Deuterium-substituted L-DOPA displays increased behavioral potency and dopamine output in an animal model of Parkinson's disease: comparison with the effects produced by L-DOPA and an MAO-B inhibitor.

The most effective treatment of Parkinson's disease (PD) L-DOPA is associated with major side effects, in particular L-DOPA-induced dyskinesia, which motivates development of new treatment strategies. We have previously shown that chronic treatment with a substantially lower dose of deuterium-substituted L-DOPA (D3-L-DOPA), compared with L-DOPA, produced equal anti-parkinsonian effect and reduced dyskinesia in 6-OHDA-lesioned rats. The advantageous effects of D3-L-DOPA are in all probability related to a reduced metabolism of deuterium dopamine by the enzyme monoamine oxidase (MAO).

Cardiovascular effects, pharmacokinetics and cross-reactivity in digitalis glycoside immunoassays of an antidiarrheal uzara root extract.

Uzara glycosides (UG) extracted from Xysmalobium undulatum are used for treating non-specific diarrhea.Cross-reactivity has been described for UG in digitalis glycoside assays but digitalis-like cardiac effects are controversially discussed. Therefore, we performed a randomized, singleblind cross-over study in 18 healthy volunteers receiving a commercially available Uzara product (Uzara® Lösung N, Stada AG, Bad Vilbel, Germany (ULN)), digoxin (1 mg, i.

Deuterium substitutions in the L-DOPA molecule improve its anti-akinetic potency without increasing dyskinesias.

Treatment of Parkinson's disease is complicated by a high incidence of L-DOPA-induced dyskinesias (LID). Strategies to prevent the development of LID aim at providing more stable dopaminergic stimulation. We have previously shown that deuterium substitutions in the L-DOPA molecule (D3-L-DOPA) yield dopamine that appears more resistant to enzymatic breakdown.

Synergistic effects of deuterium oxide and gemcitabine in human pancreatic cancer cell lines.

Purpose: Pancreatic cancer still remains a treatment-refractory cancer. Standard therapy for metastatic cancer is gemcitabine (dFdC) chemotherapy. Since heavy water (deuterium oxide, D2O) was shown to be active in pancreatic cancer in vitro, we examined the simultaneous or sequential cytotoxic effects of D2O and dFdC in pancreatic cancer cell lines (AsPC-1, BxPC-3, and PANC-1).

Changed phosphodiesterase selectivity and enhanced in vitro efficacy by selective deuteration of sildenafil.

In order to explore whether selective deuteration of sildenafil affects selectivity and efficacy of the drug, the inhibitory activity of sildenafil (1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl-sulfonyl] -4-methylpiperazine citrate, CAS 139755-83-2) and three deuterated sildenafil derivatives, D8-piperazine-sildenafil (BDD-10402), D3-methyl-D8-piperazine-sildenafil (BDD-10403) and D5-ethoxy-Sildenafil (BDD-10406) against phosphodiesterases 1-6 was compared. Furthermore, the relaxant effect of sildenafil and its deuterated derivatives in a contractility assay on rabbit corpus cavernosum strips from New Zealand rabbits was investigated. BDD-10406 exhibits a 2-fold higher selectivity for phosphodiesterase 5 versus phosphodiesterase 6 than sildenafil.

Enhanced plasma concentration by selective deuteration of rofecoxib in rats.

The plasma concentrations of BDD-11602 (4-[4- (methanesulfonyl)phenyl]-3-(pentadeuterophenyl)-5H-furan-2-one), a rofecoxib derivative in which the positions 2',3;4',5' and 6' of the phenyl ring were deuterated, and rofecoxib (4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one, CAS 162011-90-7) were compared in order to explore the effects of selective deuteration on the systemic availability. The COX-2 selectivity in vitro was also compared. Following oral gavage administration of 0.

Hypericum extract LI 160 and fluoxetine in mild to moderate depression: a randomized, placebo-controlled multi-center study in outpatients.

Efficacy and tolerability of Hypericum LI 160 was compared to fluoxetine and placebo in mild to moderate Major Depression (DSM-IV) in a 4-week randomized, double-blind trial. One hundred and sixty-three outpatients from 15 general practitioner centers received either 900 mg Hypericum LI 160, 20 mg fluoxetine, or placebo daily. Amelioration was measured by the Hamilton and the Montgomery-Asberg Depression scales.

Evaluation of the efficacy of a combined formulation (Grippostad-C) in the therapy of symptoms of common cold: a randomized, double-blind, multicenter trial.

Background: The aim of the present trial was to evaluate the efficacy of a combined product in the treatment of common cold and to examine the contribution of the separate components. In the published literature there is conflicting data on the efficacy of agents used in the treatment of common cold, especially when given in drug combinations.

Methods: A prospective, randomized, double-blind, multicenter, 4-arm, controlled trial was carried out in 1,167 patients with common cold treated with one of the following medications: Grippostad-C, a combination of acetaminophen, caffeine, chlorpheniramine and ascorbic acid (verum), ascorbic acid (control), chlorpheniramine and ascorbic acid (reference 1), as well as acetaminophen, caffeine, and ascorbic acid (reference 2).

Balm mint extract (Lo-701) for topical treatment of recurring herpes labialis.

A double-blind, placebo-controlled, randomized trial was carried out with the aim of proving efficacy of standardized balm mint cream [active ingredient: 1% Lo-701--dried extract from Melissa officinalis L. leaves (70:1)] for the therapy of herpes simplex labialis. Sixty six patients with a history of recurrent herpes labialis (at least four episodes per year) in one center were treated topically; 34 of them with verum and 32 with placebo.

Influence of the cytochrome P4502D6*4 allele on the pharmacokinetics of controlled-release metoprolol.

Aim: The aim of the present paper was to compare the pharmacokinetics of metoprolol in homozygous Caucasian volunteers for the wild-type CYP2D6 allele (CYP2D6*1/CYP2D6*1) and heterozygous (CYP2D6*1/CYP2D6*4) Caucasians.

Methods: Thirty-six unrelated healthy male Caucasians were screened for two of the most frequently occurring mutant alleles (CYP2D6*3 and CYP2D6*4) using polymerase chain reaction (PCR). Twenty-four volunteers with a genotype suggesting a rapid hydroxylator phenotype were enrolled in a bioequivalence trial and each received in a randomized, cross-over fashion one of the three formulations compared.

Efficacy and tolerance of repeated oral doses of tolperisone hydrochloride in the treatment of painful reflex muscle spasm: results of a prospective placebo-controlled double-blind trial.

The efficacy and safety of oral tolperisone hydrochloride (Mydocalm) in the treatment of painful reflex muscle spasm was assessed in a prospective, randomized, double-blind, placebo-controlled trial. A total of 138 patients, aged between 20 and 75 years, with painful reflex muscle spasm associated with diseases of the spinal column or proximal joints were enrolled in eight rehabilitation centers. Patients were randomized to receive either 300 mg tolperisone hydrochloride or placebo for a period of 21 days.

Absolute bioavailability of oral immediate and slow release fluphenazine in healthy volunteers.

Objective: The present study was conducted with the aim of investigating the absolute bioavailability of fluphenazine in healthy volunteers after administration of immediate and slow release oral formulations.

Methods: The oral dose was 12 mg fluphenazine hydrochloride. The intravenous bolus dose was 2.

Influence of food on the bioavailability and some pharmacokinetic parameters of diprafenone--a novel antiarrhythmic agent.

Objective: The present study was done to investigate the effect of food on the bioavailability of diprafenone.

Methods: The most important pharmacokinetic parameters (Cmax, t1/2, AUC) and the relative oral availability of a solid oral preparation of racemic diprafenone were investigated when administered to fasting subjects and 10 min after a standard meal, in an open, randomised, crossover trial. Single oral doses of 100 mg were given on two different occasions, at least 1 week apart.

Effect of diprafenone on the pharmacokinetics of digoxin.

This study was conducted to investigate the effect of diprafenone on the steady-state pharmacokinetics of digoxin. Twelve healthy men, all rapid hydroxylators of debrisoquine, received digoxin (0.5 mg per day over 7 days with a loading dose of 2 x 1 mg) or digoxin and diprafenone (3 x 100 mg per day) in three different phases, without a wash-out period (phase 1, digoxin alone; phase 2, digoxin + diprafenone; phase 3, digoxin alone).

Clinical and urodynamic effects of propiverine in patients suffering from urgency and urge incontinence. A multicentre dose-optimizing study.

The efficacy and tolerability of propiverine hydrochloride (15, off 45, 60 mg/d) were evaluated in the treatment of 185 patients suffering from urgency/urge incontinence in an open, randomized, multicentre parallel-group trial lasting 21 days. The effects on bladder volume and pressure were assessed on the basis of urodynamics and micturition frequency. Subjective adverse reactions were recorded.

[The bioequivalence of two oral propafenone preparations].

The bioequivalence of two oral racemic propafenone (CAS 54063-53-5) preparations was tested in an open, randomised, crossover trial with administration of single doses of 300 mg on two different occasions with a washout period of 7 days. 24 healthy, male volunteers, all proved to be rapid hydroxylators of debrisoquine, were enrolled in the trial. The concentrations of R(+)-, S(-)-propafenone and 5-hydroxypropafenone (5-OH-propafenone) were measured up to 12 h after administration by means of a sensitive and specific HPLC method that allowed the simultaneous quantification of all three substances in plasma.

Serum concentration of piroxicam and inhibition of platelet aggregation in patients with rheumatoid arthritis and M. Bechterew.

An open trial was conducted in 22 in-patients with classic or definite rheumatoid arthritis (RA) and 17 in-patients with M. Bechterew with the aim to investigate the effect of increasing concentrations of piroxicam in vivo on the platelet aggregation in such patients. In all patients therapy with piroxicam (10 mg/d) was started after withdrawing other non-steroidal antiinflammatory drugs.

[Clinical and urodynamic effects of oral propiverine therapy in neurogenic urinary incontinence. A multicenter study for optimizing dosage].

The efficacy and tolerability of propiverine hydrochloride (in doses of 15, 30, 45 and 60 mg/day) were evaluated in the treatment of 66 patients suffering from neurogenic incontinence for 21 days in an open, randomized, multicentre, parallel-group trial. Evaluation of efficacy was based on changes in cystometry, flow measurements and micturition and that of safety on adverse reactions and blood chemistry. The bladder volume increased and bladder pressure decreased dose dependently; the ratio of the two increased by 0.

[Absolute bioavailability of chlorpromazine, promazine and promethazine].

The absolute bioavailability of the three phenothiazine neuroleptics, promazine (Sinophenin, CAS 58-40-2), chlorpromazine (Propaphenin, CAS 50-53-3) and promethazine (Prothazin, CAS 60-87-7) was tested in three single-dose cross-over studies. In each trial 12 to 14 healthy volunteers were enrolled. The single doses for promazine, promethazine and chlorpromazine were 100, 75 and 150 mg (orally) and 20, 50 and 50 mg (intravenously), resp.

Differences in the bioavailability of dihydrotachysterol preparations.

The bioavailability of four preparations containing dihydrotachysterol (DHT2) was tested in two separate trials with administration of single, oral doses of 1 mg per individual. The relative bioavailability of corresponding preparations (capsules vs capsules and oral solution vs oral solution) was tested in a randomised, cross-over pattern within the same group of volunteers. Two different groups of 24 healthy volunteers took part in each trial.

Digoxin concentrations in serum and cantharides blister fluid: correlations with cardiac response.

The relationship between the pharmacokinetics and dynamics of digoxin was investigated using a skin blistering technique that allows experimental access to tissue fluid concentrations. Eight healthy volunteers received digoxin, 1.0 mg, and placebo intravenously according to a double-blind crossover design.