CD4 count, viral load and parasite density of HIV positive individuals undergoing malaria treatment with dihydroartemisinin in Benin City, Edo state, Nigeria.

BACKGROUND & OBJECTIVES: A prospective study on 72 HIV infected and 33 HIV negative individuals undergoing malaria treatment with dihydroartemisinin (Cotecxin) was undertaken to compare CD4 cells count, viral load and parasite density at two time-points, a baseline visit and a 9-day post-treatment visit. METHODS: CD4 count and viral load of the subjects were estimated using Dynabeads T4-T8 Quantification Protocol (Dyneal Biotech, Norway) and Amplicor HIV-1 Monitor Test respectively (Roche, United Kingdom). RESULTS: There was a significant decrease in CD4 count at 9-day post-treatment when compared with baseline value (p < 0.05) in HIV infected individuals with CD4 < or =200 cells/microl. Also, the 9-day post-treatment viral load value was statistically higher than the baseline value (p < 0.05). In HIV positive patients with CD4 >200 cells/microl, a marked significant increase was obtained when the mean viral load at baseline was compared to the 9-day post-treatment visit value (p <0.05). The mean parasite density in HIV positive subjects was statistically higher when compared to that of HIV negative individuals at baseline and 9-day post-treatment (p < 0.05). INTERPRETATION & CONCLUSION: The study as such may not confirm the impact of malaria infection on progression to AIDS, incorporating effective malaria control in HIV management programmes may improve tremendously the quality of life of HIV infected individuals.

Minor liver profile dysfunctions in Plasmodium vivax, P. malaria and P. ovale patients and normalization after treatment

Liver function tests were performed in 61 vivax, 54 malariae and 15 ovale malaria patients who were admitted to Bangkok Hospital for Tropical Diseases between 2001 and 2004. The objective of the study was to evaluate changes in hepatic biochemical indices before and after treatment with artemisinin derivatives. On admission and prior to treatment, hepatic dysfunction was found among the 3 groups. Serum liver function tests and physical examinations were performed weekly during the 28-day follow-up period. Initially elevated serum bilirubin and diminished albumin returned to normal within 2 weeks of treatment. Serum alkaline phosphatase and aminotransferases returned to within normal limits within 3 weeks. We conclude that patients with Plasmodium vivax, P. malariae and P. ovale infections had slightly elevated serum bilirubin, aminotransferase and alkaline phosphatase levels, and hypoalbuminemia. These minor abnormalities returned to normal within a few weeks after treatment with therapies based on artemisinin derivatives.

Management of severe falciparum malaria.

Plasmodium falciparum is the most common cause of severe and life-threatening malaria. Falciparum malaria causes over one million deaths every year. In Africa, a vast majority of these deaths occur in children under five years of age. The presentation of severe malaria varies with age and geographical distribution. The mortality rate is higher in adults than in children but African children develop neuro-cognitive sequelae following severe malaria more frequently. The management of severe malaria includes prompt administration of appropriate parenteral anti-malarial agents and early recognition and treatment of the complications. In children, the complications include metabolic acidosis (often caused by hypovolaemia), hypoglycaemia, hyperlacticacidaemia, severe anaemia, seizures and raised intracranial pressure. In adults, renal failure and pulmonary oedema are more common causes of death. In contrast, concomitant bacterial infections occur more frequently in children and are associated with mortality in children. Admission to critical or intensive care units may help reduce the mortality, and the frequency and severity of sequelae related to severe malaria.

Management of severe malaria.

Prompt diagnosis and early institution of therapy is an important determinant of outcome in severe falciparum malaria. Thick smears are the gold standard for diagnosis; in situations where reliable microscopy is not available, tests based on HRP-2 antigen/parasite LDH are useful. As there is widespread resistance to chloroquine in P falciparum in India, the choice for specific antimalarial therapy is between quinine and artermisinin derivatives. Randomized controlled trials have not revealed any significant benefit of the artemisinin derivatives over quinine in quinine sensitive areas. Also, if quinine is administered in the recommended way, the side effects are no greater than artemisinins. However, as the artemisinin derivatives are easier to administer, their use in severe malaria in India is increasing. It is vital that we use these drugs in a rational and judicious manner to prevent development of drug resistance. Supportive care, early diagnosis and management of complications are as essential as antimalarial therapy. The role of exchange blood transfusion in the management of severe malaria is still controversial. It may be considered in the presence of high parasites counts (>10%) with multiorgan dysfunction if adequate quantities of safe blood are available.

A comparative clinical trial of artemether and quinine in children with severe malaria.

OBJECTIVE: To compare the efficacy of artemether and quinine in the treatment of severe malaria in hospitalized children. STUDY DESIGN: Open randomized trial. SETTING: Pediatric ward of a tertiary care center. METHODS: All children admitted with clinical manifestations of severe malaria (as per WHO criteria) and asexual forms of Plasmodium falciparum demonstrated on peripheral smear were randomized to receive either artemether or quinine. Their clinical status and smears for parasite count were assessed every 12 hours until two successive blood films were negative. The primary end point of the study was death in the hospital and residual damage to the organ involved. The secondary end points were clearance of parasites and fever, length of time of recovery from coma and normal functions of the involved system. RESULTS: Forty-six cases completed the study protocol, 23 assigned to each drug group. Cerebral malaria was the commonest manifestation (76.1%). Mean age in artemether versus quinine group (6.6 +/- 3.5 and 5.8 +/- 2.4 years) as well as degree of parasitemia at admission (55,800 and 60,300 per microlitre) were comparable. The overall mortality rate was 23.9% with no significant difference between the two groups. Twenty six cases (56.5%) presented with more than one manifestations of severe malaria. The mortality rate was 100% with four coexisting manifestations of severe malaria. Fever clearance time in artemether and quinine group was 44.5 and 45.9 hours respectively (P >0.05). Parasite clearance time was significantly shorter in artemether group (40.9 vs. 51.9 hours; P<0.001). Recovery from coma was shorter in artemether group (34.8 vs. 38.1 hours; P<0.05). CONCLUSION: Cerebral malaria is the most common manifestation of severe malaria in children. Artemether is a good alternative drug to quinine for P. falciparum malaria. Mortality rate is directly proportional to the number of coexisting manifestations of severe malaria.

Drug resistant falciparum malaria and the use of artesunate-based combinations: focus on clinical trials sponsored by TDR.

Antimalarial drug resistance has now become a serious global challenge and is the principal reason for the decline in antimalarial drug efficacy. Malaria endemic countries need inexpensive and efficacious drugs. Preserving the life spans of antimalarial drugs is a key part of the strategy for rolling back malaria. Artemisinin-based combinations offer a new and potentially highly effective way to counter drug resistance. Clinical trials conducted in African children have attested to the good tolerability of oral artesunate when combined with standard antimalarial drugs. The cure rates of the different combinations were generally dependent on the degree of resistance to the companion drug. They were high for amodiaquine-artesunate, variable for sulfadoxine/pyrimethamine-artesunate, and poor for chloroquine-artesunate.

Red cell exchange using cell separator (therapeutic erythrocytapheresis) in two children with acute severe malaria.

Red cell exchange using a cell separator (therapeutic erythrocytapheresis) has been used successfully in a large number of clinical conditions including acute severe cases of malaria. We report two children suffering from severe malaria (Plasmodium falciparum) with infestation rates of 75% and 67% respectively. They were treated successfully with erythrocytapheresis in combination with antimalarial treatment.

Role of mast cells in gastrointestinal mucosal defense

The purpose of this review, based on studies from our laboratory as well as from others, is to summarize salient features of mast cell immunobiology and to describe their associations with gastrointestinal mucosal defense. Gastrointestinal mast cells are involved in many pathologic effects, such as food hypersensitivity. On the other hand, they also play a protective role in defense against parasitic and microbial infections. Thus, they have both positive and negative effects, but presently the mechanisms that control the balance of these various effects are poorly known. It has been suggested that stabilization of mast cells may be a key mechanism to protect the gastrointestinal tract from injury. Few molecules are known to possess both mast cell stabilizing and gastrointestinal cytoprotective activity. These include zinc compounds, sodium cromoglycate, FPL 52694, ketotifen, aloe vera, certain flavonoids such as quercetin, some sulfated proteoglycans such as chondroitin sulfate and dehydroleucodine. Dehydroleucodine, a sesquiterpene lactone isolated from Artemisia douglasiana Besser, exhibits anti-inflammatory and gastrointestinal cytoprotective action. The lactone stimulates mucus production, and inhibits histamine and serotonin release from intestinal mast cells. The lactone could act as a selective mast cell stabilizer by releasing cytoprotective factors and inhibiting pro-inflammatory mast cell mediators.

Tratamento de crianças com malária pelo Plasmodium falciparum com derivados da artemisinina / Treatment of children with malaria Plasmodium falciparum with derivatives artemisinin

No período compreendido entre janeiro de 1996 e dezembro de 1998, administramos derivados da artemisinina em 108 crianças com malária por Plasmodium falciparum, para avaliar a resposta clínica e terapêutica. Foram incluídas apenas crianças com clínica de malária moderada ou grave. No Grupo I, incluímos 62 pacientes e administramos artesunate por via endovenosa. Clinicamente, 50,8 por cento tinham malária moderada e 49,2 por cento malária grave; a parasitemia foi baixa em 53,2 por cento, média em 22,6 por cento e alta em 24,2 por cento; no D2 a parasitemia estava negativa em 58,1 por cento. No Grupo II,incluímos 46 pacientes que receberam artemeter (Paluter®) intramuscular. Clinicamente, 67,4 por cento apresentavam malária moderada e 32,6 por cento malária grave; a parasitemia foi baixa em 52,2 por cento, média em 36,2 por cento e alta em 15,2 por cento; em D2, 56,5 por cento apresentaram negativaçäo da parasitemia. Nos dois grupos, a melhora clínica e evoluçäo da parasitemia näo mostraram diferença estatística; no D7 havia clareada a parasitemia em todos os pacientes. Para evitar recrudescência usamos mefloquina ou clindamicina

An open randomized clinical trial of Artecom vs artesunate-mefloquine in the treatment of acute uncomplicated falciparum malaria in Thailand.

The efficacy and safety of Artecom were assessed in an open randomized trial in adults presenting with acute, uncomplicated Plasmodium falciparum malaria in Thailand. Three hundred and fifty-two patients were randomly enroled at the ratio of 2:1 into group A:B and received Artecom (group A) and the standard combination of artesunate and mefloquine (group B) respectively. All patients had rapid initial clinical and parasitological responses. There were no significant differences in fever clearance time and parasite clearance time between the two groups. The 28-day cure rates were high as 97% in both groups. Artecom was effective and well-tolerated as artesunate-mefloquine, the current treatment in this area of multidrug-resistant P. falciparum malaria.

A safety and efficacy trial of artesunate, sulphadoxine-pyrimethamine and primaquine in P falciparum malaria.

OBJECTIVE: To determine effectiveness and safety of the combination of artesunate, sulphadoxine + pyrimethamine and primaquine in the treatment of P falciparum malaria. DESIGN: A hospital based prospective study. SETTING: Base Hospital, Moneragala. METHODS: In 30 P falciparum infected patients admitted to the hospital, blood was taken for estimation of haemoglobin, white cell counts, and serum levels of aspartate aminotransferase, alanine aminotransferase, bilirubin and creatinine. They were administered artesunate, sulphadoxine + pyrimethamine (S + P) and primaquine on day 0 (artesunate 4 mg/kg, sulphadoxine 25 mg/kg, pyrimethamine 1.25 mg/kg and primaquine 0.75 mg/kg), and only artesunate on days 1 and 2 (artesunate 4 mg/kg each day). Blood was examined for malarial parasites, and patients were assessed on days 1, 2, 7, 14, 21 and 28. Patients assessed the severity of selected symptoms. Biochemical analyses were done on day 0 and repeated on days 7 and 28. RESULTS: Eight patients presented with fever which resolved in 7 patients in 48 hours. Asexual parasites were cleared in 80% of the 30 patients within 24 hours of treatment and in all 30 by day 7. Gametocytaemia cleared in all patients by day 14. There were no adverse effects experienced by the patients. The white cell and differential counts, liver enzymes and creatinine levels were within normal limits on all follow up days. CONCLUSIONS: The combination of artesunate, S + P and primaquine was found to be effective and safe in the treatment of uncomplicated P falciparum malaria.

A comparative clinical trial of combinations of dihydroartemisinin plus azithromycin and dihydroartemisinin plus mefloquine for treatment of multidrug resistant falciparum malaria.

With the deteriorating situation of multidrug resistant falciparum malaria, a new drug or drugs in combinations are urgently needed. We conducted a study comparing a combination of dihydroartemisinin 240 mg and mefloquine 1,250 mg given over 3 days (Group 1) and a combination of dihydroartemisinin 240 mg and azithromycin 1,500 mg given over 3 days (Group 2), to determine safety, efficacy and tolerability. All of the patients stayed in a non-malaria endemic area during the study. By the third day after drug administration, most patients were free of parasites and none had serious adverse events. The cure rates at day 28 were 100% and 69.7% in Group 1 and Group 2, respectively (p<0.01). We conclude that a combination of dihydroartemisnin and azithromycin was safe and effective and may be another interesting regimen of the treatment of uncomplicated multidrug resistant Plasmodium falciparum malaria in Thailand.

Blackwater fever treated with artemether.

Blackwater fever is a rare manifestation of falciparum malaria characterized by sudden intravascular hemolysis followed by fever and hemoglobinuria. We present a case of blackwater fever, having occurred after administration of quinine, which was treated successfully with artemether.

A multicentric study with arteether in patients of uncomplicated falciparum malaria.

Two hundred and sixty seven patients of uncomplicated P. falciparum malaria completed study in a multicentric phase III clinical trial of Arteether. Arteether was given intramuscularly in a dose of 150 mg daily for three consecutive days. Each patient was followed upto 28 days of alpha, beta arteether therapy. The cure rate was 97% with fever clearance time between 1-7 days (24-168 hours) and parasite clearance time between 1-3 days (24-72 hours). Parasite reappearance rate was found to be 3% and reported at only three of the centres. Following the treatment no adverse effect was observed on haematological, biochemical and vital clinical parameters.

Frequency of early rising parasitemia in falciparum malaria treated with artemisinin derivatives.

To define the frequency of the early rising of parasitemia in falciparum malaria patients treated with artemisinin derivatives, a retrospective chart review of 497 patients admitted to the Hospital for Tropical Diseases, Bangkok in 1996 was carried out. Early rising parasitemia, defined as an increase in the parasite count over the baseline pretreatment level during the first 24 hours of treatment, was found in 59/229 episodes (25.8%) of uncomplicated, and 111/268 episodes (41.3%) of complicated falciparum malaria. All uncomplicated cases were successfully treated without developing any complications. There were 2 deaths and 13 changes of drug regimen in the complicated group. Only one of these unfavorable responses was due to parasite response. Early rising parasitemia was very common in falciparum malaria treated with artemisinin derivatives, despite their ability to clear the parasitemia, and did not indicate failure of the drug used.

Guideline in management of severe malaria.

Severe malaria remains a major cause of mortality in the world. Malaria can mimic many diseases and there is no absolute diagnostic clinical features. High index of suspicion is clue for clinical diagnosis. Previous travel history to endemic area should be elicited in all, and in particular, febrile patients. Management of severe malaria needs potent antimalarial drug and intensive care. Artemisinin derivatives can be of altemative use to quinine. Dexamethasone and mannitol have no beneficial value in the management of cerebral malaria. In pulmonary oedema patients whose hydration assessments are difficult to monitor, central venous pressure evaluation may be useful. Acute renal failure patients may need dialysis until uraemic syndrome subsides or patients can void urine. Most severe malaria patients have thrombocytopenia; however, platelet concentrate transfusion is indicated only in patients with systemic bleeding. Morbidity and mortality will be reduced in severe malaria patients with early diagnosis and prompt treatment.