Efficacy of six doses of artemether-lumefantrine (benflumetol) in multidrug-resistant Plasmodium falciparum malaria.

The new oral fixed combination artemether-lumefantrine (CGP 56697) has proved to be an effective and well-tolerated treatment of multi-drug resistant Plasmodium falciparum malaria, although cure rates using the four-dose regimen have been lower than with the currently recommended alternative of artesunate-mefloquine. Two six-dose schedules (total adult dose = 480 mg of artemether and 2,880 mg of lumefantrine) were therefore compared with the previously used four-dose regimen (320 mg of artemether and 1,920 mg of lumefantrine) in a double-blind trial involving 359 patients with uncomplicated multidrug-resistant falciparum malaria. There were no differences between the three treatment groups in parasite and fever clearance times, and reported adverse effects. The two six-dose regimens gave adjusted 28-day cure rates of 96.9% and 99.12%, respectively, compared with 83.3% for the four-dose regimen (P < 0.001). These six-dose regimens of artemether-lumefantrine provide a highly effective and very well-tolerated treatment for multidrug-resistant falciparum malaria.

A randomized, double-blind, comparative trial of a new oral combination of artemether and benflumetol (CGP 56697) with mefloquine in the treatment of acute Plasmodium falciparum malaria in Thailand.

CGP 56697, a new oral fixed combination of artemether and benflumetol, was tested in a double-blinded, randomized trial in 252 adult patients treated either with CGP 56697 (4 x 4 tablets each containing 20 mg of artemether and 120 mg of benflumetol, given at 0, 8, 24, and 48 hr), or with mefloquine (three tablets of 250 mg at initial diagnosis, followed by two tablets of 250 mg at 8 hr). Baseline data of the two groups were comparable. The 28-day cure rate with CGP 56697 was lower than with mefloquine (69.3% versus 82.4%; P = 0.002). However, CGP 56697 was more effective than mefloquine in parasite clearance time (43 hr versus 66 hr; P < 0.001) fever clearance time (32 hr versus 54 hr; P < 0.005), and gametocyte clearance time (152 hr versus 331 hr; P < 0.001). This study revealed that CGP 56697 is effective against multidrug-resistant Plasmodium falciparum malaria in Thailand, but higher doses will probably be needed to improve the cure rate.

The pharmaceutical industry and oncology in central and eastern Europe.

Major opportunities exist for patients, investigators and the pharmaceutical industry in oncology drug development in Central and Eastern Europe. Novel therapeutics may be offered for investigational use in selected centres capable of adherence to Good Clinical Practice (GCP). Requirements for participation in oncology clinical trials include the availability of experienced qualified investigators highly motivated to conform with the principles of GCP (International Harmonization (ICH) guidelines); availability of appropriate Institutional Review Board for Human Subjects (IRB), access to appropriate patient populations, access to individual patient data, acceptance of possible audit by sponsoring companies and the Food and Drug Administration (FDA), and a willingness to participate in the generation of new knowledge. Patients gain through access to novel therapeutics. We have had success in performing clinical trials to international standards in Central and Eastern Europe. This experience will be described.

A randomized controlled trial of artemether/benflumetol, a new antimalarial and pyrimethamine/sulfadoxine in the treatment of uncomplicated falciparum malaria in African children.

We report here the results of a randomized double blind trial comparing coartemether (CGP56697), a combination of artemether and benflumetol, with pyrimethamine/sulfadoxine (P/S). Two hundred eighty-seven children 1-5 years of age with uncomplicated falciparum malaria were enrolled at two centers in The Gambia between July 1996 and December 1996. Following treatment, children were visited at home every 24 hr until a blood film free of asexual parasites was obtained. Genotyping of parasites was used to distinguish recrudescence from new infections. Three days after the start of treatment, 133 (100%) of the CGP56697-treated children compared with 128 (93.4%) of children treated with P/S had cleared their parasites (P = 0.003). The day 15 cure rate was 93.3% for CGP56697 and 97.7% for P/S (P = 0.13). Within the third and fourth week after initiation of therapy, 20 children treated with CGP56697 and one of the P/S-treated children returned with second malaria episodes (P < 0.0001). Genotyping suggested that the majority (19 of 23 [82.6%]) of these second episodes were due to new infections, supporting the World Health Organization recommendation that longer follow-up is not relevant for the assessment of drug efficacy. At the two-week follow-up, 28.9% of the P/S treated children but none of the CGP56697-treated children carried gametocytes (P < 0.0001). This study showed that CGP56697 is safe in African children with acute uncomplicated falciparum malaria, clears parasites more rapidly than P/S, and results in fewer gametocyte carriers. More frequent new infections within the third and fourth week following treatment with CGP56697 than treatment with P/S are likely to be due to the short prophylactic effect of CGP56697.

Randomized comparison of artemether-benflumetol and artesunate-mefloquine in treatment of multidrug-resistant falciparum malaria.

An open, randomized comparison of artemether-benflumetol (CGP 56 697; Novartis) with artesunate-mefloquine was conducted in 617 patients with acute uncomplicated multidrug-resistant falciparum malaria on the western border of Thailand. Both treatments rapidly and reliably cleared fever and parasitemia, and there was no significant difference in the initial therapeutic response parameters. Parasite genotyping was used to distinguish recrudescences from new infections. The 63-day cure rate for artesunate-mefloquine (94%) was significantly higher than the cure rate for artemether-benflumetol (81%) (P < 0.001). Both regimens were well tolerated. Nausea, vomiting, dizziness, sleep disorders, and other neurological side effects were between two and four times more common in the artesunate-mefloquine group than in the artemether-benflumetol group (P < 0.001). Artemether-benflumetol is effective and very well tolerated in the treatment of multidrug-resistant falciparum malaria. A higher dose than that used in the present study may improve efficacy.

Treatment of African children with uncomplicated falciparum malaria with a new antimalarial drug, CGP 56697.

New antimalarial drugs are urgently needed. The use of short courses of the new antimalarial drug artemether as monotherapy has been limited by secondary malaria episodes following parasite clearance. Therefore, a new antimalarial drug, CGP 56697, has been developed, which combines artemether with a longer-acting antimalarial agent, benflumetol. A safety trial was undertaken in 60 Gambian children 1-6 years old with uncomplicated Plasmodium falciparum malaria. All children treated with CGP 56697 cleared their parasites 72 h after the start of treatment. No neurologic, cardiac, or other adverse reactions were observed. Second episodes of falciparum malaria were recorded in 16 (27%) of the children. Second infections were more frequent during the rainy season than during the dry season. Molecular epidemiologic studies suggested that 12 of the 14 second episodes of malaria in children treated with CGP 56697 were due to new infections. CGP 56697 proved to be a safe and effective antimalarial drug in African children.

Serum alpha 1-protease inhibitor in diabetes mellitus: reduced concentration and impaired activity.

We investigated possible alterations in serum alpha 1-protease inhibitor (alpha 1-PI) concentration and activity from insulin-dependent diabetic subjects (IDDs) and in vitro in serum samples containing high glucose concentrations. The in vivo measurements were compared to others taken from normal reference subjects and the in vitro measurements were performed in serum samples containing 0, 10, 20, and 40 mmol/l of glucose. The diabetics had a significantly lower mean alpha 1-PI concentration in their serum than did the reference subjects (1.74 +/- 0.1 g/l vs. 2.1 +/- 0.1 g/l, P less than 0.05), as well as a lower total alpha 1-PI inhibitory activity (201 +/- 0.7 vs. 246.9 +/- 13.5 U/l, P less than 0.02). Addition of glucose to the serum samples in the in vitro study significantly reduced the mean alpha 1-PI concentrations (P less than 0.01 in the case of 10 mmol/l glucose, and P less than 0.001 in the cases of 20 and 40 mmol/l). Added glucose also significantly reduced the mean serum alpha 1-PI activity as determined by the percentage of elastase inhibition in 1, 2, and 3 microliters of reference serum (P less than 0.02 in the case of 10 mmol/l glucose, P less than 0.01 in 20 mmol/l, and P less than 0.001 in 40 mmol/l). Hyperglycaemia thus impaired serum alpha 1-PI concentration and activity both in vivo and in vitro. While the underlying mechanisms and clinical implications of these observations are unknown, the abnormally low alpha 1-PI activity in diabetics may worsen the severity and contribute to the chronicity of their infections.

Serum alpha-1-protease inhibitor activity and pulmonary function in young insulin-dependent diabetic subjects.

Abnormalities of lung function have previously been described in patients with impaired alpha 1-protease inhibitor (alpha 1-PI) function and more recently in insulin-dependent diabetic subjects. This study was undertaken to test the hypothesis that impaired alpha 1-PI activity may be implicated in the pathogenesis of lung function abnormalities in young insulin-dependent diabetic patients. Twelve young (16.23 +/- 4.51 years), non-smoking insulin-dependent diabetic subjects and 12 reference subjects were evaluated in respect of lung mechanics, absolute serum alpha 1-PI levels and the functional ability of alpha 1-PI to inhibit elastase. Results of the ventilatory mechanics showed that the mean value for the volume-independent index of lung elasticity Kst(L) was significantly greater in the diabetic group (0.149 +/- 0.05 vs. 0.116 +/- 0.03; p less than 0.05). The absolute serum alpha 1-PI levels in the insulin-dependent diabetic subjects was significantly lower than in reference subjects (1.74 +/- 0.11 vs. 2.06 +/- 0.09 g/l; p less than 0.05). While the specific alpha 1-PI activity of the diabetic sera showed no significant difference from that of the reference sera, the total alpha 1-PI inhibitory activity in the diabetic sera was significantly lower than reference values (201.9 +/- 9.7 vs. 246.9 +/- 13.5 U/L; p less than 0.02). Although these findings indicate impairment of both ventilatory mechanics and alpha 1-PI activity in the insulin-dependent diabetic subjects, the pathogenesis of these findings and their functional implications are at present unknown.

Interaction of liposomes with human leukocytes in whole blood.

The uptake of multilamellar liposomes into human leukocytes in whole blood in vitro was evaluated on the basis of the cellular association of liposomal markers (3H-labelled cholesterol, lipid phase; [14C]inulin, aqueous phase). The entry of liposomes into human blood leukocytes was linear for 60 min and was mediated by a saturable mechanism displaying affinity constants of 0.28 +/- 0.17 and 0.16 +/- 0.05 mM liposomal lipid (means +/- S.E.) for liposomal lipid and aqueous phase markers, respectively. Amicon filtration analysis of incubation mixtures containing blood and liposomes (phosphatidylcholine:dicetyl phosphate:cholesterol, 70:20:10) showed that 34% of [14C]inulin was lost (neither liposome-associated nor cell-associated) after 60 min. By preincorporating sphingomyelin (35 mol%) into multilamellar liposomes, the leakage of the model aqueous phase marker inulin was reduced to 8% after 60 min, thus enhancing the drug carrier potential of liposomes in blood. As a consequence of their interaction with liposomes, the polymorphonuclear leukocytes in whole blood decreased in apparent buoyant density, while maintaining their viability. These results indicate that blood leukocytes in their natural milieu of whole blood are capable of interacting with, and taking up multilamellar liposomes.