Rainer Trittler

Linezolid and rifampin: Drug interaction contrary to expectations?

To the Editor: A recent article in the Journal provided a comprehensive review of the health risks of herbal remedies. In this letter, I draw attention to herbal medicines in Malaysia. The Drug Control Authority (DCA) Malaysia implemented the phase III registration of traditional medicines on January 1, 1992, with special emphasis on the quality, efficacy, and safety in all pharmaceutical dosage forms of traditional medicine preparations. The registration criteria for traditional medicines in Malaysia included limits for heavy metals (Poison Act 1952, revised 1989), limits for microbial contamination, absence of steroids and other adulterants (Poison Act 1952, revised 1989), limits on disintegration time (Pharmacopoeial Standards), claimed indications (Medicines Act, Advertisement and Sale, 1956; revised 1983), prohibition of herbs with known adverse effects, prohibition of endangered animal species (Wildlife Protection Act, 1972), compliance with Good Manufacturing Practice standards, and approved marketing authorization from the importing countries. Since then, traditional products form the largest group of medicines that have been registered (37.1%), as compared with prescription drugs (32.2%) and nonprescription (overthe-counter) drugs (23.9%). At this time, more than 9000 herbs are registered with the DCA Malaysia for safety and quality. Adulteration refers to the presence of undeclared chemical or synthetic substances or other active ingredients in the products, mainly to boost the efficacy of the product. As such, 397 traditional medicines were tested by the DCA Malaysia for the presence of adulterants in 2002. It was found that 106 of 397 traditional medicines (26.7%) were positive for the following adulterants: sildenafil, 38 of 103 traditional medicines (36.9%); slimming agents, 17 of 131 traditional medicines (13.0%); antihistamines-antitussives, 21 of 45 traditional medicines (46.7%); whitening agents, 16 of 22 traditional medicines (72.8%); steroids, 13 of 60 traditional medicines (21.7%); and camphor, 1 of 1 traditional medicine (100%). Nonsteroidal anti-inflammatory drugs and hormones were absent in 23 and 3 traditional medicines tested, respectively. In addition, benzodiazepine, antidiabetics, and laxatives were absent in each of 2 traditional medicines tested, whereas quinine, terbutaline-albuterol (INN, salbutamol), and antiepileptics were each absent in 1 traditional medicine tested. Hooi-Hoon Ang, BPharm(Hons), PhD School of Pharmaceutical Sciences University Science Malaysia Minden, Penang, Malaysia E-mail: hhang@usm.my

Tormentil for active ulcerative colitis: an open-label, dose-escalating study.

Background Tormentil extracts (TE) have antioxidative properties and are used as a complementary therapy for chronic inflammatory bowel disease. In individual patients with ulcerative colitis (UC) positive effects have been observed. Goals To assess the safety, pharmacology, and clinical effects of different doses of TE in patients with active UC. Study Sixteen patients with active UC [clinical activity index (CAI) ≥5] received TE in escalating doses of 1200, 1800, 2400 and 3000 mg/d for 3 weeks each. Each treatment phase was followed by a 4-week washout phase. The outcome parameters were side effects, CAI, C-reactive protein, and tannin levels in patient sera. Results Mild upper abdominal discomfort was experienced by 6 patients (38%), but did not require discontinuation of the medication. During therapy with 2400 mg TE per day, median CAI and C-reactive protein improved from 8 (6 to 10.75) and 8 (3 to 17.75) mg/L at baseline to 4.5 (1.75 to 6) and 3 (3 to 6) mg/L, respectively. During therapy, the CAI decreased in all patients, whereas it increased during the washout phase. Neither undegraded nor metabolized tannins could be detected by liquid-mass spectrometry (LC-MS) in patient sera. Conclusions TE appeared safe up to 3000 mg/d. Tannins from TE are not systemically absorbed. The efficacy in patients with UC should be further evaluated.

Determination of the antifungal agent posaconazole in human serum by HPLC with parallel column-switching technique.

Posaconazole is a new broad-spectrum antifungal agent that is currently only available as an oral suspension and shows high intra- and inter-individual differences in oral bioavailibility. Pre-existing methods for the determination of the substance involve the use of internal standards or require a quite complicated and time-consuming sample pre-treatment. Our HPLC method is fast and fully-automated and there is no need for any manual sample pre-treatment. On-line transfer of posaconazole from the extraction column was followed by chromatographic separation on a C18 column and fluorescence detection (lambda(ex): 261 nm, lambda(em): 357 nm). Retention time of posaconazole was about 11.7 min, the lower limit of quantification was found to be 0.1 mg/l. A linear calibration curve was obtained over the concentration range of 0.1-5 mg/l using a 50 microl sample (r(2)=0.999). The relative standard deviations of intra-day variations ranged from 2.3% to 9.4%, intra-day accuracy from 88.8% to 114.8%.

New and rapid fully automated method for determination of tazobactam and piperacillin in fatty tissue and serum by column-switching liquid chromatography.

A sensitive and rapid HPLC assay for determining tazobactam and piperacillin in fatty tissue and serum is described. While the common methods need liquid-liquid extraction before the injection in a automated column switching HPLC, the new method works by direct injection of the filtered tissue extract or diluted serum in a automated column switching HPLC without any other pre-treatment. This was performed by the use of a NH2-precolumn and enrichment/transfer at different pH-level. During the analyses, the NH2-precolumn was automatically regenerated with acetonitrile-water. The chromatogram peaks for piperacillin and tazobactam were identified by the retention time and quantified by peak area. The calibration curve was linear between 1 and 16 microg/ml. The quantification limit of tazobactam was about 1 microg/ml in fatty tissue extracts and in diluted serum (calculated for pure serum 2 microg/ml), respectively. For piperacillin it was less. The described procedure allows sample clean-up and determination of the antibiotic within 35 min. The chromatograms with this easy sample treatment had the same quantity of matrix peaks and in contrast to liquid-liquid extraction no loss of piperacillin. Because of the automatically rinsing of the NH2-precolumn during the chromatographic separation, more than 50 different biological samples could be measured with one NH2-precolumn without loss of performance.

A new, rapid, fully automated method for determination of fluconazole in serum by column-switching liquid chromatography

A sensitive and rapid HPLC assay for the determination of fluconazole in serum is described. HPLC-integrated sample preparation allows direct injection of serum samples without any pretreatment. The in-line extraction technique is carried out by automatically switching from the extraction column (Lichrospher® ADS C8) to the analytic column (Nucleosil C18). After 6 minutes the matrix passes the extraction column, and the retained analyte is quantitatively transferred to the analytic column, where separation by isocratic HPLC is performed. The extraction eluent is sodium dihydrogen phosphate buffer, pH 5.0 (50 mM), and the analytic eluent is acetonitrile/sodium dihydrogen phosphate buffer, pH 5.0 (50 mM) (26.8/73.2, vol/vol). Fluconazole is detected according to its absorption maximum at 210 nm. The lower limit of quantification (LLOQ) is 0.65 μg/mL, the limit of detection (LOD) is 0.2 μg/mL, and the quantification range is 0.65–23.3 μg/mL. The assay was precise with a between-run coefficient of variation of ≤ 5.59%. The within-run accuracy was 99.8% and 103.4%, and the between-run accuracy was 99.2% and 99.7%, respectively, for the concentrations 23.3 μg/mL and 1.3 μg/mL. The recovery was 78%. The described procedure allows sample cleanup and determination within 20 minutes, thereby facilitating drug monitoring in clinical routine. The method was applied successfully.

Krankenhausapotheke: Hygienische Maßnahmen

Krankenhausapotheken versorgenf ambulante und stationare Patienten mit einer breiten Palette an Arzneimitteln. Neben Fertigarzneimitteln kommen dabei auch Medikamente zum Einsatz, die in der Krankenhausapotheke entweder als patientenindividuelle Rezepturen oder in Stuckzahlen von bis zu 100 pro Tag als Defekturarzneimittel hergestellt werden. Dabei muss auf jeden Fall vermieden werden, dass die Patienten einer Gefahr durch Arzneimittel aufgrund von Bedenklichkeit, ungenugender Qualitat oder fehlender Wirksamkeit ausgesetzt werden Besonders die Vermeidung von Kontaminationen spielt im Arzneimittelbereich eine wichtige Rolle. Bei industriell gefertigten Arzneimitteln ist die Qualitat durch das Zulassungsverfahren gesichert. Fur Praparate, die von der Krankenhausapotheke aus pharmazeutischen Grund- und Wirkstoffen selbst hergestellt oder aus den bereits industriell gefertigten Arzneimitteln zubereitet bzw. gemischt werden, gelten die im Folgenden hier aufgefuhrten Gesetzeswerke und Richtlinien, da an diese Zubereitungen die gleichen Qualitatsanspruche gestellt werden wie an industriell gefertigte Arzneimittel.

Rosemary has immunosuppressant activity mediated through the STAT3 pathway

OBJECTIVE In Europe extracts of Rosmarinus officinalis were traditionally used for the treatment of rheumatic diseases. We investigated the capacity of standardized aqueous extracts of Rosmarinus officinalis on human primary lymphocyte function in vitro, as activated lymphocytes are an important mediator of rheumatic diseases. METHODS Lymphocyte proliferation was measured using membrane-permeable dye carboxyfluorescein diacetate succinimidyl ester (CFSE). Apoptosis was analysed by surface staining of phosphatidylserine (annexin V-assay) and necrosis was analysed by staining with propidium iodide. Modification of cell activity was detected by surface staining of CD69 and CD25. The activity of STAT3 in T-lymphocytes was determined by intracellular staining of STAT3 molecules. All endpoints were analyzed by using flow cytometry. The Rosmarinus officinalis extract was investigated at concentrations of 0.05-25 mg/mL. Analysis of the extract was performed using HPLC methods. RESULTS Rosmarinus officinalis inhibited proliferation of human lymphocytes and CD4+ T-cells in a dose-dependent manner (3.1-25 mg/mL) through induction of apoptosis. The intracellular signalling pathway STAT3 in T-cells, but not NF-kappaB and ERK1/2 in T- and B-cells was inhibited in a dose-dependent manner by Rosmarinus officinalis (0.2-6.2 mg/mL). Rosmanol, carnosolic acid, carnosol and trans-caffeic acid were tested in the same cellular models as the crude extract. From these, only trans-caffeic acid inhibited lymphocyte proliferation and STAT3 (30-100 μg/mL). Trans-caffeic acid was found in the extract in a concentration of 14.7 μg/mL. CONCLUSIONS We conclude that an immunosuppressive effect of Rosmarinus officinalis is mostly due to the effect of trans-caffeic acid. It results in inhibition of the activity of STAT3 causing induction of apoptosis and inhibition of proliferation of T-lymphocytes.

Successful Treatment of Severe Pneumonia Caused by Burkholderia cenocepacia With Intravenous Antibiotics and Immunosuppression Under Extracorporal Membrane Oxygenation

Purulent destruction–complicated pneumonia is a rare and serious disease of multifactorial genesis. In many cases, the diagnosis cannot be established by microbiological analysis of bronchial aspirates or transbronchial biopsies. In our present case, isolation of the pathogen was only possible by collecting specimens via open surgical lung biopsy. A 57-year-old otherwise healthy man was transferred to our department from another hospital. He presented with progressive respiratory failure while computed tomographic scan showed severe bilateral necrotising pneumonia. With open surgical lung biopsy, we could prove evidence of Burkholderia cenocepacia as causative pathogen. As the patients pulmonary condition deteriorated and he developed septic multiorgan failure, we initiated extracorporeal membrane oxygenation (ECMO) and commenced aggressive treatment with 4 intravenous antibiotics, cyclosporine, and corticosteroids. With this therapy, the patients situation rapidly improved; and he was successfully weaned from ECMO andmechanical ventilation. Pneumonia caused by B cenocepaciawithout underlying pulmonary disease such as cystic fibrosis is an absolute rarity. According to the severity of cepacia syndrome, an interdisciplinary approach including ECMO aggressive antibiotic treatment and immunosuppression was decisive for a successful therapy.