Volume 45, No. 2/2007(February)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Pharmacodynamics
Acute hemodynamic effects of moderate doses of nebivolol versus metoprolol in patients with systolic heart failure
F. Triposkiadis, G. Giamouzis, G. Kelepeshis, G. Sitafidis, J. Skoularigis and V. Demopoulos
Abstract
F. Triposkiadis, G. Giamouzis, G. Kelepeshis, G. Sitafidis, J. Skoularigis and V. Demopoulos
Department of Cardiology, Larissa University Hospital, Larissa, Greece
Objectives: To determine the acute hemodynamic effect of moderate doses of nebivolol (vasodilating b1-selective blocker) vs. metoprolol tartrate (non-vasodilating b1-selective blocker) in systolic heart failure (SHF). Material and methods: 20 stable patients with SHF (left ventricular (LV) ejection fraction £ 35%) underwent right heart catheterization. Once a reproducible baseline was obtained, patients were randomized to 5 mg nebivolol PO (n = 10) or metoprolol tartrate 50 mg PO (n = 10). Hemodynamic studies were repeated hourly for the first 4 hours and at 6 hours. Results: Both agents caused bradycardia. Nebivolol caused additionally a decrease in systemic vascular resistance (SVR) and no significant change in pulmonary capillary wedge pressure (PCWP), and cardiac output (CO). In contrast, metoprolol caused a deterioration of LV systolic function characterized by a decrease in cardiac output, and an increase in SVR and PCWP. Conclusions: Treatment initiation with moderate doses of nebivolol is not associated with the adverse hemodynamic effects of metoprolol in patients with SHF. These findings suggest that a long up-titration period may not be necessary with nebivolol.Correspondence to:
F. Triposkiadis, MD, FESC, FACC Associate Professor of Cardiology, Director Department of Cardiology, Larissa University Hospital, P.O. Box 1425, 411 10 Larissa, Greece
Email: admin@triposkiadis.com
Therapeutics
Aspirin reduces cutaneous flushing after administration of an optimized extended-release niacin formulation
E.A. Cefali, P.D. Simmons, E.J. Stanek, M.E. McGovern and C.J. Kissling
Abstract
E.A. Cefali, P.D. Simmons, E.J. Stanek, M.E. McGovern and C.J. Kissling
1Kos Pharmaceuticals, Inc., Cranbury, NJ, 2MDS Pharma Services, Inc., Lincoln, NE, USA
Objective: Niacin is an effective treatment for dyslipidemia due to its favorable effects on multiple lipid parameters. Clinical utility of niacin is sometimes limited, however, because of cutaneous flushing. A once-daily, extended-release (ER) niacin formulation has been shown to significantly reduce flushing compared to immediate-release niacin. An optimized (reformulated) version of niacin ER has recently been developed and was shown in a previous study to significantly reduce flushing intensity (severity) compared to the non-optimized (commercial) formulation. The current study was designed to evaluate the effect of aspirin on various indices of flushing when administered with the optimized niacin ER formulation. Method: This was a randomized, double-blind, double-dummy, placebo-controlled flush provocation crossover study in healthy males. To increase the probability of flushing, subjects received a single dose of reformulated niacin ER 2,000 mg, which is the upper limit of the approved dosage range. Subjects received 650 mg aspirin orally either 30 minutes before or concomitantly with niacin ER, or placebo with niacin ER, in 3-way crossover fashion. The primary endpoint was the number of subjects who reported at least one flushing event. Secondary endpoints included the perceived intensity and duration of flushing symptoms. Results: In the 148 men who completed all treatments, aspirin significantly reduced flushing incidence (the primary endpoint) following administration of niacin ER compared with placebo. Among subjects receiving placebo, 77% of subjects reported flushing with niacin ER. Among subjects receiving aspirin, 53 – 61% of subjects reported flushing (pretreatment and concomitant treatment, respectively, both p < 0.001 compared with placebo) with niacin ER. Aspirin also significantly reduced intensity and duration of flushing (by 30 – 40%) compared with no aspirin. The two aspirin-containing treatments (i.e. pre- or concomitant treatment) were similar in their effects on flushing incidence, intensity and duration. Median intensity on a 100 mm visual analogue scale (VAS) was reduced from 33 mm with placebo to 19 – 23 mm with aspirin. Median duration was reduced from approximately 1 hour with placebo to 37 – 48 minutes with aspirin. Conclusion: Aspirin significantly reduced the incidence, intensity and duration of flushing associated with reformulated niacin ER. These results support the administration of aspirin prophylactically to decrease niacin-induced cutaneous flushing and to improve patient adherence and acceptability of chronic niacin treatment at therapeutic doses.Correspondence to:
M.H. Adams, PharmD, PhD; 8930 State Road 84, #141, Davie, FL 33324-4456, USA
Email: marijke@bellsouth.net
Therapeutics
Ibuprofen sodium dihydrate, an ibuprofen formulation with improved absorption characteristics, provides faster and greater pain relief than ibuprofen acid
P. Schleier, A. Prochnau, A.M. Schmidt-Westhausen, H. Peters, J. Becker, T. Latz, J. Jackowski, E.U. Peters, G.E. Romanos, B. Zahn, J. Lüdemann, J. Maares and B. Petersen
Abstract
P. Schleier, A. Prochnau, A.M. Schmidt-Westhausen, H. Peters, J. Becker, T. Latz, J. Jackowski, E.U. Peters, G.E. Romanos, B. Zahn, J. Lüdemann, J. Maares and B. Petersen
1Department of Maxillofacial Surgery/Plastic Surgery, Friedrich Schiller University, Jena, 2Department of Oral Surgery and Dental Radiology, Charité Universitätsmedizin Berlin, 3Department of Oral Surgery and Central Admittance, University Clinic of Düsseldorf, 4Department of Oral Surgery, School of Dental Medicine, University of Witten/Herdecke, 5Department of Oral Surgery and Implantology, University of Frankfurt am Main, Germany, 6Bayer Consumer Care AG, Basle, Switzerland, and 7Schlossweg 3, Grenzach-Wyhlen, Germany
Objective: The objective of this 6-hour study was to compare rate of pain relief, analgesic efficacy and tolerability of a novel ibuprofen formulation, ibuprofen sodium dihydrate, with that of ibuprofen acid in subjects with postoperative dental pain. Material and methods: The test formulation of ibuprofen sodium dihydrate (256 mg sodium salt) and the reference product both contain 200 mg ibuprofen. Subjects with moderate-to-severe pain after extraction of third molars were randomized to receive two tablets of either ibuprofen sodium dihydrate (198 subjects) or ibuprofen (198 subjects) in this double-blind, multicenter trial. Pain was measured using traditional descriptor scales and onset of analgesia assessed using the stopwatch method. Results: Median time to substantial pain relief occurred 14 minutes earlier in the ibuprofen sodium dihydrate group (p < 0.001). The first sign of pain relief, an increase in relief and time until the pain was half gone occurred significantly earlier and faster in the ibuprofen sodium dihydrate-treated patients (p < 0.02 – 0.00003). Corresponding numbers needed to treat were in the range 5 – 11. Reduction in pain intensity was evident within 5 minutes (p < 0.01) in the ibuprofen sodium dihydrate group compared to 15 minutes in the ibuprofen group. Pain intensity was reduced to half after 30 and 57 minutes in the ibuprofen sodium dihydrate and ibuprofen groups, respectively (p < 0.025). The overall analgesic efficacy in terms of summed pain intensity differences (SPID), total pain relief (TOTPAR) and remedication times in the two groups were similar. Both treatments were well tolerated and no serious events occurred. Conclusion: Ibuprofen sodium dihydrate provides faster and more efficacious pain relief during the first hour after intake when compared to a conventional ibuprofen acid formulation. The tolerability profiles are similar.Correspondence to:
B. Petersen; Bayer Consumer Care AG, Peter Merian-Straße 84, Postbox, 4002 Basel, Switzerland
Email: birte.petersen.bp@bayer.ch
Immunomodulation
Ethnic sensitivity study of fingolimod in white and Asian subjects
J.M. Kovarik, A. Slade, B. Voss, H. Schmidli, G.J. Riviere, F. Picard, Y. Sugita, R. Kawai, D. Mee-Lee and R.L. Schmouder
Abstract
J.M. Kovarik, A. Slade, B. Voss, H. Schmidli, G.J. Riviere, F. Picard, Y. Sugita, R. Kawai, D. Mee-Lee and R.L. Schmouder
1Novartis Pharmaceuticals, Basle, Switzerland, 2Hawaii Clinical Research Center, Honolulu, HI, USA
Objective: The authors compared the pharmacokinetics and pharmacological effects of the immunomodulator fingolimod in healthy white and Asian subjects for potential ethnic differences. Methods: White and Asian (Japanese) healthy subjects were demographically matched for sex, age and weight. Subjects received single 1.25 mg doses of fingolimod (6 ethnic pairs), 2.5 mg (7 pairs), 5 mg (6 pairs) or 5 mg/day for 7 days (6 pairs). The pharmacokinetics of fingolimod, major metabolites, peripheral blood lymphocyte counts and heart rate were characterized over 1 month after single-dose and 2 months after multiple-dose administration. Results: There were no clinically relevant differences in the fingolimod dose Cmax or dose AUC relationships between Asian subjects (slopes 0.84 and 1.05) versus white subjects (slopes 1.13 and 1.26) after single-dose administration. During multiple-dose administration, there were no clinically relevant interethnic differences in fingolimod accumulation ratios (6.6 ± 0.4 for whites, 7.0 ± 0.7 for Asians), area under the concentration-time curve (390 ± 73 versus 382 ± 106 ng ´ h/ml), or elimination half-life (7.4 ± 0.8 versus 7.9 ± 2.0 days). The acute decrease in lymphocyte counts after single- and multiple-dose fingolimod were similar in the two ethnic groups. The lymphocyte recovery rate to baseline after a 5 mg single dose and 5 mg/day multiple dose was reduced by 36 and 15% in Asian subjects compared with white subjects. The transient, acute decrease in heart rate after the first dose of fingolimod and the subsequent return to baseline was similar in the two ethnic groups. Conclusion: There were no marked differences between healthy white and Asian subjects in fingolimod single-dose and multiple-dose pharmacokinetics, lymphocyte trafficking and heart rate responses.Correspondence to:
J.M. Kovarik; Novartis Pharma Building WSJ103.426, 4002 Basle, Switzerland
Email: john.kovarik@Novartis.com
Pharmacokinetics
Considerable interindividual variation in the pharmacokinetics of tolperisone HCl
J.W. Bae, M.J. Kim, Y.S. Park, C.S. Myung, C.G. Jang and S.Y. Lee
Abstract
J.W. Bae, M.J. Kim, Y.S. Park, C.S. Myung, C.G. Jang and S.Y. Lee
1College of Pharmacy, Sungkyunkwan University, Suwon, 2University of Ulsan College of Medicine, Asan Medical Center, Seoul, 3College of Pharmacy, Chungnam National University, Daejeon, Korea
Objective: The aim of this study was to determine the pharmacokinetic profiles of oral tolperisone hydrochloride in healthy volunteers. Methods: After the oral administration of tolperisone hydrochloride, the plasma concentrations of tolperisone were measured in 15 healthy male Korean volunteers. The tolperisone concentration was determined using high-performance liquid chromatography with a C18 reverse-phase column. Results: Very large interindividual differences in the AUC and Cmax were detected after oral tolperisone HCl. The AUC0-¥ varied from 125.9 – 1,241.3 ng/ml ´ h, and the Cmax varied from 64.2 and 784.9 ng/ml. The tmax of tolperisone was 0.90 ± 0.31 h and the mean half-life was 1.00 ± 0.28 h. Conclusion: These results suggest that the pharmacological effect of oral tolperisone HCl varies between individuals, and the oral tolperisone HCl dose might need to be individualized.Correspondence to:
S.Y. Lee, PhD, Professor, Lab. of Pharmacology, College of Pharmacy, Sungkyunkwan University, Chunchun-dong, Suwon 440-746, Republic of Korea
Email: sylee@skku.ac.kr
Pharmacokinetics
Exenatide effects on statin pharmacokinetics and lipid response
P.A. Kothare, H. Linnebjerg, Z. Skrivanek, S. Reddy, K. Mace, A. Pena, J. Han, M. Fineman and M. Mitchell
Abstract
P.A. Kothare, H. Linnebjerg, Z. Skrivanek, S. Reddy, K. Mace, A. Pena, J. Han, M. Fineman and M. Mitchell
1Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA, 2Eli Lilly and Company, Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey, United Kingdom, 3Amylin Pharmaceuticals, San Diego, CA, USA
Objective: Exenatide is an adjunctive treatment for type 2 diabetes. Many patients with type 2 diabetes have dyslipidemia, which requires treatment with three hydroxy-3-methyl glutaryl coenzyme (HMG-CoA) reductase inhibitors (statins), hence, concurrent use of exenatide and statins is likely. Exenatide slows gastric emptying, which may alter the absorption rate of co-administered oral medications. Thus, the potential interaction between exenatide and statins was evaluated in two study settings. Methods: In an open-label, fixed-sequence, clinical pharmacology study, the plasma pharmacokinetics of lovastatin (40 mg after breakfast) in the presence and absence of exenatide (10 mg before breakfast and dinner) was evaluated in 21 healthy subjects. In a second clinical setting, changes in lipid profiles and statin dosage over 30 weeks in patients with type 2 diabetes were retrospectively compared (n = 180 exenatide 10 mg twice daily (BID), n = 168 placebo BID) in a combined analysis of three placebo-controlled, randomized exenatide Phase 3 trials. Results: In healthy subjects, exenatide decreased mean lovastatin area under the plasma concentration time curve from zero to infinity (AUC0-¥) and maximum plasma concentration (Cmax) by 40 and 28%, respectively, and increased median time to maximum plasma concentration (tmax) by 4 hours. In the exenatide Phase 3 trials, 30-week changes from baseline for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol, triglycerides and statin dosage were not significantly different between the exenatide and placebo groups treated with statins. Conclusions: Despite observed changes in lovastatin bioavailability in the pharmacokinetic drug interaction study, exenatide did not negatively affect long-term lipid profiles or statin dosage in patients with concurrent statin therapy. Thus, co-administration of exenatide does not require adjustment in statin dosage.Correspondence to:
P. Kothare, PhD; Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
Email: kotharep@lilly.com
TDM
Evaluation of therapeutic drug level monitoring of phenobarbital, phenytoin and carbamazepine in Iranian epileptic patients
A. Babaei and M.H. Eslamai
Abstract
A. Babaei and M.H. Eslamai
1Department of Pharmacology, 2Department of Neurology, Yazd University of Medical Sciences, Yazd, Iran
Objective: The antiepileptic drugs phenobarbital, phenytoin and carbamazepine are widely used for the treatment of partial and tonic-clonic seizures. Large inter-individual differences in pharmacokinetics of these drugs, and the intermittent nature of epileptic attacks, increase the need for therapeutic drug level monitoring of these drugs. Material and methods: In this study, data from the therapeutic drug monitoring of phenobarbital, carbamazepine and phenytoin in 328 epileptic patients were evaluated. Serum levels of drugs were determined in a University Department of Pharmacology by high-performance liquid chromatography. Results: In this study, approximately 56% of patients were treated with 1; 30% with 2; and 14% with 3 antiepileptic drugs. In patients receiving 1 antiepileptic drug, the percentages treated with phenobarbital, carbamazepine and phenytoin were 41, 38 and 21%, respectively. In patients who received carbamazepine, serum levels in 40% of the patients were in the range of 4 – 8 mg/ml and more than in the range 4 – 12 mg/ml in 74% of the patients. In phenobarbital-treated patients, serum levels in 73% of the patients were in therapeutic range of 10 – 40 mg/ml, and about 44% of phenytoin-treated patients had serum levels in therapeutic range of 10 – 20 mg/ml. Approximately 50% of carbamazepine- and phenytoin-treated patients and approximately 70% of phenobarbital-treated patients were completely controlled. The frequency of concentrations within the therapeutic ranges decreased in patients using more than 1 antiepileptic drug. In patients who received both phenobarbital and sodium valproate, serum levels of phenobarbital were significantly (p < 0.05) greater than in patients who were taking this drug in combination with carbamazepine or phenytoin. Conclusion: Our results indicate that serum levels of antiepileptic drugs, and the percentage of patients with complete seizure control are comparable with results obtained in other populations in previous studies.Correspondence to:
Dr. A. Babaei; Department of Pharmacology, Yazd University of Medical Sciences, Yazd, Iran
Email: A_BABAII@yahoo.com
Bioavailability Section
Comparative in vivo bioequivalence and in vitro dissolution of two cyclosporin A soft gelatin capsule formulations
A. Avramoff, A. Laor, R. Kitzes-Cohen, D. Farin and A.J. Domb
Abstract
A. Avramoff, A. Laor, R. Kitzes-Cohen, D. Farin and A.J. Domb
1Department of Medicinal Chemistry and Natural Products, School of Pharmacy-Faculty of Medicine, The Hebrew University, Jerusalem, 2Dexxon’s Center for Pharmacokinetic Evaluations, Or-Akiva, 3Clinical Pharmacology Unit and 4Department of Internal Medicine A, Carmel Medical Center, Haifa, Israel
Objective: A study was conducted to establish the bioequivalence between a newly developed cyclosporin A (CsA) oral formulation, Deximune® soft-gelatin capsules (Dexcel Ltd.) and Sandimmune Neoral® (Novartis Inc.). Materials and methods: The clinical investigation was designed as a randomized, open-labeled, two-period, two-treatment crossover study, in 24 healthy fasted male volunteers. The subjects were administered a single 200 mg CsA dose of either formulation. Serial venous blood samples were obtained over 24 hours after each administration to measure CsA in whole blood by a specific TDx-immunoassay. In addition, the comparative drug release rate was assessed using a dissolution apparatus test according to the USP-24 method. Results: For both treatments, a mean maximum blood concentration (Cmax) of approximately 1,200 ng/ml was obtained at about 1.6 hours (tmax) after administration and the geometric mean of the area under the blood concentration-time curve (AUC) both for test and reference was approximately 4,900 ng × h/ml. Bioequivalence was conclusively demonstrated for both rate (Cmax and tmax) and extent (AUC) of CsA absorption, between the two treatments. Moreover, the CsA blood concentration measurement at 2 hours after administration (C2), demonstrated equivalent results between the two products. The point estimates and their 90% confidence intervals were within the respective equivalence ranges for the pharmacokinetic parameters and were included in the range for drugs with a narrow therapeutic index. The comparative dissolution test for both formulations showed an in vitro release rate of more than 90% within 15 minutes. Conclusions: Based on the results, the two oral CsA formulations compared are bioequivalent and can be interchanged without need for dosage adjustment.Correspondence to:
Mgr. A. Avramoff, MPh; Department of Medicinal Chemistry and Natural Products, School of Pharmacy-Faculty of Medicine, The Hebrew University, Jerusalem, Israel
Email: rnd@dexxon.co.il
