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.
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.
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 (AUC
) of postprandial blood glucose was calculated for 1 h (AUC
) and 2 h (AUC
).
After the consumption of white bread and whole grain bread, the AUC
did not differ between CGM and IV or C. AUC
of CGM showed no difference compared to C. Correlation analyses revealed a positive association of age with glucose AUC
(
= 0.768;
= 0.004) and WG AUC
(
= 0.758;
= 0.004); fasting blood glucose correlated with WG AUC
(
= 0.838;
< 0.001).
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 AUC
and AUC
postprandial glucose response with age or fasting blood glucose could be shown.
Background
The herbal medicinal product Bronchipret® TP film-coated tablets contains a fixed combination of thyme and primula dry extracts (BRO) and has long and successfully been used for the ...treatment of acute bronchitis. However, the underlying pharmacological mechanisms of action have not been determined so far. We report a tiered approach applying in vivo and in vitro studies to investigate the pharmacodynamic activity and underlying mechanisms of action, and to identify possible active ingredients contributing to the product’s pharmacodynamic activity.
Results
In an LPS-induced rat model of bronchoalveolitis oral administration of BRO effectively ameliorated the influx of leukocytes into the lung. This was accompanied by reduced levels of leukotriene (LT) B
4
, cysteinyl-LTs (cysLT), and prostaglandin (PG) E
2
. We also found that BRO potently reduced the production of LTB
4
in vitro in rat whole blood stimulated with the Ca
2+
-ionophore A23187 whereas the effect on PGE
2
was much less pronounced. The transferability of these findings to human cells was assessed by measuring the effects of BRO on A23187-stimulated human monocytes and neutrophils. BRO and thyme extract were potent inhibitors of LTB
4
and cysLT production. We further investigated the effects of BRO, thyme extract as well as single compounds of thyme extract on enzymatic activity of 5-lipoxygenase (5-LO). 5-LO activity was potently reduced by BRO and thyme extract. Of the single ingredients, thymoquinone and rosmarinic acid showed most potent inhibitory activity against 5-LO, with lower potency for thymol and carvacrol.
Conclusion
BRO attenuates inflammation-induced leukotriene formation in vivo and affects leukotriene biosynthesis in vitro via 5-LO inhibition. This inhibitory activity appears to be primarily related to the thyme extract component. However, none of the single ingredients tested seems to fully account for the activity of thyme extract alone. Rather, the interaction of different compounds seems to be required for its overall inhibitory effect on leukotriene production.
Abstract
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.
Abstract 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/m2 range, 19.3–27.0 kg/m2 ). 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 AUC0-last (test, 504.21 h · ng/mL; reference, 361.28 h · 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.
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.
Background
Acute upper respiratory tract infections (ARI) in children are quite common and often recurrent. Overuse of antibiotics must be avoided, and thus herbal remedies are a useful therapeutic ...option, as most ARIs can be treated without antibiotics. The aim of this observational study was to demonstrate the effectiveness and tolerability of the herbal combination preparation Tonsilgon® N in Russian children aged 2–11 years in routine practice.
Methods
In a prospective, non-interventional study a total of 518 paediatric patients (boys and girls) with ARI were enrolled at 14 study sites in Russia (2013 - 2014). Patients must have had at least two episodes of ARI in the last 6 months prior to enrolment (day 1 = visit 1). Tonsilgon® N was given as coated tablets or oral drops in age-corresponding dosages. Treatment duration was approximately 14 days (day 15 = visit 2) with a subsequent 30-day follow-up period (to day 45).
The effectiveness of the therapy was assessed on the basis of objective symptoms (mucosal hyperemia and swelling of tonsils; investigator assessment at visits 1 and 2), subjective symptoms (achiness/fatigue, sore throat, pain in the extremities, headache, loss of appetite, cough, and hoarseness; parents rated and recorded the subjective symptoms in patient diaries) and responder rate. Further study parameters included time to symptom resolution, treatment compliance and concomitant medication intake. Adverse drug reactions were recorded to assess the tolerability.
Results
Patient distribution by age and gender was similar in both age groups (2–5; 6–11 years). The three most common inclusion diagnoses were nasopharyngitis, pharyngitis or tonsillitis. For these indications, the objective symptoms hyperemic mucosa and swollen tonsils nearly completely disappeared by visit 2 (range of relief: 93.4 % to 97.9 % of patients). Most subjective symptoms resolved within 4 days compared to 7 days in previous ARIs. Overall, a 3-day-shorter time to symptom resolution was achieved. 99.5 % of the patients were treatment responders, and 97 % tolerated the herbal medicine well or very well. Treatment compliance was very good (88.2 %).
Conclusions
Tonsilgon® N is a safe and effective treatment of acute upper respiratory tract infections in young children (aged 2–11 years) and is likely to reduce the duration of symptoms of ARI.
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.
The objective of this study was to compare the rate and extent of nifedipine bioavailability after single dose administration of Adalat OROS 30 (Reference) and Nifedipine Sandoz retard 30 tablets ...(Test). Both modified release formulations are marketed in Member States of the European Union. Prior to the clinical study the in vitro dissolution characteristics were investigated. There was a significant pH dependency observed with the Test product but drug release with the Reference product was almost independent of the experimental conditions used. In the subsequent open, randomized, controlled, 4-way crossover study both pharmaceutical products were administered to 28 healthy male volunteers, either after fasting overnight or immediately after a high-fat American breakfast. Blood sampling was performed over 48 hours post-dose for the determination of pharmacokinetic profiles of nifedipine. Considerable differences were observed between the two formulations when administered to fasted subjects where maximum nifedipine plasma concentration (C(max)) were higher in the case of the Test formulation. Differences were even more pronounced after a high-fat American breakfast. Under these conditions a significant food interaction was detected in the case of Nifedipine Sandoz retard 30 with a three-fold increase in the mean C(max) when compared to values obtained in fasting subjects. In contrast, food intake had no clinically relevant effect on bioavailability of nifedipine (rate and extent) in the case of Adalat OROS 30. The pharmacokinetic findings in this study were reflected in the adverse event pattern which indicated a potential tolerability problem in the case of Nifedipine Sandoz retard 30. The results confirm the relationship between the in vitro dissolution profile results and the effects of the drug in vivo. Dose dumping after intake of a high-fat meal could be shown. Nifedipine Sandoz retard 30 is not bioequivalent to Adalat OROS 30 and produced highly variable and poorly predictable nifedipine plasma concentrations. The differences observed between the two products investigated may have direct therapeutic relevance when switching from one formulation to the other and, in particular, when administration conditions change i.e. administration in the fasting state and administration with a meal, since the pharmacological and therapeutic actions of nifedipine are closely associated with the concentration.
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