Amodiaquine-Ciprofloxacin: a potential combination therapy against drug resistant malaria.

Emergence of malaria parasites resistant to artemisinin necessitates the need for development of new antimalarial therapies. Ciprofloxacin (CFX) a second generation quinolone antibiotic possesses some antimalarial activities. We investigated the in vivo antimalarial activities of CFX in combination with amodiaquine in mice infected with chloroquine-resistant Plasmodium berghei ANKA. Animals were treated orally with 80 or 160 mg kg-1 body weight of CFX alone given twice daily or in combination with amodiaquine (AQ) 10 mg kg-1 body weight. Parasitological activity and survival of the animals were assessed over 21 days. Peak parasitaemia in the untreated control group was 72.51%. Treatment with AQ alone resulted in clearance of parasitaemia by day 4 while treatment with CFX 80 and 160 mg kg-1 alone suppressed parasitaemia by 13.94-54.64% and 35.6-92.7%, respectively. However, the combination of CFX with AQ significantly enhanced response of infection in the animals to treatment (P < 0.05) resulting in complete resolution of parasitaemia throughout follow up period with CFX 160 mg kg-1, delayed recrudescence time with CFX 80 mg kg-1 and significant increase in survival rate of the animals. The results demonstrate beneficial interaction between AQ and CFX which may provide a clinically relevant antimalarial/antibiotic therapeutic option in the management of malaria.

Open randomized study of artesunate-amodiaquine vs. chloroquine-pyrimethamine-sulfadoxine for the treatment of uncomplicated Plasmodium falciparum malaria in Nigerian children.

BACKGROUND: Artemisinin-based combination antimalarials are currently considered effective alternatives for the treatment of malaria in Africa, but there are few studies of such combinations in Nigerian children. We assessed the safety, treatment efficacy and effects on gametocyte carriage of the combination of artesunate plus amodiaquine and chloroquine plus pyrimethamine-sulfadoxine in children. METHODS: We evaluated 153 children who were aged 12 years or younger who had uncomplicated Plasmodium falciparum malaria. Patients were randomly assigned a combination of artesunate (4 mg/kg of body weight daily for 3 days) plus amodiaquine (30 mg/kg over 3 days), or chloroquine (25 mg/kg over 3 days) plus pyrimethamine-sulfadoxine (25 mg/kg of the sulfadoxine component at presentation). The primary endpoints were the proportions of children with adequate clinical and parasitological response, late parasitological failure, late clinical failure and early treatment failure. The parasitological cure rates on days 14-28 were also used as the primary endpoints. RESULTS: Both regimens were well tolerated; no child was withdrawn because of drug intolerance. All children treated with artesunate plus amodiaquine had adequate clinical and parasitological response (ACPR), while all but five children treated with chloroquine plus pyrimethamine-sulfadoxine had similar response. Fever clearance times were similar in the two treatment groups. However, the proportion of patients whose parasitaemia cleared by day 2 was significantly higher (100 vs. 50%, P = 0.00001) and parasite clearance was significantly faster (1.7 +/- 0.4 vs. 2.5 +/- 0.8 days, P = 0.0001) in children treated with artesunate plus amodiaquine. The cure rates on days 21 (100%vs. 94%, P = 0.03) and 28 (100%vs. 90%, P = 0.003) were also significantly higher in children treated with artesunate plus amodiaquine than in those treated with chloroquine plus pyrimethamine-sulfadoxine. Overall, a significantly higher proportion of children treated with chloroquine plus pyrimethamine-sulfadoxine carried gametocytes at least once during follow-up compared with those treated with artesunate plus amodiaquine [5 of 50 (10%) vs. 1 of 103 (0.97%), P = 0.01]. CONCLUSION: The combination of artesunate plus amodiaquine is therapeutically superior to a combination of chloroquine plus pyrimethamine-sulfadoxine, and significantly reduced gametocyte carriage following treatment.

Efficacy of herbal remedies used by herbalists in Oyo State Nigeria for treatment of Plasmodium falciparum infections--a survey and an observation.

In the course of evaluating the contribution of phytomedicine to possible drug discovery of antimalarial drugs, an ethnomedical survey of specialized children traditional clinics was done. In the observational multi center study, efficacy of eight different herbal remedies, each consisting of 3-8 ingredients and administered by herbalists were investigated in clients enrolled in the six traditional clinics in Oyo (urban center) and Otu (rural center) of Oyo State, Nigeria. The clients, aged between six months and fifteen years with clinical symptoms of malaria were enrolled in the clinics of the herbalists, as their usual practice. Oral informed consents were obtained from their parents or guardians. Microscopic diagnosis of malaria infection was used to evaluate parasitaemia and validate efficacy of herbal remedies. Results of the analysis showed that, of the 163 clients of the herbalists, only 62 (30 from Oyo, 32 from Otu) had microscopically confirmed P. falciparum infection. Only results from 54 clients (29/30 (Oyo) and 25/32 (Otu) with P. falciparum infection could be evaluated. Plasmodium falciparum infection in 88% (23/29) of clients from Oyo responded to treatment with the herbal remedies while cure rate in clients from Otu was 42% (13/25). Parasite densities ranged from 171 to 53,613 parasites/microl blood and 87 to 36,209 parasites/microl blood in patients from Oyo and Otu respectively. The herbalists administered the remedies and Gossypium arboreum, Anarcadium occidentalis, Citrus medica, Phyllanthus amarus and Lippia multiflora were the main ingredients in the efficacious remedies. The herbalists gave detailed descriptions of each of the 8 herbal remedies proffered. The results confirm the efficacy of two of the eight herbal remedies, thereby validating the role of ethnomedicine as a possible source for the discovery of new chemotherapeutic agents in the treatment of P. falciparum malaria.

Comparative efficacy of chloroquine plus chlorpheniramine and pyrimethamine/sulfadoxine in acute uncomplicated falciparum malaria in Nigerian children.

The efficacy of pyrimethamine/sulfadoxine (PS) and chloroquine plus chlorpheniramine, a histamine H1 receptor blocker which reverses chloroquine insensitivity in Plasmodium falciparum in vitro, was evaluated in 100 consecutive children with acute symptomatic uncomplicated falciparum malaria. Parasitaemia on day 3 following initiation of treatment, fever and symptom clearance times were significantly lower in the chloroquine/chlorpheniramine (CQ/CP) combination group than in the PS group. The cure rate was also significantly higher in the combination group. The combination cured all children who had failed PS treatment. Gametocytaemia and the gametocyte carrier rate following therapy were significantly lower in the combination group than in those receiving PS. Both treatments were well tolerated but adverse drug reactions were commoner in the children given PS. CQ/CP is effective in PS treatment failure in Nigerian children and may be useful for this condition in African children in general.

Plasmodium falciparum: evaluation of lactate dehydrogenase in monitoring therapeutic responses to standard antimalarial drugs in Nigeria.

The correlation of P. falciparum lactate dehydrogenase (pLDH) activities and patent infections was evaluated for monitoring therapeutic responses and drug resistance in 70 patients with microscopically confirmed P. falciparum malaria in Nigeria. Each patient was treated with standard dosages of artemether (53 patients), chloroquine (7 patients), sulfadoxine-pyrimethamine (6 patients), or halofantrine (4 patients). Response of infection to treatment was monitored by microscopic examination of thick and thin blood smears, clinical symptoms, and levels of pLDH activities in blood products. pLDH activity was determined using an antibody capture technique and 3-acetyl pyridine adenine dinucleotide developed to enhance sensitivity of the enzyme detection. All patients treated with artemether were cured while 5 patients treated with chloroquine, 1 treated with sulfadoxine-pyrimethamine, and 2 treated with halofantrine suffered recrudescent infections after treatment. pLDH activity was detected in blood products obtained from patients with patent or recrudescent infections determined by microscopy and clinical symptoms. Levels of pLDH activities in whole blood and packed cells from the patients correlated with qualitative detection of parasites in blood smears and in patients with high gametocyte counts. Gametocyte counts in the patients after treatment ranged from 40 gametocytes/microliter of blood to 4923 gametocytes/microliter of blood. There is a consistent relationship between patent infection and pLDH activities that could easily be determined in whole blood and packed cells from the patients. Further development of the procedure will enhance its valuable application in clinical management of drug-resistant malaria in the endemic areas.

Artemether treatment of recrudescent Plasmodium falciparum malaria in children.

Intramuscular artemether given for five days was evaluated prospectively in 32 patients with acute recrudescent Plasmodium falciparum malaria. All patients had experienced one or more treatment failures with one or more courses of the following drugs: chloroquine, amodiaquine, sulphadoxine-pyrimethamine and erythromycin given alone or in combination. There was a prompt response to treatment with fever and parasite clearance times of 10.7 (3.6) h (range 6-24) and 32.3 (8.3) h (range 24-48) respectively. Parasite reduction at 24 h was 93.2 (7.8)% (range 75-100). The cure rate on day 14 was 100%. The drug was well tolerated. These results suggest that artemether is rapidly effective in acute recrudescent Plasmodium falciparum malaria and is without deleterious side effects.

Open comparison of artemether and mefloquine in uncomplicated Plasmodium falciparum hyperparasitaemia in children.

The efficacy of intramuscular artemether given for 5 days and a single oral dose of mefloquine, 25 mg/kg/body-weight, was evaluated in 84 children with uncomplicated Plasmodium falciparum hyperparasitaemia ( > 5% parasitized erythrocytes). Follow-up was for 14 days in the artemether group and 28 days in the mefloquine group. Artemether produced a significantly higher parasite reduction at 24 hours [mean 90.6 vs 63.3%, 95% confidence interval 10.7-43.9] and significantly shorter parasite clearance time [mean 38.4 vs 49.3 hours, 95% confidence interval 5.5-16.3] than mefloquine. Fever clearance times were similar, presumably because of the use of an antipyretic in both treatment groups. Cure rate was 98% with artemether on day 14 and 100% with mefloquine on day 28. One child in the artemether group who had recurrence of parasitaemia on day 14 responded promptly to mefloquine with clearance of parasitaemia and fever at 24 hours. Although both drugs were well tolerated, mefloquine produced more episodes of abdominal pain with or without diarrhoea and vomiting. These results suggest that both drugs are effective in uncomplicated Plasmodium falciparum hyperparasitaemia in children from an endemic area of south-west Nigeria.

Efficacy of artemether in severe falciparum malaria in African children.

The clinical efficacy of intramuscular artemether was studied in 144 children suffering from severe non cerebral malaria. Fifty-three children with chloroquine-resistant and 27 children with sulfadoxinepyrimethamine-resistant falciparum malaria were also studied. Greater than 95% of pre-treatment parasitaemia was cleared by 24 h after commencement of treatment in all groups. The parasite and fever clearance times were 35.4 +/- 8.0 and 18.6 +/- 6.3 h respectively, in children suffering from severe non cerebral malaria 36.3 +/- 7.9 and 15.6 +/- 3.8 h, respectively, in the chloroquine-resistant and 36.8 +/- 8.8 and 16.5 +/- 4.2 h, respectively, in the sulfadoxine-pyrimethamine-resistant groups. The cure rate in all groups on day 14 was 100%. Side effects following treatment were minimal and comprised pain with mild tenderness at site of injection in two children and bradycardia, on the second or third day of treatment, in another two patients. No patient had pruritus. These data suggest that artemether is rapidly effective in falciparum malaria in children irrespective of previous drug treatment and especially in chloroquine- or sulphadoxinepyrimethamine-resistant infection and in this study was without deleterious side effects.

Artemether in moderately severe and cerebral malaria in Nigerian children.

Intramuscular artemether was compared with intramuscular sulfadoxine-pyrimethamine in Nigerian children with moderately severe malaria requiring parenteral therapy. Artemether produced significantly shorter parasite and fever clearance times but a higher parasite recrudescence rate than sulfadoxine-pyrimethamine. There was no significant difference in their initial parasitological cure rates--100% for artemether, 98% for sulfadoxine-pyrimethamine. In a separate study intramuscular artemether was compared with intravenous quinine in children with cerebral malaria. There was no significant difference between the 2 drugs in parasite and fever clearance times, time to regain consciousness, or recrudescence rate. There was an overall mortality of 16.7%, with 12% in the artemether group and 21% in the quinine group. Artemether was well tolerated. There was no abnormal change in haematological and biochemical features monitored and there was no adverse clinical reaction. These results show that artemether is a potentially useful drug for moderate and severe malaria and its place in the chemotherapy of malaria deserves further study.

Parenteral therapy of moderately severe malaria: comparison of intramuscular artemether and intramuscular sulfadoxine-pyrimethamine.

We have compared the efficacy of intramuscular artemether against intramuscular sulfadoxine-pyrimethamine in an open randomized study in children with severe but uncomplicated malaria. Parasite clearance time and fever clearance time were faster with artemether. The parasitological clearance on day 14 was 100% for artemether and 98% for sulfadoxine-pyrimethamine, but 8 patients in the artemether group and 1 in the other group had a recrudescence of parasitaemia. There was no toxic reaction of note in either group. We therefore suggest that artemether is a good alternative to the currently used drugs in the parenteral treatment of severe but uncomplicated malaria and may be useful in preventing the possible development of cerebral malaria.

Innate resistance to new antimalarial drugs in Plasmodium falciparum from Nigeria.

The rapid dissemination of chloroquine-resistant Plasmodium falciparum in West Africa has been well documented and represents a significant health threat to autochthonous populations. The methodical development of alternative chemotherapeutic agents demands that dispensing new antimalarial drugs (mefloquine, halofantrine, and artemisinine [qinghaosu]) be closely monitored in order to protect their clinical utility. Indeed, mefloquine-resistant strains of P. falciparum have been reported. We present data from experiments in vitro on the innate resistance of P. falciparum isolates to mefloquine as well as a disturbing observation of transient resistance to artemisinine. The implications for the extended efficacy of these new antimalarial drugs are addressed.