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Therapeutics

Anti-anginal and anti-ischemic effects of the selective b-blocker talinolol in patients with stable angina pectoris

H.-D. Faulhaber, I. Weigmann, U. Lang, F. Weinsberg and B. Terhaag

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Volume 43 p. 63 - 70

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: [email protected]

Pharmacokinetics

Pharmacokinetics of oral talinolol following a single dose and during steady state in patients with chronic renal failure and healthy volunteers

M. Krueger, H. Achenbach, B. Terhaag, H. Haase, K. Richter, R. Oertel and R. Preiss

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Volume 39 p. 61 - 66

Abstract

M. Krueger¹, H. Achenbach², B. Terhaag³, H. Haase³, K. Richter⁴, R. Oertel⁴ and R. Preiss¹

¹Institute of Clinical Pharmacology, University of Leipzig, ²Department of Nephrology, University of Leipzig, ³Arzneimittelwerk Dresden GmbH, ASTA MEDICA AG and ⁴Institute of Clinical Pharmacology, Faculty of Medicine, University of Technology, Dresden, Germany
Objective: The objective of this study was to investigate the effect of renal impairment on the pharmacokinetics of the selective b1-receptor antagonist talinolol. Methods: Pharmacokinetic data were obtained in 12 healthy volunteers, 12 patients with renal impairment and 8 patients with terminal renal insufficiency after the oral administration of 100 mg talinolol and under steady state conditions (100 mg talinolol daily). Concentrations of talinolol in plasma, urine and dialysate during hemodialysis were measured with a validated HPLC-method. Results: Talinolol is absorbed quite rapidly from the gastrointestinal tract (tmax 2.5 – 4 h). Steady state conditions were reached within 3 – 4 days depending on renal function. The calculated mean elimination half-life (t1/2z) in healthy volunteers (11 male, 1 female) was about 12 h. After an oral dose of 100 mg, about 55% of the bioavailable talinolol is eliminated unchanged in the urine. This fraction is reduced to 25% in patients with moderate to severe renal failure. A strong correlation was found between the renal elimination of talinolol and creatinine clearance. In patients with renal failure, the delayed elimination leads to an increase in t1/2z and to a decrease in the apparent total body clearance. Steady state trough levels in these patients are about 2.2-fold higher than in volunteers. The hemodialysability of talinolol was low. Conclusion: The disposition of talinolol shows a strong dependence on the renal function. On the basis of the kinetic data for talinolol, dose reductions of 30 – 50% are recommended in subjects with moderate to severe renal impairment.Correspondence to:
Prof. Dr. R. Preiss; Institute of Clinical Pharmacology, University of Leipzig, Haertelstr. 16 – 18, 04107 Leipzig, Germany
Email: [email protected]

Original

Bioavailability of a new effervescent tablet of diclofenac

B. Terhaag, A. Hoffmann, M. Barkworth and B. Vens-Cappell

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Volume 38 p. 546 - 551

Abstract

B. Terhaag¹, A. Hoffmann¹, M. Barkworth² and B. Vens-Cappell²

¹Corporate Research and Development, ASTA Medica Group, Arzneimittelwerk Dresden, Radebeul, and ²Phoenix International McKnight, Hamburg,Germany
Objective: The bioavailability of a newly developed effervescent tablet containing 50 mg diclofenac Na (DIC-effervesc) was investigated and compared with an enteric-coated dragée (DIC-enteric). Subjects and method: 24 healthy, male and informed volunteers (mean body weight 78.8 kg, mean age 31.9 years) received in a randomized cross-over design a single dose of 50 mg diclofenac as DIC-effervesc and DIC-enteric. A total of 19 blood samples were obtained before and up to 12 h after administration according to the different properties of the galenic formulation. Diclofenac was analyzed by a sensitive HPLC method with a lower limit of quantification of 20 ng/ml. The bioavailability was compared as ratios of the geometric means of AUC0-¥ and Cmax. Results: DIC-effervesc shows no lag time, a tmax within 30 min and a double peak of Cmax in 15/24 subjects. The mean Cmax (arithm. mean ± SD) for DIC-effervesc is 950 ± 341 ng/ml (first Cmax) and for DIC-enteric 1364 ± 335 ng/ml. The mean AUC0-¥ (arithm. mean ± SD) amounts to 1097 ± 210 ng/ml´h for DIC-effervesc and 1262 ± 220 ng/ml´h for DIC-enteric. Based on the point estimator and the 90% interval DIC-effervesc is bioequivalent in respect to amount absorbed (86.4%; 81.8 – 91.3%). DIC-effervesc was well tolerated. Conclusion: The new effervescent tablet of diclofenac Na shows a rapid absorption without lag time, the same amount of absorption and a slightly lower Cmax (caused by a double peak phenomenon) in comparison to the enteric-coated dragée. A rapid onset of therapeutic effect is postulated in acute pain disorders.Correspondence to:
Prof. Dr. B. Terhaag; Arzneimittelwerk Dresden GmbH, Department of Medical Research, Meißner Straße 35, D-01445 Radebeul, Germany

Original Research

Efficacy and tolerability of flupirtine in subacute/ chronic musculoskeletal pain – results of a patient level, pooled re-analysis of randomized, double-blind, controlled trials

M.A. Ueberall, G.H.H. Mueller-Schwefe and B. Terhaag

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Volume 49 p. 637 - 647

Abstract

Hier wird der Text (inkl. Abbildungen und Tabellen) dem Verlag gestellt.

Efficacy and tolerability of flupirtine in subacute/ chronic musculoskeletal pain – results of a patient level, pooled re-analysis of randomized, double-blind, controlled trials

M.A. Ueberall¹, G.H.H. Mueller-Schwefe² and B. Terhaag³

¹Institute for Quality Assurance in Pain Therapy and Palliative Care Medicine, Nuremberg, ²Palliative- and Pain Center, Göppingen and ³TEVA/AWD.pharma, Radebeul, Germany
Introduction: Flupirtine, a nonopioid analgesic without antipyretic or antiphlogistic properties, constitutes a unique class within the group of WHO-I analgesics. First approved in Germany on a national level in 1989, this selective neuronal potassium channel opener evolved rapidly into one of the most preferred analgesics for the treatment of musculoskeletal pain in some European countries. However, its use outside Europe was limited due to a discrepancy between the empirical application of the drug and supporting evidence. As a consequence, the German Pain Society commissioned an independent research institute to perform a pooled re-analysis of all available data from randomized controlled trials (including some trial not yet published). Methods: A retrospective pooled analysis of the individual patient data from 8 randomized controlled Phase III – IV clinical trials was carried out which included patients with sub-acute and chronic musculoskeletal pain. The efficacy and tolerability of flupirtine at dosages of 100 – 400 mg/d were compared to placebo and/or active comparators. Data were pooled by treatment and by subject. The primary endpoint was the average change in pain intensity for the overall maintenance period. Results: A total of 1,046 patients was evaluated for efficacy and 1,095 patients for safety. Based on 3,337 pain assessments, treatment with flupirtine and active comparators resulted in significant reductions in pain intensity compared to baseline beginning from Day 4 (flupirtine) and Day 5 (comparators) and continuing up to the end of the study period as well as during the overall maintenance period (all p < 0.001). Flupirtine prooved to be non-inferior to the active comparators (p < 0.001) but showed a superior tolerability profile with a significantly lower number of patients reporting treatment emergent adverse events (28.6 vs. 39.1%, p < 0.001) and a significantly lower percentage of patients who prematurely discontinued study medication due to these adverse events (7.1 vs. 11.7%, p = 0.013). Limitations: The limitations in the study were confined to those inherent in the retrospective and pooled analysis design. Conclusion: On the basis of this pooled analysis of individual data from 8 controlled clinical trials involving patients suffering from sub-acute/chronic musculoskeletal pain, the efficacy of flupirtine was superior to placebo across its effective and approved dosage range. Flupirtine was at least as active as the active comparators and showed a superior tolerability profile with a significantly lower treatment discontinuation rate.Correspondence to:
Michael A. Ueberall, MD
Medical Director
Institute for Quality Assurance in Pain Therapy and Palliative Care Medicine
Institute for Neurological Sciences, Algesiology and Pediatrics
Theodorstraße 1
90489 Nuremberg, Germany
Email: [email protected]

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