renal function as well as the susceptibility of Staphylococcus aureus. AIM To estimate the vancomycin pharmacokinetic profile in adult ICU patients and to assess vancomycin dosages for increasing the likelihood of optimal exposure. METHODS Five hundred and sixty-nine concentration,time data from 191 patients were analysed using a population pharmacokinetic approach (NONMENÔ). External model evaluation was made in 46 additional patients. The 24 h area under the concentration,time curve (AUC(0,24 h)) was derived from the final model. Minimum inhibitory concentration (MIC) values for S. aureus were obtained from the EUCAST database. AUC(0,24 h) : MIC , 400 was considered as PK/PD efficacy index. The probability of different dosages attaining the target considering different strains of S. aureus and patient subgroups was estimated with Monte Carlo simulation. RESULTS Vancomycin CL showed a significant dependence on patient age and renal function whereas CrSe > 1 mg dl,1 increased V more than twofold. For our representative ICU patient, 61 years, 73 kg, CrSe= 1.4 mg dl,1, measured CLCr= 74.7 ml min,1, the estimated values were CL = 1.06 ml min,1 kg,1 and V= 2.04 l kg,1. The cumulative fraction of response for a standard vancomycin dose (2 g day,1) was less than 25% for VISA strains, and 33% to 95% for susceptible S. aureus, depending on patient characteristics. CONCLUSIONS Simulations provide useful information regarding the initial assessment of vancomycin dosing, the conventional dosing regimen probably being suboptimal in adult ICU patients. A graphic approach provides the recommended dose for any selected probability of attaining the PK/PD efficacy target or to evaluate the cumulative fraction of response for any dosing regimen in this population. [source] Single- and multiple-dose pharmacokinetics of ziprasidone under non-fasting conditions in healthy male volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue S1 2000J. J. Miceli Aims, To evaluate the pharmacokinetics and tolerability of single and multiple oral doses of ziprasidone in healthy male volunteers, and to determine the influence of ziprasidone on serum prolactin levels. Methods, Single and multiple doses of ziprasidone were given orally (as two divided daily doses), at fixed dosages of 10 and 40 mg day,,1, and using titrated regimens of 40,80 and 40,120 mg day,,1, for 14 days. All dosages were taken immediately after food. The study adopted a randomized, double-blind, placebo-controlled design. Prolactin response, sedative properties, tolerability, and extrapyramidal symptoms were also investigated. Results, Steady-state exposure to ziprasidone was attained after 1 day of dosing. Mean Cmax and AUC(0,12 h) increased with increasing dose, with apparent dose-proportionality between the 20 and 60 mg dose levels. Trough-to-peak ratios at steady state ranged from 2 to 5. Accumulation ratios for the fixed-dose regimens were 1.49 and 1.48 at the 5 and 20 mg dose levels, respectively. Ziprasidone was associated with transient prolactin elevation but levels of prolactin returned to baseline within the dosing interval at steady state. There was a marginal, transient increase in serum prolactin levels which was not dose-related at the 80 and 120 mg day,,1 doses, and which was noted to attenuate with chronic dosing. Ziprasidone was generally well tolerated. The most frequent side-effect was mild or moderate headache. A minority of patients suffered first-dose postural hypotension. Ziprasidone was also associated with a mild sedative effect that became less pronounced as treatment continued. There were no drug-related changes in electrocardiogram or clinical laboratory variables that were of clinical importance. Conclusions, Ziprasidone is characterized by a predictable pharmacokinetic profile resulting in symptoms that reflect its pharmacological action. [source] Characterization of the anticonvulsant profile and enantioselective pharmacokinetics of the chiral valproylamide propylisopropyl acetamide in rodentsBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2003Nina Isoherranen Propylisopropyl acetamide (PID) is a new chiral amide derivative of valproic acid. The purpose of this study was to evaluate the anticonvulsant activity of PID in rodent models of partial, secondarily generalized and sound-induced generalized seizures which focus on different methods of seizure induction, both acute stimuli, and following short-term plastic changes as a result of kindling, and to assess enantioselectivity and enantiomer,enantiomer interactions in the pharmacokinetics and pharmacodynamics of racemic PID and its pure enantiomers in rodents. Anticonvulsant activity of (S)-PID, (R)-PID and racemic PID was evaluated in the 6 Hz psychomotor seizure model in mice, in the hippocampal kindled rat, and in the Frings audiogenic seizure susceptible mouse. The pharmacokinetics of (S)-PID and (R)-PID was studied in mice and rats. In mice (S)-PID, (R)-PID and racemic PID were effective in preventing the 6 Hz seizures with (R)-PID being significantly (P<0.05) more potent (ED50 values 11 mg kg,1, 46 mg kg,1 and 57 mg kg,1 at stimulation intensities of 22, 32 and 44 mA, respectively) than (S)-PID (ED50 values 20 mg kg,1, 73 mg kg,1 and 81 mg kg,1 at stimulation intensities of 22, 32 and 44 mA, respectively). (S)-PID, (R)-PID and racemic PID also blocked generalized seizures in the Frings mice (ED50 values 16 mg kg,1, 20 mg kg,1 and 19 mg kg,1 respectively). In the hippocampal kindled rat a dose of 40 mg kg,1 of (R)- and (S)-PID prevented the secondarily generalized seizure, whereas racemic PID also blocked the expression of partial seizures following an i.p. dose of 40 mg kg,1. Racemic PID also significantly increased the seizure threshold in this model. Mechanistic studies showed that PID did not affect voltage-sensitive sodium channels or kainate-, GABA- or NMDA- evoked currents. The pharmacokinetics of PID was enantioselective following i.p. administration of individual enantiomers to mice, with (R)-PID having lower clearance and longer half-life than (S)-PID. In rats and mice, no enantioselectivity in the pharmacokinetics of PID was observed following administration of the racemate, which may be due to enantiomer,enantiomer interaction. This study demonstrated that PID has both enantioselective pharmacokinetics and pharmacodynamics. The better anticonvulsant potency of (R)-PID in comparison to (S)-PID may be due to its more favorable pharmacokinetic profile. The enhanced efficacy of the racemate over the individual enantiomers in the kindled rat may be explained by a pharmacokinetic enantiomer,enantiomer interaction in rats. This study also showed the importance of studying the pharmacokinetics and pharmacodynamics of chiral drugs following administration of the individual enantiomers as well as the racemic mixture. British Journal of Pharmacology (2003) 138, 602,613. doi:10.1038/sj.bjp.0705076 [source] | ||||||||||||||||||||||||||||||||||