Two doses of artemether/mefloquine or artesunate/mefloquine combination for multidrug resistant falciparum Malaria.

Plasmodium falciparum in Southeast Asia is highly resistant to chloroquine, sulfadoxine/ pyrimethamine, quinine and even mefloquine. The use of two doses of short course artemether/mefloquine combination has been shown to be effective in a recent study. In the present study, we have assessed the efficacy of short course treatment with artesunate/mefloquine, in comparison with artemether/mefloquine in patients with multidrug resistant falciparum malaria. Ninety-nine Thai male patients who sought consultation at Makham Malaria Clinic, Chantaburi (eastern part of Thailand), were randomized to receive either the combination of artemether (150 and 100 mg; group A) or artesunate (150 and 100 mg; group B) with mefloquine (750 and 500 mg) at 24 hours apart. The follow-up was on days 1, 2, 7, 14, 21, 28, 35 and 42. Patients in both groups showed a rapid initial response to treatment; fever and parasite were cleared within 48 hours in 100 and 100% vs 91.8 and 96%, for group A vs B, respectively. All patients in group A had completed the 42 day-follow up; however, two patients in group B did not finish the 42-day follow-up. The cure rate was 100% in either group. No serious adverse effects were found. Artemether or artesunate with mefloquine given two doses at 24 hours apart can be used as effective alternative treatment regimens for multidrug resistant falciparum malaria.

Quinine-tetracycline for multidrug resistant falciparum malaria.

Plasmodium falciparum in Southeast Asia is highly resistant to chloroquine and sulfadoxine/ pyrimethamine. Quinine-tetracycline has been used as a second line treatment for uncomplicated falciparum malaria, but duration of treatment varies from place to place. The 7-days course of this combination has been shown to be very effective. However, due to the cinchonism adverse effects, the patient compliance has not been satisfactory. We have evaluated the efficacy of a 7-days course of tetracycline in combination with either 5 or 7-days course of quinine. Ninety male Thai patients who were admitted to the Bangkok Hospital for Tropical Diseases were randomized to receive tetracycline 250 mg qid for 7 days in combination with either quinine 600 mg tid for 5 days (Q5T7; group A) or quinine 600 mg tid for 7 days (Q7T7; group B). The patients were hospitalized for 28 days. Patients in both groups had a comparable initial response to treatment, with the clearance of fever and parasites within 4 days. There were 46 and 40 patients in group A and B, respectively, who completed the 28 day of follow-up. The cure rates were 87 and 100%, respectively for group A and B. No serious adverse effects were found in either group; transient nausea, vomiting and tinnitus were common findings. The incidence of adverse effects was not different between the two groups. The results from the present study suggest that a short course treatment of quinine (Q5T7) had significantly decreased the cure rate. In areas with quinine resistant falciparum malaria, a full course of 7-days quinine, in combination with 7-days course of tetracycline is recommended for hospital treatment. However, an alternative shorter course of antimalarials is suggested for home treatment.

Artemether 5 versus 7 day regimen for severe falciparum malaria.

Twenty-eight male Thai patients with severe falciparum malaria were randomized to receive either artemether for a 5 (300 mg initial dose followed by 100 mg for another 4 days) or a 7 days regimen (160 mg initial dose, followed by 80 mg daily for another 6 days). Thirteen patients received a 5 day regimen and 15 received 7 day regimen. The follow-up period was 28 days. The patients in both groups were comparable in age, body weight, admission parasitemia, hematocrit and white cell count. There were 4 patients in each group who presented with cerebral malaria. The median values of parasite and fever clearance times (PCT and FCT) in the 5 and 7 days regimens were 52 vs 60 hours, and 85 vs 68 hours, respectively. There were 8 and 4 patients, respectively who had recrudescence during days 15 to 25. The cure rates were 38% (95% CI = 14-68%) and 73% (95% CI - 50-96%), respectively for 5 and 7 day regimens. None died in either group. No patients in either group had neurological sequelae after recovery of consciousness. Clinically adverse effects in either group were transient pain at the site of injection. No drug related biochemical or ECG changes were noted in either group. The duration of treatment is the determinant of the cure rate; however, the duration of even 7 days still resulted in high recrudescence rate. It may be necessary to combine artemether with other longer half-life antimalarials to improve the cure rate.

Quinine toxicity when given with doxycycline and mefloquine.

The pharmacokinetic and dynamic interactions among 3 antimalarials, ie quinine, doxycycline and mefloquine was observed in a 26-year-old Thai male patient with falciparum malaria. During the acute episode of the infection, the patient was treated with an intravenous dose of quinine hydrochloride at 600 mg qid, together with an oral dose of doxycycline 100 mg bid. Due to nausea, tinnitus and the persistence of parasitemia in peripheral blood smears, the dose of quinine was reduced 2 days after the first treatment to 300 mg; concurrently oral mefloquine 750 mg was given as 2 divided doses at 24 hours apart. During the course of treatment, the patient developed hearing loss; deafness of the right ear lasted for one week after stopping quinine administration. Higher plasma quinine and lower whole blood mefloquine concentrations than would be expected from the simulation profiles were detected 4 days after the first treatment. However, the concentration of mefloquine was increased upon the cessation of quinine treatment.

Mefloquine level monitoring in patients with multidrug resistant Plasmodium falciparum on the Thai Myanmar border.

A total of 42 patients with uncomplicated falciparum malaria who attended the malaria clinic in Mae Sot, Tak Province were treated with single oral dose of MSP 3 tablets (Fansimef, equivalent to 750 mg of mefloquine) concurrently with primaquine (30 mg). They all contracted the infection from Cambodia. The aim of the study was to monitor the efficacy of MSP 3 tablets for the treatment of this highly multiple drug resistant strains of Plasmodium falciparum in this area. Of the 39 patients included for efficacy assessment, 13 (33.3%) patients had sensitive responses, whereas 15 (38.5%) and 8 (20.5%) had RI and RII types of response, respectively. Melfoquine concentrations on Day-3 after treatment in patients with sensitive and treatment failure groups were comparable; the respective mean (SD) values were 665 (279) and 772 (264) ng/ml.

Mefloquine monitoring in acute uncomplicated malaria treated with Fansimef and Lariam.

Mefloquine levels were compared between Plasmodium falciparum malaria patients with sensitive response and those with treatment failure who received 3 drug regimens of mefloquine (46 patients with MSP 3 tablets (Fansimef), 38 and 34 with mefloquine (Lariam) 750 mg and 1,250 mg). Mefloquine concentrations on Day-1 in any regimens in patients with treatment failure were significantly lower than those from the sensitive response, whereas there was no difference in the concentrations on Day-7. However, MIC values of mefloquine prior to drug treatment were comparable in both groups. The study suggests that pre-treatment in vitro sensitivity testing was a non-reliable indicator of clinical outcome. Mefloquine concentration on the first day after treatment is a better predictor of the treatment outcome.

Mefloquine levels in patients with mefloquine resistant Plasmodium falciparum in the eastern part of Thailand.

A total of 99 patients with uncomplicated falciparum malaria who attended the malaria clinic in Bo Rai, Trat Province were treated with a single oral dose of MSP 3 tablets (Fansimef; equivalent to 750 mg of mefloquine) concurrently with primaquine (30 mg). The aim of the study was to detect RII and RIII types of response with 3 tablets of MSP. Seven (8.1%) and 22 patients (25.3%) had RII and RIII types of response, respectively, and 58 (66.8%) had no parasitemia on Day-7 (S or RI response). Mefloquine concentrations on Day-3 after treatment in patients in the S/RI group were significantly higher than those with early treatment failure (RII, RIII), with the respective mean (SD) values of 1,959 (696) and 1,622 (863) ng/ml. The mean concentrations of mefloquine in these patients with RII and RIII types of response were higher than those with a sensitive response in a previous study. The result suggests that Plasmodium falciparum strains in this part of the country are highly resistant to mefloquine and that blood levels of mefloquine on Day-3 may also be a good indicator of treatment outcome in this particular area.

Intramuscular artemether in female patients with uncomplicated falciparum malaria.

Thirty-three female patients suffering from acute uncomplicated falciparum malaria were treated with intramuscular artemether for 5 days during May-October 1990. Fourteen patients received 160 mg as an initial dose, followed by 80 mg daily for 4 days. Nineteen patients with low body weight (mean weight of 36.5 kg) were given artemether at 3.2/kg as a loading dose and followed by 1.6 mg/kg/dose for another 4 days. The geometric mean of parasitemia was 17,378/microliters (range 640-234,720). The mean fever (FCT) and parasite clearance time (PCT) were 41.8 and 49.4 hours, respectively. Two patients had probable intercurrent infection with FCT of over 7 days. Thirty-one patients had completed the 28-day follow-up. The cure rate was 90.3% (28/31). Three patients had RI type of response. Mild and transient adverse effects were experienced in eleven patients; these consisted of pain at the injection sites, vomiting, dizziness, abdominal pain, palpitation and diarrhea. These symptoms may in part be due to symptom complex of malaria. The MIC of chloroquine, quinine, quinidine and mefloquine was performed in all patients but only 25 isolates were successfully cultured and tested. The MIC of all tested drugs were shown to be higher than that of previous studies, suggesting that there is a rapid increase of mefloquine resistant strains of falciparum malaria. In conclusion, artemether proves to be effective against multiple drug resistant falciparum malaria (including mefloquine resistant strains) and can be considered as an alternative antimalarial to mefloquine. The drug was well tolerated in female patients with mild and transient side-effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical trials with halofantrine in acute uncomplicated falciparum malaria in Thailand.

The antimalarial efficacy of halofantrine was compared with mefloquine in an open-label, randomized comparative trial in adult male patients with acute uncomplicated falciparum malaria. Twenty-eight patients received halofantrine and 27 received mefloquine. Halofantrine was administered in 3 doses of 500 mg at 6 hour intervals and mefloquine was administered in divided doses of 1,250 mg or 1,500 mg depending on whether the patients weighed less than or more than 60 kg. The patients were followed for 42 days and observed for drug tolerance and evidence of recrudescence. Response to treatment was favorable with both drugs, but three patients (two treated with halofantrine and one with mefloquine) did not completely eliminate malaria parasites from peripheral blood films in seven days. The parasite and fever clearance times were 75.6 and 55.7 hours, and 80.1 and 61.3 hours, respectively for halofantrine and mefloquine. However, 12 patients recrudesced during the 42 day follow-up period. Nine of these had been treated with halofantrine and three with mefloquine. The 42-day cure rate for the two drugs was 56% and 84%, respectively. The side-effects of halofantrine and mefloquine were comparable and transient. These are diarrhea, dizziness, orthostatic hypotension and black out. However, vomiting was found to be more common in mefloquine group (41% vs 22%).

Fansimef for prophylaxis of malaria: a double-blind randomized placebo controlled trial.

At a time when Fansimef, the fixed combination of mefloquine, sulfadoxine and pyrimethamine was considered for prophylaxis of falciparum malaria, a randomized double-blind study comparing the efficacy and tolerability of Fansimef with that of Lariam (mefloquine), Fansidar, chloroquine and placebo in malaria prophylaxis was performed in Thailand from July 1987 to January 1988. The study population of 602 adult males was recruited in Pak Tongchai District, some 360 km North-East of Bangkok, where multiresistant P. falciparum is endemic. All active treatments and placebo were given once weekly for 24 weeks with doses as follows: Fansimef: 125 mg mefloquine + 250 mg sulfadoxine + 12.5 mg pyrimethamine (1 half-strength tablet); Lariam: 125 mg mefloquine (1 half-strength tablet); Fansidar: 500 mg sulfadoxine + 25 mg pyrimethamine; chloroquine; 300 mg. A loading dose of 2 half-strength tablets was given in the Fansimef group in weeks 1 and 2 and in the Lariam group in weeks 1 to 4. The incidence of acute episodes of P. falciparum per 100 person months of prophylaxis was 0.17 each in the Fansimef and the Lariam groups, 1.18 in the Fansidar group, 0.69 in the chloroquine group and 0.64 in the placebo group (differences statistically not significant). Clinically adverse events were reported by 170 subjects (Fansimef 28, Lariam 29, Fansidar 41, choroquine 43, placebo 29; differences statistically not significant). The most frequent adverse events in all groups were headache, sleepiness, dizziness and weakness.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug resistant malaria, with special reference to Thailand.

Drug resistance of malaria parasites is a major problem confronting efforts to treat and control malaria. Starting with chloroquine, the emergence of resistance to other drugs has led to multi-drug resistance patterns that pose increasing threats for the future. This report reviews work carried out over the past decades at the Hospital for Tropical Diseases, Bangkok, which monitors patients from many areas, including the Thai-Cambodian border, which harbors the world's most severe multi-drug resistant Plasmodium falciparum.

Pharmacokinetics of quinine, quinidine and Cinchonine when given as combination.

Pharmacokinetics of quinine, quinidine and cinchonine when given as a combination were evaluated in Thai patients with falciparum malaria during acute infection and convalescence. The combination of quinine, quinidine and cinchonine was randomly given to thirteen patients at 400 mg or 600 mg (consisting of one-third of each component; 7 patients were enrolled in 400 mg regimen and 6 in 600 mg regimen) intravenously every 8 hours for 7 days. The drug combination was given again at day 35 to define the pharmacokinetics of each drug during convalescence. All patients with the 600 mg regimen had good response with 100% cure rate while patients with the 400 mg regimen had a good initial response but one patient recrudesed on day 46. This particular patient had plasma concentrations of all three drugs lower than the mean values of patients with sensitive responses. The plasma levels of quinine and quinidine obtained from the present study were higher than that expected from one-third of the conventional dose (600 mg) when given alone, suggesting drug combination interaction. The terminal half-lives of each of the three components were prolonged during acute malaria when compared to those obtained during convalescence.

Preliminary report: a comparative clinical trial of artemether and quinine in severe falciparum malaria.

Twenty-six patients with severe falciparum malaria were randomized to be treated with quinine or artemether. Twelve patients received quinine at the standard dose and fourteen patients received artemether intramuscularly at a total dose of 640 mg over 7 days. The patients were kept in the hospital for at least 7 days. Peripheral smear was performed 6-hourly until there was no parasitemia, then daily until discharged. Adverse effects were monitored through physical examination, laboratory findings and questionnaires. Laboratory examination was performed on admission, day 2, day 4 weekly until discharged. The patients in both groups were comparable in age, body weight, admission parasitemia, hemoglobin and white blood cell count. The survival rates were 93% and 58% in artemether and quinine groups, respectively (p = 0.052 at 95% confidence, using Fisher's exact test). The parasite and fever clearance times, and the time taken to gain consciousness in cerebral malaria patients were not significantly different between the two groups. Adverse effects in the quinine group consisted of dizziness and vertigo which were found in 4 patients. No adverse effects were noticed in the artemether group. This preliminary report suggests that artemether is a good alternative drug for severe falciparum malaria and seems to be better than quinine regarding survival rate and side effects. Confirmation of these findings in a larger study size is needed.

Artemether in the treatment of multiple drug resistant falciparum malaria.

Artemether has the potential to be an alternative antimalarial for multiple drug resistant falciparum malaria. However, it has been associated with high recrudescent rates which may be due to incorrect dosage regimens. The dosage regimens are varied from country to contry. We have carried out a comparative study of two dosage regimens, ie 480 mg and 600 mg total dose given over 5 days in uncomplicated and severe falciparum malaria. 167 patients were included in the study, 61 with acute uncomplicated falciparum malaria and 106 with severe malaria. All patients showed a good initial response. The difference in total dose had no effect on the parasite or fever clearance time (PCT or FCT). However, the severity of the disease did have some influence of these times. The PCT and FCT from either regimen of uncomplicated malaria were significantly faster than those of severe malaria (p < 0.005 and = 0.05, respectively). The cure rate seems to have some correlation with the amount of drug given and severity of the disease. The cure rates in uncomplicated malaria were 84 and 92%, respectively, for 480 mg and 600 mg. In severe malaria the cure rates dropped to 65 and 76%, respectively, for 480 and 600 mg. We conclude that artemether can be considered as an alternative antimalarial for multiple drug resistant falciparum malaria. However, the cure rate of severe falciparum malaria in this study is not considered satisfactory in areas with multiple drug resistant falciparum malaria. Further studies are needed to assess the curative efficacy with different dosage regimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Overview: clinical pharmacology of antimalarials.

The effectiveness of antimalarials depends on its pharmacodynamics ie inhibitory effect on the parasites and unwanted effects on the host. It also depends on the pharmacokinetics of the drugs. The ideal antimalarials are drugs that show curative activity in the absence of toxicity to the host. Recommendation for antimalarial dosage regimens should be based on pharmacokinetic and pharmacodynamic studies in appropriate populations ie ethnic groups, adults children, and in pregnancy. Chloroquine remains the drug of choice for treating malaria caused by Plasmodium species other than P. falciparum. Even in the presence of chloroquine resistance the drug may still be quite useful, especially in areas with high communal immunity. In general sulfadoxine/pyrimethamine (S/P) should be used as an alternative antimalarial when chloroquine fails. The decision to change to S/P from chloroquine depends on many factors. Quinine still remains the drug of choice for severe chloroquine-resistant falciparum malaria. Resistance to mefloquine has appeared the exact mechanism being unknown. In general, before the use of any combination of antimalarial drugs the superiority (efficacy and side-effects) over each of the individual drugs should be clearly demonstrated. The combination of mefloquine with sulfadoxine/pyrimethamine was made on the grounds that the combination would delay the resistance to mefloquine. Desferrioxamine will hardly be an agent to be used on its own for treating malaria due to the high recrudescent rate. However, a recent report indicated that its association with antimalarial drugs in the management of severe and complicated falciparum malaria shortens fever and parasite clearance time and resolves complications faster than the standard antimalarial drug alone. Clinical trials with halofantrine has been done in several countries in the region from 1988 to the present with diverse results. Further studies on a larger scale should be carried out to ascertain whether these are due to variation in drug absorption or drug resistance. An improved formulation of halofantrine must be developed to ensure adequate absorption and bioavailability. The artermisinin group of antimalarials is known to be highly effective and independent, in its mode of action, from standard malaria drugs but associated with high recrudescent rate. Phase II studies are needed for determining/optimizing therapeutic dose regimens and to ensure safer and more effective use of these compounds.

Clinical trials of mefloquine with tetracycline.

A comparative trial of the combination of mefloquine or MSP with tetracycline was carried out in fifty-one adult Thai male patients with acute falciparum malaria. The patients were randomized to receive either the combination of tetracycline (250 mg qid for 7 days) with mefloquine 4 tablets (1,000 mg) or with MSP 4 tablets (one tablet contains 250 mg mefloquine, 500 mg sulfadoxine and 25 mg pyrimethamine). Fifty patients had a complete 28-day follow-up period. Both regimens produced similar efficacy with no difference in adverse effects. In the mefloquine plus tetracycline group, the cure rate was 72% (18/25). One patient had an RIII response, the others showed initial response to the treatment with FCT and PCT of 40.7 +/- 27.4 and 76.2 +/- 34.2 hours (mean +/- SD) respectively. However, 6 patients developed recrudescence between days 17 and 29 (RI), 3 of these had vomiting. In the MSP plus tetracycline group, the cure rate was 76% (19/25). The means (+/- SD) of FCT and PCT were 44.7 +/- 38.0 and 80.6 +/- 25.0 hours, respectively. Six patients had recrudescence between days 17 and 31 (RI), 2 of these had vomiting. Although the addition of tetracycline improved the cure rate of mefloquine when compared with standard dose of mefloquine alone (3 tablets), these combinations seem to be useful in areas where alternative drugs are not available.

Effect of mefloquine on electrocardiographic changes in uncomplicated falciparum malaria patients.

Asymptomatic sinus bradycardia and sinus arrhythmia have been noted in malarial patients receiving mefloquine. The present study was designed to assess the effect of mefloquine on electrocardiogram in malarial patients. The study was carried out in 102 acute uncomplicated falciparum malarial patients who were treated with mefloquine 750 mg and 1,250 mg regimens and 18 healthy male volunteers receiving 750 mg of mefloquine. Electrocardiogram was performed at intervals after mefloquine administration for a period of 42 days. PR, QRS, QT, QTc, RR interval and cardiac arrhythmia were measured and read by EKG-analyser with confirmation by a cardiologist. Sinus bradycardia and sinus arrhythmia were found in 61.8% and 45.1%, respectively during the first week after treatment. The patients' heart rate decreased significantly on day 6 after mefloquine administration when compared to day 0. The occurrence of sinus bradycardia and sinus arrhythmia were significantly higher in malarial patients when compared with findings in healthy subjects of the same age group. It is unlikely that these changes are associated with mefloquine concentration as mefloquine peaks around 12-24 hours after administration. There were no significant changes in PR-interval, QRS-interval and QTc interval on the electrocardiogram. The findings in this study suggest that cardiotoxicity from mefloquine is unlikely. Bradycardia may be the result of autonomic control modulation after resolution of high fever.

Double blind randomised clinical trial of oral artesunate at once or twice daily dose in falciparum malaria.

A double blind randomised comparative trial of the efficacy of daily dose (200 mg as an initial dose followed by 100 mg daily for another 4 days) and twice daily dose (100 mg 12 hourly for 2 doses on the first day, followed by 50 mg 12 hourly for another 8 doses) regimens of oral artesunate at 600 mg was studied in 59 Thai patients with uncomplicated falciparum malaria. Fifty patients had a complete 28-day follow-up period. Both regimens produced similar efficacy with no difference in adverse effects. The patients with the daily artesunate regimen had mean fever and parasite clearance times of 20 and 40 hours, respectively. The cure rate was 72%. Eight patients had recrudescence during days 15 to 28 while 8 showed P. vivax in their peripheral blood between days 12 and 21. The patients with the twice daily regimen had mean fever and parasite clearance time of 28 and 40 hours, respectively. The cure rate was 76%. Six patients had recrudescence during days 15 and 27 while 7 showed P. vivax during days 12 and 23. We suggest that the duration of the treatment may be a more important factor determining the efficacy of artesunate rather than the frequency of the doses. Further studies based on pharmacokinetics are therefore needed to improve the cure rate to 100% to prevent the spread of P. falciparum, particularly in areas where there are high numbers of multi-drug resistant strains.