The influence of propiverine hydrochloride on cardiac repolarization in healthy women and cardiac male patients.

OBJECTIVE: Two comprehensively designed mono-centric ECG studies were performed to investigate the influence of propiverine hydrochloride and its main metabolite propiverine-N-oxide on cardiac function with regard to QTc prolongation, QTc dispersion and T-wave shape. METHODS: The first study was conducted on 24 healthy females, followed by a second study on 24 male patients with coronary heart disease (CHD) and a pathological Pardee-Q-wave in the ECG. Both studies were placebo-controlled and compared the effects of single (30 mg s.i.d.) and multiple dosing (15 mg t.i.d.) of propiverine hydrochloride in a crossover design over 6 and 13 days, respectively. In CHD patients, the ECG was recorded under standardized exercise stress conditions. RESULTS: An effect of propiverine on cardiac safety in healthy women and male patients with CHD could not be determined by the evaluation of QTc intervals derived from ECG under the following conditions: (1) single dosage; (2) steady-state and elevated dosage; (3) healthy female volunteers and male CHD patients; (4) resting and stress conditions in CHD patients. Moreover, other ECG parameters like QT dispersion, T-wave shape, and U-wave occurrence were not affected by propiverine compared to placebo after single or repeated dosing to reach steady-state conditions. CONCLUSION: These results reflect and confirm preclinical data as well as clinical observations on hundreds of volunteers and numberless patients suffering from overactive bladder syndrome and neurogenic detrusor overactivity who were treated with propiverine hydrochloride over nearly three decades in Europe and Japan.

Observational study on the tolerability and safety of film-coated tablets containing ivy extract (Prospan® Cough Tablets) in the treatment of colds accompanied by coughing.

The only saponin drug currently prescribed in any significant amount in monotherapy medicines is ivy. This post-marketing surveillance study (PMSS) aimed at investigating the tolerability and safety of film-coated tablets containing ivy leaves dry extract (extracting medium: ethanol 30%, DER 5-7.5:1 [Prospan® Cough Tablets]) under practice conditions. Adults and children aged 11-85 years of both genders were included. A total of 330 patients suffering from colds accompanied by coughing or from chronic, inflammatory bronchial diseases were scheduled to undergo treatment for a period of at least seven days. The tolerability of the tablets was rated by means of questionnaires. The results of this PMSS reflect the good to very good tolerability of the tablets in the global assessment by both, the practitioner (98.5%) and by the patient (96.4%). This is one of the reasons for the high acceptance and compliance (rated as 'good' in 98.8% of all cases). The safety not only regarding the administration form but also regarding the active substance is thus underlined once again.

Differences in bioavailability between 60 mg of nifedipine osmotic push-pull systems after fasted and fed administration.

OBJECTIVES: This study was designed to evaluate and compare the bioavailability of two osmotically active formulations of 60 mg nifedipine, Gen-Nifedipine extended release Test tablets (Genpharm ULC, Etobicoke, ON, Canada) and Adalat XL Reference tablets (Bayer Healthcare AG, Leverkusen, Germany) after single dose fasted and fed administration. MATERIALS AND METHODS: The study was performed following a 4-period crossover design with both investigational products obtained from marketed batches. The complete pharmacokinetic evaluation was carried out in 26 healthy male subjects with a median age of 29.5 years (range 18 - 44 years), mean weight of 79.7 kg (range 66.0 - 97.5 kg), and a mean body mass index (BMI) of 24.1 kg/m(2) (range 22.1 - 26.9 kg/m(2)). Tablets were administered with tap water either under fasting conditions or immediately following a high-fat, high-calorie breakfast. Blood samples were taken predose and at pre-defined time points until 48 h post dosing. Samples were protected from light during handling and frozen until analysis. A validated LC-MS/MS method was used for the quantification of nifedipine in plasma samples. All kinetic parameters were determined model-independently for each treatment directly from measured concentrations. Monitoring of subject safety was accomplished by routine monitoring of blood pressure, heart rate and probing for adverse events. RESULTS: In-vitro dissolution curves show later onset and considerably lower quantity of nifedipine release from Test compared to Reference tablets. Under fasting conditions total and maximum exposure, represented by geometric mean AUC(0-tlast)- and C(max)-values, respectively were 466.7 h*ng/ml (AUC(0-tlast)) and 21.9 ng/ml (C(max)) for Test and 507.8 h*ng/ml (AUC(0-tlast)) and 22.0 ng/ml (C(max)) for Reference tablets. However, the Test product exhibited a notably longer lag-time and less rapid onset of absorption than the Reference tablets. Moreover, the plateau phase is maintained for about 14 hours on Test but for almost 20 hours on Reference. Point estimates (PE) and associated 90% confidence intervals (CI) were determined as 91.8% and 79.9 - 105.5% for AUC(0-tlast), as well as 99.8% and 88.6 - 112.4% for C(max). Larger differences were found for AUC(0-9h) (PE: 54.8%; CI: 45.8 - 65.5%) determined as parameter for early exposure. Under fed conditions, although the mean plasma concentration time curves look similar in shape, concentrations of Test compared to Reference tablets are considerably lower at all time points until 36 hours after dosing. Again the lag time in onset of drug absorption is notably longer for the Test product. Both, total and maximum exposure, represented by geometric mean values for AUC(0-tlast) and C(max), were considerably lower (differences also statistically significant) after administration of Test with 481.8 h*ng/ml for AUC(0-tlast) and 25.3 ng/ml for C(max) in comparison to Reference tablets with 595.9 h*ng/ml for AUC(0-tlast) and 31.9 ng/ml for C(max). Test/Reference point estimates (PE) and associated 90% confidence intervals (CI) were determined as 80.7% and 73.7 - 88.5% for AUC(0-tlast), as well as 79.6% and 70.3 - 90.0% for C(max). Differences were also even more expressed for AUC(0-9h) (PE: 54.9%; CI: 47.4 - 63.5%) determined as parameter for early exposure. CONCLUSION: The results indicate that although both products are osmotic release systems they are not bioequivalent according to the accepted standards. This difference between both osmotic delivery systems might be substantiated by the fact that the core of the Test product is designed as a monolayer system (containing both, the active ingredient and the osmotic component) while Reference tablets consist of two separate layers. The observed pharmacokinetic differences may have an impact on blood pressure control in patients and thus, should be kept in mind when switching during treatment.

Characterization of the behavior of alginate-based microcapsules in vitro and in vivo.

OBJECTIVES: Functional formulations providing protection of nutritional products against gastric juice or a capable of delivering them to distinct areas of the gastrointestinal tract are increasingly utilized by the food industry. However, the application of functional excipients that are established in pharmaceutical applications is limited in case of food products, as they are typically not classified as Generally Recognized As Safe (GRAS). MATERIALS: Accordingly, we investigated whether two alginate-based microcapsule preparations (capsule diameter 1 - 2 mm) either based on alginate and maize starch (MS-type) or alginate and casein (OCF27-type) and both created from ingredients classified as food supplements provide functional properties with respect to regional gastrointestinal targeting. METHODS: For this purpose the in vitro disintegration and swelling of the microcapsules was tested in various media. Furthermore, individual microcapsules, magnetically labelled with 100 - 200 microg black iron oxide, were ingested by healthy volunteers under fasting and fed conditions. Gastrointestinal transit as well as the gastrointestinal disintegration behavior were determined by using Magnetic Marker Monitoring. RESULTS: The results of in vitro and in vivo investigations show that both types of microcapsules are resistant to gastric juice for approximately 10 hrs under fasting and fed conditions. However, the disintegration characteristics of the two types of microcapsules within the intestines are different. CONCLUSION: Whilst the MS-type of capsules disintegrated predominantly within the small intestine shortly after gastric emptying, the OCF27-type of capsules underwent a rather slow disintegration predominantly in the colon.

Critical evaluation of the effect of valerian extract on sleep structure and sleep quality.

A carefully designed study assessed the short-term (single dose) and long-term (14 days with multiple dosage) effects of a valerian extract on both objective and subjective sleep parameters. The investigation was performed as a randomised, double-blind, placebo-controlled, cross-over study. Sixteen patients (4 male, 12 female) with previously established psychophysiological insomnia (ICSD-code 1.A.1.), and with a median age of 49 (range: 22 to 55), were included in the study. The main inclusion criteria were reported primary insomnia according to ICSD criteria, which was confirmed by polysomnographic recording, and the absence of acute diseases. During the study, the patients underwent 8 polysomnographic recordings: i.e., 2 recordings (baseline and study night) at each time point at which the short and long-term effects of placebo and valerian were tested. The target variable of the study was sleep efficiency. Other parameters describing objective sleep structure were the usual features of sleep-stage analysis, based on the rules of Rechtschaffen and Kales (1968), and the arousal index (scored according to ASDA criteria, 1992) as a sleep microstructure parameter. Subjective parameters such as sleep quality, morning feeling, daytime performance, subjectively perceived duration of sleep latency, and sleep period time were assessed by means of questionnaires. After a single dose of valerian, no effects on sleep structure and subjective sleep assessment were observed. After multiple-dose treatment, sleep efficiency showed a significant increase for both the placebo and the valerian condition in comparison with baseline polysomnography. We confirmed significant differences between valerian and placebo for parameters describing slow-wave sleep. In comparison with the placebo, slow-wave sleep latency was reduced after administration of valerian (21.3 vs. 13.5 min respectively, p<0.05). The SWS percentage of time in bed (TIB) was increased after long-term valerian treatment, in comparison to baseline (9.8 vs. 8.1% respectively, p<0.05). At the same time point, a tendency for shorter subjective sleep latency, as well as a higher correlation coefficient between subjective and objective sleep latencies, were observed under valerian treatment. Other improvements in sleep structure - such as an increase in REM percentage and a decrease in NREM1 percentage - took place simultaneously under placebo and valerian treatment. A remarkable finding of the study was the extremely low number of adverse events during the valerian treatment periods (3 vs. 18 in the placebo period). In conclusion, treatment with a herbal extract of radix valerianae demonstrated positive effects on sleep structure and sleep perception of insomnia patients, and can therefore be recommended for the treatment of patients with mild psychophysiological insomnia.

Single daily doses of saquinavir achieve HIV-inhibitory concentrations when combined with baby-dose ritonavir.

Dual protease inhibitor (PI) therapy has been established either in order to increase plasma concentrations of one PI or to combine synergistic effects of two PI's on viral load. Studies with saquinavir (SQV) and small doses of ritonavir (RTV) as well as experiences from our therapeutic drug monitoring suggest that single daily doses may result in sufficient SQV serum levels throughout an interval of 24 h. A controlled, randomized trial with 20 healthy men was conducted for the comparison of serum levels with 1600 mg SQV (group 1) or 1600 mg SQV/200 mg RTV (group 2). The dosages were selected in order to use RTV as an inhibitor of cytochrome P450 3A4 and SQV as protease inhibitor. The volunteers received single daily doses following a standardized breakfast on 3 consecutive days. Serum samples were analyzed for SQV and RTV employing LC-tandem mass spectrometry. The minimum concentration of saquinavir after 24 hours, the AUC, the maximum concentration and the serum half-lives on day 3 served as target parameters. The minimum SQV concentration amounted to 469.4 ng/ml, when combined with RTV and proved to be significantly higher (p <0.05) than the corresponding concentration with SQV alone (127.3 ng/ml). The SQV maximum concentration was raised approximately 6fold and the AUC 9fold when RTV was coadministered. In combination with 200 mg of RTV the predominant elimination half-life of SQV increased from 2.6 to 6.45 hours. These data prove that under single daily doses of 1600 mg SQV/200 mg RTV HIV-inhibitory concentrations of SQV can be achieved for 24 hours. Due to the high variability of the concentrations, which can be seen with all PI s, we recommend continuous therapeutic drug monitoring of serum trough levels.

The absolute and relative bioavailability of dipyridamole from different preparations and the in vitro-in vivo comparison.

The in vitro liberation and the bioavailability (BV) of dipyridamole (D) in three different brands (A, B, C) were determined in a three way cross-over study on 12 healthy subjects. Also, the pharmacokinetics of D given intravenously was investigated. The in vitro liberation of B is only to be achieved by repeated touching. The tmax for the preparations, expressed as mean +/- s mean amounts as follows: A: 0.8 +/- 0.06; B: 1.1 +/- 0.1; C: 0.8 +/- 0.09 hours and is in the case of B significantly different (p less than 0.05) from the others. The cmax values (A: 1.01 +/- 0.25; B: 1.16 +/- 0.15; C: 1.51 +/- 0.3 mumol X l-1) and the AUC values (A: 3.8 +/- 0.9; B: 3.1 +/- 0.5; C: 3.8 +/- 0.7 mumol X h X l-1) are not different. The absolute BV of D is 27 +/- 5.5% (range: 11-44%) independent of the used brand. In 4 subjects a second tmax at the 4th-6th hour is to be observed irrespective of the way of dosing. An enterohepatic circulation is assumed. It is concluded that the determination of the in vitro liberation is a necessary and useful parameter, but cannot be used alone for characterization of the BV in every case, as e.g., for problem drugs.