Inhibition of merozoite invasion and transient de-sequestration by sevuparin in humans with Plasmodium falciparum malaria.

SEVERE MALARIA: Even with the best available treatment, the mortality from severe Plasmodium falciparum malaria remains high. Typical features at death are high parasite loads and obstructed micro- vasculature. Infected erythrocytes (IE) containing mature parasites bind to the host receptor heparan sulfate, which is also an important receptor for merozoite invasion. To block merozoite invasion has not previously been proposed as an adjunctive therapeutic approach but it may preclude the early expansion of an infection that else leads to exacerbated sequestration and death. SEVUPARIN IN PHASE I STUDY: The drug sevuparin was developed from heparin because heparan sulfate and heparin are nearly identical, so the rationale was that sevuparin would act as a decoy receptor during malaria infection. A phase I study was performed in healthy male volunteers and sevuparin was found safe and well tolerated. SEVUPARIN IN PHASE I/II CLINICAL STUDY: A phase I/II clinical study was performed in which sevuparin was administered via short intravenous infusions to malaria patients with uncomplicated malaria who were also receiving atovaquone/proguanil treatment. This was a Phase I/II, randomized, open label, active control, parallel assignment study. Sevuparin was safe and well tolerated in the malaria patients. The mean relative numbers of ring-stage IEs decreased after a single sevuparin infusion and mature parasite IEs appeared transiently in the circulation. The effects observed on numbers of merozoites and throphozoites in the circulation, were detected already one hour after the first sevuparin injection. Here we report the development of a candidate drug named sevuparin that both blocks merozoite invasion and transiently de-sequesters IE in humans with P. falciparum malaria. TRIAL REGISTRATION: ClinicalTrials.gov NCT01442168.

Determinants of use of insecticide treated nets for the prevention of malaria in pregnancy: Jinja, Uganda.

BACKGROUND: One established means of preventing the adverse consequences of malaria during pregnancy is sleeping under an insecticide treated net (ITN) throughout pregnancy. Despite increased access to this intervention over time, consistent ITN use during pregnancy remains relatively uncommon in sub-Saharan Africa. METHODOLOGY/PRINCIPAL FINDINGS: We sought to identify determinants of ITN use during pregnancy. Utilizing a population-based random sample, we interviewed 500 women living in Jinja, Uganda, who had been pregnant in the past year. ITN ownership at the start of pregnancy was reported by 359 women (72%) and 28 women (20%) acquired an ITN after the first trimester of pregnancy. Among 387 ITN owners, 73% reported either always sleeping under the ITN during all trimesters of pregnancy, or after acquiring their net. Owning more than 1 net was slightly associated with always sleeping under an ITN during pregnancy (RR: 1.13; 95% CI: 1.00, 1.28). Women who always slept under an ITN during pregnancy were more likely to be influenced by an advertisement on the radio/poster than being given an ITN free of charge (RR: 1.48; 95% CI: 1.24, 1.76). No differences were found between other socio-demographic factors, pregnancy history, ANC use or socio-cultural factors. CONCLUSIONS/SIGNIFICANCE: While self-reported ITN ownership and use was common throughout pregnancy, we were unable to pinpoint why a sizable fraction of Ugandan women did not always adhere to recommendations for use of an ITN during pregnancy. More data are needed on the capacity of individual households to support the installation of ITNs which may provide insight into interventions targeted at improving the convenience and adherence of daily ITN use.

Patterns of anti-malarial drug treatment among pregnant women in Uganda.

BACKGROUND: Prompt use of an effective anti-malarial drug is essential for controlling malaria and its adverse effects in pregnancy. The World Health Organization recommends an artemisinin-based combination therapy as the first-line treatment of uncomplicated malaria in the second and third trimesters of pregnancy. The study objective was to determine the degree to which presumed episodes of uncomplicated symptomatic malaria in pregnancy were treated with a recommended anti-malarial regimen in a region of Uganda. METHODS: Utilizing a population-based random sample, we interviewed women living in Jinja, Uganda who had been pregnant in the past year. RESULTS: Self-reported malaria during the index pregnancy was reported among 67% (n = 334) of the 500 participants. Among the 637 self-reported episodes of malaria, an anti-malarial drug was used for treatment in 85% of the episodes. Use of a currently recommended treatment in the first trimester was uncommon (5.6%). A contraindicated anti-malarial drug (sulphadoxine-pyrimethamine and/or artemether-lumefantrine) was involved in 70% of first trimester episodes. Recommended anti-malarials were used according to the guidelines in only 30.1% of all second and third trimester episodes. CONCLUSIONS: Self-reported malaria was extremely common in this population and adherence to treatment guidelines for the management of malaria in pregnancy was poor. Use of artemether-lumefantrine combined with non-recommended anti-malarials was common practice. Overuse of anti-malarial drugs, especially ones that are no longer recommended, undermines malaria control efforts by fueling the spread of drug resistance and delaying appropriate treatment of non-malarial febrile illnesses. Improved diagnostic capacity is essential to ultimately improving the management of malaria-like symptoms during pregnancy and appropriate use of currently available anti-malarials.

Determinants of use of intermittent preventive treatment of malaria in pregnancy: Jinja, Uganda.

BACKGROUND: Maternal malaria is associated with serious adverse pregnancy outcomes. One recommended means of preventing malaria during pregnancy is intermittent preventive therapy (IPTp) with sulfadoxine/pyrimethamine (SP). We sought to identify determinants of preventive use of SP during pregnancy among recently pregnant women in Uganda. Additionally, we characterized the timing of and indications for the administration of SP at antenatal care (ANC) visits and missed opportunities for SP administration. METHODOLOGY/PRINCIPAL FINDINGS: Utilizing a population-based random sample, we interviewed 500 women living in Jinja, Uganda who had been pregnant in the past year. Thirty-eight percent (192/500) of women received SP for the treatment of malaria and were excluded from the analysis of IPTp-SP. Of the remaining women, 275 (89.3%) reported at least two ANC visits after the first trimester and had an opportunity to receive IPTp-SP according to the Ugandan guidelines, but only 86 (31.3%) of these women received a full two-dose course of IPTp. The remaining 189 (68.7%) women missed one or more doses of IPTp-SP. Among the 168 women that were offered IPTp, 164 (97.6%) of them took the dose of SP. CONCLUSIONS/SIGNIFICANCE: Use of IPTp in Uganda was found to be far below target levels. Our results suggest that women will take SP for IPTp if it is offered during an ANC visit. Missed opportunities to administer IPTp-SP during ANC were common in our study, suggesting provider-level improvements are needed.

Use of antenatal care, maternity services, intermittent presumptive treatment and insecticide treated bed nets by pregnant women in Luwero district, Uganda.

BACKGROUND: To reduce the intolerable burden of malaria in pregnancy, the Ministry of Health in Uganda improved the antenatal care package by including a strong commitment to increase distribution of insecticide-treated nets (ITNs) and introduction of intermittent preventive treatment with sulphadoxine-pyrimethamine for pregnant women (IPTp-SP) as a national policy in 2000. This study assessed uptake of both ITNs and IPTp-SP by pregnant women as well as antenatal and maternity care use with the aim of optimizing their delivery. METHODS: 769 post-partum women were recruited from a rural area of central Uganda with perennial malaria transmission through a cross-sectional, community-based household survey in May 2005. RESULTS: Of the 769 women interviewed, antenatal clinic (ANC) attendance was high (94.4%); 417 (57.7%) visiting initially during the 2nd trimester, 242 (33.5%) during the 3rd trimester and 266 (37.1%) reporting > or = 4 ANC visits. About 537 (71%) and 272 (35.8%) received one or > or = 2 IPTp-SP doses respectively. Only 85 (15.8%) received the first dose of IPTp-SP in the 3rd trimester. ITNs were used by 239 (31.3%) of women during pregnancy and 314 (40.8%) delivered their most recent pregnancy outside a health facility. Post-partum women who lacked post-primary education were more likely not to have attended four or more ANC visits (odds ratio [OR] 3.3, 95% confidence interval [CI] 1.2-9.3). CONCLUSION: These findings illustrate the need to strengthen capacity of the district to further improve antenatal care and maternity services utilization and IPTp-SP uptake. More specific and effective community health strategies to improve effective ANC, maternity services utilization and IPTp-SP uptake in rural communities should be undertaken.

Patient and health service delay in pulmonary tuberculosis patients attending a referral hospital: a cross-sectional study.

BACKGROUND: Delays in diagnosis and initiation of effective treatment increase morbidity and mortality from tuberculosis as well as the risk of transmission in the community. The aim of this study was to determine the time taken for patients later confirmed as having TB to present with symptoms to the first health provider (patient delay) and the time taken between the first health care visit and initiation of tuberculosis treatment (health service delay). Factors relating to these 'delays' were analyzed. METHODS: A cross-sectional survey, of 231 newly diagnosed smear-positive tuberculosis patients was conducted in Mulago National referral Hospital Kampala, from January to May 2002. Socio-demographic, lifestyle and health seeking factors were evaluated for their association with patient delay (> 2 weeks) and health service delay (> 4 weeks), using odds ratios with 95% confidence intervals (CI) including multivariate logistic regression. RESULTS: The median total delay to treatment initiation was 12 weeks. Patients often presented to drug shops or pharmacies (39.4%) and private clinics (36.8%) more commonly than government health units (14%) as initial contacts. Several independent predictors of 'patient delay' were identified: being hospitalized (odds ratio [0R] = 0.32; 95% CI: 0.12-0.80), daily alcohol consumption (OR = 3.7; CI: 1.57-9.76), subsistence farming (OR = 4.70; CI: 1.67-13.22), and perception of smoking as a cause of TB (OR = 5.54; CI: 2.26-13.58). Independent predictors of 'health service delay' were: > 2 health seeking encounters per month (OR = 2.74; CI: 1.10-6.83), and medical expenditure on TB related symptoms > 29 US dollars (OR = 3.88; CI: 1.19-12.62). Perceived TB stigma and education status was not associated with either form of delay. CONCLUSION: Delay in diagnosis of TB is prolonged at the referral centre with a significant proportion of Health service delay. More specific and effective health education of the general public on tuberculosis and seeking of appropriate medical consultation is likely to improve case detection. Certain specific groups require further attention. Alcoholics and subsistence farmers should be targeted to improve accessibility to TB treatment. Continuing medical education about TB management procedures for health providers and improvement in the capacity of TB control services should be undertaken.