[Experimental investigation on the reproducibility of ensemble-averaged electromyographic gait analysis data in the area of experimental and clinical orthopaedics]. / Experimentelle Untersuchungen zur Reproduzierbarkeit von Ensemble-gemittelten elektromyographischen Ganganalysedaten im Bereich der experimentellen und klinischen Orthopädie.

With suitable application and signal processing methods, surface electromyography is a comparatively simple instrument for investigating the temporal pattern of the muscular activity of a walking subject. The influence of changes both in the external experimental conditions (e.g. orthopedic shoe design) and in the human locomotor system (due to disease or therapy) on the individual muscular gait characteristics can be documented in this way. The usefulness of this kind of investigation is basically limited by the reproducibility of the gait analytical findings of the subject, who is examined at different times with unchanged bodily state and under identical experimental conditions unchanged. In our experiments we observed that the reproducibility of electromyographic activity curves obtained by ensemble averaging over a sufficiently high number of full strides differs for different muscles and in different subjects. Within the same experimental session it is very high and considerably better than in experiments done on different days. In examinations done on different days the basic characteristics of the activity curves are reproduced better than the absolute height of the amplitudes. In view of these findings the differences observed in the gait analysis of patients in the course of operative or conservative therapy have to be interpreted very carefully as to their true origin.

Treatment of knee osteoarthritis with a topical non-steroidal antiinflammatory drug. Results of a randomized, double-blind, placebo-controlled study on the efficacy and safety of a 5% ibuprofen cream.

The efficacy and safety of a 5% ibuprofen cream (Dolgit cream) in primary knee osteoarthritis was assessed in this double-blind, randomized, placebo-controlled, parallel-group study with an adaptive sequential design. The background of the study was the need to confirm the efficacy of ibuprofen cream. Patients aged 40-75 years, with a visual analog scale (VAS) score of pain on motion of 40 mm, a Lequesne index score of 5-13 points, and a Kellgren and Lawrence radiographic score of grade II-III were enrolled between September 1999 and November 2000. The study medication was applied in a 10-cm strip t.i.d. for 7 days on the more painful knee. In the active group, each strip contained approximately 200 mg ibuprofen. The main outcome measure was the response rate to the treatment compared between both groups. Response was defined as a reduction of pain on motion, self-assessed on a VAS, of > or = 20 mm compared with baseline. The planned interim analysis after inclusion of 2 x 50 patients showed a response rate of 32 (64.0%) in the ibuprofen group and 15 (30.0%) in the placebo group (p = 0.000615). The study could then be terminated. All secondary endpoints, pain at rest, pain on pressure, Lequesne index and overall assessment, also confirmed the statistically significant differences between the groups. No drug-related adverse events were recorded. The study confirmed the efficacy of ibuprofen cream by demonstrating its statistically significant and clinically relevant superiority over the placebo cream in the treatment of primary knee osteoarthritis.

Antidepressant action of sulpiride. Results of a placebo-controlled double-blind trial.

The purpose of this multicenter, randomized, double-blind, placebo-controlled parallel-group comparative study was to prove the efficacy and tolerance of sulpiride (150-300 mg) against placebo in mild to moderate depressive syndrome. The primary criterion of efficacy was the course of the HAMD total score from day 1 to day 42, compared between the two treatment groups. The duration of the treatment was six weeks, preceded by a one-week placebo run-in phase. The HAMD, CGI and KUSTA scores were determined, the tolerance assessed, and the laboratory parameters and serum prolactin levels determined before, during and at the end of the trial. 177 outpatients aged from 18 to 70 years with mild to moderate depressive syndrome (ICD-10: F32.0, F32.1, F33.0, F33.1) and a score of 18-27 points on the 21-item HAMD scale were randomized, 171 of whom (sulpiride: n=83; placebo: n=88) were included in the intention-to-treat analysis. All the baseline data recorded for the two groups displayed comparable values. The decrease of the HAMD score between day 1 and day 42 yielded a difference of 2.5 points in favour of the sulpiride group. This difference is statistically significant (p = 0.0007). The evaluations of the cases treated for at least 14 days or for 42 days (per protocol) showed consistent values. The analysis of the CGI values showed similarly distinct and clinically relevant differences for sulpiride in comparison with placebo. The evaluation of the KUSTA scores yielded mostly comparable values for the two groups. Adverse events occurred with about the same type and frequency in both groups, with severe adverse events occurring only in two placebo patients. The laboratory parameters revealed no significant differences between the treatment groups, with the exception of prolactin which moderately exceeded the range of normal in 50% of the patients treated with sulpiride. This trial proved that sulpiride is effective and well-tolerated when given in a mean dose of 181 mg per day for mild and moderate depression.

Double-blind, randomised, placebo-controlled study of two concentrations of azelastine eye drops in seasonal allergic conjunctivitis or rhinoconjunctivitis.

This double-blind, randomised, placebo-controlled study was carried out to assess the efficacy and safety of 0.025% and 0.05% azelastine eye drops twice daily administered for 14 days to patients with seasonal allergic conjunctivitis or rhinoconjunctivitis. A total of 278 patients were recruited and 226 patients were evaluable for per protocol analysis. The target parameter was the response rate. Four eye symptoms, including the main symptom (itching) were recorded by patients in diaries and eight symptoms were assessed by physicians before and after seven and 14 days of treatment. Severity of symptoms was measured on a four-point scale. The response rates for itching (improvement of at least one score point within the first three days) according to patient assessment were 43% for placebo, 52% for 0.025% and 56% for 0.05% azelastine (NS). However, a more objective assessment of the three main eye symptoms by physicians showed a concentration-dependent improvement in response rate compared with placebo (a decrease of > or = 3 points from a baseline total score of > or = 6), which reached statistical significance for 0.05% azelastine on Day 7 (p < 0.002). In the evaluable patient population, the scores of the three main eye symptoms as well as of all eight recorded eye symptoms, as assessed by the physician, were significantly (p < 0.05) lower in the 0.05% azelastine eye drops group in comparison with the placebo group at Day 7. Inefficacy was the cause of withdrawal in five and three patients on 0.025% and 0.05% azelastine, respectively, and in six patients on placebo. Adverse drug effects, mainly a mild, transient irritation and a bitter or unpleasant taste, were reported by 14% (0.025%), 20% (0.05%) and 15% (placebo) of the patients. No serious side-effects occurred. Azelastine eye drops are effective and well tolerated at a concentration of 0.05% for the treatment of seasonal allergic conjunctivitis.

[Bioavailability of two verapamil formulations following repeated administration in steady-state conditions. An open, two-period, crossover study]. / Bioverfügbarkeit von zwei Verapamil-Zubereitungen nach Mehrfachapplikation unter Steady-state-Bedingungen. Eine offene Zwei-Perioden-Crossover-Studie.

The relative bioavailability of a new formulation of verapamil (CAS 52-53-9, Veramex 40) in comparison to a standard formulation was investigated in an open two-period cross-over study in 16 healthy volunteers under steady state conditions of 7 days duration each. For the estimation of verapamil a selective HPLC-method was used with fluorescence detection after direct injection and enrichment by column switching enabling a simultaneous separation and analysis of verapamil and N-norverapamil. The bioavailability was estimated using areas under the concentration-time curves (AUC), maximum serum concentrations (Cmax) and peak-trough fluctuation (PTF). Bioequivalence was tested calculating the 90% confidence intervals (ANOVAlog). The mean verapamil plasma profile after the test substance was up to 1.5 h slightly lower than the corresponding curve after the reference substance, thereafter slightly higher plasma levels up to 7 h were observed after the test substance. The individual plasma profiles had a similar variance, and hardly any difference was discernible between the two drugs. A similar behaviour was also seen for N-norverapamil. A mean relative bioavailability of 101% was observed after the test substance both for verapamil and N-norverapamil. The mean maximum plasma concentrations for verapamil and N-norverapamil were 50.0 and 49.7 ng/ml, respectively. After the standard formulation the corresponding values were 50.4 and 50.3 ng/ml. The mean PTF-values for verapamil and N-norverapamil were 178 and 76.6% after the test substance and 182 and 79.6% after the standard formulation, respectively. The 90% confidence intervals for AUC, Cmax and PTF for verapamil and N-norverapamil are completely within the accepted range of 80 to 125% for AUC, Cmax and PTF. Therefore bioequivalence between both formulations can be stated.

Ultrasound studies of the effect of trospium chloride on gall-bladder kinetics.

In a randomized double-blind study the effects of increasing doses of trospium chloride (Spasmo-lyt, CAS 10405-02-4), 0.2, 0.5, 1.0, and 1.5 mg i.v., on gall-bladder contractility were compared among themselves and against placebo and n-butylscopolamine bromide (20 mg i.v.) by an intraindividual 5-fold crossover technique. Gall-bladder volumes after drug-induced contraction (fat stimulus with sodium iopodate) were measured by ultrasound scanning conducted by a single examiner. Serial measurements, carried out in 6 female subjects without any evidence of gall-bladder disease, demonstrated a dose-dependent trend of inhibition of gall-bladder motility produced by trospium chloride. In the maximal doses employed (1.0 and 1.5 mg i.v.) trospium chloride effected almost total inhibition of motility. The response to n-butylscopolamine bromide tested in a nonblind comparison, showed a dose-effect ratio of roughly 40:1 between trospium chloride and n-butylscopolamine bromide given intravenously. This work confirms that ultrasound measurement of gall-bladder volume is a suitable pharmacodynamic model for testing the dose-effect relationships of antispasmodic agents.

The importance of pharmacokinetic data on sulpiride: results of a bioequivalence study of two sulpiride 200 mg preparations following oral administration.

In a within-subject comparative trial in 16 healthy volunteers, the bioequivalence of two sulpiride 200 mg preparations was tested using a model-free method of calculation as well as assuming 2- and 3-compartment models. As to AUC act., AUC inf. and Cmax, the test preparation was shown to be significantly superior. Some other differences were found depending on which calculation method was used. The Cmax of the test preparation showed therapeutically relevant plasma concentrations of greater than 400 ng/ml, compared with about 300 ng/ml for the reference preparation. Based upon the raw data obtained, it was the aim of this study to gain further knowledge about other kinetic parameters on which only few data is available. T1/2 beta, clearance, volume of distribution and MRT were calculated using 2- and 3-compartment models. Comparisons with literature data were made and it resulted that a better description of the sulpiride kinetics was obtained when a 3-compartment model was used. Finally, the course of the plasma level was calculated by computer extrapolation assuming a thrice daily administration of sulpiride 200 mg. As a result, steady-state is reached after 3-4 days showing plasma concentrations around 650 ng (reference preparation) and 850 ng (test preparation).

[Pharmacokinetics and bioequivalence of two ibuprofen formulations]. / Pharmakokinetik und Bioäquivalenz von zwei Ibuprofen-Formulierungen.

In an open controlled randomized cross-over study in 16 healthy male and female volunteers the bioavailability of ibuprofen (CAS 15687-27-1) sugar-coated tablets (Dolo-Dolgit) was tested versus film-coated tablets containing ibuprofen 600 mg. As it results from the AUC evaluation, the bioavailability of both preparations is very good and almost identical. The ibuprofen concentrations achieved after administration of the test preparation, however, are significantly higher (Cmax = 52.03 micrograms/ml) than those achieved after the reference preparation showing a Cmax of 40.32 micrograms/ml. The tmax of 1.0 h is also significantly shorter than after the reference preparation (tmax = 1.5 h). The t1/2 beta after both the test and the reference preparation is within the known range, i.e. 1.8 h and 1.4 h, respectively. Even in long-term treatment with high dosages, administered 3-4 times daily, there is no accumulation of the active ingredient. Concerning the therapeutic relevance, special attention is to be given to the different time-dependent drug concentrations in the central compartment and in the target compartment. Both the higher Cmax and the shorter tmax achieved following administration of the test preparation are of therapeutic relevance.

Clinical chronopharmacology of oral nitrates.

The clinical-chronopharmacological investigations with oral nitrates (ISDN, IS-5-MN) demonstrate that the drugs' pharmacokinetics and/or hemodynamic effects are circadian phase-dependent. For both an immediate-release and a sustained-release preparation of IS-5-MN peak drug concentrations coincided with peak drug effects after morning but not after evening drug application. Results indicate a circadian phase-dependency in the dose-response relationship of oral nitrates.