Volume 43, No. 2/2005(February)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Therapeutics
Anti-anginal and anti-ischemic effects of the selective b-blocker talinolol in patients with stable angina pectoris
Abstract
H.-D. Faulhaber, I. Weigmann, U. Lang, F. Weinsberg and B. Terhaag
1Berlin, 2AWD.pharma GmbH and Co. KG, Clinical Research, Dresden and 3FOCUS Clinical Drug Development GmbH, Neuss, Germany
Objective: To determine the dose dependency of the anti-anginal and anti-ischemic effects of the selective b-blocker talinolol administered once-daily in a randomized, double-blind, placebo-controlled multicenter study in patients with stable angina pectoris. Methods: Standardized bicycle ergometry at baseline and after 3 and 6 weeks of treatment was used to assess exercise capacity. The primary endpoint was the change in the maximum exercise time (MET) 24 ± 1 h after the last intake of study medication compared to baseline. Secondary efficacy parameters were time to onset of angina, time to 1 mm ST segment depression, angina attacks, consumption of short-acting nitrates, blood pressure and pulse rate. Patients were randomly allocated to treatment with talinolol (100, 200 or 300 mg once daily) or placebo for a period of 6 weeks. Results: A total of 241 outpatients (204 male and 37 female) aged between 34 and 83 years, were randomized in 31 centers in Germany, Poland and the Czech Republic. At the end of treatment, the primary endpoint (change in MET compared to baseline) showed no significant difference between the talinolol groups and placebo. The means of MET prolongation ranged from 27.4 sec under placebo to a maximum of 47.6 sec in the 200 mg group. However, the time to 1 mm ST segment depression during exercise increased markedly with talinolol, the difference to placebo reaching statistical significance with the 200 mg/d dose (80.1 ± 32.7 sec, p = 0.0182) and 300 mg/d dose (82.0 ± 31.6 sec, p = 0.0127). In the case of the other secondary variables, the most pronounced effects were recorded for talinolol doses of 200 and 300 mg/d. Talinolol significantly inhibited the exercise-induced increase in heart rate and blood pressure. The decrease in rate pressure product at 100 W workload was statistically significant with all administered talinolol doses (D from baseline to final visit 3090, 4351 and 4291 for 100, 200 and 300 mg/d, respectively, p < 0.0001). Despite once-daily dosing, talinolol at doses up to 300 mg/d was very well tolerated. No unexpected adverse drug reactions were observed. Conclusion: The results show that talinolol administered once daily in a dosage of 200 – 300 mg/d is effective and safe in the management of chronic stable angina.Correspondence to:
I. Weigmann
AWD.pharma GmbH and Co. KG
Clinical Research
Leipziger Straße 7–13
01097 Dresden, Germany
Email: Ingo.Weigmann@awd-pharma.com
Therapeutics
Benfotiamine in the treatment of diabetic polyneuropathy – a three-week randomized, controlled pilot study (BEDIP Study)
Abstract
E. Haupt1, H. Ledermann2 and W. Köpcke3
1Saale-Klinik, Bad Kissingen, 2Eleonorenklinik, Lindenfels, and 3Institut für medizinische Informatik, Westfälische Wilhelms-Universität, Münster, Germany
Objective: The aim of the study was to evaluate the efficacy of benfotiamine administered over three weeks (allithiamine; a lipid-soluble vitamin B1 prodrug with high bioavailability) to patients with diabetic polyneuropathy in a randomized, placebo-controlled, double-blind, two-center pilot study. Material and methods: Forty inpatients (23 male, 18 female, age range 18 – 70 years) with a history of type 1 or 2 diabetes and polyneuropathy of not longer than two years, were included in the study. Twenty Patients received two 50 mg benfotiamine tablets four times daily and 20 patients received placebo over the three-week study period. Two clinical units were involved with 10 patients receiving placebo and 10 patients benfotiamine in each. The neuropathy score according to Katzenwadel et al. [1987] was used to evaluate symptoms of polyneuropathy, vibration perception threshold and both the physician’s and the patient’s own assessment were documented. Results: A statistically significant (p = 0.0287) improvement in the neuropathy score was observed in the group given active drug when compared to the placebo-treated controls. There was no statistically significant change observed in the tuning fork test. The most pronounced effect on complaints was a decrease in pain (p = 0.0414). More patients in the benfotiamine-treated group than in the placebo group considered their clinical condition to have improved (p = 0.052). No side effects attributable to benfotiamine were observed. The differences between the groups cannot be attributed to a change in metabolic parameters since there were no significant alterations in the HbA1 levels and blood sugar profiles. The body mass index of the two groups did not differ. Conclusion: This pilot investigation (BEDIP Study) has confirmed the results of two earlier randomized controlled trials and has provided further evidence for the beneficial effects of benfotiamine in patients with diabetic neuropathy.Correspondence to:
Prof. Dr. E. Haupt
Saale-Klinik
Pfaffstraße 10
97688 Bad Kissingen, Germany
Email: BfA.Saaleklinik@t-online.de
Pharmacokinetics
Duloxetine pharmacokinetics in cirrhotics compared with healthy subjects
Abstract
A. Suri, S. Reddy, C. Gonzales, M.P. Knadler, R.A. Branch and M.H. Skinner
1Eli Lilly and Company, Indianapolis, IN, 2UPMC Health System,
Pittsburgh, PA, and 3Neurocrine Biosciences, Inc.,
San Diego, CA, USA
Objective: To compare the pharmacokinetics of single-dose duloxetine in cirrhotic and healthy subjects. Methods: An open-label inpatient study compared duloxetine pharmacokinetics in six subjects with moderate liver cirrhosis (Child-Pugh class B) to those in six healthy subjects. Subjects received a single 20 mg capsule of duloxetine following overnight fasting. Blood samples were collected up to 120 h post dose for determination of plasma concentrations of duloxetine and its major metabolites using a validated LC/MS/MS method. Plasma concentration-time data for duloxetine and its major metabolites were analyzed by noncompartmental methods. Specific pharmacokinetic parameters were assessed statistically using a mixed-effects model. Results: Duloxetine apparent clearance was significantly lower (24 vs 160 l/h, p < 0.05) and AUC values were substantially higher (775 vs 268 ng × (h/ml) in cirrhotic compared to healthy subjects. The half-life of duloxetine was about three times longer (47.8 vs 13.5 h) in cirrhotic than in healthy subjects (p < 0.05). In contrast, there was no significant difference in Cmax or apparent volume of distribution between the two groups. The metabolites exhibited lower levels and longer half-lives in cirrhotic subjects compared to healthy subjects. The lower clearance and slower elimination of duloxetine in cirrhotic individuals is likely attributable to impaired duloxetine metabolism. Conclusions: The rate of duloxetine elimination is reduced for cirrhotic subjects, making dosage adjustments appropriate. Based on simulations, the duloxetine dose for at least an initial treatment period may need to be reduced and/or less frequently administered for patients with moderate cirrhosis.Correspondence to:
A. Suri, PhD
Lilly Corporate Center
Drop Code 0724
Indianapolis, IN 46285, USA
Email: Suri_Ajit@lilly.com
Pharmacokinetics
Pharmacokinetics of prednisolone in man during acute and chronic exposure to high altitude
Abstract
A. Arancibia1, M.N. Gai1, J. Chávez1, C. Paulos1, E. Pinilla1, C. González1, S. Villanueva1 and W.A. Ritschel2
1Faculty of Chemical and Pharmaceutical Sciences, University of Chile,
Santiago, Chile, and 2Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati, OH, USA
Introduction: The exposure to high altitude (H) produces several physiologic alterations which may induce changes in the pharmacokinetics of drugs. This hypothesis has been confirmed in previous studies which suggest that drugs which are highly bound to plasma proteins are most likely to exhibit altered pharmacokinetics. Objectives: To further elucidate the influence of H on pharmacokinetics, prednisolone was selected, since it is highly bound to plasma proteins, renally excreted and poorly bound to red blood cells. Subjects, materials and methods: Prednisolone (80 mg) was given orally to three groups of young healthy volunteers. One group was residing at sea level (L): the same volunteers were studied again after 15 hours of exposure to high altitude (3600 m, HA group), and volunteers living at H for at least six months (group HC). Results: There were no statistically significant differences in the pharmacokinetic parameters calculated from plasma data in the three situations studied. When calculated from whole blood data, however, AUC and Cmax were increased and both volume of distribution and clearance diminished after exposure to H, either acute or chronically. Binding to proteins increased significantly after H exposure from 57% in group L to 75% and 94% in group H and HC, respectively. Binding to erythrocytes also increased with H exposure from 43.7% in group L to 50.6% and 61.6% in group HA and HC, respectively. The prednisolone/prednisone ratio in urine was 11.1 in group L, 7.3 in group HA and 45.6 in group HC. Conclusion: Since prednisone has very little intrinsic glucocorticoid activity and has to be converted to prednisolone for therapeutic effect, the alteration of the prednisolone/prednisone ratio, as a result of high altitude exposure could be clinically relevant. Additional experiments are desirable to further evaluate this observation.
Correspondence to:
Prof. Dr. A. Arancibia
Facultad de Ciencias Químicas y Farmacéuticas
Universidad de Chile
PO Box 233
Santiago 1, Chile
Email: aarancib@uchile.cl
Pharmacodynamics
Attenuation of the kaluretic properties of furosemide by triamterene (Dyrenium®) in healthy volunteers
Abstract
B. Levinson, M. Shenouda and D. Stypinski
1WellSpring Pharmaceutical Corporation, Neptune, NJ, and
2MDS Pharma Services, Neptune, NJ, USA
Objective: To examine if concomitant administration of furosemide, a loop diuretic, with the potassium- and magnesium-sparing diuretic triamterene would decrease loss of potassium and magnesium while improving diuresis. Methods: In this open-label, three-way crossover study, healthy subjects were randomized to receive treatment with 40 mg furosemide, with 150 mg triamterene, or treatment with 40 mg furosemide and 150 mg triamterene. Urine samples were collected 24 hours before dosing and between 0 – 1, 1 – 2, 2 – 3, 3 – 4, 4 – 6, 6 – 8, 8 – 12, and 12 – 24 hours post-dosing. Sodium and potassium levels were measured by an ion-selective electrode method. Magnesium was measured colorimetrically using a xylidyl blue reaction. Results: Co-administration of furosemide with triamterene resulted in enhanced diuresis, particularly in the first 0 – 12 hours post-dose, compared with either furosemide or triamterene alone. Compared to individual treatments, combination therapy significantly increased urinary sodium excretion (p = 0.0001) while significantly decreasing urinary potassium excretion (p = 0.0001); importantly, the magnesium-sparing characteristic of triamterene was retained with furosemide co-administration. Conclusion: Triamterene, when used in combination with the loop diuretic, furosemide, preserves intracellular potassium and magnesium while enhancing the natriuretic effect of furosemide.Correspondence to:
Dr. B. Levinson
Vice-President of Drug Development
WellSpring Pharmaceutical Corporation
1430 State Route 34
Neptune, NJ 07753-6807, USA
Email: blevin@wellspringpharm.com
Pharmacodynamics
Propranolol increases the complexity of heart rate fluctuations – a mode of antiarrhythmic action?
Abstract
A. Lepoluoto1, J. Nino1, K. Tahvanainen2, R. Ylitalo1, T. Kuusela3, M. Kähönen1,2 and T. Kaila4
1Department of Pharmacological Sciences, University of Tampere and
Department of Clinical Chemistry, Tampere University Hospital, Tampere, 2Department of Clinical Physiology, Tampere University Hospital, Tampere, 3Department of Physics, University of Turku, and
4Department of Occupational Medicine, Kuusamo Health Center, Kuusamo, Finland
Objective: To study the b-blocking effect of propranolol on heart rate and arterial blood pressure fluctuations in healthy subjects using linear methods and a set of nonlinear models. Methods: In a randomized, double-blind, placebo-controlled study, healthy young adults received a 40 mg oral dose of propranolol (n = 12) or placebo (n = 12). The effects of propranolol and placebo were assessed using time series of the RR interval (RRI) and systolic arterial blood pressure (SAP) obtained from continuous ECG and blood pressure signal recordings. Heart rate and systolic arterial blood pressure fluctuations were analyzed using nonlinear and linear methods of time series statistics. Results: Propranolol significantly increased the complexity of heart rate fluctuations in terms of symbol dynamic (SymDyn) entropy and symbol dynamic percentage of forbidden words. Propranolol augmented cross entropy between RRI and SAP and increased fractal dimension of RRI. b-blockade also affected linear measures of RRI fluctuations by increasing parasympathetic, respiration-related high-frequency (HF) variability and arterial baroreflex-related low-frequency (LF) variability. Propranolol administration, however, had no effect on the complexity of SAP fluctuations assessed using nonlinear time series statistics. Conclusions: b-blockade by propranolol has a differential effect on RRI and SAP fluctuations in healthy subjects. Propranolol increases the complexity of RRI fluctuations. The effect is associated with the cardiac vagotonic drug action of propranolol. SAP fluctuations are almost unchanged. The increased complexity of RRI fluctuations may be a beneficial feature of b-blockade, since many cardiovascular diseases decrease the complexity of RRI time series by dampening cardiovascular reflex actions.Correspondence to:
Dr. A. Lepoluoto
Department of Pharmacological Sciences
University of Tampere
33014 Tampere, Finland
Email: ahto@lepoluo.to
Bioavailability Section
Simultaneous itraconazole bioequivalence assessment and CYP3A phenotyping in South American subjects
Abstract
F.E. Estevez-Carrizo, S. Ruiz, B. Bellocq, C. Leal, M.T. Siri and M.J. del Campo
1Center for Biomedical Sciences, University of Montevideo,
2AllQuimia BioResearch Lab, Montevideo, Uruguay
Objective: The present study evaluates the acute effect of a single-dose itraconazole administration on CYP3A phenotype, as measured by cortisol MR ratio in urine. Methods: Twenty-four healthy Uruguayan subjects recruited according to strict inclusion criteria participated in an open-label, randomized, two-period, crossover study designed to evaluate the bioequivalence of an itraconazole formulation (Traconal® 100 mg, Achê Labs, São Paulo, Brazil). The study comprised two treatment periods separated by a wash-out period of 14 days. In each period a series of venous blood samples were drawn over 48 hours. Three urine samples were obtained for CYP3A phenotyping: pre-dose, 24 and 48 hours after dosing. Blood and urine samples were assayed for itraconazole, b-hydroxycortisol and cortisol using a validated chromatographic method. Results: The ratio of the mean AUC0-inf.T/AUC0-inf.R was included in the bioequivalence range, however, due to high variability, the CI90% was not. It was found that the cortisol metabolic ratio (MR) showed inhibition relative to basal activity in a proportion of subjects 24 hours (68 ± 6.1%, mean ± CI95%) and 48 hours (80 ± 7.3%, mean ± CI95%) after ingestion of itraconazole. A significant correlation was found between itraconazole AUC0-inf. and normalized basal CYP3A MR for the reference (r = 0.62, t = 3.72, p = 0.001) and the test product (r = 0.74, t = 5.22, p = 0.00003). A good correlation existed between basal cortisol MR and the elimination half-life of itraconazole. Conclusions: The findings are in line with the hypothesis that the determination of the bioavailability of highly variable CYP3A substrates might be improved by simultaneous non-interfering phenotyping. If this is confirmed, a new methodological paradigm may need to be developed in order to take account of metabolic variability in bioequivalence evaluation of this group of drugs.Correspondence to:
F.E. Estevez-Carrizo, M
Center for Biomedical Sciences
University of Montevideo
Prudencio de Pena 2440
Montevideo 11600, Uruguay
Email: festeve2@adinet.com.uy
