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Kirste S.,University Hospital Freiburg | Treier M.,University Hospital Freiburg | Wehrle S.J.,University Hospital Freiburg | Becker G.,University Hospital Freiburg | And 6 more authors.
Cancer | Year: 2011

BACKGROUND: Patients irradiated for brain tumors often suffer from cerebral edema and are usually treated with dexamethasone, which has various side effects. To investigate the activity of Boswellia serrata (BS) in radiotherapy-related edema, we conducted a prospective, randomized, placebo-controlled, double-blind, pilot trial. METHODS: Forty-four patients with primary or secondary malignant cerebral tumors were randomly assigned to radiotherapy plus either BS 4200 mg/day or placebo. The volume of cerebral edema in the T2-weighted magnetic resonance imaging (MRI) sequence was analyzed as a primary endpoint. Secondary endpoints were toxicity, cognitive function, quality of life, and the need for antiedematous (dexamethasone) medication. Blood samples were taken to analyze the serum concentration of boswellic acids (AKBA and KBA). RESULTS: Compared with baseline and if measured immediately after the end of radiotherapy and BS/placebo treatment, a reduction of cerebral edema of >75% was found in 60% of patients receiving BS and in 26% of patients receiving placebo (P =.023). These findings may be based on an additional antitumor effect. There were no severe adverse events in either group. In the BS group, 6 patients reported minor gastrointestinal discomfort. BS did not have a significant impact on quality of life or cognitive function. The dexamethasone dose during radiotherapy in both groups was not statistically different. Boswellic acids could be detected in patients' serum. CONCLUSIONS: BS significantly reduced cerebral edema measured by MRI in the study population. BS could potentially be steroid-sparing for patients receiving brain irradiation. Our findings will need to be further validated in larger studies. © 2011 American Cancer Society.

Bohnet J.,Central Laboratory of German Pharmacists | Schmitz M.,Sanofi S.A. | Kamlot S.,Sanofi S.A. | Abdel-Tawab M.,Central Laboratory of German Pharmacists
Journal of Diabetes Science and Technology | Year: 2013

Background: The introduction of the FlexTouch® (FT; N ovo N ordisk; i nsulin a spart), a p refilled i nsulin p en w ith a s pringloaded mechanism, has created more insulin pen options. The present study compared the dosing accuracy of the FT with that of the manually operated SoloSTAR® (SS; Sanofi; insulin glulisine). The volumetric flow rate of insulin delivery with the FT was also evaluated. Methods: Thirty unused pens from one batch of each pen type were used to test dosing accuracy at minimum (1 U), mid (40 U), and maximum dose (80 U). Statistical analysis was performed using Student's t-test. Insulin flow was determined with 20 FT pens ejecting 80 U three times per pen using a mass flow meter. Results: Both insulin pens revealed excellent dosing accuracy, delivering all doses within the limits set by ISO 11608- 1:2000. The average relative deviation of the actual dose from the target dose was +6.86% and +3.87% at the minimum, -0.72% and -1.01% at the mid, and -0.68% and -1.06% at the maximum dose for the SS and FT, respectively. The diference at maximum dose was statistically significant (p = .006) i n favor of t he S S. The F T showed a mean maximum flow rate of 15.61 U/s, with 80.52% of the total dose delivered at an injection speed exceeding 10 U/s. Conclusions: This study demonstrated excellent dosing accuracy for the SS and FT at all tested dosage levels. The average maximum injection speed of the FT was considerably higher than the usual range of 6-10 U/s assumed for a smooth and painless injection. Further investigations should confirm the clinical relevance. © Diabetes Technology Society.

Krzywon M.,Central Laboratory of German Pharmacists | Van Der Burg T.,Sanofi S.A. | Fuhr U.,University of Cologne | Schubert-Zsilavecz M.,Central Laboratory of German Pharmacists | And 2 more authors.
Diabetes Technology and Therapeutics | Year: 2012

Background: Improved patient comfort and optimal glycemic control have led to the widespread use of insulin pens, particularly in Europe. Most of the former studies on the dose accuracy of insulin pens included only a small number of doses and pens. In extension to our previous large-scale study testing the dosing accuracy following a randomized dosing sequence with each pen, the present study was more directed toward the dose accuracy for one specific dose dispensed repeatedly with the same pen. This is the first study providing detailed comparative data on the accuracy of repeated dose delivery with prefilled disposable insulin pens at low, middle, and high doses, dispensed over the entire pen volume. Materials and Methods: In total, 15 previously unused insulin pens from two lots of each pen type (SoloSTAR® [sanofi-aventis, Paris, France], FlexPen® [Novo Nordisk A/S, Bagsværd, Denmark], Next Generation FlexPen [Novo Nordisk], and KwikPen™ [Eli Lilly, Indianapolis, IN]) were used to deliver 5-unit (low), 30-unit (middle), and 60-unit (high) doses, respectively, dispensed four times from each pen in a nonrandomized manner. Actual doses were determined gravimetrically taking the density of the respective insulin into account and were evaluated according to the guidelines (DIN EN ISO 11608-1:2000) of the International Organization for Standardization (ISO). Results: All tested insulin pens met the requirements for accuracy with none of the single values being outside the defined range of the ISO recommendations (1±1 units, 30±1.5 units, and 60±3 units, respectively). Conclusion: The present study demonstrated a consistent and accurate dose delivery at all dosage levels for all tested insulin pens, with no clinically relevant differences among the products. © Copyright 2012, Mary Ann Liebert, Inc. 2012.

Gerbeth K.,Central Laboratory of German Pharmacists | Meins J.,Central Laboratory of German Pharmacists | Werz O.,University of Tubingen | Schubert-Zsilavecz M.,Central Laboratory of German Pharmacists | And 2 more authors.
Planta Medica | Year: 2011

Recent studies revealed that the non-prenylated acylphloroglucinol myrtucommulone (MC) from myrtle (Myrtus communis) potently suppresses the biosynthesis of eicosanoids by direct inhibition of cyclooxygenase-1, microsomal prostaglandin E2 synthase (mPGES)-1, and 5-lipoxygenase at ICvalues in the range of 1 to 29 μ M. Moreover, MC showed potent efficacy in animal models of inflammation after intraperitoneal administration. Since the main prerequisite for therapeutic efficacy is sufficient bioavailability, it is important to evaluate whether the concentrations of MC achieved in plasma coincide with the pharmacological active concentrations determined in vitro. For that reason, a sensitive LC/MS/MS method has been developed and validated for the determination of MC in human plasma. This method is based on liquid-liquid extraction of plasma samples with 20 % ethyl acetate in tert-butyl methyl ether using the structurally related acylphloroglucinol hyperforin as the internal standard. Chromatographic separation was achieved on a Gemini C6 Phenyl column using a mixture of acetonitrile/water (85: 15 v/v) containing 6 mM ammonium formate in a run time of 15 min at a flow rate of 1 mL/min, a column temperature of 40 °C, and an autosampler temperature of 5 °C. Mass spectrometric quantification was carried out in the negative ion mode using electrospray ionization (ESI) and multiple-reaction monitoring (MRM). The most intense [M-H] MRM transition at m/z 667.4 m/z 194.9 was used for quantification of MC and the transition at m/z 535.4 to m/z 383.2 was used to monitor hyperforin. The method was linear in the range of 1-100 ng/mL with r > 0.998, an intra- and inter-day RSD of 1.1-8.4 and 7.1-11.8 %, respectively, and a maximum R. E. of 13.8 % at the lowest concentration level. Moreover, cross validation revealed the suitability of the developed LC/MS method for application in rat studies. © Georg Thieme Verlag KG.

Abdel-Tawab M.,Central Laboratory of German Pharmacists | Werz O.,Pharmaceutical Institute | Schubert-Zsilavecz M.,Central Laboratory of German Pharmacists | Schubert-Zsilavecz M.,Goethe University Frankfurt
Clinical Pharmacokinetics | Year: 2011

Non-steroidal anti-inflammatory drug (NSAID) intake is associated with high prevalence of gastrointestinal or cardiovascular adverse effects. All efforts to develop NSAIDs that spare the gastrointestinal tract and the cardiovasculature are still far from achieving a breakthrough. In the last two decades, preparations of the gum resin of Boswellia serrata (a traditional ayurvedic medicine) and of other Boswellia species have experienced increasing popularity in Western countries. Animal studies and pilot clinical trials support the potential of B. serrata gum resin extract (BSE) for the treatment of a variety of inflammatory diseases like inflammatory bowel disease, rheumatoid arthritis, osteoarthritis and asthma. Moreover, in 2002 the European Medicines Agency classified BSE as an 'orphan drug' for the treatment of peritumoral brain oedema. Compared to NSAIDs, it is expected that the administration of BSE is associated with better tolerability, which needs to be confirmed in further clinical trials.Until recently, the pharmacological effects of BSE were mainly attributed to suppression of leukotriene formation via inhibition of 5-lipoxygenase (5-LO) by two boswellic acids, 11-keto-β-boswellic acid (KBA) and acetyl-11-keto-β-boswellic acid (AKBA). These two boswellic acids have also been chosen in the monograph of Indian frankincense in European Pharmacopoiea 6.0 as markers to ensure the quality of the air-dried gum resin exudate of B. serrata. Furthermore, several dietary supplements advertise the enriched content of KBA and AKBA. However, boswellic acids failed to inhibit leukotriene formation in human whole blood, and pharmacokinetic data revealed very low concentrations of AKBA and KBA in plasma, being far below the effective concentrations for bioactivity in vitro. Moreover, permeability studies suggest poor absorption of AKBA following oral administration. In view of these results, the previously assumed mode of action that is, 5-LO inhibition is questionable. On the other hand, 100-fold higher plasma concentrations have been determined for β-boswellic acid, which inhibits microsomal prostaglandin E synthase-1 and the serine protease cathepsin G. Thus, these two enzymes might be reasonable molecular targets related to the anti-inflammatory properties of BSE. In view of the results of clinical trials and the experimental data from in vitro studies of BSE, and the available pharmacokinetic and metabolic data on boswellic acids, this review presents different perspectives and gives a differentiated insight into the possible mechanisms of action of BSE in humans. It underlines BSE as a promising alternative to NSAIDs, which warrants investigation in further pharmacological studies and clinical trials. © 2011 Adis Data Information BV. All rights reserved.

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