Thomas D Bethke

Universitätsklinikum Tübingen · Division of Clinical Pharmacology

The objective of this project was to evaluate the quality and quantity of initial applications for a clinical trial according to § 7 of the German Good Clinical Practice (GCP) ordinance (German: GCP-Verordnung, GCP-V), the quality of evaluations of those applications by Ethics Committees (ECs)/Investigational Review Boards (IRBs) in Germany as well...

Osteoporosis leads to increased bone fragility and susceptibility to fracture. Additionally, the disease is often accompanied by pain and a reduced quality of life (QOL). These aspects have rarely been addressed in previously published studies of PTH, which have instead focused on bone density and fractures. The aim of the present study was to eval...

Roflumilast is a novel, orally active, selective phosphodiesterase 4 inhibitor recently approved in the European Union for the treatment of severe COPD. Roflumilast and its metabolites are mainly (70% of total radioactivity) eliminated via the kidneys as glucuronides. The potential impact of renal impairment on the pharmacokinetics of roflumilast a...

To investigate whether a pharmacokinetic drug-drug interaction exists between theophylline (THEO), a CYP1A2 substrate with a narrow therapeutic index, and the concomitant substrate roflumilast (ROF), a novel selective PDE4 inhibitor partially metabolized by CYP1A2. In an open-label, 2-period, crossover study, Treatment A (oral ROF 500 μg q.d. on Da...

Roflumilast is a novel, orally active, selective phosphodiesterase 4 inhibitor recently approved for the treatment of severe COPD. The pharmacological effect is mediated mainly by its active metabolite roflumilast N-oxide. This doubleblind, 2-period cross-over study was conducted to investigate the potential effects of concomitant roflumilast on ph...

Since more than two decades anti-inflammatory effects of inhibitors of phosphodiesterase-4 have been described in numerous cellular and animal studies and were finally confirmed in clinical trials. The path from an early, pioneering study with Ro20-1724 showing reduction of psoriatric plaque size in 1979 to modern PDE4 inhibitors such as oral aprem...

Osteoporosis is a progressive bone disorder. Its medical therapy typically involves calcium, vitamin D and antiresorptive drugs. The anabolic parathyroid hormones (PTHs) represent a major advance since they stimulate new bone formation. Two forms of recombinant human PTH (rhPTH) have been evaluated: the 34-amino acid fragment rhPTH(1-34) and the in...

To establish basic intravenous (IV) pharmacokinetics of roflumilast (ROF) and its pharmacologically active metabolite roflumilast N-oxide (R-NO) and to determine the absolute bioavailability of ROF in humans. In a randomized, open-label, 2-period, 2-sequence crossover study 12 healthy male subjects were randomized to receive ROF either orally (PO)...

Numerous interactions are known for digoxin, which is a drug with a narrow therapeutic index and a substrate of P-glycoprotein (P-gp). This study investigated potential effects of coadministration on pharmacokinetics and safety of both drugs when a single dose of digoxin was concomitantly administered with roflumilast under steady-state conditions....

The efficacy and safety profile of ciclesonide (CIC) in the treatment of asthma was evaluated in a large patient population in a real-life setting in Germany. 24,037 patients with persistent mild/moderate bronchial asthma were enrolled into three observational studies with identical design. Data were pooled and analyzed. Patients received ciclesoni...

After the regulatory approval has been obtained, epidemiological studies are acknowledged scientific medical research methods for a new drug which provide additional knowledge about routine application of the drug in clinical daily routine. These studies are performed according to the recommendations of both international and national expert associ...

The human circadian system is known to affect the pharmacokinetics and pharmacodynamics of several classes of respiratory disease medications. The current study involving 16 healthy adults investigated if the time-of-day of dosing of roflumilast, a novel phosphodiesterase-4 inhibitor, affects its pharmacokinetics. The rate of drug absorption (t(max...

A randomized, double-blind, 2-way crossover trial of 24 healthy volunteers investigated the influence of esomeprazole (CAS 119141-88-7) and pantoprazole (CAS 102625-70-7), both 1 x 40 mg orally for 11 days, on the pharmacokinetics and pharmacodynamics of diazepam (CAS 439-14-5). Single-dose intravenous diazepam 0.1 mg/kg was administered on day 6....

Rationale: Roflumilast (ROF) ist ein oral anwendbarer PDE4 Inhibitor, der bei Patienten mit COPD die Lungenfunktion verbessert und Exazerbationen reduziert. Die Bestimmung der pharmakokinetischen (PK) Charakteristika der Substanz sind zur Abschatzung der Sicherheit und Vertraglichkeit von entscheidender Bedeutung. Methoden: In 5 Phase I Studien wur...

Rationale: Der orale Phosphodiesterase 4 (PDE4)-Inhibitor Roflumilast (ROF) verbessert bei COPD-Patienten (Pts) die Lungenfunktion. Untersucht wurde, ob bei gleichzeitiger Gabe von ROF und dem langwirksamen Bronchodilatator Tiotropium (TIO) eine weitere Verbesserung der Lungenfunktion moglich ist. Methode: Bei Pts mit moderater bis schwerer COPD mi...

Research into the therapeutic efficacy of a preparation, its safety and tolerability in the human body, as well as its development into a medicinal product is governed by strict legal provisions and regulations such as those stipulated in the German Drug Law (AMG) and the German Ordinance for Good Clinical Practice in Trials on Medicinal Products f...

Roflumilast is an orally administered phosphodiesterase 4 inhibitor that has potential for use in pediatric patients with asthma. The pharmacokinetics of roflumilast and roflumilast N-oxide were examined in adolescents and children with stable mild to moderate asthma in an open-label crossover study with age-stratification and 2 treatment periods (...

Roflumilast is a targeted oral once-daily administered phosphodiesterase 4 (PDE4) inhibitor with clinical efficacy in chronic obstructive pulmonary disease (COPD). Results from in vitro studies with roflumilast indicate that it has anti-inflammatory properties that may be applicable for the treatment of COPD. In a crossover study, 38 patients with...

This open-label, randomized, 3-period crossover study evaluated the pharmacokinetic interaction potential of roflumilast and budesonide following repeated coadministration to healthy male subjects (N = 12). Treatments consisted of oral roflumilast 500 mug, once daily, orally inhaled budesonide 800 mug, twice daily, and concomitant administration of...

Ciclesonide is an onsite-activated inhaled corticosteroid (ICS) for the treatment of asthma. This study compared the efficacy, safety and effect on quality of life (QOL) of ciclesonide 160 microg (ex-actuator; nominal dose 200 microg) vs. budesonide 400 microg (nominal dose) in children with asthma. Six hundred and twenty-one children (aged 6-11 yr...

The dose-proportional, intraindividual, single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor under investigation for chronic obstructive pulmonary disease and asthma, was investigated in healthy subjects. In an open, randomized, 2-period, 2-sequence crossover study, 15 subjects received immedi...

Evaluation of the response of gastroesophageal reflux disease (GERD) symptoms to treatment would be facilitated by a brief, valid, reliable and responsive, self-assessed GERD-sensitive scale. We therefore developed the Reflux Questionnaire (ReQuest). This publication describes the psychometric evaluation and validation of ReQuest. This second phase...

Roflumilast is an oral, once-daily phosphodiesterase 4 inhibitor under investigation for the treatment of chronic obstructive pulmonary disease and asthma. In clinical practice, the drug is likely to be co-administered with inhaled bronchodilating beta2-adrenoceptor agonists. Therefore, this study investigated the pharmacokinetic characteristics of...

This open, randomized, single-dose crossover study investigated effects of a high-fat meal on the pharmacokinetics of roflumilast and its major active N-oxide metabolite. Twelve healthy subjects received oral roflumilast 500 microg (2 x 250 microg) after overnight fasting and after breakfast. Blood was sampled up to 54 hours for pharmacokinetic pro...

BACKGROUND: Pantoprazole is a substituted benzimidazole which is a potent inhibitor of gastric acid secretion by its action upon H+, K+- ATPase. METHODS: Pantoprazole 40 mg and 80 mg were compared in a randomized double-blind study in 192 out-patients with stage II or III (Savary-Miller classification) reflux oesophagitis. Patients received either...

Ciclesonide is an inhaled corticosteroid that provides safe and effective control of persistent asthma. Ciclesonide is administered as an aerosol solution in a metered-dose inhaler, using hydrofluoroalkane-134a as a propellant. It is activated in the lung to form its only active metabolite, desisobutyryl-ciclesonide (des-CIC). A spacer may be used...

Drug deposition is an important factor that contributes to safety and efficacy outcomes of inhaled steroid therapy. Ciclesonide is a nonhalogenated, inhaled corticosteroid under investigation for the treatment of asthma. Therefore, this study was performed to assess lung deposition of ciclesonide. Technetium-99m (99mTc)-labeled ciclesonide (where t...

To evaluate whether the inflammatory process and bronchial constriction associated with asthma influence the pulmonary distribution and airway penetration of inhaled ciclesonide by investigating the pharmacokinetics of ciclesonide and its active metabolite, desisobutyryl-ciclesonide (des-CIC) in patients with asthma and matched healthy subjects. 12...

Chronic obstructive pulmonary disease (COPD) is characterised by progressive airflow limitation associated with chronic inflammation. There are few treatment options for the disease. This study assessed the efficacy and safety of roflumilast, a phosphodiesterase-4 inhibitor, in patients with moderate to severe COPD. This phase III, multicentre, dou...

To investigate whether systemic exposure to desisobutyrylciclesonide (des-CIC) (the pharmacologically active metabolite of ciclesonide) and erythromycin are affected by combined administration of ciclesonide and erythromycin. 18 healthy subjects were enrolled in a Phase 1, open-label, randomized, three-period crossover study. Each subject received...

Inhaled corticosteroids may cause oropharyngeal side effects if deposited in the oropharynx in active form. Ciclesonide, an inhaled corticosteroid with low glucocorticoid receptor affinity, is activated primarily in the lung by esterases to an active metabolite, desisobutyryl-ciclesonide (des-CIC), with high glucocorticoid receptor affinity. We stu...

Roflumilast (ROF) is an oral PDE4 inhibitor in development for COPD and asthma. To date, the pharmacokinetics (PK) of ROF and its active N-oxide metabolite (RNO) have been characterized only in adults.Methods13 children (c; 6-10y) and 12 adolescents (a; 11-16y) with mild asthma enrolled in an open, 2-period parallel study stratified by age. subject...

Background/Aims: Evaluation of the response of gastroesophageal reflux disease (GERD) symptoms to treatment would be facilitated by a brief, valid, reliable and responsive, self-assessed GERD-sensitive scale. We therefore developed the Reflux Questionnaire (ReQuest™). This publication describes the psychometric evaluation and validation of ReQuest™...

RationaleCiclesonide, a novel inhaled corticosteroid for the treatment of asthma, is administered via MDI as a solution-aerosol with high lung deposition (52%). Although a spacer is generally not required, some patients may benefit from the use of such a device. Therefore, as a surrogate for lung deposition, the pharmacokinetics of ciclesonide when...

RationaleMany immune effector cells that are implicated in asthma express phosphodiesterase 4 (PDE4). Inhibition of PDE4 decreases eosinophil chemotaxis and tissue infiltration. Roflumilast is a novel, potent, selective PDE4 inhibitor in clinical development for the treatment of asthma and COPD.

RationaleRoflumilast is a novel, potent, selective phosphodiesterase 4 (PDE4) inhibitor in clinical development for the treatment of COPD and asthma. In humans, Roflumilast is metabolized to the pharmacologically active compound Roflumilast N-oxide. This study determined the bioavailability of Roflumilast after oral administration and assessed phar...

Ciclesonide is a novel inhaled corticosteroid developed for the treatment of asthma. To investigate the extent of oral absorption and bioavailability of ciclesonide referenced to an intravenous infusion. This information provides an estimate for the contribution of the swallowed fraction to systemic exposure to ciclesonide after oral inhalation. In...

Unlabelled: The new inhalative glucocorticoid ciclesonide which is activated in lung to a more potent metabolite was hypothesized to have low risk for systemic and local side-effects in man. Therefore, a placebo-controlled, randomized, double-blind, four-period, change-over equivalence study in 12 healthy male volunteers (age 21-28 yr, body weight...

Roflumilast is a new phosphodiesterase 4 (PDE4) inhibitor developed by Byk Gulden Pharmaceuticals for the treatment of chronic obstructive pulmonary disease and asthma. A placebo-controlled, randomized, double-blind, two-period crossover study was performed to investigate the safety and efficacy of roflumilast in 16 patients with exercise-induced a...

The beneficial effects of phosphodiesterase 4 (PDE4) inhibitors in allergic asthma have been shown in previous preclinical and clinical studies. Because allergic rhinitis and asthma share several epidemiologic and pathophysiologic factors, PDE4 inhibitors might also be effective in allergic rhinitis. The main objective of this study was to investig...

The dose-dependency of budipine pharmacokinetic characteristics was studied. Eighteen healthy male subjects were given 10, 20 and 30 mg oral single doses according to a randomized, open, 3-period crossover design. Additionally, the steady state conditions were investigated after repeated intake of 10 mg t.i.d for 10 days and compared to the 10 mg s...

The aim of this study was to compare the efficacy and tolerability of low dose pantoprazole (20 mg) (a gastric proton pump inhibitor) with standard dose ranitidine (300 mg) (a histamine-receptor antagonist), in their ability to relieve symptoms and heal oesophageal lesions associated with gastrooesophageal reflux disease (GORD). Patients with endos...

Background and aim: The aim of this study was to compare the efficacy and tolerability of low dose pantoprazole (20 mg) (a gastric proton pump inhibitor) with standard dose ranitidine (300 mg) (a histaminereceptor antagonist), in their ability to relieve symptoms and heal oesophageal lesions associated with gastrooesophageal reflux disease (GORD)....

To investigate the efficacy and safety of an intravenous-oral regimen using the gastric proton pump inhibitor pantoprazole. Outpatients, with endoscopically diagnosed moderate or severe gastro-esophageal reflux disease (GERD stage II and III, respectively, Savary-Miller classification), were recruited from ten hospitals or private practice centers...

Objective: Eradication of Helicobacter pylori (H. pylori) is recommended as the first-line therapeutic concept for reliable long-term prevention of duodenal ulcer (DU) relapse. Current treatment regimens vary in efficacy, complexity, and compliance. To assess the efficacy of pantoprazole in H. pylori eradication in parallel groups of patients using...

Eradication of Helicobacter pylori (H. pylori) is recommended as the first-line therapeutic concept for reliable long-term prevention of duodenal ulcer (DU) relapse. Current treatment regimens vary in efficacy, complexity, and compliance. To assess the efficacy of pantoprazole in H. pylori eradication in parallel groups of patients using two eradic...

Pantoprazole is a substituted benzimidazole which is a potent inhibitor of gastric acid secretion by its action upon H+, K+-ATPase. Pantoprazole 40 mg and 80 mg were compared in a randomized double-blind study in 192 out-patients with stage II or III (Savary-Miller classification) reflux oesophagitis. Patients received either pantoprazole 40 mg (n...

The effects of HN-10200 (2-(3-methoxy-5-methylsulfinyl-2-thienyl)-1H-imidazo(4,5-c)-pyridine HCl) and its derivatives HN-10201-sulfide and HN-10202-sulfone on the activities of the phosphodiesterase (PDE) isoenzyme activities isolated from ventricular myocardium of failing human hearts (end-stage myocardial failure, NYHA IV) were investigated. Four...

In a randomized, double-blind, two-period crossover study, pantoprazole 40 mg or placebo were given orally to 12 male volunteers for 2 weeks each. There was a wash-out period of at least 1 week between the two treatment periods. The effects of pantoprazole or placebo on cortisol and testosterone (primary criteria), and tri-iodothyronine, thyroxine,...

MCI-154 (0.3-100 microM) exerted a concentration-dependent positive inotropic effect in isolated guinea pig papillary muscles (EC50 0.8 microM). The efficacy of MCI-154 (253% of predrug value) was 1.7-fold higher than that of saterinone but comparable to that of milrinone. Carbachol markedly reduced the increase in force of contraction (FOC) of MCI...

The present study compared the cyclic nucleotide phosphodiesterase (PDE) activities in cardiomyocytes and ventricular cardiac tissue from guinea‐pigs. The aim of the study was to determine whether PDE activities in ventricular tissue accurately reflect the isoenzymes present in cardiomyocytes. In homogenates of cardiomyocytes and multicellular vent...

The effects of enoximone (MDL 17043, Perfan, CAS 77671-31-9) on the activities of the phosphodiesterase (PDE) isoenzymes I-IV and on force of contraction were investigated in ventricular preparations isolated from failing (end-stage myocardial failure, NYHA IV) and non-failing human hearts. In both tissues four PDE isoenzymes (PDE I-IV) with simila...

The phosphodiesterase (PDE) inhibitor isomazole increased the force of contraction to 278.3 +/- 89.1% (n = 7) of the predrug value in ventricular trabeculae carneae isolated from nonfailing human hearts. This effect can be attributed mainly to a PDE III or a combined PDE III/IV inhibition since at the concentration of the maximal positive inotropic...

The effects of the triazolopyrimidine trapidil (5-methyl-7-diethylamino-s-triazolo [1,5-alpha]pyrimidine, CAS 15421-84-8) on force of contraction, beating frequency and phosphodiesterase (PDE) activity were investigated in isolated preparations from guinea-pig hearts. The effects of 3-isobutyl-1-methylxanthine (IBMX), theophylline and milrinone wer...

1. The effects of adibendan (BM 14.478; 7,7-dimethyl-2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-fl benzimidazole-6-one) on force of contraction and beating frequency were analysed in guinea-pig electrically driven papillary muscles and spontaneously beating right auricles, respectively. The effects of 3-isobutyl-l-methylxanthine (IBMX) and milrino...

Aus: Naunyn-Schmiedeberg's Arch. Pharmacol. 337. 1988, S. 576 - 582 u.d.T.: Bethke, Thomas u.a. : Mechanism of action and cardiotonic activity of a new phosphodiesterase inhibitor, the benzimidazole derivative adibendan (BM 14.478), in guinea-pig hearts Hamburg, Univ., Diss., 1989.