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Biomedical subjects

T Harinasuta

Publications and source records attributed to T Harinasuta.

At least 37 records · Page 2Linked to original sources
PubMed1992

Comparison of oral artemether and mefloquine in acute uncomplicated falciparum malaria.

Plasmodium falciparum malaria in Thailand is highly resistant to available antimalarials, and alternative drugs are needed urgently. Artemether is effective against falciparum malaria but associated with a high recrudescence rate. The proper dosage regimen remains to be defined. We have done a clinical trial comparing mefloquine 1250 mg in divided doses with oral artemether at 700 mg total dose given over 5 days in acute uncomplicated falciparum malaria. 46 patients, admitted to the Bangkok Hospital for Tropical Diseases, were randomised to receive either mefloquine (12) or artemether (34). Hospital follow-up was 28 days for the artemether group and 42 days for the mefloquine group. Oral artemether gave a significantly faster parasite clearance time than mefloquine (30 vs 64 h), and a significantly better cure rate (97 vs 64%) with fewer episodes of dizziness and vomiting. Oral artemether at 700 mg given over 5 days is effective and well tolerated. The cure rate with this regimen is higher than that reported by previous studies with 600 mg intramuscular artemether given over 5 days. Oral artemether can be considered as an alternative drug for multiple-drug-resistant falciparum malaria.

Acute Disease↗
PubMed1992

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.

Animals↗
PubMed1992

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)

Adolescent↗
PubMed1992

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.

Acute Kidney Injury↗
PubMed1992

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.

Adult↗
PubMed1992

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)

Adolescent↗
PubMed1992

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.

Antimalarials↗
PubMed1992

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.

Acute Disease↗
PubMed1992

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.

Adolescent↗
PubMed1991

Clinical trial of artesunate and artemether on multidrug resistant falciparum malaria in Thailand. A preliminary report.

A 5-day course of oral artesunate at total doses of 1200, 600, 650 mg and intramuscular artemether 480 mg proved effective (90-100% cured) in the treatment of multidrug resistant falciparum malaria in Thailand. Shorter courses yielded high recrudescence rates. The fever clearance and parasite clearance times were short. The side effects were mild and transient including occasional abnormal electrocardiograms and pain at the injection site. Slight reduction of neutrophil leucocytes and reticulocytes was observed. Further studies of artesunate and artemether should be carried out to find the optimum dosage regimen and to clarify the hematological effects.

Administration, Oral↗
PubMed1991

Pharmacokinetics of prophylactic mefloquine.

The pharmacokinetics of the prophylactic dose of mefloquine (Lariam: 500 mg every 4 weeks, with a loading dose of 750 mg on the first week) was studied in six healthy Thai male volunteers. Mefloquine was well tolerated during the study period of 16 weeks. The only side-effects found were nausea and diarrhea in 2 volunteers after the first dose of mefloquine. The mean minimum concentration of mefloquine at steady state ranged from 290 to 460 ng/ml. The maximum concentration on week 16 after the last dose was 1558 +/- 48 ng/ml at the mean time of 38 +/- 19 hours. The other pharmacokinetic parameters obtained were: absorption half life = 6.6 +/- 3.0 hours; distribution = 5.1 +/- 3.1 days; terminal half life = 12.9 +/- 2.2 days; apparent volume of distribution = 10.5 +/- 2.3 l/kg; area under the concentration-time curve = 26.9 +/- 2.2 mg/dl. Although this prophylaxis regimen is ideal when considering the compliance, the minimum concentration obtained was much too low for optimum therapeutic concentration. We therefore suggest that weekly prophylaxis schedule should be a better regimen as the difference between minimum and maximum mefloquine concentration would be smaller.

Absorption↗
PubMed1991

Pharmacokinetics of mefloquine in treatment failure.

The pharmacokinetics of mefloquine at the therapeutic dose of 750 mg single orally were compared between cured and recrudescent patients with acute uncomplicated falciparum malaria. Mefloquine was well-tolerated during the study. The side-effects found were nausea, vomiting and diarrhea. Five patients showed R-I and two showed R-II types of response. All recrudescent patients came from the eastern border of Thailand. The time taken to clear the parasites (PCT) was significantly longer in patients with recrudescence (99.6 +/- 36.9 and 63.0 +/- 8.9 hours); however, there was no difference regarding fever clearance time (FCT: 39.0 +/- 16.1 and 31.0 +/- 21.3 hours). The maximum concentration (Cmax) and the concentration on the first and second days in cured patients were significantly higher than those of treatment failure patients. Other pharmacokinetic parameters appeared to be similar in both groups. The present study indicates the existence of mefloquine-resistant falciparum malaria in the eastern border of Thailand. Inadequate mefloquine concentration may play an important role in this aspect. In addition, this study also suggests that Cmax or the concentrations on the first or second day of treatment may be used as guidelines to predict the outcome of treatment.

Absorption↗
PubMed1991

Double blind randomised clinical trial of two different regimens of oral artesunate in falciparum malaria.

A double blind randomized comparative trial of the efficacy of 7-day and 5-day courses of oral artesunate at 600 mg was studied in 89 Thai patients with uncomplicated falciparum malaria. Eighty patients completed the 28-day follow-up period. Artesunate was found to be well tolerated in either regimen. There was an increase of 7% in the cure rate obtained from a 7-day regimen. In 43 patients with a 7-day regimen, the cure rate was 92.5% and 15 patients showed P. vivax in their peripheral blood between days 12 and 34. The mean fever and parasite clearance times were 20 and 40 hours, respectively. In 46 patients with a 5-day regimen, the cure rate was 85% and 8 patients showed P. vivax during days 13 and 24. The mean fever and parasite clearance times were 29 and 40 hours, respectively. Although the cure rates of oral artesunate were high in both regimens, the efficacy was considered unsatisfactory since the aim of the treatment is to achieve 100% cure rate. We suggest however that the extension of the duration of treatment to 7 days together with the increase in total dose may improve therapeutic efficacy of artesunate in falciparum malaria.

Administration, Oral↗
PubMed1991

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.

Administration, Oral↗
PubMed1991

Pharmacokinetics and pharmacodynamics of mefloquine in Thai patients with acute falciparum malaria.

A double-blind randomized comparative study of the pharmacokinetics and pharmacodynamics of a single oral dose of 750 mg or 1250 mg of mefloquine was carried out on 20 Thai male patients with acute uncomplicated falciparum malaria. In the 750-mg group, one patient exhibited an RII response, while the others responded to the treatment with a mean fever clearance time of 50.2 +/- 28.2 hours and a mean parasite clearance time of 70.2 +/- 17.3 hours. The main adverse effects were dizziness, nausea, vomiting, abdominal pain, and diarrhoea. Electrocardiogram monitoring detected sinus bradycardia in three patients and sinus arrhythmia in three others. In the 1250-mg group, one patient exhibited an RII response, while the others responded to the treatment with a mean fever clearance time of 43.4 +/- 36.6 hours and a mean parasite clearance time of 73.4 +/- 25.2 hours. However, during the follow-up period, two patients recrudesced on day 23 and on day 31 (RI response). Dizziness, nausea, vomiting, abdominal pain, and diarrhoea were the major adverse effects, with dizziness being more frequent compared with the 750-mg group. Sinus bradycardia occurred in four patients and sinus arrhythmia in four others. The pharmacokinetics of the two regimens were similar, with the absorption of mefloquine increasing linearly with the dose; however, vomiting within an hour of taking the drug reduced the whole blood mefloquine concentrations. The results do not indicate that there is any advantage in using a single dose of 1250 mg of mefloquine rather than 750 mg.

Adolescent↗
PubMed1991

Pharmacokinetics of prophylactic mefloquine in Thai healthy volunteers.

Malaria constitutes one of the most serious public health problems in Thailand. The disease undermines the health of the people and threatens the economy and security of the country as it is most prevalent in the rural region in forested mountain areas along the border where government officials (border police) have to perform their duties. A safe and effective prophylactic drug for use by these government officials is needed. Nine healthy border police volunteers who were working on the Thai-Cambodia border, aged between 22 to 50 years, and whose weight ranged between 48 and 61 kg, with no history of liver or kidney disease were recruited into the study. 375 mg of mefloquine (as Fansimef tablets) was given as a loading dose, followed by 250 mg every 4 weeks for 4 doses. Whole blood concentrations of mefloquine were measured by high performance liquid chromatography at intervals for 19 weeks. None of the volunteers developed malaria during study period. Seven volunteers had mild adverse effects which required no specific treatment. No changes in liver or renal function or in blood profiles occurred during 19 weeks of observation. Pharmacokinetic analysis revealed a mean maximum concentration of 420 +/- 141 ng/ml a time to peak concentration of 12 +/- 8 hours, terminal half-life was 14.93 +/- 4.43 days, apparent volume of distribution (Vd/f) was 16.5 +/- 5.6 l/kg and total clearance was 0.99 +/- 0.62 ml/min/kg. The mean minimum whole blood mefloquine concentration derived from this study was approximately 100 ng/ml which is considered to be low for treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Plasma quinine levels in patients with falciparum malaria when given alone or in combination with tetracycline with or without primaquine.

Quinine has been an effective drug for severe chloroquine-resistant falciparum malaria. However, there has been a decline in the sensitivity of Plasmodium falciparum to quinine. In 1978-1979 the cure rate was 94% compared to 86% in 1979-1980 and 76% in 1980-1981. The combination of quinine and tetracycline has improved the cure rate to 95-100%. However, the mechanism responsible for this has not been identified. We have compared plasma quinine levels on day 2, day 5 and day 7 (before and at 2 hours after dosing) in twenty-one patients with acute falciparum malaria who were treated with quinine alone (8 patients) or quinine in combination with tetracycline (8 patients) or quinine with tetracycline and primaquine (5 patients). All patients who received combination of quinine and tetracycline with or without primaquine responded well to the treatment with no recrudescence. Two patients who were treated with quinine alone had RI responses. Plasma quinine concentrations from the quinine alone group were significantly lower than those obtained from combination groups on days 2, 5 and 7. The minimal plasma quinine levels from quinine alone group were all lower than MIC, ie below 10 micrograms/ml while those obtained from the combination group were higher than MIC for 7 days. The results from the present study suggest that tetracycline has influence on the maintenance of plasma quinine levels above MIC throughout the treatment period. Therefore, this must be one possible explanation for the better cure rate.

Adolescent↗