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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 | Kirste S.,University Hospital Freiburg | Momm F.,University Hospital Freiburg | And 3 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2011

Until now, dexamethasone is the medication of choice to reduce peritumoral edema associated with primary and secondary brain tumors. Because of the severe side effects accompanying such a treatment the interest in alternative agents that may be co-administered with glucocorticoids and help to reduce the required dose is constantly increasing. Boswellia serrata gum resin extracts (BSE), which have been designated an orphan drug status by the European Medicines Agency (EMA) in 2002 for the treatment of peritumoral edema, may represent a promising supplemental herbal remedy. However, clinical studies on the effect of BSE on brain edema as well as analyzes of serum levels are very scarce. Based on that background a prospective, placebo controlled, and double blind clinical pilot trial was conducted on 14 patients applying for the first time a high dose of 4200. mg BSE per day and 13 patients receiving placebo. For monitoring the serum levels of all major boswellic acids (BAs) a highly sensitive HPLC-MS method has been developed that allows the determination of KBA and AKBA from 5.0. ng/ml to 3000. ng/ml and of αBA, βBA, AαBA and AβBA from 0.5. ng/ml to 12,000. ng/ml. It is the first validated method that covers such a wide concentration range, which makes it suitable to be used as standard method in clinical trials as it compensates for the great pharmacokinetic variability in the plasma levels of BAs observed in clinical practice. Average steady concentrations (ng/ml) in the range of 6.4-247.5 for KBA, 0-15.5 for AKBA, 36.7-4830.1 for αBA, 87.0-11948.5 for βBA, 73.4-2985.8 for AαBA and 131.4-6131.3 for AβBA were determined in the verum group. The here quantified steady state levels suggest βBA to be a possible candidate for the anti-inflammatory and anti-edemateous effects of BSE. In general, the serum level analysis underlines the promising clinical results of BSE on cerebral edema. © 2011 Elsevier B.V.


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.


Queckenberg C.,University of Cologne | Wachall B.,InfectoPharm Arzneimittel und Consilium GmbH | Erlinghagen V.,University of Cologne | Di Gion P.,University of Cologne | And 4 more authors.
Clinical Therapeutics | Year: 2011

Background: Dexamethasone is a glucocorticoid used widely worldwide for immunosuppressive treatment, allergies, bronchiolitis, and croup, among others. For children, liquid formulations are especially suitable because, compared with other dosage forms, both exact dosing and proper intake are facilitated. Objective: The objective was to evaluate the pharmacokinetics, pharmacodynamics, and comparative bioavailability of a commercial liquid oral dexamethasone formulation intended for pediatric use relative to those of a tablet. Methods: In a randomized, controlled, crossover study in 24 healthy adult volunteers, we administered single doses of the liquid and tablet formulation, containing 2 mg of dexamethasone each. Blood samples were taken up to 24 hours postdose. Quantification was carried out using a validated specific and sensitive high-pressure liquid chromatography with UV detector method. Noncompartmental pharmacokinetic parameters were compared between treatments according to European Medicines Agency (EMA) bioequivalence guidelines. For AUC 0-t and C max, the 90% CI for the ratio of the test and reference products should be contained within the predetermined acceptance interval of 80% to 125%. As a pharmacodynamic variable, we measured suppression of endogenous cortisol (predose and postdose). Results: Both preparations showed similar pharmacokinetic and pharmacodynamic profiles but high between-subject variability of pharmacokinetic key parameters and endogenous cortisol concentrations (>30%). Mean AUC 0-t, AUC 0-∞, and C max were 37.8 ng/mL/h, 46.0 ng/mL/h, and 9.35 ng/mL, respectively, for the liquid and 41.3 ng/mL/h, 48.1 ng/mL/h, and 9.17 ng/mL, respectively, for the tablet formulation. T max was 0.89 hour (liquid) and 0.97 hour (tablet). The point estimates and 90% CIs for AUC 0-t, AUC 0-∞, and C max ratios (liquid vs tablet) were 91.42% (82.05%-101.86%), 95.72% (84.46%-108.5%), and 102.04% (86.94%-119.76%), respectively. Thus, point estimates and 90% CIs were within the bioequivalence range of 80% to 125% for all relevant parameters, including the pharmacodynamic parameter AUEC (area under the effect curve). Conclusions: This single-dose study suggests that the test and reference products met the EMA regulatory criteria to assume bioequivalence in these fasting healthy male and female volunteers. German Register of Clinical Trials registration number: DRKS00000785. © 2011 Elsevier HS Journals, Inc.


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.


Husch J.,Central Laboratory of German Pharmacists | Gerbeth K.,Central Laboratory of German Pharmacists | Fricker G.,Institute of Pharmacy and Molecular Biotechnology | Setzer C.,Phospholipid Research Center | And 5 more authors.
Journal of Natural Products | Year: 2012

Boswellia serrata gum resin extracts are used widely for the treatment of inflammatory diseases. However, very low concentrations in the plasma and brain were observed for the boswellic acids (1-6, the active constituents of B. serrata). The present study investigated the effect of phospholipids alone and in combination with common co-surfactants (e.g., Tween 80, vitamin E-TPGS, pluronic f127) on the solubility of 1-6 in physiologically relevant media and on the permeability in the Caco-2 cell model. Because of the high lipophilicity of 1-6, the permeability experiments were adapted to physiological conditions using modified fasted state simulated intestinal fluid as apical (donor) medium and 4% bovine serum albumin in the basolateral (receiver) compartment. A formulation composed of extract/phospholipid/pluronic f127 (1:1:1 w/w/w) increased the solubility of 1-6 up to 54 times compared with the nonformulated extract and exhibited the highest mass net flux in the permeability tests. The oral administration of this formulation to rats (240 mg/kg) resulted in 26 and 14 times higher plasma levels for 11-keto-μ-boswellic acid (1) and acetyl-11-keto-μ-boswellic acid (2), respectively. In the brain, five times higher levels for 2 compared to the nonformulated extract were determined 8 h after oral administration. © 2012 The American Chemical Society and American Society of Pharmacognosy.


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 | Abdel-Tawab M.,Central Laboratory of German Pharmacists | Van Der Burg T.,Sanofi S.A. | Fuhr U.,University of Cologne | And 2 more authors.
Current Medical Research and Opinion | Year: 2010

Objective: The present study aimed to assess the dosing accuracy of commonly used disposable insulin pens including SoloStar (SR)*, FlexPen (FP)†, Next Generation FlexPen (NGFP)†, and KwikPen (KP)‡. It is the first comparative study covering the whole dosing range from 1 U to 60 U. It also covers the accuracy of SR at 80 U. *SoloStar (SR) is a registered trademark of sanofi-aventis. †FlexPen (FP) and Next Generation FlexPen (NGFP) are registered trademarks of Novo Nordisk A/S. ‡KwikPen (KP) is a registered trademark of Eli Lilly. Research design and method: A total of sixty insulin pens from two lots of each pen type were used. From each pen 1 U, 10 U, 30 U, 40 U, 60 U and 80 U were dispensed in random order. The 80 U dose was only evaluated for the SR as the other insulin pens do not deliver this dose in one injection. The actual doses were determined gravimetrically taking density of the different insulin preparations into account. The evaluation of dose accuracy was based on the regulations of the International Organization for Standardization (DIN EN ISO 11608-1:2000). Results: All tested insulin pens met the requirements for accuracy with none of the single values at all dose levels being outside the defined range of the ISO recommendations (1±1 U, 10±1 U, 30±1.5 U, 40±2 U, 60±3 U and 80±4 U). For the investigated dosage levels the absolute average deviation of all insulin pens ranged between 0.09 and 0.81 U. Conclusion: The present study demonstrates an excellent dosing accuracy for all tested insulin pens, with no clinically relevant differences between the products. © 2010 Informa UK Ltd All rights reserved.


PubMed | Indena S. p. A., Central Laboratory of German Pharmacists and Goethe University Frankfurt
Type: Journal Article | Journal: Planta medica | Year: 2016

In consideration of the increasing popularity of frankincense and the widely published quality problems associated with botanical dietary supplements, a survey was conducted for the first time on the quality of frankincense containing botanical dietary supplements. Six US products representing 78% of the units sold and 70% of the market value, and 11 European products representing 30% of the units sold and 40% of the market value were tested for their boswellic acid composition profile, label compliance, and claimed health benefits. Special focus was also set on the statements made with regard to the frankincense applied.Only five products out of seventeen disclosed all relevant information for the Boswellia extract, mentioning the species, the part of plant used, and the boswellic acid content. Whereas all products but one claimed to use Boswellia serrata, three products did not mention the resin as the part applied and 10 products did not declare the boswellic acid content. Apart from the different boswellic acid composition determined with a sensitive LC/MS method, 41% of the products did not comply with the label declaration. Hence, one product from Italy did not contain any of the six characteristic boswellic acids (KBA, AKBA, BA, BA, ABA, ABA) at all and another US product contained only traces, suggesting the absence of frankincense or the use of Boswellia frereana instead of B. serrata. In another product, the ratios of the individual boswellic acids were different from B. serrata gum resin, indicating the use of another species such as Boswellia sacra or Boswellia carterii. Furthermore, two products revealed different boswellic acid contents from those declared on the label. Further, two products did not declare the use of manipulated Boswellia gum resin extract being enriched in acetyl-11-keto-boswellic acid content reaching up to 66%. In addition, consumers could be misled by outdated literature or references to in vitro studies performed at dosages that can never be achieved in humans following oral administration.In summary, this survey reveals that in spite of increased regulations on botanical dietary supplements, the problem of mislabeling still exists and needs to be addressed by the manufacturers, so that consumers get greater confidence in the botanical dietary supplements they use.


PubMed | Central Laboratory of German Pharmacists, AQUANOVA AG and University of Hohenheim
Type: | Journal: Plant foods for human nutrition (Dordrecht, Netherlands) | Year: 2016

Curcumin, the active constituent of Curcuma longa L. (family Zingiberaceae), has gained increasing interest because of its anti-cancer, anti-inflammatory, anti-diabetic, and anti-rheumatic properties associated with good tolerability and safety up to very high doses of 12g. Nanoscaled micellar formulations on the base of Tween 80 represent a promising strategy to overcome its low oral bioavailability. We therefore aimed to investigate the uptake and transepithelial transport of native curcumin (CUR) vs. a nanoscaled micellar formulation (Sol-CUR) in a Caco-2 cell model. Sol-CUR afforded a higher flux than CUR (39.23 vs. 4.98gmin

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