Opinion on the use of the antitumor drug trastuzumab (Herceptin) in patients with metastatic breast cancer in the county Mecklenburg-Vorpommern.

The recombinant humanized anti-HER-2 monoclonal antibody trastuzumab (Herceptin) is directed against the human epidermal growth factor receptor on the surface of breast cancer cells. Herceptin was approved in Germany in September 2000 after evaluation in clinical trials involving women with metastatic breast cancer who had tumors overexpressing HER-2/neu. A prerequisite for its use is the diagnosis of the HER-2/neu receptor status in individual patients because trastuzumab is only effective in patients with a high (score +3) overexpression of the HER-2/neu receptor. The only approved diagnostic method is the immunohistochemical DAKO-Hercep test. Clinical experience with this novel biological agent has been obtained in 2 Phase III trials involving 469 and 222 patients, where trastuzumab was used as first- or second-line therapy. The addition of trastuzumab to chemotherapy regimens was associated with longer time to progression, a higher rate and duration of response and longer survival. When used as a single agent in metastatic breast cancer that had progressed after chemotherapy, there was an overall response rate of 15%. The median duration of response was 9.1 months and median survival was 13 months. Unwanted effects included potentially severe cardiotoxicity and in 40% of patients infusion-associated fever and/or shivering that usually occurred only during the first infusion. In patients with moderate HER-2/neu expression, unwanted drug effects outweigh a relatively weak therapeutic effect. In cases of high overexpression, the cancer may go into regression and survival may be prolonged with a relatively small impairment in the life quality. The costs of trastuzumab-therapy are high amounting to an additional 48,000 DM per patient per year. Recommendations for diagnosis and therapy in Mecklenburg-Vorpommern have been formulated in discussions between oncologists, practitioners, scientists and regulatory authorities.

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

OBJECTIVE: 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.

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.

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

OBJECTIVES: 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, 15 h prior to surgery). At the beginning of cataract extraction, 50-100 microl aqueous fluid was aspirated from the anterior chamber and immediately stored at -80 degrees C. Antibiotic concentrations were measured using fluorescence polarisation immunoassays (aminoglycosides) or high-performance liquid chromatography (fluoroquinolones). RESULTS: After soaking for 1h in 0.3% eye drop solutions, Acuvue contact lenses released about 190-250 microg aminoglycoside and ofloxacin and 1000 microg ciprofloxacin. These amounts are considerably lower or in the same order of magnitude than obtained with application of eye drops (1350 microg). 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) microg x ml(-1) vs 0.49 (0.79) microg x ml(-1)), ciprofloxacin (1.23 (0.60) microg x ml(-1) vs 0.38 (0.33) microg x ml(-1)) and ofloxacin (5.55 (2.53) microg x ml(-1) vs 0.56 (0.37) microg x 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.

[Corneal penetration of various aminoglycosides and quinolones]. / Hornhautpenetration verschiedener Aminoglycoside und Chinolone.

BACKGROUND: Penetration of the aminoglycosides gentamicin and tobramycin and chinolones ciprofloxacin and ofloxacin applied as eyedrops and soaked disposable lenses (ACUVUE), used as antibiotic prophylaxis, was investigated. MATERIALS AND METHODS: 217 patients received before undergoing cataract extraction 0.3% solutions of these antibiotics as eyedrops or by soaked ACUVUE-lenses. During surgery 50-100 microliters aqueous humor was aspirated; concentration of gentamicin and tobramycin was analysed by fluorescence polarisation immuno assay, concentration of ciprofloxacin and ofloxacin was analysed by high pressure liquid chromatography. RESULTS: After application of gentamicin and ofloxacin as eyedrops and via soaked ACUVUE-lenses as drug delivery system (DDS) we found higher concentrations than after application of tobramycin and ciprofloxacin by the same modes. After using of soaked lenses as DDS the aqueous humor concentrations of all tested substances were higher than the concentrations after the frequent instillation of eyedrops. CONCLUSIONS: Penetration of gentamicin through normal human cornea is higher than penetration of tobramycin; penetration of ofloxacin through normal human cornea is higher than penetration of ciprofloxacin. The aqueous humor concentrations of ofloxacin applied as eyedrops and DDS, of ciprofloxacin and gentamicin applied as DDS allow their use as antibiotic prophylaxis in cataract surgery.

Penetration of ciprofloxacin, norfloxacin and ofloxacin into the aqueous humours of patients by different topical application modes.

OBJECTIVE: A prospective study was undertaken to determine the transcorneal penetration of three topically applied fluoroquinolones into aqueous humour. METHODS: Two hundred and twenty-four patients undergoing cataract extraction received 0.3% ciprofloxacin, norfloxacin or ofloxacin eye drops by two different administration modes with different frequencies and intervals of application. At the beginning of cataract extraction (0.5-3 h after the last drop), 50-100 microliters aqueous fluid was aspirated from the anterior chamber and immediately stored at -80 degrees C. Antibiotic concentrations were measured using high-performance liquid chromatography. RESULTS: Generally, topical ofloxacin and ciprofloxacin yielded aqueous humour levels higher than topical norfloxacin. The highest concentrations of all tested fluoroquinolones were measured after using an application mode, in which one drop was given every 15 min between 0600 hours and 0800 hours, prior to operation. When applied by this mode, ciprofloxacin achieved a mean aqueous level of 0.380 (+/- 0.328) microgram.ml-1 (range 0.033-1.388 micrograms.ml-1), norfloxacin 0.182 (0.118) microgram.ml-1 (range 0.038-0.480 microgram.ml-1) and ofloxacin 0.564 (0.372) microgram.ml-1 (range 0.064-1.455 micrograms.ml-1). These mean concentrations were above the minimum inhibitory concentration (MIC90), concentrations required for inhibition of 90% of pathogen strains in vitro of gram-negative bacteria, such as Proteus mirabilis and Escherichia coli. Therapeutic values above the MIC90 of Staphylococcus epidermidis, the pathogen causing eye infections most frequently, were reached by 67.5% of patients after ofloxacin and by 41% after ciprofloxacin, but never after norfloxacin treatment. CONCLUSION: Of the currently available topical fluoroquinolones, ofloxacin achieved the highest aqueous humour concentration. This fluoroquinolone may be an useful ophthalmic agent for topical antibacterial management, but it does not seem to be prophylactically effective against Streptococcus pneumoniae or Pseudomanas aeruginosa.

Ecto-ATPase activity in rat and mouse thymocytes and cytotoxic effects of various chemical substances in vitro.

Ecto-ATPase was present in thymocytes of mice and rats with higher activity in rat thymocytes. In rat but not in mouse thymocytes the ecto-ATPase was inhibited in vitro by HgCl2, tricyclohexyltin chloride, di-n-butyltin dichloride, DDT, gamma HCH and desipramine. The EC50 values ranged from 8 X 10(-7) mol/l for HgCl2 to 4 X 10(-4) mol/l for desipramine. Ecto-ATPase activity in thymocytes was not a valuable indicator of the cytotoxic effects of chemicals in vitro. Inhibition of the enzyme was not accompanied by changes of the electrophoretic mobility of thymocytes. A decrease of the spontaneous mitotic activity of thymocytes in vitro is a very sensitive parameter of cytotoxic and cytostatic drug effects.

[Ecto-ATPases in leukocytes and its modification by drugs]. / Ekto-ATPasen an Leukozyten und ihre Beeinflussung durch Pharmaka.

The ecto-ATPase is located on the external surface of the plasma membrane of intact cells. The enzyme splits exogeneous ATP in the presence of Mg2+ into ADP and inorganic phosphate. This enzyme has been found on a variety of cells of various species in different activities. In leukocytes sulfhydryl groups are essential for the structure and function of the ecto-ATPase. The physiological and biochemical significance of the ecto-ATPase for cells remains unclear. Drugs may influence ecto-ATPase activity and simultaneously various cell functions. Tricyclic antidepressants and phenothiazine tranquilizers in micromolar concentrations inhibit the ecto-ATPase in granulocytes and reduce the phagocytic activity of the cells. The inhibition of the ecto-ATPase of rat thymocytes by organic tin compounds is not connected with a reduced spontaneous migration of the cells in vitro. Newer results indicate, that the ecto-ATPase activity of thymocytes and other cells is changing during maturation and differentiation.