Bernd Drewelow

Pharmacokinetics and bioavailability of quercetin glycosides in humans

Due to its potentially beneficial impact on human health, the polyphenol quercetin has come into the focus of medicinal interest. However, data on the bioavailability of quercetin after oral intake are scarce and contradictory. Previous investigations indicate that the disposition of quercetin may depend on the sugar moiety of the glycoside or the plant matrix. To determine the influence of the sugar moiety or matrix on the absorption of quercetin, two isolated quercetin glycosides and two plant extracts were administered to 12 healthy volunteers in a four‐way crossover study. Each subject received an onion supplement or quercetin‐4′‐O‐glucoside (both equivalent to 100 mg quercetin), as well as quercetin‐3‐O‐rutinoside and buckwheat tea (both equivalent to 200 mg quercetin). Samples were analyzed by HPLC with a 12‐channel coulometric array detector. In human plasma, only quercetin glucuronides, but no free quercetin, could be detected. There was no significant difference in the bioavailabilityand pharmacokinetic parameters between the onion supplement and quercetin‐4′‐O‐glucoside. Peak plasma concentrations were 2.3 ± 1.5 μg•mL−1 and 2.1 ± 1.6 μg•mL−1 (mean ± SDJ and were reached after 0.7 ± 0.2 hours and 0.7 ± 0.3 hours, respectively. After administration of buckwheat tea and rutin, however, peak plasma levels were—despite the higher dose—only 0.6 ± 0.7 μg•mL−1 and 0.3 ± 0.3 μg•mL−1, respectively. Peak concentrations were reached 4.3 ± 1.8 hours after administration of buckwheat tea and 7.0 ± 2.9 hours after ingestion of rutin. The terminal elimination half‐life was about 11 hours for all treatments. Thus, the disposition of quercetin in humans primarily depends on the sugar moiety. To a minor extent, the plant matrix influences both the rate and extent of absorption in the case of buckwheat tea administration compared with the isolated compound. The site of absorption seems to be different for quercetin‐4′‐O‐glucoside and quercetin‐3‐O‐rutinoside. The significance of specific carriers on the absorption of quercetin glycosides, as well as specific intestinal b‐glucosidases, needs to be further evaluated.

Hyperforin in St. John’s wort drug interactions

Recently, interactions of herbal medicines with synthetic drugs came into focus of particular interest. In the past 3 years, more than 50 papers were published regarding interactions between St. John’s wort (Hypericum perforatum L.; SJW) and prescription drugs. Co-medication with SJW resulted in decreased plasma concentrations of a number of drugs including amitriptyline, cyclosporine, digoxin, indinavir, irinotecan, warfarin, phenprocoumon, alprazolam, dextrometorphane, simvastatin, and oral contraceptives. Sufficient evidence from interaction studies and case reports indicate that SJW is a potent inducer of cytochrome P450 enzymes (particularly CYP3A4) and/or P-glycoprotein. Recent studies could show that the degree of enzyme induction by SJW correlates strongly with the amount of hyperforin found in the product. Products that do not contain substantial amounts of hyperforin (<1%) have not been shown to produce clinically relevant enzyme induction. On the other hand, some evidence suggests that hyperforin may also contribute to the antidepressant activity of SJW. However, clinical studies using SJW preparations with a low hyperforin amount (<1%) clearly demonstrated the superiority of this plant extract over placebo and its equivalence to imipramine and fluoxetine in the treatment of mild to moderate forms of depression. In the present paper clinical significant SJW interactions are critically evaluated against the background of hyperforin.

Effect of St John's Wort Dose and Preparations on the Pharmacokinetics of Digoxin

St Johns wort preparations vary in composition, main constituents, formulation, and daily dose administered. The aim of the study was to evaluate the possible pharmacokinetic interaction of marketed St Johns wort formulations and doses with digoxin.

Improved penetration of aminoglycosides and fluoroquinolones into the aqueous humour of patients by means of Acuvue contact lenses

AbstractObjectives: In order to improve the penetration of topically applied drugs in ophthalmology, the suitability of hydrophilic contact lenses (Acuvue, Vistacon, power −1.0 D) as a drug delivery system for antibiotics was tested. A prospective study was undertaken to determine the transcorneal penetration of five topically applied aminoglycosides and fluoroquinolones into the aqueous humour of patients. Methods: Two hundred and sixty-five patients undergoing cataract extraction received 0.3% gentamicin, kanamycin, tobramycin, ciprofloxacin or ofloxacin solution by two different modes of administration: either as eye drops (nine drops every 15 min, starting 2 h prior to surgery) or by means of a drug delivery system (Acuvue contact lenses soaked for 1 h in eye drop solution without preservatives, 1–5 h prior to surgery). At the beginning of cataract extraction, 50–100 μl aqueous fluid was aspirated from the anterior chamber and immediately stored at −80 °C. Antibiotic concentrations were measured using fluorescence polarisation immuno-assays (aminoglycosides) or high-performance liquid chromatography (fluoroquinolones). Results: After soaking for 1 h in 0.3% eye drop solutions, Acuvue contact lenses released about 190–250 μg aminoglycoside and ofloxacin and 1000 μg ciprofloxacin. These amounts are considerably lower or in the same order of magnitude than obtained with application of eye drops (1350 μg).From the aminoglycosides tested, only gentamicin and tobramycin, but not kanamycin, were able to penetrate into the aqueous humour of patients. After the wearing of antibiotic-soaked lenses, mean aqueous humour concentrations were higher than after the use of eye drops. This difference reached significance in tobramycin (1.09 (1.30) μg · ml−1 vs 0.49 (0.79) μg · ml−1), ciprofloxacin (1.23 (0.60) μg · ml−1 vs 0.38 (0.33) μg · ml−1) and ofloxacin (5.55 (2.53) μg · ml−1 vs 0.56 (0.37) μg · ml−1).The percentage of patients with aqueous humour concentration above the MIC90 of Staphylococcus epidermidis, the most common cause of postoperative endophthalmitis, was 92% and 100% after wearing ciprofloxacin- or ofloxacin-soaked lenses, respectively. Conclusion: Gentamicin and tobramycin penetrated into the aqueous humour of patients, whereas kanamycin was not able to overcome the corneal barrier. Acuvue contact lenses soaked in 0.3% eye drop solutions can release sufficient amounts of gentamicin, ciprofloxacin and ofloxacin to produce bacteriostatic concentrations in the humor aquosus. Acuvue contact lenses can be recommended as a drug delivery system for fluoroquinolones.

Pharmacokinetics of Piperacillin-Tazobactam in Anuric Intensive Care Patients during Continuous Venovenous Hemodialysis

ABSTRACT The pharmacokinetics of piperacillin-tazobactam were investigated in eight anuric intensive care patients treated by continuous venovenous hemodialysis (CVVHD). The elimination half-life of piperacillin was 4.3 ± 1.2 h, and that of tazobactam was 5.6 ± 1.3 h. The contribution of CVVHD to the overall elimination was relevant (>25%) for both drugs.

Perioperative antibiotic prophylaxis in maxillofacial surgery: penetration of clindamycin into various tissues.

Although clindamycin is recommended for prophylactic use in oral and maxillofacial surgery, there is little data available regarding its ability to provide sufficient tissue concentrations at the operative site. We investigated tissue samples from 31 patients, who had to undergo oral and maxillofacial surgery and who received at least one dose of 600 mg clindamycin i.v. preoperatively, to determine clindamycin tissue concentrations in muscle, oral mucosa, fatty tissue, skin and bone between 15 min and 8 h after administration. After homogenization, clindamycin concentration was determined by bioassay. It was demonstrated that clindamycin concentrations above the MIC90 of those pathogens most likely to cause contamination were reached in all kinds of tissues investigated. Already 15 min after administration, tissue concentrations above the MIC90 were reached and were still detectable in the last samples taken between 4 and 8 h after the last clindamycin administration. From the pharmacokinetic point of view, clindamycin is suitable for perioperative prophylaxis during oral and maxillofacial surgery providing sufficient tissue concentrations with no intraoperative additional dosage necessary unless procedures exceed 4 h duration.

Penetration of Ertapenem Into Different Pulmonary Compartments of Patients Undergoing Lung Surgery

Ertapenem is approved for the treatment of community‐acquired pneumonia (CAP), but its in vivo penetration into lung tissue (LT), epithelial lining fluid (ELF), and alveolar cells (AC) is unknown. Fifteen patients undergoing thoracotomy were treated with 1 g intravenously for perioperative prophylaxis. Bronchoalveolar lavage was performed 1, 3, and 5 hours after ertapenem infusion. Normal LT was sampled at the time of lung extraction. Blood was collected before and at different time points up to 24 hours after infusion. Mean concentrations of ertapenem in plasma, ELF, and AC were at 1.0 hour, 63.1, 4.06, 0.004 mg/L; at 3.0 hours, 39.7, 2.59, 0.003 mg/L; and at 5.0 hours, 27.2, 2.83, 0.007 mg/L. Mean (range) concentration in LT was 7.60 (2.5–19.4) mg/kg tissue 1.5 to 4.5 hours after infusion. In plasma, ertapenem exhibited a Cmax of 94.7 ± 23.3 mg/L and an AUC0‐last of 501.1 ± 266.3 mg•h/L. These results, combined with the reported (MIC)90 of most CAP bacteria, support the previously observed clinical efficacy of ertapenem in the treatment of CAP.

Comparison of several approaches of therapeutic drug monitoring of cyclosporin A based on individual pharmacokinetics

AbstractObjective: The clinical outcome of patients after organ transplantation is correlated with cyclosporin A (CyA) exposure. It is generally accepted that the area under the concentration–time curve (AUC) provides a reliable means for drug exposure. However, in routine therapeutic drug monitoring (TDM) of CyA, trough levels are mostly used. Currently, a number of different new concepts of CyA-TDM, including approaches such as single, double or triple time-point and abbreviated AUC determinations, have been introduced. The purpose of this study was to compare the predictive value of the different strategies of TDM. Methods: Calculations were based on 40 individual concentration–time profiles after oral administration of CyA to patients who had been included into an ongoing prospective clinical trial. Non-compartmental analysis was used to calculate the AUC0–12h. Multiple linear regression was performed to describe the relationship between the different sets of blood concentrations and the respective AUC0–12h as well as to evaluate their predictive value regarding AUC. Predictive performance was assessed by prediction bias and prediction precision, which were estimated as the mean prediction error and root mean squared error, respectively. Results: When comparing the various combinations of time points, it was found that one-point approaches showed the strongest differences with regard to the predictive value; the associated r2 values differed from 0.203 to 0.792. The two and three time-point approaches showed lower differences – r2 0.802–0.972. The four-point and five-point approaches (r2 0.942–0.982) were the strongest predictors for CyA AUC0–12h. Relative bias ranged from −27.7% to 63.8% and changed significantly when multiple-point predictors were used. In those cases, the predictive performance improved. Considering the predictive performance as well as the smallest bias and highest prediction precision, C3, C1 + C3, C1 + C3 + C6 and C1 + C2 + C3 + C6 were the best predictors. Conclusion: The results of this study indicate that in kidney transplant patients a clinically sufficient precise estimation of the CyA AUC is possible using two or three concentration–time points.

Penetration of ciprofloxacin, norfloxacin and ofloxacin into the aqueous humor using different topical application modes

Abstract · Background: A prospective study was undertaken to determine the transcorneal penetration of three topically applied fluoroquinolones into aqueous humor. · Methods: Cataract patients (n=224) preoperatively received topically applied gyrase inhibitors (0.3% ciprofloxacin, 0.3% norfloxacin, 0.3% ofloxacin) in two different application modes. In application mode I, patients received on the day before operation 3×1 eye drop at 2-h intervals, and on the day of operation 3 drops at 1-h intervals. In application mode II, patients received 9 drops at 15-min intervals on the day of operation only. Just before cataract surgery 50–100 μl aqueous humor was aspirated and stored at –80 °C. The HPLC method was used for measuring the concentration. · Results: The highest concentrations of all tested antibiotics were measured after the mode of application in which one drop was given every 15 min between 06:00 and 08:00 hours before operation. In this mode, ciprofloxacin achieved a mean aqueous level of 379.8±327.8 μg/l (range 33–1388 μg/l), norfloxacin 182.1±118.1 μg/l (range 38–480 μg/l) and ofloxacin 563.9±372.1 μg/l (range 64–1455 μg/l). These mean concentration are all above the MIC90 of gram-negative bacteria like Proteus mirabilis and Escherichia coli. In some cases the concentrations of ciprofloxacin and ofloxacin, but never norfloxacin, reached therapeutic values above the MIC90 of Staphylococcus aureus and Staphylococcus epidermidis · Conclusions: The mean concentration value of 0.3% ciprofloxacin and of 0.3% ofloxacin in the aqueous humor reached the MIC90 values of the frequently occurring gram-positive and gram-negative bacteria. Of the currently available topical fluoroquinolones, ofloxacin achieved the highest aqueous humor concentration. Considering the higher antimicrobial activity of ciprofloxacin, both ciprofloxacin and ofloxacin may be useful ophthalmic agents in antibacterial management, but they are not efficient against Streptococcus pneumoniae and Pseudomonas aeruginosa.

Placebo-controlled randomized clinical trial on the immunomodulating activities of low- and high-dose bromelain after oral administration - new evidence on the antiinflammatory mode of action of bromelain.

Bromelain has been used for treatment of inflammatory diseases for decades. However, the exact mechanism of action remains poorly understood. While in vitro investigations have shown conflicting effects on the release of various cytokines, no in vivo data were available. In this study, the effects on inflammation‐related cytokines of two doses of bromelain were tested in a single dose placebo‐controlled 3 × crossover randomized clinical trial. Cytokine circadian profiles were used to investigate the effects of bromelain on the human immune system by using stimulated whole‐blood leukocytes. The effects seen in these cultures demonstrated a significant shift in the circadian profiles of the Th1 cell mediator interferon gamma (IFNγ; p < 0.043) after bromelain 3000 FIP (Fédération Internationale Pharmaceutique) units, and trends in those of the Th2‐type cytokine IL‐5 as well as the immunosuppressive cytokine interleukin (IL)‐10. This suggests a general effect on the antigen‐specific (T cell) compartment of the human immune system. This is the first time that bromelain has been shown to modulate the cellular responses of lymphocyte after oral use. It is postulated that the immunomodulating effect of bromelain observed in this trial is part of its known antiinflammatory activities. Further investigations will be necessary to verify the relevance of these findings to a diseased immune system. Copyright