Efficacy and safety of an artesunate/mefloquine combination, (artequin) in the treatment of uncomplicated P. falciparum malaria in Kenya.

BACKGROUND: Although artesunate and mefloquine have been used as monotherapies in the treatment of malaria in Kenya for a long time, there is insufficient data on the clinical outcome when used as combination therapy in this population. OBJECTIVE: To derive data on the efficacy and safety profile of artesunate-mefloquine combination in the treatment of uncomplicated Plasmodium falciparum malaria in Kenya. DESIGN: An open label single arm clinical trial. SETTING: Bungoma district Hospital. Study area was Bungoma District of Kenya, an endemic area of malaria. The study was conducted between January 2004 and April 2004. SUBJECTS: A total of 200 males and females with uncomplicated plasmodium falciparum malaria weighing 35kg and above were recruited in the study. RESULTS: In the evaluable patient population the day 28 cure rate was 98.4% while day 14 and 7 cure rates were 98.4% and 99.2% respectively. There was rapid relief of symptoms the median time of fever clearance was one day and the most common drug related adverse events were headache dizziness and asthenia. There was no significant derangement in the haematological, biochemical and ECG parameters in the patients on treatment. CONCLUSION: Artesunate-mefloquine combination given simultaneously was found to be highly effective and safe in the treatment of uncomplicated malaria.

A diagnostic ELISA for visceral leishmaniasis, based on antigen from media conditioned by Leishmania donovani promastigotes.

Leishmania donovani promastigotes were cultured in a protein-free medium for 3-5 days and the spent medium used to prepare antibody-detection ELISA plates. When the plates were used to test 29 Kenyan and 16 Nepalese patients with visceral leishmaniasis (VL; kala-azar), all the sera collected at diagnosis were found to have high levels of parasite-specific IgG. The levels of these antibodies dropped 6-12 months post-initiation of antileishmanial therapy in all but one of the patients. Although the levels in sera from 59% of the treated patients fell to those measured in sera from healthy controls, those in sera from 17% of the patients did not drop below those seen at diagnosis. The antigen used did not cross-react with sera from patients with parasitological diagnosis of malaria, filariasis, African trypanosomiasis or echinococcosis. Antibodies to antigens in the spent medium were detected, by western blot, in all the sera from Nepalese patients with VL. Promastigote-conditioned media could be the source of cheap antigen for the immunodiagnosis of leishmaniasis.

Efficacy and safety of liposomal amphotericin B (AmBisome) for visceral leishmaniasis in endemic developing countries.

Reported are the results of a study to determine the efficacy and safety of liposomal amphotericin B (AmBisome) for treating visceral leishmaniasis (kala-azar) in several developing countries where the disease is endemic (Brazil, India, and Kenya). At each study site, sequential cohorts of 10 patients each were treated with AmBisome at a dose of 2 mg.kg-1.day-1 (2 MKD). The first cohort received regimen 1:2 MKD on days 1-6 and day 10 (total dose: 14 mg/kg). If the efficacy with this regimen was satisfactory, a second cohort received regimen 2:2 MKD on days 1-4 and 10 (total dose: 10 mg/kg); and a third cohort received regimen 3:2 MKD on days 1, 5, and 10 (total dose: 6 mg/kg). In India, regimens 1, 2, and 3 (which were studied concurrently) each cured 100% of 10 patients. In Kenya, regimen 1 cured all 10 patients, regimen 2 cured 90% of 10 patients, but regimen 3 cured only 20% of 5 patients. In Brazil, regimen 1 was only partially curative: 5 of 13 patients (62%). Therefore, 15 patients were administered regimen 4 (2 MKD for 10 consecutive days; total dose, 20 mg/kg) and 13 patients were cured (83%). These results suggest that for the treatment of kala-azar the following doses of AmBisome should be administered: in India and Kenya, 2 mg/kg on days 1-4 and day 10; and in Brazil, 2 mg/kg on days 1-10.

PIP: The efficacy and safety of liposomal amphotericin B (AmBisome) for the treatment of visceral leishmaniasis (kala-azar) were evaluated in a phase II clinical trial conducted in Brazil, India, and Kenya--countries where kala-azar is endemic. At each study site, sequential cohorts of 10 patients each received three different dosage regimens of AmBisome. The first cohort received 2 mg/kg/day (MKD) on days 1-6 and day 10 (total dose, 14 mg/kg). If the efficacy of this regimen was satisfactory, the second cohort received 2 MKD on days 1-4 and day 10 (total dose, 10 mg/kg) and a third cohort was administered 2 MKD on days 1, 5, and 10 (total dose, 6 mg/kg). In India, all three regimens (studied concurrently) cured 100% of the total of 30 patients. In Kenya, the first regimen cured all 10 patients (100%), the second cured 9 of 10 patients (90%), and the third cured only 1 of 5 patients (20%). In Brazil, since the first regimen cured only 5 of 13 patients (62%), the next 15 patients were given 2 MKD for 10 consecutive days (total dose, 20 mg/kg); this intensified regimen cured 13 of the 15 patients (83%). Adverse effects were minor, primarily fever and chills associated with infusion and irregular pulse. These findings suggest that leishmaniasis patients in India and Kenya should receive 2 mg/kg of AmBisome on days 1-4 and day 10, while those in Brazil should be given 2 mg/kg on days 1-10. AmBisome treatment is especially recommended for those for whom standard agents are likely to be ineffective, toxic, or difficult to administer.

Acute phase protein concentrations predict parasite clearance rate during therapy for visceral leishmaniasis.

Visceral leishmaniasis (VL) remains a major health problem in Kenya and other parts of Africa, Central America and Asia. Currently, splenic aspirate smear and culture are the standard methods of monitoring therapy and relapse. Acute phase reactant markers, C-reactive protein (CRP), serum amyloid A protein (SAA) and alpha 1-acid glycoprotein (AGP) were evaluated as less invasive techniques for monitoring therapy in 59 patients with VL before, during and after therapy. CRP, SAA and AGP were elevated in VL patients at admission and the concentrations decreased with effective therapy to reach normal levels by the end of therapy (SAA and AGP) or by 3 months follow-up (CRP). Two groups of patients were selected on the basis of rate of parasite clearance. The acute phase protein concentrations were significantly raised in those slower to clear parasites. Analysis of sensitivity and specificity of acute phase proteins as predictors of parasite clearance suggested that they might represent useful non-invasive markers for monitoring disease activity, response to therapy and relapse in VL.

Problems in the treatment of kala-azar: case report.

Frequent relapses after treatment for visceral leishmaniasis and apparent parasitological cure is not commonly reported. Seven year old boy who relapsed four times with clinical and parasitological evidence of the disease at each two months follow-up period is presented. He had Leishimania donovani Kenya strain. After treatment, review would be after two months, six months and twelve months periods. Splenic aspirates were routinely done weekly and on the last day of each treatment. The drugs administered for varying periods included intravenous sodium stibogluconate 20 mg/kg daily, P20 in combination with allopurinol 21 mg/kg three times daily, and Pentamidine 4 mg/kg three times weekly and antituberculous drugs. The presence of abundant extra cellular leishmania donovani bodies in the bone marrow and possible pulmonary tuberculosis might have precipitated the frequent relapses. It is not clear which of the drugs effected the cure. It was observed that inspite of prolonged antileishmanial drug administration no side effects were noted.

Phase 2 efficacy trial of an oral 8-aminoquinoline (WR6026) for treatment of visceral leishmaniasis.

The efficacy of an oral 8-aminoquinoline (8-[[6-(diethylamino)hexyl]amino]-6-methoxy-4-methylquinoline) (WR6026) in the treatment of 16 patients with kala azar was evaluated. The first 8 patients received therapy for 2 weeks at a dosage of 0.75-1.00 mg/(kg.d); 1 patient was cured, and in regard to the other 7, a 1-logarithm decrease in the number of splenic parasites and clinical improvement were noted. The next 8 patients received therapy for 4 weeks at the same daily dosage (1 mg/[kg.d]); 4 were cured, and for the other 4, 1- to 2-log decreases in the number of parasites and clinical improvement (in regard to weight, liver and spleen size, hemoglobin level, and leukocyte count) were noted. The therapy was associated with minimal toxicity; adverse effects included gastrointestinal distress, headache, and methemoglobinemia. The fact that one-half of the patients were cured indicates that future trials with longer regimens and higher dosages are warranted and should include patients for whom existing treatment methods have failed.

Relationship between direct agglutination test and splenic aspirate smear parasite load in visceral leishmaniasis at Baringo District, Kenya.

Direct agglutination test was carried out in Baringo District on 100 persons presenting with signs and symptoms suggestive of visceral leishmaniasis. Splenic aspirate smears and cultures were done on these 100 persons in order to parasitologically confirm the findings of the direct agglutination test. It was found that the direct agglutination test positively detected all 79 (79%) patients parasitologically confirmed to have visceral leishmaniasis. Irrespective of the splenic aspirate smear parasite rate, whether 1+ or 6+ on a logarithmic scale, direct agglutination test was positive. There were 21% false positives, two of whom had Schistosoma mansoni in their stools. It was not immediately known about the cause of the other false positives. It was concluded that the direct agglutination test is a good provisional serodiagnostic test for visceral leishmaniasis and should be considered for wider field application.

Is one year follow-up justified in kala-azar post-treatment?

Sixty-five patients, 51 males and 14 females, with clinical and parasitological evidence of visceral leishmaniasis were initially treated as follows: 44.6% were on intravenous sodium stibogluconate (pentostam) 20 mg/kg/d for 30 days, 35.4% was on a combination of pentostam as above and allopurinol 21 mg/kg/d in three divided doses for 30 days while 20% was on pentostam 10 mg/kg thrice/d intravenously for 10 days. All patients were parasitologically negative by the end of their respective treatment regimen. All patients were reviewed at 2 months, 6 months, and 12 months periods in order to evaluate the relapse rates and optimal follow-up period. Thirteen patients (20%) relapsed at 2 months and one patient (1.5%) relapsed at 6 months follow-up periods respectively. There was no relapse between 6 months and 12 months follow-up period. The mean liver and spleen sizes in responders showed a dramatic reduction at 2 months follow-up and thereafter a gradual reduction occurred in the next 10 months. Weight gain continued throughout the year. Apart from platelet count which showed a sustained high level from discharge to 12 months follow-up, the peripheral blood indices stabilized from 2 months follow-up. Relapses were retreated until parasitologically negative twice and then followed up, for a period of 12 months. At follow-up the liver and spleen sizes reduced gradually in the next 12 months.(ABSTRACT TRUNCATED AT 250 WORDS)

The efficacy and safety of ketoconazole in visceral leishmaniasis.

This study was an open evaluation of the efficacy and safety of Ketoconazole, 15 mg/kg/day orally for 3 weeks in 7 evaluable patients with Visceral Leishmaniasis in Kenya. Of all the seven patients who received ketoconazole, none had appreciable clearance of parasites from the splenic aspirate smears that were microscopically examined. All the splenic aspirate cultures done on these patients in the three weeks remained positive for leishmania parasites. Splenic sizes of these patients generally remained unchanged throughout the study period. The mean haemoglobin at the start of treatment was not different from that at the end of treatment. Liver function tests throughout treatment remained unchanged, i.e. within normal limits. It is concluded that Ketoconazole, 15 mg/kg/day orally given to these patients was not effective as an antileishmania drug although there was a one log drop in the parasite load. However, no serious side effect were noted in all of the patients during treatment.

Immunoglobulin G subclass responses to mycobacterial lipoarabinomannan in HIV-infected and non-infected patients with tuberculosis.

Immunoglobulin G subclass responses to lipoarabinomannan (LAM) of Mycobacterium tuberculosis were determined by ELISA in both HIV-1 antibody positive (n = 31) and negative (n = 43) patients with tuberculosis (TB). Responses were also studied in a group of healthy controls (n = 16) and HIV-1 antibody positive (n = 60) individuals without TB. IgG2 antibodies were the predominant subclass, being present in 25 of 43 non-HIV-infected TB patients (58%) and in 11 of 31 HIV-infected TB patients (35%). However, HIV+ TB patients also showed IgG4 (n = 16; 52%), and IgG1 (n = 4, 13%) responses to LAM, whereas these subclasses were absent in sera from HIV-TB patients. Individuals in both non-tuberculous control groups showed no antibody responses to LAM. The influence of HIV infection on B cell responses to LAM, and possible mechanisms for antibody-mediated regulation of immunity to TB, are explored.