Studies of the neurotoxicity of oral artemisinin derivatives in mice.

Intramuscular injections of high doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether produce an unusual pattern of selective damage to brain stem centers in experimental mammals, predominantly those involved in auditory processing and vestibular reflexes. We have shown recently in adult Swiss albino mice that parenteral artesunate, a water-soluble derivative, is significantly less neurotoxic than intramuscular artemether in this murine model. Using the same model, in which the drugs were administered daily for 28 days, the neurotoxic potential of the oral drugs was assessed and compared with the parenteral routes of administration. The dose causing neurotoxicity or death in 50% of animals (ED50), was approximately 300 mg/kg/day of oral artemether and artesunate compared to 50 mg/kg/day of intramuscular artemether. Doses of intramuscular artemether > 100 mg/kg/day were uniformly lethal. When oral artemether was given in peanut oil there was an increase in neurotoxicity and mortality compared with the aqueous suspension (P = 0.002), and when the food pellets were coated with artemether in oil, giving relatively constant oral intake, neurotoxicity was further increased; ED50 = 150 mg/kg/day (P = 0.017). These data indicate that once-daily oral administration of artesunate or artemether is relatively safe, presumably because the central nervous system is exposed transiently, whereas constant exposure either from depot intramuscular injection of oil-based drug, or constant oral intake carries relatively greater neurotoxic potential.

Therapeutic responses to quinine and clindamycin in multidrug-resistant falciparum malaria.

Therapeutic responses to clindamycin in combination with quinine were assessed in adult Thai patients with uncomplicated multidrug-resistant Plasmodium falciparum malaria. In total 204 patients were randomized to receive a 7-day oral treatment regimen of quinine (Q(7)) either alone (n = 68), in combination with clindamycin (Q(7)C(7); n = 68), or in combination with tetracycline (Q(7)T(7); n = 68). All patients had uncomplicated recoveries with no serious adverse effects. Fever clearance times for both of the two combination regimens (median of 47 h and range of 8 to 120 h for Q(7)C(7) and median of 36 h and range of 8 to 117 h for Q(7)T(7)) were significantly shorter than that for the Q(7)-only regimen (median, 56; range, 4 to 152 h) (P = 0.002). Parasite clearance times (overall mean +/- standard deviation, 78 +/- 23 h) were not significantly different between the three treatment groups (P = 0. 98). The cure rates assessed at 28 days of follow-up were 100% for Q(7)C(7) and 98% for Q(7)T(7), whereas the cure rate was 87% for the Q(7)-only regimen (P < or = 0.04). Clindamycin in combination with quinine is a safe and effective treatment for multidrug-resistant P. falciparum malaria. This combination may be of particular value in children and pregnant women, in whom tetracyclines are contraindicated.

Therapeutic responses to different antimalarial drugs in vivax malaria.

The therapeutic responses to the eight most widely used antimalarial drugs were assessed in 207 adult patients with Plasmodium vivax malaria. This parasite does not cause marked sequestration, so parasite clearance can be used as a direct measure of antimalarial activity. The activities of these drugs in descending order were artesunate, artemether, chloroquine, mefloquine, quinine, halofantrine, primaquine, and pyrimethamine-sulfadoxine (PS). Therapeutic responses to PS were poor; parasitemias did not clear in 5 of the 12 PS-treated patients, whereas all the other patients made an initial recovery. Of 166 patients monitored for > or =28 days, 35% had reappearance of vivax malaria 11 to 65 days later and 7% developed falciparum malaria 5 to 21 days after the start of treatment. There were no significant differences in the times taken for vivax malaria reappearance among the different groups except for those given mefloquine and chloroquine, in which all vivax malaria reappearances developed >28 days after treatment, suggesting suppression of the first relapse by these slowly eliminated drugs. There was no evidence of chloroquine resistance. The antimalarial drugs vary considerably in their intrinsic activities and stage specificities of action.

Assessment of the neurotoxicity of parenteral artemisinin derivatives in mice.

In all experimental mammals tested (rats, dogs, primates), intramuscular injections of the oil-soluble antimalarial artemisinin derivatives artemether and arteether have produced an unusual pattern of selective damage to brain stem centers predominantly involved in auditory processing and vestibular reflexes. Artesunate, the most widely used of these compounds, is a water soluble hemisuccinate derivative given parenterally either by intravenous or intramuscular injection. The neurotoxic potential of parenteral artesunate and artemether was compared in a murine model. Adult Swiss albino mice were assigned randomly to 28-day regimens of intramuscular artemether or artesunate in doses ranging from 30 to 100 mg/kg/day. At 30 mg/kg/day, no abnormalities were detected with either drug. At 50 mg/kg/day, abnormalities were observed in six of 12 artemether recipients and two of 12 artesunate recipients. These were reversible in all but one (artemether) mouse. At 100 mg/kg/day, eight of 36 artemether recipients, two of 36 artesunate recipients, and one of 18 control mice died. All but four surviving mice in the artemether group (86%) showed obvious and usually irreversible abnormalities of balance and equilibrium, whereas only four artesunate recipients (11%) exhibited abnormalities, and these were reversible in each case (P < 0.001). At this dose the relative risk (95% confidence interval) for death or disability was 5.3 (2.6-11.2) for artemether recipients. Intramuscular artemether is significantly more neurotoxic than intramuscular artesunate in this murine model.

Use of delipidized antigens of Taenia solium metacestodes in IgG-ELISA for detection of neurocysticercosis.

The development of IgG-ELISA for detecting neurocysticercosis is aimed at the routine laboratory, and requires a particular antigen preparation, an acceptable number of serum samples to be tested (both homologous and heterologous) and patients with a diversity of helminthic infections to rule out cross-reactions. This study characterizes IgG-antibodies from cases of neurocysticercosis by assaying the sera against ether-delipidized antigens (5 microg/ml) prepared from metacestodes of Taenia solium. The test had a sensitivity of 90% and a specificity of 83%. IgG-antibodies from heterologous serum samples elicited a number of false positives (25/147) from six different helminthic infections, ie paragonimiasis, echinococcosis, opisthorchiasis, ascariasis, taeniasis and fascioliasis. In additional tests to detect antibody levels to these stage-related antigens, one of three serum samples from T. solium-infected cases gave negative at OD value of 0.187 while the others yielded 0.472 and 0.576. Conversely, assays of all serum samples from neurocysticercosis cases reacted against antigens from Echinococcus granulosus cystic fluid, Paragonimus heterotremus and Opisthorchis viverrini adult worms. In comparison, the antigens from these three species yielded higher mean OD values when assayed against the corresponding infected serum samples. Furthermore, neurocysticercosis cases yielded OD values that are separate and distinct from those of paragonimiasis cases.

Monotherapy with sodium artesunate for uncomplicated falciparum malaria in Thailand: a comparison of 5- and 7-day regimens.

We compared the safety and efficacy of two treatment regimens using sodium artesunate in 91 randomized patients with uncomplicated falciparum malaria acquired in Thailand. One group of 45 patients received 400 mg of artesunate on the first day of treatment and then 200 mg daily for 4 days for a total of 1200 mg (group I: 5-day treatment). A second group of 46 patients received 400 mg of artesunate on the first day of treatment and then 200 mg daily for 6 days for a total of 1600 mg (group II: 7-day treatment). Both regimens were well tolerated. All patients were followed for a total of 28 days. By the third day of treatment, most patients were blood smear negative for parasites. Eighty-two patients completed the 28-day follow-up period and were used for describing the cure rate. All patients treated with the 5-day regimen were cured. In the 7-day treatment group, 98% (39 of 40) of the patients were cured; one patient developed late recrudescence (RI). There were no significant differences in fever clearance or parasite clearance between the two groups. However, 13 patients (five in group I and eight in group II) developed Plasmodium vivax infection during the follow-up period. We conclude that 5- or 7-day regimens of sodium artesunate with a total dose of 1200-1600 mg are effective and safe in treating falciparum malaria acquired in Thailand.

Open randomized trial of oral artemether alone and a sequential combination with mefloquine for acute uncomplicated falciparum malaria.

One hundred fifty-one patients with acute uncomplicated falciparum malaria were enrolled in a randomized, open-label study of oral artemether given alone for five or seven days or a sequential treatment of oral artemether followed by mefloquine. Forty patients received oral artemether, 100 mg initially, then 50 mg every 12 hr for a total dose of 500 mg over a five-day period: Group I. Fifty-eight patients received oral artemether, 100 mg initially, then 50 mg every 12 hr for a total dose of 750 mg over a seven-day period: Group II. Fifty-three patients received oral artemether, 200 mg every 8 hr for a total dose of 600 mg, followed 8 hr later with mefloquine (1,250 mg divided into two doses given 6 hr apart: Group III. All patients were admitted to the hospital for 28 days to exclude reinfection and 131 patients remained through the 28-day follow-up. Only two, nine, and nine patients in Groups I, II, and III, respectively, left the hospital prior to study completion for reasons unrelated to their treatment. Cure rates for the three groups were 74% (28 of 38) for Group I, 98% (48 of 49) for Group II, and 98% (43 of 44) for Group III. Mean fever and parasite clearance times were not significantly different (32.8, 27.5, and 31.4 hr for fever clearance times and 40.2, 40.6, and 36.7 hr for parasite clearance times of Groups I, II, and III, respectively) nor were any adverse effects seen. In vitro drug susceptibility testing of admission and recrudescent parasite isolates was conducted for 10 patients. These data showed no decreased response to artemether or dihydroartemisinin in recrudescent isolates when compared with admission isolates. The results of this study suggest that sequential treatment for two days with oral artemether (600 mg) followed by mefloquine (1,250 mg) is effective and well-tolerated in patients with acute uncomplicated falciparum malaria and may be an alternative treatment for multidrug-resistant falciparum malaria, particularly useful for treating patients in rural areas where the period of admission to the hospital should be as short as possible. A seven-day regimen of artemether alone (750 mg) is also very effective, yet requires prolonged administration of drug after malaria symptoms disappear.

Disposition of proguanil in Thai patients with uncomplicated falciparum malaria.

The objective of this study was to examine the disposition of proguanil in malaria-infected Thai patients with acute uncomplicated falciparum malaria. Eleven patients were administered 500 mg of proguanil twice a day for three days (total dose = 3,000 mg). Four patients were tentatively classified as extensive metabolizers (EMs) and seven as poor metabolizers (PMs). The mean plasma clearances of proguanil for EMs and PMs were 1.31 and 1.10 L/hr/kg, respectively. The mean elimination half-life of proguanil was statistically longer in PMs than EMs (19.6 hr versus 16.1 hr; P = 0.01). Plasma clearance and elimination half-life of proguanil in the malaria patients were comparable with those reported in the literature for healthy Thai volunteers. In contrast to other ethnic groups. Thai EM patients had relatively low plasma concentrations of cycloguanil, the active metabolite of proguanil. None of the 11 patients treated with proguanil were cured of malaria and their phenotype status did not affect the treatment outcome. Although high levels of parasite resistance to cycloguanil were probably responsible for the poor response to proguanil treatment, the inability of Thai EM and PM patients to produce cycloguanil may have also contributed to the treatment outcome.

Plasma macrophage colony-stimulating factor and P-selectin levels in malaria-associated thrombocytopenia.

Thrombocytopenia is a common finding in malaria. In clinical trials, recombinant macrophage colony-stimulating factor (M-CSF) causes a reversible, dose-dependent thrombocytopenia, and high M-CSF has been reported in autoimmune thrombocytopenias. P-selectin, which is secreted into the plasma following platelet/endothelial activation or damage, is elevated in certain consumptive thrombocytopenic disorders. The relationships between thrombocytopenia, M-CSF and P-selectin were analysed in 63 patients with severe (n = 13) or uncomplicated (n = 26) P. falciparum (PF) or P. vivax (PV) malaria (n = 24). On admission, 69% of PF patients and 75% of PV patients were thrombocytopenic (platelets < 150 x 10(9)/l). M-CSF was elevated in PF (3021 +/- 1844 pg/ml) and PV (2602 +/- 1668 pg/ml) patients, compared to controls (589 +/- 200 pg/ml). The platelet count was inversely correlated with M-CSF in PF (r = -0.681), and in PV malaria (r = -0.548). Elevated P-selectin was found in severe PF malaria, but not in PV malaria. Severe PF malaria was associated with marked thrombocytopenia, very high M-CSF, elevated P-selectin and compelling evidence of disseminated intravascular coagulopathy (DIC). Platelet counts, M-CSF and P-selectin returned to control values in 7-14 days. These data suggest that elevated M-CSF in malaria, by enhancing macrophage activity, may result in increased macrophage-mediated platelet destruction. Further, platelet/endothelial activation or damage, as measured by P-selectin, or DIC could intensify thrombocytopenia in severe PF malaria, but does not appear to contribute to thrombocytopenia in uncomplicated PF or PV malaria.

Antimalarial activity and interactions between quinine, dihydroquinine and 3-hydroxyquinine against Plasmodium falciparum in vitro.

The antimalarial activities of quinine, dihydroquinine (a natural impurity found in commercial pharmaceutical formulations of quinine) and 3-hydroxyquinine (the principal metabolite of quinine in humans) were tested both individually and in pairs against 5 strains of Plasmodium falciparum isolated from patients in Thailand. The median inhibitory concentrations (IC50) were similar for quinine (168 nmol/L, range 68-366), and dihydroquinine (129 nmol/L, range 54-324), and both were significantly lower than that of 3-hydroxyquinine (1160 nmol/L, range 378-3154) (P = 0.027). When these drugs were tested in combination, there was no evidence of synergy or antagonism, as determined by fractionary inhibitory indices and isobolograms. Quinine and its impurity, dihydroquinine, have equivalent antimalarial activities which are approximately 10 times greater than that of the metabolite 3-hydroxyquinine. These 2 compounds, which are not usually measured in specific drug assays, contribute to antimalarial activity after quinine administration.

Serum laminin and basic fibroblast growth factor concentrations in patients with complicated Plasmodium falciparum malaria.

Serum concentrations of laminin and basic fibroblast growth factor (FGF) were measured in 20 patients suffering from complicated Plasmodium falciparum malaria in Bangkok. Significant higher mean serum concentrations of laminin were determined prior to treatment (1973 ng/ml) and 7 days after starting medication (1025 ng/ml) in comparison to the control (412 ng/ml). The values remained numerically higher for at least 21 days. With regard to serum basic FGF concentrations, a peak was found 7 day after starting treatment (35.61 pg/ml). In addition, a significant correlation was found for parasite clearance time and basic FGF concentration on day 7 (P < 0.01). These increased values of laminin and basic FGF may be the consequence of endothelial and basement membrane damage induced by sequestration of the parasites. Furthermore, basic FGF might play a role in endothelial repair mechanisms after the clearance of the parasites.

Elevated levels of soluble CD14 in serum of patients with acute Plasmodium falciparum malaria.

Serum sCD14, tumour necrosis factor-alpha (TNF-alpha), IL-6, and endotoxin were analysed in 45 patients with complicated malaria, in 14 patients with Gram-negative septicaemia and in 24 healthy subjects by ELISA. Malaria patients with renal failure (n = 16) had higher levels than patients without renal failure (n = 29) (8116 + 1440 micrograms/l versus 9453 + 1017 micrograms/l; P < 0.05) and both had higher levels than patients with septicaemia (6155 + 1635 micrograms/l) and normal subjects (2776 + 747 micrograms/l). A significant correlation between sCD14 and IL-6 (r = 0.756) and TNF (r = 0.822) existed. However, no relation between sCD14 and serum endotoxin or indices of clinical disease severity (parasitaemia, fever, parasite or fever clearance time) was seen. Although the role of sCD14 in malaria remains to be determined, elevated levels may participate in the inflammatory response in complicated malaria.

Therapeutic effects of chloroquine in combination with quinine in uncomplicated falciparum malaria.

The efficacy and toxicity of oral quinine combined with oral chloroquine were studied in 50 Thai men with uncomplicated falciparum malaria. All were treated for 7 days with quinine sulphate (10 mg salt/kg every 8 h). Twenty-five of the patients, selected at random, were also given oral tetracycline (4 mg/kg four times daily) over the same period and the remainder were given chloroquine (25 mg base/kg over the first 3 days). There were no serious adverse effects. Overall fever-clearance times (FCT) and parasite-clearance times (PCT) in the chloroquine and tetracycline groups were not significantly different, with mean (S.D.) values of 51 (33) and 41 (27) h for FCT and 80 (25) and 83 (21) h for PCT, respectively. Most of the patients (18 in each group) were followed for > or = 2 months. Recrudescence rates (R1) were significantly higher in the chloroquine group than in the tetracycline group (39% v. 6%; P = 0.02), all recrudescences occurring within 4 weeks (18-25 days) of starting treatment. Subsequent parasitaemia with Plasmodium vivax, however, occurred less frequently in the chloroquine group (11%) than in the tetracycline group (33%) (P = 0.11) and took longer to develop in the chloroquine group [51 or 59 days compared with a mean (S.D.) value of 29 (10) days in the tetracycline group; P = 0.01]. Within the chloroquine group, FCT and PCT were both shorter in those with cure than in those with R1 resistance, with mean (S.D.) values of 41 (25) and 70 (33) h for FCT (P = 0.09) and 72 (20) and 100 (18) h for PCT (P = 0.01), respectively. Chloroquine does not potentiate the clinical response to quinine against resistant strains of uncomplicated falciparum malaria, nor does it convey any useful antipyretic effect.

Serum levels of erythropoietin in acute Plasmodium falciparum malaria.

The pathophysiologic backgrounds of anemia in malaria are complex and multifactorial. The purpose of the present study was to measure serum concentrations of erythropoietin (EPO) and to evaluate the adequacy of EPO production in patients suffering from acute Plasmodium falciparum malaria. Fifteen patients with complicated malaria were included in the study. Serum samples were taken on the day of admission, and days 7, 14, 21 and 28. Serum EPO concentrations were measured using an enzyme-linked immunosorbent assay. The median serum EPO concentration was 15.6 mU/ml on the day of admission (range 0.5-567) mU/ml, 10.6 mU/ml (1.2-863) on day 7, 11.8 mU/ml (0.5-72.8) on day 14, 10 mU/ml (0.5-74.6) on day 21, and 8.3 mU/ml (2.2-61.6) on day 28. Inadequate EPO production was found in 46.6% of the patients on the day of admission, which increased to 67% and 68% on days 7 and 14, and reached a maximum of 80% on day 21. Almost 54% of patients had inadequate EPO production on day 28. Our data indicate inadequate EPO production in patients suffering from acute P. falciparum malaria, which might contribute to the prolonged anemia observed in these patients.

Clinical study of pyronaridine for the treatment of acute uncomplicated falciparum malaria in Thailand.

One hundred one adult patients with acute uncomplicated falciparum malaria were treated with pyronaridine. All patients were admitted to the Bangkok Hospital for Tropical Diseases for 28 days to exclude reinfection. Sixty-nine patients (Group I) received pyronaridine 1,200 mg over a three-day period and 32 patients (Group II) received 1,800 mg pyronaridine over a five-day period. Cure rates for the two groups were 63% (38 of 60) for Group I and 88% (23 of 26) for Group II (P<0.05). No RII or RIII type response was seen. Mean fever and parasite clearance times were not significantly different in the two groups. The drug was well-tolerated. In vitro drug sensitivity tests of the paired parasite isolates obtained prior to treatment and after recrudescence indicated that the Plasmodium falciparum isolates of the successfully treated patients had a lower mean concentration for 50% inhibition of growth (IC50) and a much narrower range of the individual IC50 values (15.69 +or- 3.82 ng per ml (mean +or- SD)) as compared with those from the recrudescence cases (22.98 +or- 12.05 ng per ml). Nevertheless, there was no evidence of an increase of the IC50 and IC95 values after recrudescence. The results of the study show that pyronaridine alone at a total dose of 1,800 mg given over five days is well-tolerated in patients suffering from acute uncomplicated malaria and has evident activity against multidrug-resistant falciparum malaria. However, it cannot be recommended for use in Thailand as long as the recrudescence rate is as high as 12%. Further studies of its combinations with other antimalarial drugs are needed.

Comparative clinical trial of artesunate followed by mefloquine in the treatment of acute uncomplicated falciparum malaria: two- and three-day regimens.

The difficulties in treating drug-resistant falciparum malaria in Thailand are compounded by the necessity of giving antimalarials over long periods of time. The resultant decrease in patient compliance not only lowers cure rates but also predisposes to the further spread of drug resistance. We compared the efficacy of two sequential treatment regimens given over two and three days in 111 patients with acute uncomplicated falciparum malaria. Sixty-seven patients received two 400-mg doses of artesunate (total dose = 800 mg) followed by two doses of mefloquine (750 mg given immediately and 500 mg 12 hr later; total dose = 1,250 mg) in Group 1. Forty-four patients (Group II) received four 200-mg doses of artesunate (total dose = 800 mg) given 12 hr apart followed by a mefloquine regimen similar to that for Group I. All patients were admitted to hospital in Bangkok for 28 days to preclude reinfection. Ninety-six patients completed the study. Cure rates for the two groups were 84% (49 of 58) for Group I and 100% (38 of 38) for Group II. The mean parasite clearance time and fever clearance time were significantly shorter in Group II (P < 0.02). There were no serious adverse reactions. All nine of the treatment failures in Group I were of the RI types. The results indicate that the sequential treatment with artesunate followed by mefloquine given over three days is effective and well-tolerated in patients with acute, uncomplicated falciparum malaria and suitable as an alternative treatment for multidrug-resistant falciparum malaria.

Treatment of acute, uncomplicated, falciparum malaria with oral dihydroartemisinin.

A clinical trial of oral dihydroartemisinin for the treatment of acute, uncomplicated, falciparum malaria involved 53 adult patients in Thailand. Each received a total dose of 480 mg over 7 days (120 mg given immediately, followed by 60 mg/day) after being admitted to the Hospital for Tropical Diseases in Bangkok for 28 days. Most (92%) completed the 28-day follow-up but four patients left the hospital early, for reasons unrelated to their treatment. Most patients showed clinical improvement 1-3 days after starting treatment and none suffered from serious adverse reactions. The cure rate was 90% (44/49). The mean (S.D.) parasite-clearance time was 40.4 (14.1) h and the mean fever-clearance time was 37.0 (30.2) h. Seven patients had a brief increase in parasitaemia after initiation of treatment but subsequent counts declined dramatically. Five patients who failed treatment (RI response) were successfully treated with quinine plus tetracycline for 7 days. No RII or RIII responses were observed. These findings indicate that treatment with oral dihydroartemisinin is effective and well tolerated, and that dihydroartemisinin may be suitable as an alternative treatment for acute, uncomplicated, falciparum malaria. Comparisons with other conventional antimalarial drugs in a large, double-blind, randomized trial and studies of dihydroartemisinin in combination with other, long-acting antimalarials are needed.

Efficacy and tolerability of a sequential, artesunate suppository plus mefloquine, treatment of severe falciparum malaria.

Thirty patients with severe falciparum malaria were each given a total of 1600-mg artesunate suppository over three consecutive days followed by 1250 mg mefloquine per os, divided into two doses which were given 12 h apart. All patients were admitted for 28 days to the Bangkok Hospital for Tropical Diseases, so that the efficacy and tolerability of the treatment could be assessed. All the patients showed clinical improvement, with mean (S.D.) parasite and fever clearance times of 50.4 (13.0) and 70.7 (44.9) h, respectively. Two patients with unrousable coma (Glasgow coma score < or = 8) on admittance regained consciousness 46 and 48 h post-treatment. One other patient had acute renal failure and required dialysis. Most patients (80%) were initially hyperparasitaemic, with a mean density of 184,344 parasites/microliters blood. No deaths occurred. Efficacy was evaluated in 25 of the patients. The cure rate 28 days post-treatment was 92%. None of the patients had major adverse effects although two had tenesmus and passed stools immediately after each suppository was administered. A fresh suppository had to be inserted when this occurred. The results indicate that artesunate suppositories followed by oral mefloquine constitute a well-tolerated regimen with a high cure rate. The combination is suitable as an alternative treatment for severe malaria, particularly in children. Further, large-scale studies are required.

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.