HIV-positive nigerian adults harbor significantly higher serum lumefantrine levels than HIV-negative individuals seven days after treatment for Plasmodium falciparum infection.

Management of coinfection with malaria and HIV is a major challenge to public health in developing countries, and yet potential drug-drug interactions between antimalarial and antiviral regimens have not been adequately investigated in people with both infections. Each of the constituent components of artemether-lumefantrine, the first-line regimen for malaria treatment in Nigeria, and nevirapine, a major component of highly active antiretroviral therapy, are drugs metabolized by the cytochrome P450 3A4 isoenzyme system, which is also known to be induced by nevirapine. We examined potential interactions between lumefantrine and nevirapine in 68 HIV-positive adults, all of whom were diagnosed with asymptomatic Plasmodium falciparum infections by microscopy. Post hoc PCR analysis confirmed the presence of P. falciparum in only a minority of participants. Day 7 capillary blood levels of lumefantrine were significantly higher in HIV-positive participants than in 99 HIV-negative controls (P = 0.0011). Associations between day 7 levels of lumefantrine and risk of persistent parasitemia could not be evaluated due to inadequate power. Further investigations of the impact of nevirapine on in vivo malaria treatment outcomes in HIV-infected patients are thus needed

MicroRNAs as biomarkers in spontaneous intracerebral hemorrhage: a systematic review of recent clinical evidence

Spontaneous intracerebral hemorrhage (SICH) is a subtype of stroke associated with high mortality and devastating disabilities. Therefore, identifying non-invasive biomarkers for SICH would have a tremendous clinical impact. MicroRNAs (miRNAs) are non-coding single-stranded RNAs containing 21-23 nucleotides that control the activity of various protein-coding genes through post-transcriptional repression. In this systematic review, we report the recent clinical evidence on the role of miRNAs as biomarkers for the prediction, prognosis, early detection, and risk stratification of SICH

Understanding the pharmacokinetics of Coartem®

Artemether and lumefantrine (AL), the active constituents of Coartem® exhibit complementary pharmacokinetic profiles. Artemether is absorbed quickly; peak concentrations of artemether and its main active metabolite, dihydroartemisinin (DHA) occur at approximately two hours post-dose, leading to a rapid reduction in asexual parasite mass and a prompt resolution of symptoms. Lumefantrine is absorbed and cleared more slowly (terminal elimination half-life 3-4 days in malaria patients), and accumulates with successive doses, acting to prevent recrudescence by destroying any residual parasites that remain after artemether and DHA have been cleared from the body. Food intake significantly enhances the bioavailability of both artemether and lumefantrine, an effect which is more apparent for the highly lipophilic lumefantrine. However, a meal with only a small amount of fat (1.6 g) is considered sufficient to achieve adequate exposure to lumefantrine. The pharmacokinetics of artemether or lumefantrine are similar in children, when dosed according to their body weight, compared with adults. No randomized study has compared the pharmacokinetics of either agent in pregnant versus non-pregnant women. Studies in healthy volunteers and in children with malaria have confirmed that the pharmacokinetic characteristics of crushed standard AL tablets and the newly-developed Coartem® Dispersible tablet formulation are similar. Studies to date in healthy volunteers have not identified any clinically relevant drug-drug interactions; data relating to concomitant administration of HIV therapies are limited. While dose-response analyses are difficult to undertake because of the low rate of treatment failures under AL, it appears that artemether and DHA exposure impact on parasite clearance time while lumefantrine exposure is associated with cure rate, consistent with their respective modes of action. In conclusion, knowledge of the pharmacokinetic profiles of artemether and lumefantrine is increasing within a range of settings, including infants and children. However, additional data would be warranted to better characterize artemether and lumefantrine pharmacokinetics in patients with hepatic impairment, in pregnant women, and in patients undergoing HIV/AIDS chemotherapy

Incidence of Nosocomial Infection with Nasal Continuous Positive Air Way Pressure Versus Mechanical Ventilation During Treatment of Respiratory Distress in Preterm Neonates

Abstract: Objective: to determine the incidence of nosocomial infections in preterm infants with respiratory distress, if treatment with continuous positive air way pressure (CPAP) compared to treatment with mechanical ventilation (MV). Patients and Methods: Sixty premature neonates admitted to the intensive care unit in Al Galaa Teaching Hospital, in their first day of life suffering from respiratory distress, the infants were divided into two groups, 1 st group include 30 patients supported by CPAP and the 2 nd group include 30 patients who were supported by mechanical ventilation. Blood cultures and early endotracheal cultures were taken in the 1 st day of life from the sixty neonates in both groups then another late endotracheal culture was taken from them in the 5 th day of life. Results: 36.67% of patients in the MV group had +ve blood culture and 63.33% had no growth, while in the CPAP group 16.67% had +ve blood culture and 83.33% showed no growth. Early endotracheal cultures showed +ve growth in 63.33% in the MV groups a 23.33% in the CPAP group. (P=0.002), on the other hand late endotracheal cultures showed +ve growth in 36.67% in the MV group and 16.67% in the CPAP group. Klebsiella was the most frequent organism in all +ve cultures. Conclusion: The incidence of positive infection in blood cultures and endotracheal cultures is higher in the MV group than in the CPAP group. The incidence of klebsiella among the whole population in the two studied groups was higher in MV group more than in the CPAP group in all the cultures. Within the cases having positive cultures, MV patients needed longer duration on ventilation than patients on CPAP (whether the cultures were taken from the blood or endotracheal)

The content of African diets is adequate to achieve optimal efficacy with fixed-dose artemether-lumefantrine: a review of the evidence

A fixed-dose combination of artemether-lumefantrine (AL, Coartem®) has shown high efficacy, good tolerability and cost-effectiveness in adults and children with uncomplicated malaria caused by Plasmodium falciparum. Lumefantrine bioavailability is enhanced by food, particularly fat

Intravenous pharmacokinetics, oral bioavailability, dose proportionality and in situ permeability of anti-malarial lumefantrine in rats

<p>Abstract</p> <p>Background</p> <p>Despite the wide spread use of lumefantrine, there is no study reporting the detailed preclinical pharmacokinetics of lumefantrine. For the development of newer anti-malarial combination(s) and selection of better partner drugs, it is long felt need to understand the detailed preclinical pharmacokinetics of lumefantrine in preclinical experimental animal species. The focus of present study is to report bioavailability, pharmacokinetics, dose linearity and permeability of lumefantrine in rats.</p> <p>Methods</p> <p>A single dose of 10, 20 or 40 mg/kg of lumefantrine was given orally to male rats (N = 5 per dose level) to evaluate dose proportionality. In another study, a single intravenous bolus dose of lumefantrine was given to rats (N = 4) at 0.5 mg/kg dose following administration through the lateral tail vein in order to obtain the absolute oral bioavailability and clearance parameters. Blood samples were drawn at predetermined intervals and the concentration of lumefantrine and its metabolite desbutyl-lumefantrine in plasma were determined by partially validated LC-MS/MS method. <it>In-situ </it>permeability study was carried in anaesthetized rats. The concentration of lumefantrine in permeability samples was determined using RP-HPLC.</p> <p>Results</p> <p>For nominal doses increasing in a 1:2:4 proportion, the C_maxand AUC_0-∞values increased in the proportions of 1:0.6:1.5 and 1:0.8:1.8, respectively. For lumefantrine nominal doses increasing in a 1:2:4 proportion, the C_maxand the AUC_0-tvalues for desbutyl-lumefantrine increased in the proportions of 1:1.45:2.57 and 1:1.08:1.87, respectively. After intravenous administration the clearance (Cl) and volume of distribution (Vd) of lumefantrine in rats were 0.03 (± 0.02) L/h/kg and 2.40 (± 0.67) L/kg, respectively. Absolute oral bioavailability of lumefantrine across the tested doses ranged between 4.97% and 11.98%. Lumefantrine showed high permeability (4.37 × 10^-5cm/s) in permeability study.</p> <p>Conclusions</p> <p>The pharmacokinetic parameters of lumefantrine and its metabolite desbutyl-lumefantrine were successfully determined in rats for the first time. Lumefantrine displayed similar pharmacokinetics in the rat as in humans, with multiphasic disposition, low clearance, and a large volume of distribution resulting in a long terminal elimination half-life. The absolute oral bioavailability of lumefantrine was found to be dose dependent. Lumefantrine displayed high permeability in the <it>in-situ </it>permeability study.</p

Why don't health workers prescribe ACT? A qualitative study of factors affecting the prescription of artemether-lumefantrine

BACKGROUND: Kenya recently changed its antimalarial drug policy to a specific artemisinin-based combination therapy (ACT), artemether-lumefantrine (AL). New national guidelines on the diagnosis, treatment and prevention were developed and disseminated to health workers together with in-service training. METHODS: Between January and March 2007, 36 in-depth interviews were conducted in five rural districts with health workers who attended in-service training and were non-adherent to the new guidelines. A further 20 interviews were undertaken with training facilitators and members of District Health Management Teams (DHMTs) to explore reasons underlying health workers' non-adherence. RESULTS: Health workers generally perceived AL as being tolerable and efficacious as compared to amodiaquine and sulphadoxine-pyremethamine. However, a number of key reasons for non-adherence were identified. Insufficient supply of AL was a major issue and hence fears of stock outs and concern about AL costs was an impediment to AL prescription. Training messages that contradicted the recommended guidelines also led to health worker non-adherence, compounded by a lack of follow-up supervision. In addition, the availability of non-recommended antimalarials such as amodiaquine caused prescription confusion. Some health workers and DHMT members maintained that shortage of staff had resulted in increased patient caseload affecting the delivery of the desirable quality of care and adherence to guidelines. CONCLUSION: The introduction of free efficacious ACTs in the public health sector in Kenya and other countries has major potential public health benefits for Africa. These may not be realized if provider prescription practices do not conform to the recommended treatment guidelines. It is essential that high quality training, drug supply and supervision work synergistically to ensure appropriate case management

Artemether-Lumefantrine versus Dihydroartemisinin-Piperaquine for Treatment of Malaria: A Randomized Trial

OBJECTIVES: To compare the efficacy and safety of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) for treating uncomplicated falciparum malaria in Uganda. DESIGN: Randomized single-blinded clinical trial. SETTING: Apac, Uganda, an area of very high malaria transmission intensity. PARTICIPANTS: Children aged 6 mo to 10 y with uncomplicated falciparum malaria. INTERVENTION: Treatment of malaria with AL or DP, each following standard 3-d dosing regimens. OUTCOME MEASURES: Risks of recurrent parasitemia at 28 and 42 d, unadjusted and adjusted by genotyping to distinguish recrudescences and new infections. RESULTS: Of 421 enrolled participants, 417 (99%) completed follow-up. The unadjusted risk of recurrent falciparum parasitemia was significantly lower for participants treated with DP than for those treated with AL after 28 d (11% versus 29%; risk difference [RD] 18%, 95% confidence interval [CI] 11%-26%) and 42 d (43% versus 53%; RD 9.6%, 95% CI 0%-19%) of follow-up. Similarly, the risk of recurrent parasitemia due to possible recrudescence (adjusted by genotyping) was significantly lower for participants treated with DP than for those treated with AL after 28 d (1.9% versus 8.9%; RD 7.0%, 95% CI 2.5%-12%) and 42 d (6.9% versus 16%; RD 9.5%, 95% CI 2.8%-16%). Patients treated with DP had a lower risk of recurrent parasitemia due to non-falciparum species, development of gametocytemia, and higher mean increase in hemoglobin compared to patients treated with AL. Both drugs were well tolerated; serious adverse events were uncommon and unrelated to study drugs. CONCLUSION: DP was superior to AL for reducing the risk of recurrent parasitemia and gametocytemia, and provided improved hemoglobin recovery. DP thus appears to be a good alternative to AL as first-line treatment of uncomplicated malaria in Uganda. To maximize the benefit of artemisinin-based combination therapy in Africa, treatment should be integrated with aggressive strategies to reduce malaria transmission intensity