Cost-minimisation analysis of sequential treatment with ofloxacin or ciprofloxacin in hospitalised patients.

This study evaluated the cost of sequential treatment with once-daily ofloxacin or twice-daily ciprofloxacin in 474 hospitalised patients in different countries. The patients were treated intravenously for at least 3 days, then orally for 7 to 10 days or for 3 days beyond the disappearance of infection-related symptoms. The overall clinical cure rate (86.8% with ofloxacin and 89.6% with ciprofloxacin) and the overall bacteriological response rate (89.9 and 89.0%, respectively) were similar, and a cost-minimisation analysis was conducted. The acquisition costs for ofloxacin and ciprofloxacin in Greece, Israel, Slovenia and Turkey were used and converted to Deutschmarks (DM), and the costs of administration were analysed for each hospital. The different cost categories for oral and intravenous (IV) treatment (e.g. antimicrobial acquisition, drug monitoring, drug delivery costs) were used to identify any differences. The total costs per patient varied between the countries involved, but were higher for ciprofloxacin (ofloxacin: DM239 to DM724; ciprofloxacin: DM540 to DM976). In a sensitivity analysis using identical daily acquisition costs for the 2 fluoroquinolones, the total cost of treatment was higher for ciprofloxacin, as a result of the lower cost of administration of ofloxacin in the once-daily regimen. Continuing IV therapy would be approximately 50% more expensive than switching to oral administration; however, whenever possible, both drugs can be switched from IV to oral treatment.

Pirarubicin in combination chemotherapy for metastatic breast cancer.

Pirarubicin is an anthracycline with broad antitumor activity, and without significant cardiotoxicity in preclinical and early clinical trials. We treated 40 evaluable patients with metastatic breast cancer and no prior exposure to chemotherapy with 5-fluorouracil, pirarubicin, and cyclophosphamide at 21-day intervals until reaching cumulative doses of 800 mg/m2 of pirarubicin, or the development of progressive disease. The median age was 56 years and the median performance status, 1. Seventeen patients had prior hormone therapy and 12 had prior radiotherapy. The median number of metastatic sites was three, with 11 patients having less than three sites. Twelve patients were premenopausal. The median disease-free interval was 6 months. Four patients achieved a complete remission and 21 a partial remission, for an overall response rate of 63%. The median response duration was 8 months and the median time to progression for all patients was 9 months. The median survival has not been reached, but will exceed 13 months. Gastrointestinal toxicity was minimal to moderate, whereas myelosuppression was severe. Complete hair loss was observed by only 58% of patients. There were two episodes of mild congestive heart failure at high cumulative doses of pirarubicin; both were controlled with medical treatment. This three-drug combination containing pirarubicin is effective in treating metastatic breast cancer, with less severe toxicity than other anthracycline-containing combinations.

A phase II study of pirarubicin in malignant pleural mesothelioma.

Thirty-five non-pretreated patients (29 male, six female) with malignant pleural mesothelioma, median age of 68.5 years (range, 29 to 78 years) and a median performance status of 80% (range, 60% to 100%) were treated with 70 mg/m2 Pirarubicin. The treatment was repeated every 3 to 4 weeks (median duration per cycle, 23 days) up to progression or severe toxicity. The median cumulative dose given was 294 mg/m2, or 4.5 cycles. All patients were evaluable regarding response. Three partial remissions were achieved, leading to a remission rate of 8.6%. The median duration of remission was 6 months. Five patients achieved minor response, and a further 14 patients were stable under treatment with Pirarubicin. The median survival time was 10.5 months. Leukocytopenia was the main dose-limiting factor and 20% of the patients experienced World Health Organization (WHO) Grades III and IV. Anemia and thrombocytopenia were mild. Nausea and vomiting, WHO Grades I and II, were observed in 46% of all patients. Alopecia, Grades I and II, was seen in 47% and Grade III in 6%. No signs of cardiac dysfunction were detectable, except for cardiac arrhythmia in four patients (11%). Pirarubicin is an active drug in the treatment of pleural mesothelioma with fewer severe side effects than doxorubicin.

A comparative study of levofloxacin and ceftriaxone in the treatment of hospitalized patients with pneumonia.

A multinational, multicentre, open, randomised study in hospitalised patients with pneumonia compared levofloxacin 500 mg twice daily with ceftriaxone 4 g i.v. once daily. Levofloxacin patients started on i.v. treatment and switched to oral on d 3-5 of therapy if signs and symptoms had improved. The minimum treatment duration was 5 d, except for treatment failure, and the median 8 d. The primary efficacy analysis was based on the per-protocol assessment of the clinical cure rate determined 2-5 d after the end of treatment in the per-protocol (PP) population (levofloxacin 127, ceftriaxone 139). Of 625 patients enrolled and randomized, 6 received no treatment, giving an intention-to-treat (ITT) population of 619 (levofloxacin 314, ceftriaxone 305). At the clinical endpoint, 2-5 d after the end of treatment, the cure rates for levofloxacin and ceftriaxone were similar in both the ITT (76% and 75%, respectively) and PP (87% and 86%, respectively) populations. Both drugs were well tolerated. Twice-daily levofloxacin 500 mg, either i.v. or as sequential i.v./oral therapy, was as effective as i.v. once-daily ceftriaxone 4 g in the treatment of hospitalized patients with pneumonia and offers the advantage of sequential therapy.

Genome structure of adenovirus 12 host range mutants adapted to growth in simian Vero cells.

Mutants of adenovirus type 12 adapted to growth in Vero cells were studied by restriction enzyme and sequence analysis. Plaque-purified mutants were isolated either after long-term passage of the virus in Vero cells (CS-1, CL-1) or from Vero cells transfected with viral DNA (11-g, 12-k). The plaque-forming activity of these mutants was equal or even slightly higher in Vero cells than in HeLa cells, whereas the activity of wild-type virus in HeLa cells exceeded that in Vero cells by about one to two orders of magnitude. All mutants tested had an insertion of variable length consisting of adenoviral sequences at the right end of the viral genome. Sizes of the insertions were determined to be 294 bp (CS-1, 12-k), 560 (11-g), or 180 bp (CL-1). Additional insertions of multiple size and less than equimolar amount were detected and seem to exist in some of the viral particles. Furthermore, all four mutants tested showed an identical 69-bp deletion in the first exon of the E1a gene.

Pirarubicin in advanced non-small cell lung cancer. A trial of the Phase I/II Study Group of the Association for Medical Oncology of the German Cancer Society.

Forty-seven patients with advanced non-small cell lung cancer (NSCLC) were treated in a multicentre phase II study with pirarubicin (THP), 4'-O-tetrahydropyranyl-doxorubicin using a dosage of 70 mg/m2 every 3 weeks. The median age of the patients was 59 years (range 45-70) and the performance status grade 0-2 (WHO). Thirty-eight patients had stage IV and 9 stage III (UICC). Twenty-six patients had an adenocarcinoma. 19 a squamous cell carcinoma, and 2 a polymorphocellular carcinoma. Six out of 45 evaluable patients achieved a partial remission leading to an overall response rate of 13%. Eighteen patients showed no change (NC), 12 were progressive (PD), 2 patients had early progression (EP), and 7 patients died during the first course with clinical signs of tumor progression (early death). The median survival time was 4.6 months. Leukocytopenia and thrombocytopenia (WHO grade 4) was experienced in 8.5% and 2.1%, nausea and vomiting (grade 2 and 3) by 32% of the patients. There was no cardiotoxicity or other severe side effects. Pirarubicin has only a moderate antineoplastic activity in patients with advanced NSCLC. Observed response rates are similar to those reported for doxorubicin, but the toxic side effects are milder.

A randomised, multinational study with sequential therapy comparing ciprofloxacin twice daily and ofloxacin once daily.

In a multinational, open, randomised, controlled clinical study, 474 hospitalised patients with moderate or severe infections were treated with sequential regimens of ofloxacin or ciprofloxacin. Ofloxacin 400 mg once daily or ciprofloxacin 200 mg twice daily were given intravenously for at least 3 days followed by oral treatment with ofloxacin 400 mg once daily or ciprofloxacin 500 mg twice daily. Overall cure rates of 86.8% (85.7%) in the ofloxacin group and 89.6 (89.5%) in the ciprofloxacin group were achieved in the intention-to-treat analysis (per protocol analysis). The overall bacteriological response rate (ofloxacin 89.5%, ciprofloxacin 89.0%) was comparable to the clinical cure rate. Both drugs were well tolerated and adverse events were rarely observed. It is concluded that ofloxacin and ciprofloxacin can be used successfully in the treatment of hospitalised patients with aerobic gram-positive and gram-negative infections. Ofloxacin has the advantage of a once-daily regimen, compared to the twice-daily regimen with ciprofloxacin.

Phase I studies of rodorubicin single bolus and daily times five, once every three weeks in patients with advanced solid tumors.

Rodorubicin (Cytorhodin S, HLB 817) is a new tetraglycosidic anthracycline with interesting preclinical antitumor activity. We have performed two sequential phase I studies with the drug. In the first study Rodorubicin was administered as a single i.v. administration over 30-360 min, once every 3 weeks. The second study concerned a daily times five i.v. bolus schedule. Thirty patients entered these studies. Regardless of schedule, the dose limiting toxicity appeared to be proteinuria, which was reversible after discontinuation of the drug. Phlebitis was a cumbersome side-effect and it was initially considered to determine the MTD in the once every 3 weeks schedule, but finally it could be prevented by giving the drug as a bolus injection into a rapidly running infusion. Nausea and vomiting were infrequent and mild. Neither myelotoxicity nor alopecia were observed. However, even at low cumulative doses the drug was found to be cardiotoxic using both schedules of administration. Seven out of 12 patients developed grade 1-3 cardiotoxicity, most of them above a cumulative dose of more than 4000 micrograms/m2. These side-effects preclude a dose recommendation for phase II studies with these schedules.

Phase II study of pirarubicin in metastatic breast cancer.

Pirarubicin is a more lipophilic derivative of doxorubicin, with a higher uptake rate of cells, lower cardiotoxicity and better antitumor efficacy in preclinical models. Thirty-four patients with metastatic breast cancer were treated in a multicenter phase II study with pirarubicin (THP) using a dosage of 75 mg/m2/every 3 weeks. The patients had a median age of 56 years (range 41-73) and a performance status of WHO grade 0-2. Patients pretreated with anthracyclines, or who were older than 75 years and without sufficient bone marrow reserve were excluded. The 32 evaluable patients received a median number of 4 cycles (range 2-8). The myelosuppression was dose-limiting and led to infections (grades 1 and 2) in 5 patients. Twenty-eight patients developed leukocytopenia grade 3 and 4 toxicity and 7 patients experienced thrombocytopenia grade 1 and 2. The drug was subjectively well tolerated and nausea, vomiting and alopecia were mild. One complete remission with a duration of 15.4 months (67 weeks) and 7 partial remissions with a median duration of 9.3 months (40 weeks) were achieved, which resulted in an overall response rate of 25%. Twenty-one patients were stable for 17 weeks (median) under the treatment with pirarubicin.