Quinine pharmacokinetics and toxicity in cerebral and uncomplicated Falciparum malaria.

Acute pharmacokinetics of intravenously infused quinine were studied in 25 patients with cerebral malaria and 13 with uncomplicated falciparum malaria. In patients with cerebral malaria receiving the standard dose of 10 mg/kg every eight hours, plasma quinine concentrations consistently exceeded 10 mg/liter, reaching a peak 60 +/- 25 hours (mean +/- 1 S.D.) after treatment was begun and then declining. Quinine total clearances (Cl) and total apparent volumes of distribution (Vd) were significantly lower than in uncomplicated malaria (Cl, 0.92 +/- 0.42 compared with 1.35 +/- 0.6 ml/min/kg, p = 0.03; Vd, 1.18 +/- 0.37 compared with 1.67 +/- 0.34 liter/kg, p = 0.0013). There was no significant difference between the two groups in elimination half-times (t/2) or renal clearances (Cu) (t/2, 18.2 +/- 9.7 compared with 16 +/- 7.0 hours; Cu, 0.21 +/- 0.16 compared with 0.21 +/- 0.08 ml/min/kg). In nine patients studied following recovery, Cl (3.09 +/- 1.18 ml/min), Vd (2.74 +/- 0.47 liter/kg), and Cu (0.53 +/- 0.22 ml/min/kg) were significantly greater (p less than or equal to 0.0004), and t/2 was significantly shorter (11.1 +/- 4.1 hours, p = 0.006) than during the acute illness. Cu accounted for approximately 20 percent of Cl in all groups. Renal failure did not alter the disposition kinetics in cerebral malaria. There was no clinical or electrocardiographic evidence of cardiotoxicity and no permanent neurotoxicity. Quinine toxicity in cerebral malaria has probably been overemphasized. The benefits of high plasma concentrations in the acute phase of this life-threatening disease appear to outweigh the risks, particularly in view of the increasing resistance of Plasmodium falciparum to quinine in Southeast Asia.

Trematode infections. Opisthorchiasis, clonorchiasis, fascioliasis, and paragonimiasis.

The parasitic diseases of the liver and lung are caused by trematodes or flukes--Opisthorchis viverrini, O. felineus, Fasciola hepatica, and Paragonimus westermani. Humans get infected by eating the second intermediate host of the fluke, for example, fish, crab, or water plant. The disease runs a chronic course. The diagnosis is made by the recover of eggs in stools or sputum, or by serodiagnosis. Praziquantel is the drug of choice except in falcioliaisis.

Anti-sporozoite antibodies induced by natural infection.

Serum samples from 120 individuals living in a malaria-endemic area, 31 patients with Plasmodium falciparum infection, and 58 healthy blood donors were tested for antibodies against P. falciparum and P. vivax sporozoites. Specific antibodies were determined by the circumsporozoite precipitation (CSP) reaction and indirect immunofluorescent (IFA) tests for IgG and IgM antibodies. It was found that a high proportion of adults living in the endemic area had IFA anti-sporozoite antibodies, usually IgG. Children and healthy donors were either negative or had low antibody titers. A positive correlation was found between IgG antibody titers against P. falciparum sporozoites and those against P. vivax sporozoites. CSP reactivity was demonstrated in 5 of 31 sera from patients with falciparum malaria, and was always associated with a high level of IFA antibodies. The anti-sporozoite antibodies were found to be stage- and species-specific.

Opisthorchis viverrini infection in Thailand: studies on the morbidity of the infection and resolution following praziquantel treatment.

A community study on opisthorchiasis was conducted in Prachinburi Province in eastern Thailand during 1990-1992. The morbidity from opisthorchiasis in the community and reversibility of biliary pathology following treatment with praziquantel at a single dose of 40 mg/kg were assessed by longitudinal investigations of clinical, laboratory, and ultrasonographic changes. A total of 913 voluntary subjects infected with Opisthorchis viverrini were randomly selected for longitudinal study, and 579 subjects without liver fluke infection were recruited as controls. The majority of the study group suffered from mild and moderate infections that were associated with nonspecific gastrointestinal symptoms. Grade I and II ultrasonographic changes, which indicated chronic inflammation of the biliary tract and gallbladder, were detected in 32% of the infected individuals. Clinical symptoms and ultrasonographic changes were common in subjects 21-40 years of age and older. Satisfactory resolution of morbidity was observed during two years follow-up on days 0, 60, 180, 360, and 720, as shown by significant clinical improvement, normalization of laboratory parameters, and downgrading of ultrasonographic abnormalities. Portable ultrasonography has proved to be a reliable noninvasive technique in the evaluation of the morbidity due to opisthorchiasis in rural areas.

Quinine loading dose in cerebral malaria.

In cerebral malaria, the use of currently recommended doses of intravenous quinine may result in subtherapeutic plasma concentrations during the critical first 24 hours of treatment. A loading dose of quinine (20 mg/kg quinine dihydrochloride, equivalent to 16.7 mg/kg base, infused over 4 hours) proved a rapid and safe method of achieving plasma concentrations above the high minimum inhibitory concentrations for Plasmodium falciparum prevalent in Eastern Thailand.

Artemether or artesunate followed by mefloquine as a possible treatment for multidrug resistant falciparum malaria.

Plasmodium falciparum in south-east Asia is highly resistant to chloroquine and sulfadoxine-pyrimethamine. Mefloquine used to be the chemosuppressant drug of choice in areas with chloroquine resistance. However, sensitivity to this drug has recently decreased in Thailand, Cambodia and Myanmar, and there is no suitable single alternative drug. We therefore investigated possible alternative combination therapies for multidrug resistant falciparum malaria. 120 male Thai patients at Makarm Malaria Clinic, Chantaburi, in eastern Thailand were allocated at random to receive either oral artemether (group A) or artesunate (group B) at a single dose of 300 mg on day 1, both followed by mefloquine, 750 and 500 mg at 24 and 30 h, respectively. Follow-up was on days 1, 2, 7, 14, 21, 28, 35 and 42. Patients in both groups had a rapid initial response to treatment; in most cases parasitaemia was cleared within 24 h, and fever was cleared within 24 h in 62% and 76.7% of the patients in groups A and B, respectively. 58 patients in group A and 57 in group B completed follow-up and cure rates were 98% and 97%, respectively. Reinfection could not be excluded for the 3 patients with recrudescences; all were cured with a repeated course of treatment. No serious adverse effect was observed in either group, only mild and transient nausea, vomiting and loss of appetite, with no significant difference between the 2 groups. These results suggest that a single oral dose of 300 mg of either artemether or artesunate followed by 1250 mg of mefloquine in 2 divided doses is effective against multiple drug resistant falciparum malaria. Either regimen can be considered as a suitable 'stand-by' in endemic areas of multiple drug resistant falciparum malaria.

A comparative clinical trial of two different regimens of artemether plus mefloquine in multidrug resistant falciparum malaria.

Plasmodium falciparum in Thailand is highly resistant to available antimalarial drugs. Artemether, a derivative of artemisinin, is a promising compound currently used to cope with this situation but the course of treatment has to be at least 5 d. An effective short treatment course of this drug is possible when used in combination with mefloquine. We now report a trial of different regimens of the combination artemether/mefloquine. Fifty-seven male Thai patients, admitted to the Bangkok Hospital for Tropical Diseases, were allocated at random to receive oral artemether 300 mg as an initial dose, followed by either the standard dose of mefloquine (750 mg) at 24 h or a higher dose of mefloquine (750 mg at 24 h, then 500 mg at 30 h). Patients were followed up in hospital for 42 d. Two patients, both in the high dose mefloquine group, were excluded as they failed to attend for follow-up. All patients had a rapid initial response to treatment with median parasite clearance times of 37 and 40 h, median fever clearance times of 33.5 and 30.5 h, and cure rates of 75 and 96% (P = 0.0248), for the standard and high doses of mefloquine respectively. No serious adverse effect was found; mild and transient dizziness, nausea, vomiting and diarrhoea were noted in half of the patients in each group. The results suggest that a 30 h short course of artemether plus mefloquine at high dose should be used in areas with documented mefloquine resistance.

Artemether-mefloquine combination in multidrug resistant falciparum malaria.

Plasmodium falciparum in Thailand is highly resistant to chloroquine and sulfadoxine/pyrimethamine and there is increasing resistance to the alternative antimalarials, quinine and mefloquine. In eastern Thailand, the cure rates of mefloquine at 750 and 1250 mg were 30% and 55%, respectively. The use of drug combinations may be necessary in areas where drug-resistant parasites exist. 159 male Thai patients in Chantaburi, eastern Thailand, were allocated at random to receive either oral artemether at a single dose of 300 mg on the first day followed by mefloquine 750 mg at 24 h and 500 mg at 30 h (group A), or oral artemether at a single dose of 300 mg on the first day, mefloquine 750 mg at 24 h and placebo at 30 h (group B). The follow-up was on days 1, 2, 7, 14, 21, 28, 35 and 42. Most patients in both groups had a rapid initial response to treatment, parasitaemia being cleared within 24 h and fever cleared within 48 h in both groups. The cure rates were 97% and 90%, respectively, for groups A and B. No serious adverse effect was seen in either group; mild and transient nausea, vomiting and loss of appetite were noted. The adverse effects did not differ between the 2 groups. The results suggested that a single oral dose of artemether (300 mg) can markedly improve the cure rate of mefloquine at a dose of 750 or 1250 mg in multiple drug-resistant falciparum malaria.

High dose of primaquine in primaquine resistant vivax malaria.

The efficacy of low dose chloroquine, characteristic pattern of relapse and the relapse rate in vivax malaria after high dose primaquine were investigated in 167 Thai patients. 87 patients were allocated at random to receive 300 mg, and 80 received 450 mg of chloroquine on the first day of admission. All patients in both groups showed a rapid response with comparable fever clearance times (27.3 vs. 26.1 h) and parasite clearance times (67.1 vs. 58.1 h). After recovery and clearance of parasitaemia, the patients were allocated at random (double blind) to receive 2 dosage regimens of primaquine, a daily dose of 15 mg or 22.5 mg for 14 d. Relapses in both groups occurred within 6 months; no patient relapsed beyond that period. The relapse rate in the primaquine 15 mg group was significantly higher than that in the 22.5 mg group (17.5% vs. 2.4%).

Opisthorchis viverrini infection in Thailand: symptoms and signs of infection--a population-based study.

A population-based study of the clinical, laboratory and ultrasonographic findings in patients suffering from mild or moderate opisthorchiasis in Prachinburi province, Thailand was conducted in 1990-1992. The effectiveness of treatment with praziquantel at 40 mg/kg body weight was evaluated. After treatment, a long-lasting, marked improvement in the well-being of the study group was observed. Symptoms common in opisthorchiasis infection decreased in intensity and the clinical response showed total or partial remission in 98% of all cases studied. Total and direct bilirubin concentrations decreased significantly and remained low up to the end of the follow-up period of 2 years, indicating a reduction in cholestasis. Also, white blood cell counts decreased initially, which can be interpreted as a reduction in inflammation intensity. No relationship was found between intensity of infection and age or clinical findings. Population-based treatment of opisthorchiasis appears to have had a significant impact on public health in north-east Thailand. However, it is also evident that drug therapy alone will not solve the opisthorchiasis problem, as indicated by the reinfection rate of almost 10% at the end of the study.

A national hospital-based survey of snakes responsible for bites in Thailand.

Snakes which had been killed and brought to hospital with the patients they had bitten were collected in 80 district and provincial hospitals throughout 67 provinces in Thailand in order to establish the geographical distribution and relative medical importance of the venomous species. Of the 1631 snakes collected, 1145 were venomous: Malayan pit vipers (Calloselasma rhodostoma), green pit vipers (Trimeresurus albolabris) and Russell's vipers (Daboia russelii) were the most numerous, while T. albolabris, C. rhodostoma and spitting cobras ('Naja atra') were the most widely distributed. In 22 cases, non-venomous species were mistaken for venomous ones and antivenom was used unnecessarily. The Malayan krait (Bungarus candidus) was confused with B. fasciatus in 5 cases and B. fasciatus antivenom was used inappropriately. The study extended the known ranges of most of the medically-important venomous species in Thailand. Correct identification of venomous snakes is especially important in Thailand because the locally-produced antivenoms are monospecific. The technique of hospital-based collection, labelling and preservation of dead snakes brought by bitten patients is recommended when rapid assessment of a country's medically important herpetofauna is required.

Comparison of artemether and quinine in the treatment of severe falciparum malaria in south-east Thailand.

One hundred and two Thai patients with severe falciparum malaria (92 males and 10 females) were allocated at random to receive either the standard regimen of quinine infusion (52 cases) or intramuscular artemether (50 cases). The patients in both groups had comparable admission clinical and laboratory data. Artemether gave a better survival rate (87.2% vs. 63.3%) and parasite clearance time (54 vs. 78 h) than quinine. Fever clearance times (79 h vs. 84 h) and time to recovery of consciousness (48 h in both groups) were comparable. Previous treatment with quinine or mefloquine had no influence on treatment outcome. The most common adverse effect in patients treated with quinine was tinnitus. Two patients had severe hearing impairment which resolved within 1 week after the end of treatment. Mild, transient pain was noted at the injection site of artemether but no abscess formed. QTc wave prolongation was seen in most patients receiving quinine; however, no arrhythmia was observed despite the high concentration of quinine in some patients who had received quinine before admission. Complications developed in 7 survivors in each treatment group. No patient in the artemether group had neurological sequelae after recovery of consciousness, but 2 in the quinine group had left facial palsy and one had a myasthenia gravis-like syndrome. No patient died with complications in he artemether group, but 7 died with pulmonary complications in the quinine group.

Studies on the chemotherapy of human opisthorchiasis in Thailand: I. Clinical trial of praziquantel.

Praziquantel (Embay 8440) was found to be effective in eliminating egg of Opishtorchis viverrini. from the stools of 49 patients. Two regimens were used: Group I patients received 25 mg/kg body weight three times daily after meals for two consecutive days: and Group II patients received 25 mg/kg body weight three times daily after meals for one day. In both groups eggs were not detected in the faeces by day 60 and up to 4-8 months post treatment. Mild transient side effects were present in approximately 80% of patients of Group I, with milder side effects reported in Group II. Severe diarrhoea was present on day 0 in one patient from each group. Side reactions included headache, dizziness, myalgia and lassitude, however, no laboratory evidence of toxicity was detected.

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.

Studies on the chemotherapy of human opisthorchiasis: III. Minimum effective dose of praziquantel.

A clinical trial of praziquantel was carried out in patients with opisthorchiasis using low dosages with 30 and 60 days follow-up. In group III, 30 patients treated with praziquantel 25 mg per kg body weight bid, for one day yielded a cure rate of 88%. In group IV, 12 patients received 25 mg per kg body weight in a single dose and gave a cure rate of 44 %. In group V, 55 patients received 40 mg per kg body weight in a single dose and yielded a cure rate of 91%. Mild and transient side effects were present in 54%, these included abdominal pain, lassitude, headache, dizziness, nausea, diarrhoea, myalgia and tachycardia. Clinical improvement was observed in most of the patients after one month and 33% of them were clinically cured in two months. The recommended dose of praziquantel for the treatment and control of opisthorchiasis in the endemic area is a single dose of 40 mg per kg body weight after meals.

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.

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)

Studies on the chemotherapy of human opisthorchiasis: effective dose of praziquantel in heavy infection.

Ninety-six patients who had heavy Opisthorchis viverrini infection were studied. Egg count per gram of faeces ranged from 10,800 to 139,000 (mean 26,044.3). Praziquantel 50 mg per kg body weight was given after a morning meal. 68 patients completed the follow up period of 60 days. The cure rate was 97.0%. The side-effects occurred in 61 patients (89.7%). The common side effects were diarrhoea, dizziness, sleepiness, epigastric pain, headache, nausea and anorexia. These side-effects were mild and transient. 62 patients (91.2%) showed clinical improvement, and 20 patients were symptom free on day 60.

Report of Episthmium caninum (Verma, 1935) Yamaguti, 1958 (Digenea: Echinostomatidae) in man.

The first finding of Episthmium sp. in man is reported. Characteristics of the worm are given in detail. The infestation is an accidental one acquired from consuming raw fish, which serves as an intermediate host of Opisthorchis viverrini. The pathogenic role of Episthmium sp. in man needs further investigations.

Quinine resistant falciparum malaria treated with mefloquine.

Twenty eight adult male patients with acute uncomplicated falciparum malaria which showed RI or RII responses to quinine sulfate at the dosage of 600 mg 8 hourly for 7, 10 or 14 days were treated with a single dose of mefloquine (Lariam); 25 patients received 1000 mg, 2 received 750 mg and 1 received 500 mg. The initial response was good; there was no RII or RIII response. Three patients were lost to followup. Of 25 patients who stayed in the Bangkok Hospital for Tropical Diseases where there was no malaria transmission for 28-65 days, only one patient in the 1000 mg group had recrudescence on day 21. The cure rate was 96%. Our prospective study suggests that mefloquine was effective in the treatment of quinine resistant falciparum malaria and the risk of cross-resistance between quinine and mefloquine in P. falciparum in vivo is very low.