Analogues of staurosporine were synthesized and their ability to inhibit protein kinases was examined. Staurosporine is a potent but non-selective inhibitor of in vitro protein kinase C(PKC) activity (IC50 6.0 nM). The derivative CGP 41 251 had reduced PKC activity with an IC50 of 50 nM but showed a high degree of selectivity when assayed for inhibition of cyclic AMP-dependent protein kinase (IC50 2.4 microM), S6 kinase (IC50 5.0 microM) and tyrosine-kinase-specific activity of epidermal growth factor receptor (IC50 3.0 microM). Staurosporine and CGP 41 251 exerted growth inhibition in the human bladder carcinoma line T-24, human promyelocytic leukemia line HL-60 and bovine corneal endothelial cells at concentrations which correlated well with in vitro PKC inhibition. In addition, both compounds inhibited the release of H2O2 from human monocytes pre-treated with 12-O-tetradecanoyl-phorbol-13-acetate at non-toxic concentrations. In vivo anti-tumor activity was examined in T-24 human bladder carcinoma xenografts in athymic nude mice. Tumor growth inhibition tests revealed significant anti-tumor activity (2p less than 0.001) at 1/10 of the maximum tolerated doses for both compounds. By contrast, a closely related derivative of staurosporine (CGP 42 700) was inactive at concentrations of over 100 microM in all in vitro enzyme and anti-proliferative assays as well as in animal tumor models. Our data suggest an association between PKC inhibition and anti-proliferative and anti-tumor activity.

Asymptomatic hepatic dysfunction is common in patients with multiple sclerosis who are treated with interferon-beta-1a, and is dose related. Adverse effects are mainly mild and transient, with little impact on adherence to therapy, although rare serious events can occur. Regular liver function monitoring during the first 6 months is recommended.

Background: Women with multiple sclerosis (MS) are advised to discontinue interferon-beta therapy before trying to conceive. Unplanned pregnancies occur and risks related to exposure remain unclear. Methods: To determine pregnancy outcomes following interferon-beta therapy, we examined pregnancies from a global drug safety database containing individual case safety reports received in the post-marketing setting and safety data from clinical trials of subcutaneous interferon beta-1a in MS. Results: One thousand and twenty-two cases of exposure to subcutaneous interferon beta-1a during pregnancy were retrieved; 679 had a documented outcome. In cases for which exposure duration was available (n ¼ 231), mean time of foetal exposure to subcutaneous interferon beta-1a before treatment discontinuation was 28 days; most pregnancies (199/231; 86.1%) were exposed for 45 days. To avoid bias, only outcomes for prospective data (n ¼ 425) in pregnancies exposed to interferon beta-1a in utero were analysed further. Of these, 324 (76.2%) resulted in normal live births and four (0.9%) in live births with congenital anomalies (3 [0.7%] were 'major'). Four (0.9%) pregnancies resulted in stillbirths (1 [0.2%] with foetal defects). There were 5 (1.2%) ectopic pregnancies, 49 (11.5%) spontaneous abortions and 39 (9.2%) elective terminations. Most pregnancies exposed to subcutaneous interferon beta-1a in utero were associated with normal live births. The rates of spontaneous abortion and major congenital anomalies in live births were in line with those observed in the general population. Conclusions: These data should be taken into account when considering options for women with MS who become pregnant or who are planning pregnancy while on treatment with subcutaneous interferon beta-1a.

Artemether-lumefantrine (A-L), a new fixed-dose oral antimalarial drug, combines the fast onset of action of artemether (an artemisinin derivative) in terms of parasite clearance with the high cure rate of lumefantrine in the treatment of acute uncomplicated Plasmodium falciparum malaria. The extensive clinical trial database of A-L has allowed a comprehensive evaluation of its tolerability and safety in a total of 1869 patients (including 243 children aged 5-12 years and 368 children aged < 5 years). The most commonly reported and possibly related adverse effects following A-L therapy involved the gastro-intestinal (abdominal pain, anorexia, nausea, vomiting, diarrhoea) and central nervous (headache, dizziness) systems. Pruritus and rash were reported by < 2% of patients. More than 90% of the reported adverse events, many of which overlapped considerably with the clinical symptomatology or evolution of acute malaria, were rated mild to moderate in intensity. Compared to A-L, significantly higher incidences of vomiting and pruritus were observed with chloroquine, dizziness, nausea and vomiting with mefloquine, somnolence with pyrimethamine + sulfadoxine, and vomiting and dizziness with quinine. There were no serious or persistent neurological side-effects related to A-L administration. A-L did not lead to any clinically relevant alterations of the laboratory parameters. Serial electrocardiographic data were available for 713 patients. The frequency of QT interval prolongations was similar to or lower than that observed with chloroquine, mefloquine, or artesunate + mefloquine; these changes were considerably less frequent than with quinine or halofantrine. All patients with QT prolongation remained asymptomatic and no adverse clinical cardiac events were reported. Artemether-lumefantrine can thus be expected to show, both in children and in adults, a favourable safety profile for the treatment of acute, uncomplicated, P. falciparum malaria; it could as well be a reserve treatment option for travellers to endemic countries.

Although haematological abnormalities are common and dose-related in patients with MS receiving interferon-beta-1a, the events are mainly mild and transient, with little impact on adherence to therapy. Haematological events are rarely of clinical significance and do not adversely affect the benefit-to-risk ratio that favours high-dose interferon-beta-1a therapy.