Food Interactions Observed in a Pharmacokinetic Investigation Comparing Two Marketed Cold Preparations (BNO1016 and ELOM-080) after Administration to Beagle Dogs - A Pilot Study.

Sinupret extract (BNO 1016) and Gelomyrtol forte (ELOM-080) represent the two top-selling cold remedies in Germany nowadays. Whereas BNO 1016 is a typical immediate release coated tablet, ELOM-080 is an enteric-coated soft gelatin capsule. The latter formulation, however, is at risk of pharmacokinetic interactions affecting absorption, especially in cases of concomitant food intake. In the present pilot study, we investigated the risk of a possible food effect in three male beagle dogs. Single doses of BNO 1016 and ELOM-80 were administered under fasting and fed conditions. Blood was sampled up to 30 h post-administration and plasma concentrations of the characteristic ingredients of BNO 1016 as well as ELOM-080 analytes were determined. Pharmacokinetic parameters focusing on the rate and extent of absorption were derived. BNO 1016 analytes demonstrated a similar course in both the fasted and fed states. ELOM-080 analytes also showed a similar picture in the fasted state. However, lag times (time from administration to first quantifiable time point in plasma) of up to 2 h post-administration with corresponding time to reach maximum concentration (obtained directly from the measured concentration) values of 3 to 4 h were observed, reflecting a longer gastric residence time. In the fed state, ELOM-080 showed significant pharmacokinetic characteristics, suggesting a clear food effect. A major observation was a double peak phenomenon that could be observed in two of three dogs. Furthermore, lag times of some analytes, up to 3 - 4 h, and corresponding time to reach maximum concentration values, up to 6 - 8 h, occurred. In contrast to BNO 1016, these findings suggest that, as with other enteric-coated formulations, there may also be a significant risk for food effects with ELOM-080 in humans.

Inflation of the type I error: investigations on regulatory recommendations for bioequivalence of highly variable drugs.

PURPOSE: We investigated different evaluation strategies for bioequivalence trials with highly variable drugs on their resulting empirical type I error and empirical power. The classical 'unscaled' crossover design with average bioequivalence evaluation, the Add-on concept of the Japanese guideline, and the current 'scaling' approach of EMA were compared. METHODS: Simulation studies were performed based on the assumption of a single dose drug administration while changing the underlying intra-individual variability. RESULTS: Inclusion of Add-on subjects following the Japanese concept led to slight increases of the empirical α-error (≈7.5%). For the approach of EMA we noted an unexpected tremendous increase of the rejection rate at a geometric mean ratio of 1.25. Moreover, we detected error rates slightly above the pre-set limit of 5% even at the proposed 'scaled' bioequivalence limits. CONCLUSIONS: With the classical 'unscaled' approach and the Japanese guideline concept the goal of reduced subject numbers in bioequivalence trials of HVDs cannot be achieved. On the other hand, widening the acceptance range comes at the price that quite a number of products will be accepted bioequivalent that had not been accepted in the past. A two-stage design with control of the global α therefore seems the better alternative.

Pharmacokinetics of Orally Applied Cannabinoids and Medical Marijuana Extracts in Mouse Nervous Tissue and Plasma: Relevance for Pain Treatment.

Cannabis sativa plants contain a multitude of bioactive substances, which show broad variability between different plant strains. Of the more than a hundred naturally occurring phytocannabinoids, Δ9-Tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) have been the most extensively studied, but whether and how the lesser investigated compounds in plant extracts affect bioavailability or biological effects of Δ9-THC or CBD is not known. We therefore performed a first pilot study to assess THC concentrations in plasma, spinal cord and brain after oral administration of THC compared to medical marijuana extracts rich in THC or depleted of THC. Δ9-THC levels were higher in mice receiving the THC-rich extract. Surprisingly, only orally applied CBD but not THC alleviated mechanical hypersensitivity in the mouse spared nerve injury model, favoring CBD as an analgesic compound for which fewer unwanted psychoactive effects are to be expected.

Determination of Postprandial Glycemic Responses by Continuous Glucose Monitoring in a Real-World Setting.

BACKGROUND: Self-monitoring of blood glucose using capillary glucose testing (C) has a number of shortcomings compared to continuous glucose monitoring (CGM). We aimed to compare these two methods and used blood glucose measurements in venous blood (IV) as a reference. Postprandial blood glucose levels were measured after 50 g oral glucose load and after the consumption of a portion of different foods containing 50 g of carbohydrates. We also evaluated the associations between postprandial glucose responses and the clinical characteristics of the participants at the beginning of the study. METHODS: 12 healthy volunteers (age: 36 ± 17 years, BMI: 24.9 ± 3.5 kg/m²) ate white bread (WB) and whole grain (WG) bread and drank a 50 g glucose drink as reference. Postprandial glucose responses were evaluated by CGM, IV and C blood glucose measurements. Incremental area under the curve (AUCi) of postprandial blood glucose was calculated for 1 h (AUCi 0-60) and 2 h (AUCi 0-120). RESULTS: After the consumption of white bread and whole grain bread, the AUCi 0-60 min did not differ between CGM and IV or C. AUCi 0-120 min of CGM showed no difference compared to C. Correlation analyses revealed a positive association of age with glucose AUCi 0-120 (r = 0.768; P = 0.004) and WG AUCi 0-120 (r = 0.758; P = 0.004); fasting blood glucose correlated with WG AUCi 0-120 (r = 0.838; P < 0.001). CONCLUSION: Despite considerable inter-individual variability of postprandial glycemic responses, CGM evaluated postprandial glycemic excursions which had comparable results compared to standard blood glucose measurements under real-life conditions. Associations of AUCi 0-60 and AUCi 0-120 postprandial glucose response with age or fasting blood glucose could be shown.

Formulation-dependent food effects demonstrated for nifedipine modified-release preparations marketed in the European Union.

The objective of this study was a comparative investigation of the influence of concomitant food intake on the bioavailability of two nifedipine-containing controlled-release formulations. Adalat OROS and CORAL were compared in a randomised, non-blind, four-way crossover design in 24 healthy, male subjects after single dose administration following a high fat American breakfast or an overnight fast of 12 h, respectively. Plasma samples were withdrawn until 48 h post-dose. In the fasted state, the bioavailability (AUC and C(max) values) was lower for CORAL than for Adalat OROS. Under fed conditions, differences in bioavailability between both products were markedly increased. With respect to the therapeutic use of both products, the most important finding was the significant dose-dumping effect observed after fed administration of CORAL, resulting in nifedipine plasma concentrations of nearly three- to four-fold in 11 of 24 volunteers. The mean ratio of C(max) was 235% comparing CORAL with Adalat OROS under these conditions. The formulation-dependent food interaction observed in this study may be therapeutically relevant, especially in the case of changing administration conditions or switching from one product to the other.

Comparison of two marketed nifedipine modified-release formulations: an exploratory clinical food interaction study.

OBJECTIVE: The objective of this study was to compare the in vitro and in vivo characteristics of 2 nifedipine modified-release tablet formulations for once-daily dosing marketed in the European community, which were expected to be bioequivalent. METHODS: In vitro dissolution was tested at different pH values prior to the clinical part of the study. Either 1 tablet of a test formulation or of the reference formulation, both containing 30 mg nifedipine, were administered to healthy white male volunteers immediately after a high-fat breakfast in a randomized, open-label, 2-period crossover design. Plasma samples obtained over the subsequent period of 48 hours were analyzed using a validated LC-MS/MS method. Safety profile and tolerability of the study medications were assessed by analysis of adverse events obtained by vital sign measurements, electrocardiography, and clinical laboratory analysis. RESULTS: Twelve volunteers were enrolled (median age, 28.0 years [range, 21-42 years]; mean body mass index, 24.2 kg/m(2) [range, 19.3-27.0 kg/m(2)]). In vitro dissolution experiments revealed a significant pH dependency in drug release from the investigational tablets, while the reference tablets were found to have pH-independent dissolution. After oral administration of both tablet formulations in the fed state, marked differences in rate and extent of bioavailability were observed. Geometric mean of AUC(0-last)(test, 504.21 h x ng/mL; reference, 361.28 h x ng/mL) was significantly higher for the test product, with a point estimate of 140% and a corresponding 90% CI of 121% to 161%. For the comparison of Cmax values, geometric means were: test, 76.46 ng/mL; reference, 19.20 ng/mL, with a point estimate of 398% and a CI of 316% to 503%. Thus, a significant difference in rate and extent of bioavailability was observed between the 2 products. CONCLUSIONS: Although both treatments were well tolerated by all volunteers, the test and reference tablets were found to have different pharmacokinetic properties when administered after a high-fat meal.

Lidocaine 8 mg sore throat lozenges in the treatment of acute pharyngitis. A new therapeutic option investigated in comparison to placebo treatment.

An acute pharyngitis is characterised by mild to severe sore throat mostly accompanied by inflammation, throat pain, pain on swallowing, and burning. This randomised, double-blind, placebo-controlled phase III study was conducted for comparison of the efficacy and safety of a newly developed lidocaine (2-(diethylamino)-N-(2,6-dimethylphenyl) acetamide, CAS 137-58-6) 8 mg lozenge formulation (Trachisan Halsschmerztabletten) for the treatment of acute sore throat not necessarily to be treated with antibiotics. 240 patients of both genders were enrolled. The study was performed in a single centre setting and consisted of two parts. A 2-h stationary phase (single dose treatment) was directly followed by a 46-h ambulatory phase, where patients were allowed to take up to a maximum of 11 further lozenges (multiple dose treatment). Pain intensity was assessed via Visual Analogue Scale during the course of the study. Moreover, the global efficacy and tolerability of the treatments were assessed. Lidocaine 8 mg sore throat lozenges were found to be superior to placebo for all efficacy parameters investigated. For the primary efficacy parameter, area under the curve of pain intensity from baseline over 2 h (AUC(0-2h)), i.e. after single-dose treatment, a significant treatment difference with a p-value of p < 0.001 in favour of the verum treatment could be demonstrated. Significant superiority could also be demonstrated for the descriptive AUC(0-48h) values, reflecting the treatment effect during the ambulatory multiple dose phase. Pain relief, minimum pain intensity, meaningful pain relief and the time of onset of meaningful pain relief as well as the assessments of global efficacy underlined the superiority of the treatment with lidocaine 8 mg sore throat lozenges. Global tolerability of the verum treatment was rated as "good" or "very good" in the majority of cases, the number of study drug related adverse events was low and evenly distributed to both treatment groups. Therefore, the results of the trial emphasise lidocaine 8 mg sore throat lozenges to be a favourable option in the treatment of pain symptoms of an acute sore throat.