Pharmacokinetics of the four combination regimens of dihydroartemisinin/mefloquine in acute uncomplicated falciparum malaria.

The pharmacokinetics of oral dihydroartemisinin and mefloquine were investigated in 40 patients (aged 16-30 y, weighing 45-60 kg) with acute uncomplicated falciparum malaria following the four combination regimens of dihydroartemisinin/ mefloquine [regimen-I: 300 mg dihydroartemisinin (h-0) plus 750 mg mefloquine (h-0); regimen-II: 300 mg dihydroartemisinin (h-0) plus 750 mg mefloquine (h-24); regimen-III: 300 mg dihydroartemisinin (h-0) plus 750 and 500 mg mefloquine (h-24 and 30); regimen-IV: 300 mg dihydroartemisinin (h-0) plus 750 and 500 mg mefloquine (h-0, 24)]. The four combination regimens were well tolerated. Patients in all treatment groups had a rapid initial response. However, 9 patients (4, 4, and 1 cases in regimens-I, II, and IV) had reappearance of parasitemia during the follow-up period. Significant changes in the pharmacokinetic parameters of both mefloquine and dihydroartemisinin were observed in patients with malaria compared with healthy subjects reported in a paralleled study. For mefloquine, Cmax (mg per dose), AUC0-day1 (mg per dose), and AUC0-day7 (mg per dose) were significantly higher in patients. Furthermore, tmax, was prolonged while V/F contracted and tl/2,z, MRT shortened in patients with malaria. For dihydroartemisinin, Cmax AUC, tmax and Vz/F were changed in the same direction as mefloquine, whereas t1/2z and MRT were prolonged. CL/F was also significantly reduced in patients with malaria. Absorption/disposition kinetics of oral dihydroartemisinin were similar among the various regimens. On the other hand, AUC0-day1 (mg per dose) of mefloquine after regimen-III was significantly higher than the other three regimens. Combination regimens with two divided doses of mefloquine (regimens-III and IV) resulted in a significantly delayed tmax (especially regimens-IV) compared with those with single dose regimens (regimens-I and II).

Successful eradication of Ascaris lumbricoides and hookworm infection after three repeated doses of albendazole.

Three repeated orally doses of albendazole 400 mg in 6 weekly intervals were evaluated in Thai hill-tribe students who had at least one kind of soil-transmitted helminths (i.e. Ascaris lumbricoides, hookworm and Trichuris trichiura). Stool examination and parasite egg count were performed using Beaver's standard direct smear method and Kato-Katz's cellophane thick smear method prior to treatment and then 1 month after the first, second and third dose of drug administrations. A single dose of albendazole was very effective against A. lumbricoides and hookworm infections, with cure rates of 98.68 per cent and 92.16 per cent, respectively. The second and third dosages eradicated A. lumbricoides and hookworm infections, respectively. Conversely, the first to third cure rates for T. trichiura infection were relatively low, being 37.76-58.16 per cent. Three repeated doses of albendazole proved to be beneficial in eradication of A. lumbricoides and hookworm infections, and decreased the prevalence of T. trichiura infected cases. For eradication of T. trichiura infection, further regimen and period of drug administration is required.

Ex vivo blood schizontocidal activities of artemisinin derivatives against Plasmodium falciparum.

Serum samples collected at intervals from eight healthy volunteers after the administration of the six regimens of artemisinin derivatives were investigated for their ex vivo blood schizontocidal activities against K1 strain Plasmodium falciparum. The regimens included single doses of (a) 300 mg oral artemether; (b) 300 mg intramuscular artemether; (c) 100 mg suppository artemether; (d) 300 mg oral artesunate (Guillin formulation); (e) 300 mg oral artesunate (Arenco formulation); (f) 300 mg oral dihydroartemisinin. Sera collected after various regimens of artemisinin derivatives showed distinct degree of ex vivo blood schizontocidal activities. Activity of sera after suppository dosing was remarkably low and variable comparing to the other two formulations (oral, intramuscular). Median values for Amax (the maximum activity normalized with dose) of sera from oral dosing were 2.4- and 118-fold, while AUA (the area under activity-time curve, normalized with dose) were 0.82- and 2,370-fold of that after the intramuscular and suppository dosing, respectively. Sera from artesunate-Arenco dosing exhibited significantly higher Amax and AUA (medians: Amax 12.4 vs 5.13 nmol/l/mg dose; AUA: 21.9 vs 8.8 nmol x h/ml/mg dose), compared to that from artesunate-Guillin dosing. Among the oral formulations of artemisinin derivatives investigated (artemether, artesunate, dihydroartemisinin), sera collected following a single dose of oral dihydroartemisinin exhibited lowest bioactivity (Amax 2.35 nmol/l/mg dose; AUA: 44 nmol x h/ml/mg dose).

Investigations of incidence of pretreatment, drug sensitivity in vitro, and plasma levels of pyrimethamine in patients with multidrug resistant falciparum malaria following the three combination regimens of artemether/pyrimethamine.

The study was carried out to investigate the status of in vitro susceptibility of Plasmodium falciparum to pyrimethamine (PYR) in multidrug resistant area of the Thai-Myanmar border, the incidence of unregulated use of the combination of PYR with sulfadoxine (Fansidar) in this area and the relevance of pharmacodynamic and pharmacokinetic factors in determining the treatment outcome from the three combination regimens of ART/PYR (1-, 2- and 3-day regimens), in patients with acute uncomplicated falciparum malaria. The majority of patients had baseline PYR concentrations in the range of 1-100 (50.6%) or 100-500 (34.8%) ng/ml, while concentrations of more than 500 ng/ml were found in only 1.1%. All of the isolates exhibited high grade resistance to PYR with the minimum inhibition concentration (MIC) of as high as 10(-5) M. No association was observed between treatment outcome and the presence of baseline plasma PYR concentrations. In addition, lack of association between plasma concentrations during the acute phase (day-1 and -2) and treatment outcome was found.

Pharmacokinetics of a single oral dose of dihydroartemisinin in Vietnamese healthy volunteers.

Pharmacokinetics of a 240 mg single dose of oral dihydroartemisinin (DHA) was investigated in 8 healthy (5 males, 3 females) Vietnamese volunteers. Plasma concentrations were measured by high-performance liquid chromatography with electrochemical detection in the reductive mode. The concentration time profile of DHA was fitted with one-compartment model with a lag time. Pharmacokinetics of DHA is comparable between males and females even when adjusted with dosage. The median (range) values of pooled pharmacokinetics of oral DHA were: t(lag) 0.41 (0.09-0.78) hours, t(1/2z) 0.58 (0.17-1.43) hours, t(max) 1.6 (1.1-2.2) hours, Cmax 466 (128-787) ng/ml. Cmax/dosage 97.7 (27.2-124.6) ng/ml, t(1/2z) 2.0 (1.5-3.4) hours, AUC 1867 (420-3535) ng x h/ml, AUC/dosage 364.3 (89.3-559.7) ng x h/ml/dosage, Cl/f 45.8 (30.0-190.0) ml/min/kg, Vz/f 8.0 (5.5-29.9) l/kg. Interindividual variation was large, the coefficients of variation (CV) were 47.8% and 45.3% respectively to AUC and Cmax. The t(max) of DHA formulation was comparable with that of DHA metabolite of artemisinin derivatives. The t(1/2z) was longer and shorter than that of DHA metabolites of oral formulations of artesunate and artemether, respectively. For monotherapeutic regimen(s) of DHA, dosing frequency of at least twice a day is suggested. Combined regimen(s) of DHA with other potent, long half-life antimalarials may also be an alternative approach.

Plasma containing artemether-pyrimethamine has ex vivo blood schizonticidal activity against Plasmodium falciparum.

Plasma samples collected at intervals from healthy volunteers, after administration of 3 drug regimens [artemether (ART) 300 mg, pyrimethamine (PYR) 100 mg, and ART 300 mg plus PYR 100 mg] were examined for blood schizonticidal activity against K1 strain and T(9/94) clone of Plasmodium falciparum ex vivo. A synergistic effect against T(9/94), a pyrimethamine sensitive clone, was observed in plasma collected after ART+PYR administration, when the test was carried out in low p-aminobenzoic acid, low folic acid medium. The maximum activity (Amax), expressed as equivalent dihydroartemisinin concentration, for plasma samples collected after the combined ART+PYR regimen [6,935 (1,330-13,400) nmol/l] was significantly higher than those for the single ART or PYR regimens [935 (397-2,000) and 9.9 (5.6-15.6) nmol/l, respectively]. In addition, the area under the activity curve (AUA) for the combined regimen [12,8397 (39,274-19,7901) nmol.h/l] was significantly higher than those for the single ART or PYR regimens [(3618 (1406-5597) or 334 (82.3-733.3) nmol.h/l, respectively]. Microscopic observation revealed that ART in the combined regimen exerted its inhibitory effect against all erythrocytic stages and that this occurred before effects of PYR activity. Prolongation of inhibitory effects for the combined ART+PYR regimen was shown to be due to PYR activity by comparison to the activity from the single ART regimen. Results clearly demonstrated no PYR activity against K1, a pyrimethamine resistant strain, in plasma samples collected after the single PYR regimen and the ART+PYR regimen. Microscopic examination confirmed that growth inhibition of K1 was caused by ART activity only.

Pharmacokinetic interactions of artemether and pyrimethamine in healthy male Thais.

The pharmacokinetics of a single oral dose of artemether (300 mg) and pyrimethamine (100 mg) given as each individual drug alone or as a drug combination (artemether 300 mg plus pyrimethamine 100 mg), were investigated in 8 healthy male Thai volunteers. Both artemether and pyrimethamine were rapidly absorbed after oral administration. Elimination of pyrimethamine was however, a relatively slow process compared with artemether, and thus resulted in a long terminal phase elimination half-life (50-106 hours). Pharmacokinetics of artemether and dihydroartemisinin following a single oral dose of artemether alone or in combination with pyrimethamine were similar. In contrast, coadministration of artemether resulted in significantly increased Cmax (medians of 818 vs 1,180 ng/ml) and contracted the apparent volume of distribution (medians of 3 vs 2.56 l/kg) of pyrimethamine.

Pharmacokinetics and ex vivo anti-malarial activity of sera following a single oral dose of dihydroartemisinin in healthy Thai males.

The pharmacokinetics of dihydroartemisinin (DHA) was studied in eight healthy male Thai subjects after a single oral dose of 300 mg. Absorption of oral DHA was rapid, Cmax of 679 (307-1000) ng/ml was observed at 1.5 (1-2.5) hours after dosing [median (range)]. Plasma concentrations declined monoexponentially and at 12 hours after administration, the levels were below the detection limit (3 ng/ml). A large variation in the AUC (approximately) 50% was observed. The median (range) AUC was 2010 (636-4079) ng h/ml. The lag time and absorption half-life (t1/2a) were 0.169 (0.111-0.277) hours and 0.709 (0.367-1.118) hours respectively. t1/2z was 1.25 (0.79-1.89) hours Vz/f and CL/f were 5.9 (3.5-8.2) l/kg and 45.3 (28.6-122.8) ml/min/kg, respectively. The pattern of its ex vivo serum activity coincided with the plasma concentrations of DHA.

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.

Effect of artemether on electrocardiogram in severe falciparum malaria.

The effect of intramuscular artemether (intramuscular loading dose of 160 mg, followed by 80 mg daily for another 6 doses), in comparison with that of quinine (intravenous infusion of loading dose of 20 mg/kg, followed by 10 mg/kg q 8 hourly for 7 days), on the electrocardiograph of severe falciparum malaria patients were investigated in 102 Thai patients (92 males, 10 females) admitted to Pra Pokklao Hospital, Chantaburi, southeast of Thailand. Fifty patients (19 with quinine and 31 with artemether) were eligible for ECG analysis. Hypotension was found significantly more common in the quinine group (13 vs 2 cases). Thirteen, 5 and 1 patients with quinine treatment, respectively, had tachycardia, non-specific T-wave change and QTc prolongation. No significant dysrhythmia was found despite high plasma quinine concentrations. Five patients died; their ECGs were not significantly different from those who survived. In the group with intramuscular artemether, 17 cases had tachycardia prior to artemether treatment. QTc prolongation and non-specific T-wave change were found in 2 and 6 cases. One patient had RBBB and second degree AV-block on Day 1, but returned to normal on Day 2. No other dysrhythmia or other significant changes in ECG tracing which would suggest any effect of artemether on cardiovascular system were observed.

Activity of artemether-azithromycin versus artemether-doxycycline in the treatment of multiple drug resistant falciparum malaria.

The efficacy of the combination of artemether with doxycycline or azithromycin was evaluated in 60 patients with acute uncomplicated falciparum malaria who attended malaria clinic in Mae Sot, Tak Province (Thai-Myanmar border). Patients (30 each) were randomized to receive (a) 300 mg artemether together with 100 mg doxycycline as initial doses, followed by 100 mg artemether plus 100 mg doxycycline at 12 hours later, then 100 mg doxycycline every 12 hours for another 4 days, or (b) 300 mg artemether together with 500 mg azithromycin, followed by 250 mg azithromycin at 24 and 48 hours. The follow-up period was 28 days. Patients in either group had a rapid initial response to treatment with comparable PCT and FCT. The cure rate of artemether-azithromycin regimen was significantly lower than that of artemether-doxycycline regimen (14.8 vs 53.3%). Low cure rate from artemether-azithromycin combination in this study was likely to be due to inadequate azithromycin dosage. However, with the low incidence of gastrointestinal adverse effects, the once daily dose of azithromycin could still be increased in order to enhance its clinical efficacy. The simplicity of drug administration and lesser incidence of adverse effects make azithromycin a more proper partner of artemether than doxycycline. Further dose-finding and pharmacokinetic study with the artemether-azithromycin combination is encouraging.

Artemether-pyrimethamine in the treatment of pyrimethamine-resistant falciparum malaria.

In vitro susceptibility and clinical response of multidrug resistant Plasmodium falciparum to the combination artemether-pyrimethamine were evaluated in patients with acute uncomplicated falciparum malaria. Sixty patients were randomized to receive 3 oral regimens of the combination artemether-pyrimethamine as follows: Regimen-I: artemether (300 mg) plus pyrimethamine (100 mg) on the first day, then placebo on the two consecutive days; Regimen-II: artemether (300 mg) plus pyrimethamine (100 mg) on the first day, then artemether (150 mg) plus pyrimethamine (50 mg) on the second day, and placebo on the third day; Regimen-III: artemether (300 mg) plus pyrimethamine (100 mg) on the first day, then artemether (150 mg) plus pyrimethamine (50 mg) on the second and third days. All patients had a rapid initial response to treatments with 95% of parasitemia being cleared within the first 24 hours. PCT24hours and PCT48hours were similar among the three drug regimens (11 vs 4, 6 vs 12, and 9 vs 11 patients for a 1-day, 2-day, and 3-day combination regimen, respectively). Fever was cleared within 48 hours in all patients in either group. Transient mild nausea, vomiting and loss of appetite were found in a few patients during the first 2 days of treatment. Seven patients did not complete the 28 day follow-up period (5 vs 2 in a 1-day vs 2-day regimen), the reason for withdrawal was not associated with drug-related adverse effects. Only 53 patients were therefore qualified for the efficacy assessment. There was 15, 13 and 5 patients in a 1-day, 2-day and 3-day combination regimens, respectively, who had reappearance of the parasitemia between days 11 and 21. The cure rates of the 3 treatment groups were statistically significantly different (0, 27.8, and 75% for a 1-day, 2-day and 3-day combination regimen, respectively). Two patients developed P. vivax malaria on days 20 and 24. All of the isolates were highly resistant to pyrimethamine, with MIC of 10(-5) M. There is potential advantage of this combination therapy in reducing the dosage and treatment period of artemisinin derivative, which is therefore likely to improve complaince in clinical practice. The use of a 3-day combination regimen (300 mg artemether plus 100 mg pyrimethamine on the first day, then 150 mg artemether plus 50 mg pyrimethamine on the second and third days) seems to be a good alternative regimen to sulfadoxine/ pyrimethamine in areas where P. falciparum is sensitive to pyrimethamine eg in Africa.

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.

Plasma concentrations of praziquantel during the therapy of neurocysticerosis with praziquantel, in the presence of antiepileptics and dexamethasone.

Plasma praziquantel concentrations were measured in 11 Thai patients with active neurocysticercosis (8 males and 3 females). Praziquantel (Biltricide 600 mg per tablet) was given at a daily dose of 45 mg/kg given in 3 divided doses for 15 consecutive days. All patients had significant improvement with resolution of symptoms and signs, and reduction of active lesions of cysticercosis shown by the brain computed tomographic scanning. After oral administration, the drug was rapidly absorbed from the gastrointestinal tract. There was substantial inter-individual variability in plasma concentrations of praziquantel. After the first dose, maximum plasma concentrations in the range of 42-540 ng/ml was attained at 30 minutes to 5 hours. In all cases, the drug almost totally disappeared from plasma within 8 hours; drug levels measured prior to the first doses on the following days showed undetectable levels. The area under the plasma concentration-time curves of praziquantel following the first dose were between 125 and 990 ng hour/ml. The results suggested that the unusual low plasma availability of the drug observed in this group of patients could be a consequence of pharmacokinetic drug interactions of the concomitant therapy with antiepileptic drugs and dexamethasone. Active metabolite(s), rather than praziquantel itself, may play a significant part in the therapy of neurocysticerosis.

Electroencephalography in cerebral malaria.

Electroencephalography (EEG) was performed in 13 male patients with cerebral malaria during the first 24 hours of admission, using a 10-channel, 10-20 system EEG machine (6 montages, 20 minute duration). The EEG patterns were of theta and delta waves from both sides of cerebral hemisphere suggesting diffused cortical dysfunction. No epileptic pattern was found in patients who had seizures prior to, or after admission. The initial EEG performed on the day of admission did not show any specific pattern attributable to any pathological condition. It was also unable to predict the prognosis of the 2 dead patients. However, one cerebral malaria patient with left hemiplegia was subsequently found to have right basal ganglia hemorrhage in CAT scan, high amplitude delta waves and theta waves in the tracings of the right hemisphere. The study suggests that a single EEG data on admission can hardly give enough information for prediction of the clinical course and outcome of cerebral malaria. Serial EEGs probably provide more useful information regarding the prognostic signs in this group of patients. Nevertheless, EEG could be useful to rule out some cerebral pathology such as space occupying lesions, epilepsy or any other causes of unconsciousness that could produce similar cerebral symptoms in malaria patients.

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.

Pharmacokinetics of praziquantel in patients with opisthorchiasis.

The pharmacokinetics of praziquantel was investigated in 9 Thai male patients with asymptomatic opisthorchiasis (stool positive) and 9 patients (6 males, 3 females) with moderately advanced infection (hepatomegaly). The geometric means of the pretreatment Opisthorchis viverrini egg count in these patients were 2,950 vs 4,468 eggs per gram of stool. The results indicate the impairment of metabolism of praziquantel in the moderately advanced stage opisthorchiasis. The pharmacokinetics of the drug in these patients during the acute infection was markedly altered when compared with that after recovery and in patients with early stage of the infection. The clearance rate (Cl/f) was significantly reduced [medians and ranges of 106 (43-242) vs 192 (112-692) and 171 (133-427) ml/min/kg] and the t1/2z and MRT were prolonged [t1/2z: 3.8 (2.0-6.2) vs 2.7 (1.7-4.3) and 2.3 (1.7-2.8) hours; MRT: 6.2 (3.2-11.0) vs 4.6 (2.7-6.2) and 4.5 (2.9-5.1) hours]. In addition, AUCo-alpha was significantly greater [6.0 (2.5-15.6) vs 3.5 (0.6-6.0) and 3.9 (1.6-5.0) micrograms hour/ml].