Biomedical subjects

J Karbwang

Publications and source records attributed to J Karbwang.

At least 109 records · Page 6Linked to original sources

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↗

PubMed1990

Fatal Plasmodium falciparum malaria after an inadequate response to quinine treatment.

A 24-year-old man with severe Plasmodium falciparum malaria died after 77 h of treatment with full parenteral doses of quinine. His peripheral parasitemia at death exceeded the level on admission. Plasma concentrations of quinine were abnormally low throughout. This case emphasizes the importance of pharmacokinetic factors in determining the therapeutic response in severe P. falciparum malaria.

Adult↗

PubMed1990

A safe and effective consecutive-infusion regimen for rapid quinine loading in severe falciparum malaria.

Recommended initial treatment of severe chloroquine-resistant falciparum malaria consists of a 4-h loading infusion of 20 mg of quinine dihydrochloride (salt)/kg of body weight. To achieve and maintain therapeutic blood quinine concentrations (10 mg/l) safely and rapidly, a consecutive-infusion regimen (7 mg of salt/kg of body weight over 30 min followed by 10 mg of salt/kg of body weight over 4 h) based on pharmacokinetic parameters in cerebral malaria has been suggested. This regimen was evaluated in 16 adults (6 male, 10 female; mean age, 25.9 years) with severe falciparum malaria. Plasma quinine concentrations (mean +/- SE) were 8.7 +/- 1.2 mg/l at 30 min and 11.0 +/- 1.8 mg/l at 4.5 h. There was no electrocardiographic evidence of serious cardiotoxicity during the 4.5-h infusion period, and systolic blood pressure fell by greater than 10 mm Hg in only one patient. Parasite clearance in 13 surviving patients (median count on admission, 438 x 10(3)/microliters; range, 500-122 x 10(4) took an average of 71 h (range, 9-115). This regimen is safe, effective, and suitable for use in an intensive care unit.

Animals↗

PubMed1990

Mefloquine antimalarial prophylaxis in pregnancy: dose finding and pharmacokinetic study.

1. A dose finding pharmacokinetic study was performed in 20 Karen women in the third trimester of pregnancy receiving antimalarial prophylaxis with mefloquine. Ten received 250 mg mefloquine base weekly and ten received identical tablets of 125 mg base/week. 2. Both dose regimens were well tolerated. Malaria was prevented effectively, there were no serious adverse effects, all pregnancies proceeded normally, and there were no abnormalities in the babies followed up to 2 years. 3. The median time from dose administration to peak whole blood mefloquine concentration was 6 (range 3-24) h. Mean (+/- s.d.) peak and trough concentrations in the seventh week were 722 +/- 279 and 488 +/- 155 ng ml-1 with the 250 mg/week dose, and 390 +/- 81 and 185 +/- 53 ng ml-1 with the 125 mg/week dose regimens respectively. These blood concentration values are lower than those reported previously in non-pregnant adults. 4. One and two compartmental models were fitted to the whole blood concentration-time data. Mean (+/- s.d.) clearance (CL/F) was 0.78 +/- 0.27 ml min-1 kg-1, and the apparent terminal elimination half-life (t1/2) was 11.6 +/- 7.9 days. 5. Further studies to determine the oral bioavailability of mefloquine are needed, but these results suggest that clearance may be increased in late pregnancy. These preliminary results of good efficacy without significant toxicity are encouraging, and a more extensive evaluation of mefloquine antimalarial prophylaxis in pregnancy is now warranted.

Birth Weight↗

PubMed1990

Comparative effects of quinine and quinidine on glucose metabolism in healthy volunteers.

1. To investigate the relative effects of quinine and quinidine on glucose metabolism, 11 healthy males aged 17-32 years were given three separate 1 h intravenous infusions; normal saline alone, quinine dihydrochloride 10 mg base kg-1 body weight (BW) in normal saline, and quinidine dihydrochloride 10 mg base kg-1 BW in normal saline. A constant infusion of 5 mg glucose kg-1 ideal BW min-1 was given for 1 h before and during each study. 2. Assessment of pancreatic beta cell function and tissue insulin sensitivity from plasma glucose and insulin concentrations at the end of the first hour using the Continuous Infusion of Glucose with Model Assessment (CIGMA) technique confirmed normal glucose tolerance for each subject on each test day. 3. Plasma glucose concentrations at 1 h were similar to those at 2 h. There was no significant difference between the plasma glucose profiles during the three infusion regimes (P greater than 0.05). Plasma insulin rose significantly during the second hour (P less than 0.0001); increments after quinine (geometric mean [-1 s.d- +1 s.d.]; 47.0 [27.8-79.4] mu l-1) were significantly greater than those after quinidine (19.8 [6.1-65.2] mu l-1) and saline (7.5 [0-21.5] mu l-1; P less than 0.05). Plasma quinine concentrations at the end of the infusion (6.5 +/- 4.4 mg l-1) correlated with insulin increments during the second hour (r = 0.662, P = 0.028) and were significantly greater than those of quinidine (3.0 +/- 0.8 mg l-1; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1990

Clinical pharmacokinetics of mefloquine.

Mefloquine, a quinoline-methanol antimalarial, is effective single dose therapy for all species of malaria infecting humans, including multi-drug-resistant Plasmodium falciparum. It is used both in prophylaxis and treatment. Mefloquine is available either as the hydrochloride salt alone, or in a combined preparation with sulfadoxine and pyrimethamine. There is no parenteral formulation. Several assay methodologies have been developed, but high performance liquid chromatography has been the most used in recent pharmacokinetic studies. These have shown in healthy volunteers that mefloquine is absorbed with a half-life of 1 to 4 hours and a time to peak concentration of 7 to 24 hours (median 16.7 hours). Mean peak blood concentrations have ranged between 50 and 110 (median 83) ng/ml/mg/kg. Estimates of total apparent volume of distribution (Vd/f) have ranged from 13.3 to 40.9 (median 19.2) L/kg, systemic clearance (CL/f) from 0.022 to 0.073 L/h/kg (median 0.026 L/h/kg), and terminal elimination half-life from 13.8 to 40.9 days (median 20 days). Systemic clearance appears to be increased in late pregnancy. In uncomplicated falciparum malaria, peak blood concentrations are 2 to 3 times higher than those in healthy subjects ranging from 112 to 209 (median 144) ng/ml/mg/kg because of contraction in the total apparent volume of distribution. Systemic clearance is usually reduced but elimination rates are increased (possibly because of reduced enterohepatic recycling). Mefloquine absorption appears to be reduced in severe falciparum malaria; plasma protein binding exceeds 98% in both healthy subjects and patients. No important drug interactions have been identified as yet, but the potential for serious interactions with quinine has not been adequately investigated. More studies are needed on the disposition of mefloquine in children.

Animals↗

PubMed1990

Pharmacokinetics of three commercial antivenoms in patients envenomed by the Malayan pit viper, Calloselasma rhodostoma, in Thailand.

The pharmacokinetics of 3 monospecific antivenoms were compared in patients envenomed by the Malayan pit viper, Calloselasma rhodostoma. There was a biphasic decline in serum concentrations following intravenous administration. The initial rapid decline was attributable to the formation of venom-antivenom complexes, as the fall in antivenom during this phase was positively correlated with the initial venom concentration (P = 0.045). The total apparent volume of distribution for each antivenom was 1.5-3 times larger than that of the central compartment, which suggests some tissue distribution in addition to complex formation. This was marked for antivenom from the Government Pharmaceutical Organization of Thailand which contained mostly F(ab)2 fragments. The terminal elimination half time was shorter for Twyford antivenom of caprine origin. Systemic clearance was lower for Thai Red Cross antivenom. In 8 of the 26 patients who experienced recurrence of non-clotting blood after initial response to antivenom, serial measurements of plasma venom and antivenom concentrations revealed that recurrence of venom antigenemia and non-clotting blood bore no direct relation to the elimination half-life of the antivenom used, but non-clotting blood recurred when serum antivenom levels fell below 10-20% of the total given. There is no substitute for close monitoring of envenomed patients so that indications for further antivenom can be detected promptly.

Adolescent↗

PubMed1990

Plasmodium falciparum hyperparasitaemia: use of exchange transfusion in seven patients and a review of the literature.

During the last 15 years, at least 35 patients with severe falciparum malaria or babesiosis have recovered following treatment by exchange of up to 10 l of blood. In a patient treated in Manchester, a parasitaemia of 2.10 X 10(6) microliters (42 per cent) was virtually eliminated over eight hours by a 3.5 litre exchange blood transfusion. However, the equipment and amounts of compatible blood required for total exchange are rarely available in areas endemic for malaria and the risks of the procedure, including transfusion-related infections, are high. Partial exchange transfusion with one to two litres of blood carried out over two to seven hours, reduced Plasmodium falciparum parasitaemias of 0.33-1.48 X 10(6)/microliters (13-38 per cent) to 0.11-0.81 X 10(6) (4-17 per cent) in six Thai patients who were receiving intravenous quinine. The reduction in parasitaemia ranged from 0.13-0.67 X 10(6) microliters (9-12 per cent) within six hours. During the same period, parasitaemia in 13 patients with cerebral malaria treated with chemotherapy alone showed little reduction from initial levels of 0.20-1.74 X 10(6)/microliters (11-42 per cent). One of the patients who were treated with exchange transfusion died with intractable hypotension before the procedure could be completed and two others developed oliguric renal failure which was controlled by peritoneal dialysis. Partial exchange transfusion is a promising and practical alternative to total exchange where facilities are limited. It deserves further assessment in the rural tropics.

Adolescent↗

PubMed1990

Pharmacokinetics of mefloquine in combination with sulfadoxine-pyrimethamine and primaquine in male Thai patients with falciparum malaria.

The pharmacokinetics of mefloquine (M) were studied in 59 male Thai patients with falciparum malaria. Mefloquine was administered alone (750 mg orally; group 1), or with primaquine (PQ, 45 mg; group 2), or in combination with sulfadoxine (1.5 g) + pyrimethamine (75 mg) (MSP; group 3), or as MSP + PQ (group 4). All patients in groups 1, 2 and 4 initially responded to treatment, but two patients from group 1 had RI recrudescent infections. One patient in group 3 failed to respond to treatment and was considered to have RII resistance, while a further patient from this group had RI recrudescence. The pharmacokinetic parameters for group 1 and group 3 were not significantly different. Co-administration of primaquine alone had no significant effect on the pharmacokinetics of mefloquine, but there was a statistically significant decrease in the terminal elimination half-life of mefloquine for group 4 relative to that for group 3.

Adolescent↗

PubMed1989

Determination of quinine and quinidine in biological fluids by high performance liquid chromatography.

A simple, specific, rapid and sensitive High Performance Liquid Chromatography (HPLC) method has been developed to measure plasma level of quinine and quinidine. The drugs were extracted successively from plasma at basic pH with chloroform and quantified on a revers-phase Z-module C18 HPLC column with fluorescence detector (excitation 340 nm, emission 425 nm). The isocratic mobile phase used was the mixture of 0.05 M ammonium formate and acetonitrile (93.5:6.5, v/v), adjusted pH to 2.0 with ortho-phosphoric acid. The limits of quantitation for these compounds were as low as 4 ng/ml of plasma, using a 0.25 ml specimen. Calibration curves were linear (R squared = 0.9994) in the range 0-7,000 ng/ml. An interassay reproducibility was 6.8%, 0.3% and 1.2% at the concentrations of 250 ng, 4,000 ng and 8,000 ng of quinine, respectively. Inter-assay coefficient of variation of quinidine was 1.8%, 2.7% and 3.7% at the concentrations of 250 ng, 1,500 ng and 3,000 ng, respectively. Recovery of quinine and quinidine were 76% and 81%, respectively. The method has been used in the analysis of quinine and quinidine in healthy volunteers receiving quinine or quinidine intravenously. The method is now being used to assay samples from field studies with satisfactory results.

Chromatography, High Pressure Liquid↗

PubMed1989

Determination of mefloquine in biological fluids using high performance liquid chromatography.

A simple, specific and sensitive High Performance Liquid Chromatography (HPLC) method for determination of whole blood of mefloquine has been developed. WR 184806 was used as internal standard, using a two step extraction procedure followed by revers phase HPLC. Acetonitrile and dichloromethane were used as extraction solvents. Octanesulphonic acid was used as an ionpairing reagent. Detection of extracted mefloquine and internal standard was achieved at 222 nm. Calibration curves for mefloquine in whole blood showed linearity with correlation coefficients of 0.9999. The limitation of detection using a 1 ml sample was 50 ng/ml. Recovery of mefloquine varied from 61% to 81%. Due to the very similar behavior of the internal standard during extraction, changes in recovery are of minor importance. Good accuracy and precision were obtained (intra-assay coefficient of variation ranged between 1.8% and 5%; inter-assay coefficient of variation were less than 10% at 100 ng/ml and less than 6% at 1,000 ng/ml). The assay employs a rapid and simple two-step extraction which requires a small sample volume. The low limit of detection of mefloquine and the short retention time make the method suitable for routine analysis of mefloquine.

Antimalarials↗

PubMed1988

Cerebral anaerobic glycolysis and reduced cerebral oxygen transport in human cerebral malaria.

In 12 patients comatose with cerebral malaria, cerebral blood flow was 52.2 (SE 4.0) ml/100 g per min, within the reported range for healthy controls, but cerebral vascular resistance was raised at 1.66 (0.19) mm Hg/ml per 100 g per min. Cerebral oxygen consumption (1.90 [0.23] ml/100 g per min), and cerebral arteriovenous oxygen content difference (3.5 [0.43] ml/dl) were subnormal, while cerebral venous pO2 (5.7 [0.2] kpA) was raised. After recovery of consciousness there were significant decreases in arterial lactate concentration (2.44 [0.45] to 1.19 [0.45] mumol/l) and cerebral lactate production (17.4 [7.9] to 5.6 [1.1] mmol/100 g per minute). These results provide evidence of cerebral anaerobic glycolysis associated with inadequate oxygen delivery to the brain consistent with either inhibition of cerebral oxidative metabolism or the microcirculatory obstruction envisaged in the "mechanical" hypothesis for cerebral malaria.

Adolescent↗

PubMed1988

A comparison of the pharmacokinetics of mefloquine in healthy Thai volunteers and in Thai patients with falciparum malaria.

We have studied the kinetics of a single oral dose of mefloquine (750 mg) in 12 Thai patients with falciparum malaria and have compared the results with those of a previous study in 12 healthy Thai volunteers. All the patients responded to treatment with a mean parasite clearance time of 66.6 h and a mean fever clearance time of 54.1 h. There was no significant difference in peak plasma concentration, time to peak, area under the curve or apparent volume of distribution between patients and controls. However, the terminal half-life (t1/2) and mean residence time (MRT) were shorter in the patients (12.2 vs 16.7 days for t1/2 and 15.5 vs 21.4 days for MRT). We conclude that there are changes in the disposition of mefloquine related to malaria, although the exact basis of the changes is not clear.

Adolescent↗

PubMed1988

In vitro inhibition studies of tolbutamide hydroxylase activity of human liver microsomes by azoles, sulphonamides and quinolines.

1. A number of compounds have been examined for their ability to inhibit tolbutamide hydroxylase activity in human liver microsomes (control value at a substrate concentration of 150 microM being 0.27 +/- 0.12 nmol min-1 mg-1 protein; mean +/- s.d.; n = 7). 2. IC50 (concentration of inhibitor producing 50% inhibition) values were determined for a range of sulphonamides, imidazoles and aminoquinoline compounds. The most potent inhibition was evident with the 1-substituted imidazole antimycotic drugs ketoconazole, clotrimazole and miconazole and the sulphonamide sulphaphenazole (IC50 values of 16.5, 2.5, 0.85 and 0.5 microM respectively). A number of compounds showed little or no inhibition of tolbutamide hydroxylase as judged by an IC50 of greater than or equal to 500 microM. 3. The Km value for tolbutamide hydroxylase was 125 microM and Vmax, 0.44 nmol min-1 mg-1 protein. All the substituted imidazoles examined in kinetic studies 1v vs 1s, Line-weaver-Burk plots) produced either non-competitive or mixed inhibition. The sulphonamides exhibited competitive inhibition, the Ki for sulphaphenazole being 0.22 microM. Primaquine showed mixed inhibition. Dixon plots confirmed the type of inhibition produced. 4. Although the competitive inhibition between some sulphonamides and tolbutamide is consistent with metabolism by the same isozyme of cytochrome P-450 it does not prove it and further studies with purified enzymes will be necessary to confirm this.

Adolescent↗