Artesunate Suppositories Research Articles

The treatment of severe malaria

In the SEAQUAMAT trial, parenteral artesunate was shown to be associated with a considerably lower mortality than quinine, and is now the recommended treatment for severe malaria in low-transmission areas and in the second and third trimesters of pregnancy. A trial is underway to establish its role in African children. The development of artesunate suppositories may provide the means to treat patients with severe disease in remote rural settings, potentially buying the time needed to reach a health care facility. The increasing availability of basic intensive care facilities in developing countries also has the potential to further reduce mortality.

CAREGIVERS’ ACCEPTANCE OF USING ARTESUNATE SUPPOSITORIES FOR TREATING CHILDHOOD MALARIA IN PAPUA NEW GUINEA

Community-based interventions using artemisinin-derived suppositories may potentially reduce malaria-related childhood mortality. However, their sociocultural acceptability is unknown in Papua New Guinea and a formal examination of caregiver's attitudes to rectal administration was needed to inform effective deployment strategies. Caregivers (n = 131) of children with uncomplicated malaria were questioned on their prior experience with, and attitudes to, rectal administration and then offered artesunate suppositories as treatment of their child. The 29% who refused this alternative were further questioned to determine their reasons for this refusal. Lack of spousal approval and fear of side effects were the most common reasons for refusal. Sixty-six percent of caregivers agreed to self-administer suppositories, which were perceived as effective (99%), safe (96%), and fast-acting (91%), but problematic to administer to a struggling child (56%). Shame, embarrassment, and hygiene were not significant concerns. Acceptability of rectal administration should be relatively high in Papua New Guinea. However, deployment must be accompanied by health education that addresses the practical aspects of administration, is appropriate for the illiterate, and is directed at fathers as well as mothers.

Artesunate Suppositories versus Intramuscular Artemether for Treatment of Severe Malaria in Children in Papua New Guinea

Drug treatment of severe malaria must be rapidly effective. Suppositories may be valuable for childhood malaria when circumstances prevent oral or parenteral therapy. We compared artesunate suppositories (n = 41; 8 to 16 mg/kg of body weight at 0 and 12 h and then daily) with intramuscular (i.m.) artemether (n = 38; 3.2 mg/kg at 0 h and then 1.6 mg/kg daily) in an open-label, randomized trial with children with severe Plasmodium falciparum malaria in Papua New Guinea (PNG). Parasite density and temperature were measured every 6 h for > or = 72 h. Primary endpoints included times to 50% and 90% parasite clearance (PCT50 and PCT90) and the time to per os status. In a subset of 29 patients, plasma levels of artemether, artesunate, and their common active metabolite dihydroartemisinin were measured during the first 12 h. One suppository-treated patient with multiple complications died within 2 h of admission, but the remaining 78 recovered uneventfully. Compared to the artemether-treated children, those receiving artesunate suppositories had a significantly earlier mean PCT50 (9.1 versus 13.8 h; P = 0.008) and PCT90 (15.6 versus 20.4 h; P = 0.011). Mean time to per os status was similar for each group. Plasma concentrations of primary drug plus active metabolite were significantly higher in the artesunate suppository group at 2 h postdose. The earlier initial fall in parasitemia with artesunate is clinically advantageous and mirrors higher initial plasma concentrations of active drug/metabolite. In severely ill children with malaria in PNG, artesunate suppositories were at least as effective as i.m. artemether and may, therefore, be useful in settings where parenteral therapy cannot be given.

DESCRIPTIVE STUDY ON THE EFFICACY AND SAFETY OF ARTESUNATE SUPPOSITORY IN COMBINATION WITH OTHER ANTIMALARIALS IN THE TREATMENT OF SEVERE MALARIA IN SUDAN

Documentation on the efficacy of artesunate in Africa is limited, and no experience of artesunate use in Sudan is documented. Severe malaria in rural areas of Sudan, where facilities for the safe and effective use of parenteral quinine are lacking, is a frequent problem. Early treatment with artesunate suppositories would provide a simple method for use by unskilled staff and would be an alternative approach to treat malaria in settings with poor resources. We describe a hospital-based study of rectal artesunate in 100 adult patients with severe falciparum malaria with a dose derived from pharmacokinetic data (200 mg every 8 hours) over 3 days, which halted progression of severe disease and had a low fatality rate. The dosage schedule led to a rapid clinical response and reduced parasite clearance and fever subsidence times of (31.5 +/- 10.1 hours) and (31.4 +/- 11.1 hours). The sequential treatment of rectal artesunate with either doxycycline or pyrimethamine/sulfadoxine or mefloquine resulted in similar clinical cure rates of around 100%, and the combination of artesunate with either doxycycline or pyrimethamine/sulfadoxine was equally effective as mefloquine in preventing recrudescence. There were no significant adverse effects or signs of toxicity related to the treatment observed during the 28-day follow-up. The combination regimens could be used in areas where there is limited access to parenteral therapy for malaria.

Management of malaria in Thailand

The purpose of treatment for uncomplicated malaria is to produce a radical cure using the combination of: artesunate (4 mg/kg/day) plus mefloquine (8 mg/kg day) for 3 days: a fixed dose of artemether and lumefantrine (20/120 mg tablet) named Coartem (4 tablets twice a day for three days for adults weighing more than 35 kg): quinine 10 mg/kg 8-hourly plus tetracycline 250 mg 6-hourly for 7 days (or doxycycline 200 mg as an alternative to tetracycline once a day for 7 days) in patients aged 8 years and over: Malarone (in adult 4 tablets daily for 3 days). In treating severe malaria, early diagnosis and treatment with a potent antimalarial drug is recommended to save the patient's life. The antimalarial drugs of choice are: intravenous quinine or a parenteral form of an artemisinin derivative (artesunate i.v./i.m. for 2.4 mg/kg followed by 1.2 mg/kg injection at 12 and 24 hr and then daily for 5 dayss; artemether i.m. 3.2 mg/kg injection followed by 1.6 mg/kg at 12 and 24 hrs and then daily for 5 days; artemether i.m. (Artemotil) with the same dose of artemether or artesunate suppository (5 mg/kg) given rectally 12 hourly for 3 days. Oral artemisinin derivatives (artesunate, artemether, and dihydroartemisinin with 4 mg/kg/day) could replace parenteral forms when patients can tolerate oral medication. Oral mefloquine (25 mg/kg divided into two doses 8 hrs apart) should be given at the end of the artemisinin treatment course to reduce recrudescence.

Clinical Malaria and Treatment of Multidrug Resistance Falciparum in Thailand.

Clinical manifestations of malaria are nonspecific and range from asymptomatic to severe. The clinical presentations reflect complex interactions between the host, the environment, and the parasites. Signs and symptoms include fever, headache, muscle pain, abdominal pain, anorexia, nausea, vomiting, hepatosplenomegaly, jaundice and dark urine. In mild malaria, these signs and symptoms cannot differentiate malaria from common cold, influenza or other systemic diseases. Fever and malaise in malaria are believed to result from the release of endogenous cytokines [e. g. interleukin 1, 6 and 8 (IL-1, IL-6, IL-8) and tumor necrotic factor-α (TNF-α)] in response to parasite antigens. Other signs and symptoms of malaria are also associated with the rupture of parasitized red cells. In severe malaria, the clinical manifestations included cerebral malaria, pulmonary edema, renal failure, anaemia, and jaundice. Signs and symptoms of cerebral malaria are as follow alteration of consciousness, coma, dysconjugated eyeballs and convulsions. Among fatal cases, 80% died within the first 48 hrs of admission while the rest, death resulted from complications such as acute renal failure, pulmonary edema, bacterial infection, and lactic acidosis. 92% of the survivors had completed recovery. Treatment of multidrug resistant falciparum malaria in Thailand is complicated. New antimalarial drugs have been investigated at the Hospital for Tropical Diseases in the recent years. Artemisinine derivatives such as artesunate, artemether, arteether, dihydroartemisinin are also tested at the Bangkok Hospital for Tropical Diseases. Artesunate and artemether alone with a total dose of 600 to 750 mg produced cure rates of 80 to 95%. Artesunate suppositories have been proved successfully for the treatment of severe malaria. The artemisinin derivatives when used in combination with mefloquine cure rates improved to 95-100%. Dihydroartemisinin alone with a total dose of 480 mg given over 5 days gave a cure rate of 90%. At present, studies with the combination of artemisinin derivatives plus mefloquine in various doses and duration of treatment are being investigated. Until proven otherwise, the drug combinations are still recommended for all adult patients suffering from acute uncomplicated falciparum malaria contracted in multidrug resistant areas.In severe malaria, the choice of antimalarial chemotherapy depends on the clinical severity, the drug sensitivity of the parasites, and the availability and preparation of the drug. Quinine is widely available drug. Qinghaosu and its derivatives have been used successfully in treating both uncomplicated and severe falciparum malaria. Their effectiveness in eliminating the parasites have been extensively documented, however, the recrudescent rate is rather high (10-30%). In treating severe malaria, early diagnosis and early treatment are vital and the aim is to save patient's life. Prompt administration of an adequate and effective antimalarial drug is needed once the diagnosis is made. Other symptomatic and supportive treatment includes careful monitoring of fluid intake and urine output, frequent observations for complications with appropriate treatment and good nursing care.

Plasma levels of artesunate and dihydroartemisinin in children with Plasmodium falciparum malaria in Gabon after administration of 50-milligram artesunate suppositories.

A thermostable suppository of artesunate (artesunic acid) has been developed. In Gabon, 12 children with Plasmodium falciparum malaria received two administrations of this suppository in a 4-hr interval. Parasitemia and fever were then measured and the plasma levels of artesunate and its active metabolite, dihydroartemisinin, were determined by means of a reversed phase high-pressure liquid chromatography method using reductive electrochemical detection. Substantial parasite clearance (97-100%) was noted 24 hr after the beginning of the treatment and body temperature had returned to normal. Absorption, metabolism, and elimination of artesunate were rapid. Mean values of maximum plasma levels (Cmax) and maximum concentration peak times (tmax) were evaluated. The Cmax of dihydroartemisinin (0.18 +/- 0.10 microg/ml [mean +/- SE]) was higher than the Cmax of artesunate (0.09 +/- 0.04 microg/ml) and the tmax of dihydroartemisinin (1.13 +/- 0.58 hr) was higher than the tmax of artesunate (0.58 +/- 0.19 hr). Plasma levels 30 min after the second suppository administration were not consistently higher than those found 30 min after the first administration.

Artesunate suppositories: an effective treatment for severe falciparum malaria in rural areas

Artesunate suppositories: an effective treatment for severe falciparum malaria in rural areas

Artesunate suppositories: an effective treatment for severe falciparum malaria in rural areas.

Artesunate is a potent antimalarial agent available in oral, parenteral and rectal formulations. Artesunate suppositories rapidly reduce and quickly clear parasitaemias. The rapidity of effect, availability and convenient dosage regimen make artesunate in suppository form a promising treatment for severe falciparum malaria, particularly in rural areas where parenteral formulations are unavailable.

Efficacy and tolerability of a sequential, artesunate suppository plus mefloquine, treatment of severe falciparum malaria

Thirty patients with severe falciparum malaria were each given a total of 1600-mg artesunate suppository over three consecutive days followed by 1250 mg mefloquine per os, divided into two doses which were given 12 h apart. All patients were admitted for 28 days to the Bangkok Hospital for Tropical Diseases, so that the efficacy and tolerability of the treatment could be assessed. All the patients showed clinical improvement, with mean (S.D.) parasite and fever clearance times of 50.4 (13.0) and 70.7 (44.9) h, respectively. Two patients with unrousable coma (Glasgow coma score < or = 8) on admittance regained consciousness 46 and 48 h post-treatment. One other patient had acute renal failure and required dialysis. Most patients (80%) were initially hyperparasitaemic, with a mean density of 184,344 parasites/microliters blood. No deaths occurred. Efficacy was evaluated in 25 of the patients. The cure rate 28 days post-treatment was 92%. None of the patients had major adverse effects although two had tenesmus and passed stools immediately after each suppository was administered. A fresh suppository had to be inserted when this occurred. The results indicate that artesunate suppositories followed by oral mefloquine constitute a well-tolerated regimen with a high cure rate. The combination is suitable as an alternative treatment for severe malaria, particularly in children. Further, large-scale studies are required.

Comparison of artemisinin suppositories with intravenous artesunate and intravenous quinine in the treatment of cerebral malaria

Seventy-nine comatose cerebral malaria patients given standard supportive treatment were randomized to receive specific antimalarial chemotherapy of intravenous quinine, intravenous artesunate, or artemisinin suppositories. Artesunate and artemisinin reduced peripheral asexual parasitaemia significantly more rapidly than quinine (90% clearance time 16 h, 18·9 h and 34·5 h respectively), but did not significantly reduce the duration of coma or mortality. The rapid lowering of peripheral parasitaemia may not ameliorate complications already present. These results demonstrate that artemisinin suppositories are as effective as artesunate and quinine given intravenously, and have economic and practical advantages for the treatment of severe malaria in areas remote from major medical centres. However, large numbers of patients will need to be studied if differences in mortality between the 3 treatment groups are to be demonstrated.