Antimalarial Combination Therapy Research Articles

Putting the genie back in the bottle? Availability and presentation of oral artemisinin compounds at retail pharmacies in urban Dar-es-Salaam

BackgroundRecently global health advocates have called for the introduction of artemisinin-containing antimalarial combination therapies to help curb the impact of drug-resistant malaria in Africa. Retail trade in artemisinin monotherapies could undermine efforts to restrict this class of medicines to more theoretically sound combination treatments.MethodsThis paper describes a systematic search for artemisinin-containing products at a random sample of licensed pharmacies in Dar-es-Salaam, Tanzania in July 2005.ResultsNineteen different artemisinin-containing oral pharmaceutical products, including one co-formulated product, one co-packaged product, and 17 monotherapies were identified. All but one of the products were legally registered and samples of each product were obtained without a prescription. Packaging and labeling of the products seldom included local language or illustrated instructions for low-literate clients. Packaging and inserts compared reasonably well with standards recommended by the national regulatory authority with some important exceptions. Dosing instructions were inconsistent, and most recommended inadequate doses based on international standards. None of the monotherapy products mentioned potential benefits of combining the treatment with another antimalarial drug.ConclusionThe findings confirm the widespread availability of artemisinin monotherapies that led the World Health Organization to call for the voluntary withdrawal of these drugs in malaria-endemic countries. As the global public health community gathers resources to deploy artemisinin-containing combination therapies in Africa, planners should be mindful that these drugs will coexist with artemisinin monotherapies in an already well-established market place. In particular, regulatory authorities should be incorporated urgently into the process of planning for rational deployment of artemisinin-containing antimalarial combination therapies.

Fever treatment and household wealth: the challenge posed for rolling out combination therapy for malaria

To investigate the variation in malaria parasitaemia, reported fever, care seeking, antimalarials obtained and household expenditure by socio-economic status (SES), and to assess the implications for ensuring equitable and appropriate use of antimalarial combination therapy. A total of 2,500 households were surveyed in three rural districts in southern Tanzania in mid-2001. Blood samples and data on SES were collected from all households. Half the households completed a detailed questionnaire on care seeking and treatment costs. Households were categorised into SES thirds based on an index of household wealth derived using principal components analysis. Of individuals completing the detailed survey, 16% reported a fever episode in the previous 2 weeks. People from the better-off stratum were significantly less likely to be parasitaemic, and significantly more likely to obtain antimalarials than those in the middle or poor stratum. The better treatment obtained by the better off led them to spend two to three times more than the middle and poor third spent. This reflected greater use of non-governmental organisation (NGO) facilities, which were the most expensive source of care, and higher expenditure at NGO facilities and drug stores. The coverage of appropriate malaria treatment was low in all SES groups, but the two poorer groups were particularly disadvantaged. As countries switch to antimalarial combination therapy, distribution must be targeted to ensure that the poorest groups fully benefit from these new and highly effective medicines.

Efficacy of chloroquine + sulfadoxine–pyrimethamine, mefloquine + artesunate and artemether + lumefantrine combination therapies to treat Plasmodium falciparum malaria in the Chittagong Hill Tracts, Bangladesh

Bangladesh faces growing levels of Plasmodium falciparum resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine (SP). Alternative antimalarial therapies, particularly combination regimens, need to be considered. Therefore, the efficacy of three antimalarial combination therapies was assessed in Chittagong Hill Tracts. A total of 364 P. falciparum patients were recruited and randomly assigned to either CQ + SP, mefloquine + artesunate (MQ + AS) or lumefantrine + artemether (Coartem). Results showed that CQ + SP therapy was less effective than the two artemisinin-based combination therapies. The day 42 PCR-corrected efficacy rate was 62.4% for CQ + SP, 100% for MQ + AS and 97.1% for Coartem. Failures occurred at a shorter interval after CQ + SP treatment than after Coartem. The artemisinin-based therapies effectively prevented development of gametocytes, whereas CQ + SP did not. All three therapies were well tolerated, although reports of mild complaints during treatment appeared higher with MQ + AS. We conclude that CQ + SP is not a viable option for replacing CQ monotherapy as first-line P. falciparum treatment in this area of Bangladesh. A change to artemisinin-based combination therapy is recommended. Both Coartem and MQ + AS appear to be good options, effective in curing P. falciparum malaria and in preventing recrudescences following treatment.

Artemisinin versus Nonartemisinin Combination Therapy for Uncomplicated Malaria: Randomized Clinical Trials from Four Sites in Uganda

BackgroundDrug resistance in Plasmodium falciparum poses a major threat to malaria control. Combination antimalarial therapy including artemisinins has been advocated recently to improve efficacy and limit the spread of resistance, but artemisinins are expensive and relatively untested in highly endemic areas. We compared artemisinin-based and other combination therapies in four districts in Uganda with varying transmission intensity.Methods and FindingsWe enrolled 2,160 patients aged 6 mo or greater with uncomplicated falciparum malaria. Patients were randomized to receive chloroquine (CQ) + sulfadoxine-pyrimethamine (SP); amodiaquine (AQ) + SP; or AQ + artesunate (AS). Primary endpoints were the 28-d risks of parasitological failure either unadjusted or adjusted by genotyping to distinguish recrudescence from new infections.A total of 2,081 patients completed follow-up, of which 1,749 (84%) were under the age of 5 y. The risk of recrudescence after treatment with CQ + SP was high, ranging from 22% to 46% at the four sites. This risk was significantly lower (p < 0.01) after AQ + SP or AQ + AS (7%–18% and 4%–12%, respectively). Compared to AQ + SP, AQ + AS was associated with a lower risk of recrudescence but a higher risk of new infection. The overall risk of repeat therapy due to any recurrent infection (recrudescence or new infection) was similar at two sites and significantly higher for AQ + AS at the two highest transmission sites (risk differences = 15% and 16%, p< 0.003).ConclusionAQ + AS was the most efficacious regimen for preventing recrudescence, but this benefit was outweighed by an increased risk of new infection. Considering all recurrent infections, the efficacy of AQ + SP was at least as efficacious at all sites and superior to AQ + AS at the highest transmission sites. The high endemicity of malaria in Africa may impact on the efficacy of artemisinin-based combination therapy.The registration number for this trial is ISRCTN67520427 (http://www.controlled-trials.com/isrctn/trial/|/0/67520427.html).

Efficacy of methylene blue and artesunate as combination antimalarial therapy in a rhesus monkey model of uncomplicated blood-stage malaria

Background/Aims Methylene blue (MB), an FDA approved drug for methemoglobinemia, also demonstrates in vitro and in vivo antimalarial activity. Artesunate (AS) is widely used to treat malaria in malaria-endemic countries. The purpose of this study was to evaluate the anti-malarial efficacy and safety of intravenous MB when given alone and in combination with intravenous AS in rhesus monkeys. Methods A Rhesus/P. cynomolgi model of uncomplicated blood stage malaria was used to evaluate different combinations of MB and AS. The study was conducted under an approved protocol in an AAALAC accredited animal facility. The study design used a 3 by 3-factorial design to compare 3 doses of MB (0, 2 and 8 mg/kg) in combination with 3 doses of AS (0, 1 and 8 mg/kg). Thirty-four healthy rhesus monkeys were randomly assigned to one of 8 different treatment groups or to an infection control group. Study drugs were administered as three once-daily intravenous injections after threshold parasitemia levels were attained. Results Parasitemia clearance and cure rates demonstrated dose-dependency. Combinations were much more likely to result in cure. Four monkeys died with clinical and necropsy findings consistent with severe malaria that were not considered to be related to study drugs. All remaining study animals recovered with no adverse sequelae. Conclusions Intravenous methylene blue was well tolerated and demonstrated dose-dependent anti-malarial efficacy, as well as apparent synergy with intravenous artesunate. Clinical Pharmacology & Therapeutics (2005) 77, P59–P59; doi: 10.1016/j.clpt.2004.12.117

ADHERENCE TO ANTIMALARIAL COMBINATION THERAPY WITH SULFADOXINE-PYRIMETHAMINE AND ARTESUNATE IN RURAL TANZANIA

Artemisinin-containing antimalarial combination therapies are recommended to confront drug-resistant Plasmodium falciparum malaria. Among the questions surrounding whether these complex multidose treatments will be practical is to what extent patients complete the recommended doses. Combination therapy through coadministration of sulfadoxine-pyrimethamine plus artesunate was introduced as a first-line treatment for uncomplicated malaria in one district in Tanzania. Interventions to optimize correct use were also implemented. We observed 453 patient encounters at one health facility and recorded key practices as health workers dispensed the combination. A total of 253 patients were followed-up at 24 or 48 hours. Complete adherence measured at 48 hours reached 75.0%, based on self-report and tablet counts. This is substantially better than reported elsewhere and compares favorably with intervention studies to optimize adherence to chloroquine. Counseling about what to do if a patient vomits appears to have been an independent risk factor for nonadherence.

Rescuing malaria treatment, or not?

In this week's Lancet, Sarah Staedke and colleagues' paper, while technically excellent, echoes some fallacies in how people think of treatment of malaria. These researchers report on the treatment efficacy of different antimalarial combination therapies in Uganda. They compared the familiar, but outdated, chloroquine plus sulfadoxine-pyrimethamine with the much more effective combinations of amodiaquine and sulfadoxine-pyrimethamine, or amodiaquine and artesunate.

Prevention of increasing rates of treatment failure by combining sulfadoxine-pyrimethamine with artesunate or amodiaquine for the sequential treatment of malaria.

Combination antimalarial therapy may delay the spread of drug resistance, but clinical data supporting this notion are limited. For 1 year, we studied Ugandan children who were treated for uncomplicated malaria with sulfadoxine-pyrimethamine (SP), SP + amodiaquine (AQ), or SP + artesunate (AS). We compared treatment responses and the prevalence of resistance-conferring mutations of new infections with those of recrudescent infections due to parasites that survived prior treatment. Recrudescent infections were associated with the selection of SP resistance-conferring mutations in all treatment groups, but responses to repeat therapy differed. Compared with initial treatments, treatment of recrudescent infections was associated with a higher rate of treatment failure (hazard ratio [HR], 2.44; P=.01), for the SP group, but with a lower rate of treatment failure (HR, 0.40; P=.08), for the SP + AS group. Treatment failure in the SP + AQ group was uncommon, limiting the analysis of recrudescent parasites. Our results suggest that the use of combination antimalarial therapy in Africa may slow the spread of drug-resistant malaria and prolong the therapeutic life span of available treatment regimens.

Acute asymptomatic hepatitis in a healthy normal volunteer exposed to 2 oral doses of amodiaquine and artesunate

Combination antimalarial therapy is being explored to delay development of resistance to falciparum malaria. This report describes an unexpected drug-induced hepatitis in a previously healthy young woman exposed to 2 doses of amodiaquine and artesunate. Use of these combinations should be closely monitored.

Annular erythema of Sjögren's syndrome in a white woman

Annular erythema of Sjögren's syndrome (AE-SS) is believed to be the Asian counterpart of subacute cutaneous lupus erythematosus (SCLE) in white persons. We report the second case of a white person with AE-SS, diagnosed by clinical and serologic findings, as well as the absence of histologic criteria for SCLE. The diagnosis of AE-SS was established by symptoms of xerophthalmia and xerostomia, as well as by examination of skin and salivary gland biopsy specimens. Evaluation showed the presence of anti-Ro(SS-A) and anti-La(SS-B) autoantibody, with the presence of anti-Ro(SS-A) antibody against the 60-kd, but not the 52-kd, epitope, a pattern frequently seen in both the Asians with AE-SS and in white patients with SCLE. Both skin and sicca symptoms were alleviated with combination antimalarial therapy, which included hydroxychloroquine and quinacrine. This case demonstrates that AE-SS can occur in white patients and that the autoantibody profile is similar to that described in Asians with this disease. (J Am Acad Dermatol 2000; 42:1069–73.)

Annular erythema of Sjögren's syndrome in a white woman

Annular erythema of Sjögren's syndrome (AE-SS) is believed to be the Asian counterpart of subacute cutaneous lupus erythematosus (SCLE) in white persons. We report the second case of a white person with AE-SS, diagnosed by clinical and serologic findings, as well as the absence of histologic criteria for SCLE. The diagnosis of AE-SS was established by symptoms of xerophthalmia and xerostomia, as well as by examination of skin and salivary gland biopsy specimens. Evaluation showed the presence of anti-Ro(SS-A) and anti-La(SS-B) autoantibody, with the presence of anti-Ro(SS-A) antibody against the 60-kd, but not the 52-kd, epitope, a pattern frequently seen in both the Asians with AE-SS and in white patients with SCLE. Both skin and sicca symptoms were alleviated with combination antimalarial therapy, which included hydroxychloroquine and quinacrine. This case demonstrates that AE-SS can occur in white patients and that the autoantibody profile is similar to that described in Asians with this disease. (J Am Acad Dermatol 2000; 42:1069–73.)

A prospective study of combination antimalarial therapy and of anaemia in Zambian children with cerebral malaria

A prospective study of combination antimalarial therapy and of anaemia in Zambian children with cerebral malaria

Antimalarial synergy of cysteine and aspartic protease inhibitors.

It has been proposed that the Plasmodium falciparum cysteine protease falcipain and aspartic proteases plasmepsin I and plasmepsin II act cooperatively to hydrolyze hemoglobin as a source of amino acids for erythrocytic parasites. Inhibitors of each of these proteases have potent antimalarial effects. We have now evaluated the antimalarial effects of combinations of cysteine and aspartic protease inhibitors. When incubated with cultured P. falciparum parasites, cysteine and aspartic protease inhibitors exhibited synergistic effects in blocking parasite metabolism and development. The inhibitors also demonstrated apparent synergistic inhibition of plasmodial hemoglobin degradation both in culture and in a murine malaria model. When evaluated for the treatment of murine malaria, a combination of cysteine and aspartic protease inhibitors was much more effective than higher concentrations of either compound used alone. These results support a model whereby plasmodial cysteine and aspartic proteases participate in the degradation of hemoglobin, and they suggest that combination antimalarial therapy with inhibitors of the two classes of proteases is worthy of further study.

The use of quinacrine (Atabrine) in rheumatic diseases: A reexamination

Atabrine has been available for nearly 60 years. It has a variety of actions and has been administered to millions of individuals. Its antirheumatic properties have been well documented but have not been exploited optimally for a variety of reasons. The drug is generally quite safe and could be used in low doses in lupus and rheumatoid arthritis patients as a steroid-sparing agent or synergistically with hydroxychloroquine. Its bothersome side effects should not deter the clinician from using it, because they are easy to deal with or prevent (Table 5). Future studies should attempt to better characterize the immunosuppressive actions of this powerful drug, particularly in the treatment of lupus erythematosus and rheumatoid arthritis. Studies of the role of combination or single-agent antimalarial therapy in combination with other “remittive” drugs could be of great potential benefit.