cgp-56697 and Acute-Disease

Artemether-lumefantrine (AL) is first-line treatment for uncomplicated malaria in many African countries. Concomitant food consumption may affect absorption of lumefantrine but data in the most important target population, i.e. children, are lacking. Therefore, we evaluated the effect of food intake on oral lumefantrine bioavailability in African children with malaria.. In a randomised, investigator-blinded, multicentre phase III efficacy trial, 899 infants and children with acute uncomplicated Plasmodium falciparum malaria received six doses of AL according to body weight over 3 days either as crushed tablets (Coartem) or as dispersible tablets. Single blood samples were obtained for lumefantrine plasma concentration determination in a subset of 621 patients, and a two-compartment pharmacokinetic model was constructed.. The mean observed lumefantrine plasma concentration for crushed tablet and dispersible tablet, respectively, was 100% and 55% higher with a concomitant meal at the time of dose intake than when taken alone. Similarly, consumption of milk (the most common meal) increased model-estimated lumefantrine bioavailability by 57% (90% CI: 29-96%) with crushed tablets and 65% (90% CI: 28-109%) with dispersible tablets compared to no food. The 28-day PCR-corrected cure rate (primary study endpoint) in the evaluable population was 582/587 [99.1% (95% CI: 98.0-99.7%)] and was not related to food intake.. AL was highly efficacious. Concomitant food intake increased lumefantrine absorption in children with malaria.

Topics: Acute Disease; Africa; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Biological Availability; Child; Child, Preschool; Diet; Drug Combinations; Ethanolamines; Female; Fluorenes; Food-Drug Interactions; Humans; Lumefantrine; Malaria, Falciparum; Male; Time Factors

The efficacy and safety of artemether-lumefantrine for the treatment of malaria in nonimmune populations are not well defined. In this study, 165 nonimmune patients from Europe and non-malarious areas of Colombia with acute, uncomplicated falciparum malaria or mixed infection including P. falciparum were treated with the six-dose regimen of artemether-lumefantrine. The parasitologic cure rate at 28 days was 96.0% for the per protocol population (119/124 patients). Median times to parasite clearance and fever clearance were 41.5 and 36.8 hours, respectively. No patient had gametocytes after Day 7. Treatment was well tolerated; most adverse events were mild to moderate and seemed to be related to malaria. There were few serious adverse events, none of which were considered to be drug-related. No significant effects on ECG or laboratory parameters were observed. In conclusion, the six-dose regimen of artemether-lumefantrine was effective and well tolerated in the treatment of acute uncomplicated falciparum malaria in nonimmune patients.

Topics: Acute Disease; Adolescent; Adult; Aged; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Middle Aged; Parasitemia; Plasmodium falciparum; Time Factors; Travel; Treatment Outcome

To determine the efficacy of artemether-lumefantrine malaria treatment, as an alternative to artesunate + mefloquine, which is becoming ineffective in some areas of the Thai-Cambodian border.. Two studies were conducted to monitor the efficacy of artemether-lumefantrine in Sampov Lun referral hospital, Battambang Province, in 2002 and 2003, and one study was conducted to assess the efficacy of mefloquine + artesunate in 2003 for comparison. The studies were performed according to the WHO standardized protocol with a follow-up of 28 days. The therapeutic efficacy tests were complemented with in vitro tests and in 2003, with the measurement of lumefantrine plasma concentration at day 7 for the patients treated with artemether-lumefantrine.. A total of 190 patients were included: 55 were treated with artemether-lumefantrine in 2002 (AL2002), 80 with artemether-lumefantrine and food supplementation in 2003 (AL2003) and 55 with artesunate + mefloquine in 2003 (AM2003). With the per-protocol analysis, the cure rate was 71.1% in study AL2002, 86.5% in study AL2003 and 92.4% in study AM2003. All the data were PCR corrected. The artemether-lumefantrine cure rate was unexpectedly low in 2002, but it increased with food supplementation in 2003. There was a significant difference (P = 0.02) in lumefantrine plasma concentrations between adequate clinical and parasitological responses and treatment failure cases. In vitro susceptibility to lumefantrine was reduced for isolates sampled from patients presenting with treatment failure, but the difference was not statistically different from isolates sampled from patients who were successfully treated.. Treatment failure cases of artemether-lumefantrine are most probably because of low levels of lumefantrine blood concentration. Further investigations are necessary to determine whether resistance of Plasmodium falciparum isolates to lumefantrine is present in the region.

Topics: Acute Disease; Adolescent; Adult; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Artesunate; Child; Dietary Supplements; Drug Combinations; Drug Therapy, Combination; Ethanolamines; Female; Fluorenes; Humans; Lumefantrine; Malaria, Falciparum; Male; Mefloquine; Parasitic Sensitivity Tests; Plasmodium falciparum; Sesquiterpenes; Treatment Failure; Treatment Outcome

Approximately one million children die from malaria each year. A recently approved artemisinin-based tablet, Coartem (co-artemether), comprising artemether 120 mg plus lumefantrine 20 mg, given in four doses, provides effective antimalarial treatment for children in many sub-Saharan countries. However, this regimen is considered insufficient for non-immune infants and in areas where multidrug-resistant Plasmodium falciparum predominates. This open-label study assessed the efficacy and safety of co-artemether administered to 310 African children weighing 5-25 kg, with acute, uncomplicated falciparum malaria. Six doses of co-artemether were given over 3 days, with follow-up at 7, 14 and 28 days. Treatment rapidly cleared parasitemia and fever. The overall 28-day cure rate was 86.5%, and 93.9% when corrected by PCR for reinfection. Cure rates at 7 and 14 days exceeded 97.0% (uncorrected) and, on day 28, were similar in infants (5-<10 kg) previously exposed to malaria infection (partially immune: 88.6% uncorrected; 93.3% corrected), and in those who were non-immune (82.5% uncorrected; 95.0% corrected). Adverse events were mostly mild. There was no electrocardiographic evidence of cardiotoxicity. The co-artemether six-dose regimen, treating acute uncomplicated falciparum malaria in African children, achieved rapid parasite clearance and a high cure rate. Treatment was generally safe and well tolerated.

Topics: Acute Disease; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Drug Administration Schedule; Drug Combinations; Ethanolamines; Female; Fluorenes; Heart Rate; Hematologic Tests; Humans; Infant; Kenya; Malaria, Falciparum; Male; Nigeria; Parasite Egg Count; Sesquiterpenes; Sex Distribution; Tanzania; Time Factors; Treatment Outcome

In India, treatment of acute, uncomplicated Plasmodium falciparum malaria is becoming increasingly difficult due to resistance to chloroquine, thus there is a need for new antimalarial drugs. CGP 56697 (co-artemether), a new drug, is a combination of artemether and lumefantrine in a single oral formulation (one tablet = 20 mg of artemether plus 120 mg of lumefantrine). In a double-blind study, 179 patients with acute uncomplicated P. falciparum malaria were randomly assigned to receive either CGP (n = 89) given as a short course of 4 x 4 tablets over a 48-hr period or chloroquine (n = 90) given as four tablets (one tablet = 150 mg of chloroquine base) initially, followed by two tablets each at 6-8, 24, and 48 hr. Due to a death in the chloroquine group and a decrease in the chloroquine cure rate to < 50% (based on the blinded overall cure rate at that time), recruitment was terminated prematurely. CGP 56697 showed a superior 28-day cure rate (95.4% versus 19.7%; P < 0.001), time to parasite clearance (median = 36 versus 60 hr; P < 0.001), and resolution of fever (median = 18 versus 27 hr; P = 0.0456). This drug provides a safe, effective, and rapid therapy for the treatment of acute uncomplicated P. falciparum malaria.

Topics: Acute Disease; Administration, Oral; Adolescent; Adult; Aged; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Chloroquine; Double-Blind Method; Drug Combinations; Electrocardiography; Ethanolamines; Female; Fluorenes; Humans; Malaria, Falciparum; Male; Middle Aged; Polymerase Chain Reaction; Sesquiterpenes; Time Factors

To test the efficacy of a new compound drug (CGP 56697) against acute, uncomplicated falciparum malaria.. Reappearing parasites were analysed by PCR-RFLP within a randomized controlled trial. 130 patients received chloroquine and 130 patients were treated with CGP 56697. Samples from 96 patients with parasitological failure were tested by PCR-RFLP for MSP2 of Plasmodium falciparum. Seven days after treatment 32 patients of the chloroquine control group with reappearing parasites were tested by PCR and one infection was unequivocally determined as a new infection. After 7 days, in the CGP 56697 group, 6 samples were tested in which one new infection was identified. Similar observations were made one and three weeks later in both groups.. Although a high multiplicity of infections on admission was observed, there was no significant correlation between multiplicity and either recrudescence or new infection. Patients in both treatment groups with subsequent recrudescent parasites had higher initial mean parasite densities than patients who cleared. Those of the patients with recrudescent parasites who were treated with CGP 56697 had higher initial parasite densities than those treated with chloroquine. The rate of re-infection increased with time as expected in holoendemic areas and appeared to be higher in chloroquine patients. Generally, CGP 56697 showed a superior clearance rate, successfully cleared higher parasite densities and suppressed new infections over a longer period of time.. The PCR analysis confirmed that reinfections beyond day 7 are significant in areas highly endemic for malaria and showed the necessity of excluding these when estimating 14 day clearance rates. Provided new infections are excluded, the 28-day clearance rate can also be used to determine the efficacy of antimalarial drugs in highly endemic areas, and adds to our knowledge of drug resistance and dynamics of infections in people living in such areas.

Topics: Acute Disease; Animals; Antimalarials; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Chloroquine; Drug Combinations; Ethanolamines; Fluorenes; Humans; Malaria, Falciparum; Plasmodium falciparum; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Recurrence; Sesquiterpenes; Tanzania; Time Factors; Treatment Outcome

A randomized, open trial involving 260 Tanzanian children, aged 1-5 years, with acute Plasmodium falciparum malaria was conducted to evaluate the efficacy of the combination antimalarial CGP 56697 (artemether and benflumetol), and to compare it with chloroquine, the standard drug used for malaria treatment in the Kilombero area. Children who had received rescue medication within the first 48 h or had a negative slide at the same time were excluded. Seven-day parasitological cure rates were 94% (95% CI 88-97.5) for CGP 56697 and 35.4% (95% CI 25.9-45.8) for chloroquine. Using the same definition, the 14-day parasitological cure rates were 86.4% (95% CI 78.5-92.2) for CGP 56697 and 10.3% (95% CI 5.1-18.1) for chloroquine. Gametocytes were more effectively suppressed by CGP 56697 than by chloroquine. There were no major adverse events with either drug. CGP 56697 is highly efficacious against P. falciparum in this area of Tanzania. The study contributes to the discussion on treatment strategies, particularly whether chloroquine may still fulfil its role as first-line drug in an area of high malaria transmission and very high levels of chloroquine resistance.

Topics: Acute Disease; Administration, Oral; Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Child, Preschool; Chloroquine; Drug Administration Schedule; Drug Combinations; Ethanolamines; Female; Fluorenes; Humans; Infant; Lumefantrine; Malaria, Falciparum; Male; Sesquiterpenes; Tanzania; Treatment Outcome

Medicines are commonly accessed and used for management of illness in children without a prescription. This potentially increases the risk of unwanted treatment outcomes. We investigated medicine use practices in management of symptoms of acute upper respiratory tract infections among children (≤12 years) in households in Nakawa division, Kampala city.. This was a cross-sectional study conducted among 390 randomly selected children. Data on use of medicines in children (≤12 years) during recent episode of acute upper respiratory tract infection was collected from their care takers using an interviewer administered questionnaire. A recall period of two weeks (14 days) was used in during data collection.. The prevalence of giving children non-prescription antimicrobial medicines was 44.8% (38.3-52.2). The most common disease symptoms that the children reportedly had included flu, 84.9% (331/390), cough, 83.1% (324/390), and undefined fever, 69.7% (272/390). Medicines commonly given to children included, paracetamol 53.1% (207/390), Coartem 29.7% (116/390), cough linctus 20.8% (81/390), amoxicillin 18.9% (74/390), Co-trimoxazole 18.5% (72/390), and diphenhydramine 15.4% (60/390). The major sources of medicines given to the children was hospital/clinic, 57.26% (223/390). Most of the children, 81% were given more than one medicine at a time. The majority, 62.3% (243/390) of the care takers who gave the children medicine during the recent illness were not aware of any medicine (s) that should not be given to children. The predictors of non-prescription use of antimicrobial medicines in managing symptoms of acute upper respiratory tract infections in children included, medicines obtained from drug shop (PR: 1.45, CI: 1.14-1.85), medicines at home (PR: 1.8, CI: 0.83-1.198) and type of medicine (antimalarial) (PR: 2.8, CI: 1.17-6.68).. Children are commonly given multiple medicines during episodes of acute upper respiratory tract infections with most antimicrobial agents accessed and used without a prescription in Kampala city, Uganda.

Topics: Acetaminophen; Acute Disease; Adult; Amoxicillin; Anti-Infective Agents; Artemether, Lumefantrine Drug Combination; Artemisinins; Child; Child, Preschool; Cough; Cross-Sectional Studies; Drug Combinations; Ethanolamines; Family Characteristics; Female; Fever; Fluorenes; Humans; Infant; Male; Nonprescription Drugs; Respiratory Tract Infections; Trimethoprim, Sulfamethoxazole Drug Combination; Uganda; Young Adult