PKC412 can be safely administered by chronic oral therapy, and 150 mg/d is suitable for phase II studies. The pharmacokinetics and lack of conventional toxicity indicate that pharmacodynamic measures may be additionally needed to optimize the drug dose and schedule.

BAL5788 is the water-soluble prodrug of BAL9141, a novel broad-spectrum cephalosporin with potent bactericidal activities against methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae. We investigated the safety and pharmacokinetics of BAL5788 in a double-blind, single-ascending-dose study with 40 healthy male subjects. The subjects were randomized to receive placebo (n ‫؍‬ 2 subjects per dose) or BAL5788 (n ‫؍‬ 6 subjects per dose) as a 200-ml intravenous infusion over 30 min. The BAL5788 doses used were 125, 250, 500, 750, and 1,000 mg (BAL9141 equivalents). All doses were well tolerated, with no severe or serious adverse events (AEs). The most frequent AE was taste disturbance. No electrocardiographic abnormalities and no trends or clinically significant changes in laboratory parameters or vital signs were observed. The maximum concentration of drug in serum and the area under the concentrationtime curve for BAL9141 were dose proportional over the dosing range. The elimination half-life of BAL9141 was about 3 h. The volume of distribution at steady state was equal to the volume of the adult extracellular water compartment, and the rate of renal clearance of free drug corresponded to the normal glomerular filtration rate for adults. More than 70% of the administered dose was excreted as BAL9141 in the urine, and almost no prodrug was detected. After the infusion of 750 mg, the mean plasma BAL9141 concentrations exceeded the MIC at which 100% of MRSA isolates are inhibited (4 g/ml) for approximately 7 h, or 58% of a 12-h dosing interval. These results indicate that infusions of 750 mg twice a day should be adequate for the treatment of infections caused by MRSA.

BAL5788 is the water-soluble prodrug of BAL9141, a novel broad-spectrum cephalosporin with potent bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae. Safety and pharmacokinetic data from a multiple-dose study with 16 healthy male volunteers are reported. Subjects were randomized to receive BAL5788 at 500 or 750 mg (as BAL9141 equivalents; n ‫؍‬ 6 subjects per dose) or placebo (n ‫؍‬ 2 subjects per dose). The doses were given as 200-ml infusions over 30 min once daily on days 1 and 8 and twice daily on days 2 to 7. BAL5788 was well tolerated, with no severe or serious adverse events (AEs) or dosing-related changes in laboratory parameters, electrocardiographic findings, or vital signs. Drug accumulation in plasma was negligible during the dosing period. The results of pharmacokinetic analyses agreed well with data reported from a previous single-ascending-dose study. The elimination half-life of BAL9141 was about 3 h. The volume of distribution at steady state was equal to the volume of the adult extracellular water compartment. BAL9141 was predominantly eliminated in urine, and renal clearance of the free drug corresponded to the normal glomerular filtration rate in adults. After multiple infusions of 750 mg, the mean concentrations of BAL9141 in plasma exceeded the MIC at which 100% of MRSA isolates are inhibited (4 g/ml) for approximately 7 to 9 h, corresponding to 58 to 75% of a 12-h dosing interval.

The combination IFN/5-FU produced a response rate, response duration, and survival duration similar to that of 5-FU alone. The addition of IFN to 5-FU in the doses and schedules used in this study did not provide any further benefit over 5-FU alone and cannot be recommended for patients with metastatic ACC. This study confirms the value of large prospective randomized clinical trials to determine the clinical value of regimens that emerge from smaller single-center phase II studies.

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PKC412 is safe, well tolerated and reduces the tumor load in chronic B-cell malignancies. Inhibition of PKC offers a novel approach to the chemotherapy of B-cell malignancies.

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Summary Fifteen post-menopausal patients with advanced breast cancer were treated with the LH-RH agonist leuprorelin (D-leu6-des-gly'0-Gn-RH-ethylamide) given in a dosage of 7.5 mg as a monthly subcutaneous depot injection, to assess the clinical activity and endocrine response (Stoll, 1979). More surprisingly, these agents have also been reputed to be effective in 16-20% of post-menopausal patients with advanced breast cancer (Harvey et al., 1981;Plowman et al., 1986). It has been suggested that response in this group may be due to a direct effect on the tumour, as some LH-RH agonists have been shown to have an inhibitory effect on breast cancer cells in vitro (Blankenstein et al., 1985;Miller et al., 1985), and LH-RH binding sites have been demonstrated in several breast cancer cell lines (Eidne et al., 1987).More recently, it has been shown that in post-menopausal breast cancer patients treated with an LH-RH agonist (goserelin), there was a significant reduction of serum testosterone levels, which was associated with a 22% fall in the level of serum oestradiol (Dowsett et al., 1988). It is therefore possible that the response of post-menopausal patients to treatment with LH-RH analogues may be due to decreased oestrogenic stimulation, rather than to a direct, inhibitory effect on the tumour.In this study, the clinical and endocrine response of 15 post-menopausal patients with advanced breast cancer was evaluated during their treatment with the LH-RH agonist leuprorelin (D-leu6-des-gly'0-Gn-RH-ethylamide) (Lederle Laboratories, Gosport, Hampshire, UK). Patients and methodsFifteen post-menopausal women with locally advanced or metastatic, histologically proven breast cancer were entered into the study. Informed consent was obtained from all patients. Their mean age was 66 ± 7.6 years (mean ± s.d.), range 49-77, the mean weight was 68.5 ± 15.8 kg, range 50.1-108.5, and all patients were at least 2 years postmenopausal. Two tumours were oestrogen receptor (ER) Correspondence: M. Dowsett.