Roflumilast, a once-daily oral phosphodiesterase 4 inhibitor, lacks relevant pharmacokinetic interactions with inhaled salbutamol when co-administered in healthy subjects.

OBJECTIVE: Roflumilast is an oral, once-daily phosphodiesterase 4 inhibitor under investigation for the treatment of chronic obstructive pulmonary disease and asthma. In clinical practice, the drug is likely to be co-administered with inhaled bronchodilating beta2-adrenoceptor agonists. Therefore, this study investigated the pharmacokinetic characteristics of roflumilast and its pharmacodynamically active metabolite roflumilast N-oxide when co-administered with orally inhaled salbutamol in healthy subjects. METHODS: In this open, randomized clinical study, 12 healthy male subjects received repeated doses of oral roflumilast 500 microg once daily, orally inhaled salbutamol 200 microg 3 times daily, and a combination of both drugs over 7 days according to a 3-period, changeover design with 14 days washout between treatments. RESULTS: Co-administration of roflumilast and salbutamol did not markedly change roflumilast or roflumilast N-oxide disposition. Point estimates (90% confidence intervals) of area under the curve from 0-24 h (AUC 0-24) and maximum plasma concentration in steady state (Cmax,ss) for roflumilast with salbutamol versus roflumilast alone were 1.05 (0.94, 1.17) and 0.97 (0.84, 1.10); the respective point estimates (90% confidence intervals) for AUC 0-24 and Cmax,ss of roflumilast N-oxide were 0.98 (0.91, 1.06) and 0.98 (0.92, 1.03). Roflumilast co-administration did not alter the pharmacokinetics of steady state salbutamol. The respective point estimates (90% confidence intervals) for AUC 0-6 and Cmax,ss of salbutamol with roflumilast versus salbutamol alone were 1.10 (0.99, 1.21), 1.08 (0.91, 1.28). The combination of both drugs was well tolerated. CONCLUSION: There were no relevant pharmacokinetic interactions between roflumilast and salbutamol at therapeutically effective doses.

Phase II study of combined 5-fluorouracil/ Ginkgo biloba extract (GBE 761 ONC) therapy in 5-fluorouracil pretreated patients with advanced colorectal cancer.

The aim of the study was to evaluate the efficacy, tolerability and quality of life in 5-fluorouracil (5-FU) pretreated colorectal cancer patients after combined 5-FU and Ginkgo biloba extract GBE 761 ONC (i.e. the Ginkgo biloba special extract EGb 761(R)) therapy. Following conventional 5-FU therapy, 44 patients (32 evaluable for response) with advanced progressive colorectal cancer were treated every 3 weeks with courses of 350 mg GBE 761 ONC as a 30 min i.v. infusion on days 1-6 followed by 500 mg/m(2)/d 5-FU as a 30 min i.v. infusion on days 2-6. The response to therapy was evaluated after the second and fourth course of treatment. The data of 32 patients could be evaluated for efficacy. We observed a progression of disease in 22 patients, no change in 8 patients and a partial response in 2 patients (overall response = 6.3%). Seventeen of 22 patients with observed progressive disease showed further progression after two cycles, two after three cycles and three after four cycles. The median survival time was 9.5 months (7.7-11.5 months). GBE 761 ONC was well tolerated. Adverse events that occurred during the study were mainly myelosuppression and gastrointestinal symptoms and were judged to be 5-FU related or consistent with liver toxicity and thus tumour related. Our results suggest a good benefit-risk ratio of the combined 5-FU and GBE 761 ONC therapy as second line treatment in metastatic colorectal cancer. The survival time was similar to that known from second line treatment according to the Ardalan scheme. Since an improvement was observed in some patients despite the failure of the conventional 5-FU pretreatment, it would be interesting to evaluate whether the application of 5-FU plus GBE 761 ONC as a first line treatment is of benefit.

The pharmacokinetics of a 1-h paclitaxel infusion.

PURPOSE: To characterize the disposition of paclitaxel (PAC) after a 1-h infusion in humans and define if possible a pharmacodynamic relationship between PAC disposition and the observed toxicity. PATIENTS AND METHODS: PAC pharmacokinetics were studied in 43 courses of therapy in 30 patients (30 first course, 13 PK third course). PAC was administered at 150, 175, 200, 225 and 250 mg/m2 by a 1-h infusion to patients with advanced cancer (lung, breast, ovarian, cervix, and head and neck). PAC was quantified by high-performance liquid chromatography (HPLC). Pharmacokinetic parameters were calculated by noncompartmental and model-dependent methods. RESULTS: Increases in the area under the curve and the peak plasma concentration were not proportional to increases in the dose. However, the deviation from linearity is rather moderate. The dose-limiting toxicity was central neuropathy which was not associated with pharmacokinetic deviations. Owing to the absence of grade 3 or 4 myelotoxicity, no clear correlation between this toxicity and pharmacokinetic parameters could be established. CONCLUSION: Within the evaluated dose range of the 1-h infusion there was only a moderate nonlinear disposition of PAC in humans and therefore a dose of 225 mg/m2 is recommended as safe. The observation of central neuropathy could not be directly related to a pharmacokinetic parameter. The complexity of the formulation which included Cremophor EL and ethanol may offer an explanation for the observed central neurotoxicity.

Phase II study with 5-fluorouracil and ginkgo biloba extract (GBE 761 ONC) in patients with pancreatic cancer.

The aim of the study was to evaluate the efficacy and tolerability of as well as the quality of life under treatment with 5-fluorouracil (CAS 51-21-8, 5-FU) combined with parenteral GBE 761 ONC (i.e. the ginkgo biloba special extract EGb 761) in patients with pancreatic cancer. Forty-eight patients with locally or metastatic advanced pancreatic cancer were treated within a phase II study. The treatment was repeated every three weeks until progression. Response to therapy was evaluated after 2 and 4 treatment courses. Thirty-two patients were evaluable for response. Progressive disease was observed in 22 (68.8%) patients, no change in 7 (21.9%) patients and partial response in 3 (9.4%) patients (overall response = 9.4%). GBE 761 ONC was well tolerated. Adverse events which occurred during the study consisted mainly of myelosuppression and gastrointestinal symptoms and were judged as 5-FU-related or consisted of liver toxicity, respectively, and were judged as tumour-related. These results suggest a good benefit-risk ratio of the combination of 5-FU and GBE 761 ONC in the treatment of pancreatic cancer. In comparison with the results of studies with either 5-FU or gemcitabine as single agents the combination of 5-FU/GBE 761 ONC shows comparable response rates. The toxicity of the 5-FU/GBE 761 ONC combination was low. This combination therapy therefore warrants further clinical investigation, such as a controlled clinical trial against 5-FU or gemcitabine monotherapy.

Linearized colorimetric assay for cremophor EL: application to pharmacokinetics after 1-hour paclitaxel infusions.

Cremophor EL (CrEL) is a polyoxyethylated castor oil surfactant used in the intravenous formulation of the anticancer drug paclitaxel (Taxol). Quantitative determination of CrEL in patient samples can be achieved by complexation of the compound with the Coomassie brilliant blue G-250 dye in protein-free extracts [Sparreboom, A., Loos, W. J., Verweij, J., De Vos, A. I., Van der Burg, M. E. L., Stoter, G., and Nooter, K., Anal. Biochem. 255, 171-175 (1998)]. A disadvantage of this method of CrEL determination is that the assay plot of absorbance at 595 nm, the peak wavelength of the CrEL-dye complex, versus the concentration of the surfactant is not linear. The present study shows that the nonlinearity is associated with a decrease in the free dye concentration and a reduction in complex formation by increasing the CrEL concentration. By measurement of the ratio of absorbances at the maxima of the red (450 nm) and blue charge forms (595 nm) of Coomassie brilliant blue G-250, a full-scale linear relationship can be obtained over the entire range studied (0.500 to 10.0 microliter/mL). Validation data revealed that transformation of the detection procedure exhibits significantly improved specificity, accuracy(

Clinical phase I study with one-hour paclitaxel infusion.

BACKGROUND: Paclitaxel (PAC) is one of the major anti-cancer drugs, effective in different tumors. Studies with 24-hour infusion with 135 mg/m2 and a three-hour infusion with 175 mg/m2 showed a significant schedule-dependent toxicity. We evaluated a one-hour infusion schedule within a phase I study to determine the dose limiting toxicity (DLT), the maximum tolerated dose (MTD), and the anti-cancer efficacy. PATIENTS AND METHODS: Patients with advanced malignant tumors were treated within cohorts by one-hour infusional paclitaxel starting with 150 mg/m2 and stepwise escalation with 25 mg/m2 increments. Therapy was repeated in three-week intervals. Cycles were repeated until progression. Toxicity was closely monitored, anti-cancer efficacy was only evaluated in those patients who received at minimum two treatment cycles. RESULTS: Thirty-four patients entered the study (11 NSCLC, five SCLC, seven ovarian cancer, one cervix cancer, nine MBC, one HN cancer). The MTD was PAC 250 mg/m2. The DLT was central and peripheral neuropathy (WHO grade 3). Other significant toxicities were fatigue, myalgia/arthralgia and paraesthesia. No significant myelotoxicity was observed. Totally twentyone patients were evaluable for response. A partial response was observed in five (24%) patients (two NSCLC, two ovarian cancer, one head and neck cancer). Three (14%) patients had stable disease and in 13 (62%) patients progressive disease was observed. CONCLUSIONS: Paclitaxel 225 mg/m2 on day 1 administered as one-hour infusion and repeated every three weeks can be given safely, featured no relevant myelotoxicity, and is the recommended dose for phase II studies.

Phase I study of paclitaxel administered as a 1-hour infusion: toxicity and pharmacokinetics.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is one of the most important new drugs used in the treatment of solid tumors. Use of paclitaxel, however, is associated with some toxicity. The main adverse side effects include myelotoxicity, neurotoxicity, hypersensitivity reactions, and asthenia. Toxicity seems to be schedule dependent. Currently, paclitaxel is routinely administered via 3- or 24-hour infusions. This study was performed to evaluate the toxicity and pharmacokinetics of a 1-hour infusion. Thirty-four patients with incurable solid tumors were included. Dose levels were escalated from 150 to 250 mg/m2. Thirty-four patients received a total of 105 courses of paclitaxel. The dose-limiting toxicity was World Health Organization grade 3 neuropathy at a dose of 250 mg/m2 in two of three patients. Two patients were not evaluable for dose-limiting toxicity because treatment was stopped after fewer than three courses due to disease progression. Neither had experienced a dose-limiting toxicity. Other toxicities were World Health Organization grade 1/2 neutropenia, asthenia, myalgia, arthralgia, and grade 1 hypersensitivity. Twenty-one patients were evaluable for preliminary anticancer efficacy. A partial response was observed in five patients (24%), stable disease in three (14%), and progressive disease in 13 (62%). The maximum tolerated dose was established at 250 mg/m2. A dose of 225 mg/m2 is recommended for further phase II trials. There was considerable interindividual and some intraindividual variability in pharmacokinetic parameters. Paclitaxel pharmacokinetics were linear up to 225 mg/m2, while a slightly overproportional increase in the peak plasma concentration and the area under the concentration-time curve was observed at 250 mg/m2, suggesting that paclitaxel's pharmacokinetic characteristics may be nonlinear at higher doses.

[A new measuring device for computer-assisted imaging of the form and flexibility of the spine]. / Ein neues Messgerät zur computergestützten Darstellung von Form und Beweglichkeit der Wirbelsäule.

Our aim is to present a new method to examine spinal mobility and spine shape excluding torsional scoliosis. In comparison to measuring devices of the spine used so far, this noninvasive and easy to use method documents altered patterns of intervertebral mobility of the lumbar and thoracic spine. This may lead to a broader application of the triflexometer as a diagnostic tool for orthopedic and rheumatologic diseases that can decrease the frequency of X-ray exposure if used in combination with radiographs. In the present investigation the triflexometer demonstrates a good reproducibility of the triflexometer-based measurements. These findings support the ability of the triflexometer to depict disease courses of spinal disorders as well as the effect of therapy and rehabilitation.