[Comparative study of the association of sulfalene and pyrimethamine and of sulfalene alone in mass chemoprophylaxis of malaria].
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The influence of acetylator phenotype on the response to sulfalene in individuals with chloroquine-resistant falciparum malaria.
The disposition of sulfalene was studied in eight individuals before and during an infection with a chloroquine-resistant strain of Plasmodium falciparum. Isoniazid acetylator phenotype was determined in each individual prior to the administration of sulfalene. Following the administration of sulfalene before infection with malaria, a significant difference in half-life of non-acetylated sulfalene and percent acetylation of sulfalene in plasma was observed between rapid and slow acetylators. When sulfalene was administered during malaria, this difference was no longer apparent. Individuals who did not respond to the therapeutic administration of sulfalene alone were treated with a combination of sulfalene and pyrimethamine. Three individuals were cured by sulfalene without pyrimethamine and one was cured by the drug combination. Three of the four individuals who were not cured by any dose of sulfalene or the drug combination were slow acetylators. There was no distinct correlation between clinical response and maximum levels or half-life of nonacetylated sulfalene. These findings suggest that acetylator phenotype does not influence the therapeutic response of individuals infected with falciparum malaria to sulfalene or to the combination of sulfalene and pyrimethamine. Further information is presented, however, to confirm the importance of an as yet unidentified host factor(s) in determining therapeutic response to these agents.
Acetylation↗
Sulfalene concentrations in plasma and blood cells of Plasmodium falciparum malaria cases after treatment with metakelfin using high-performance liquid chromatography.
A reversed-phase high-performance liquid chromatographic method using acetonitrile-methanol-1 M perchloric acid-water (25:9:0.8:95, v/v/v) at a flow-rate of 1.0 ml min(-1) on LiChrospher 100 RP 18 column (250 x 4 mm; 5 microm) with UV (254 nm) detection has been developed for the determination of sulfalene in plasma and blood cells after oral administration of the antimalarial drug metakelfin. Calibration curves were linear in the range 0.5-100 microg ml(-1). The limit of quantification was 50 ng ml(-1). Within-day and day-to-day coefficients of variation averaged 3.84 and 5.31%, respectively. Mean extraction recoveries of sulfalene from plasma and blood cells were 87.21 and 84.65%, respectively. Mean concentrations of sulfalene in plasma of P. falciparum cases on days 2, 7 and 15 were 44.58, 14.90 and 1.70 microg ml(-1), respectively; in blood cells concentrations of sulfalene were 7.77, 3.25 and 0.75 microg ml(-1), respectively, after oral treatment with two tablets (1000 mg) of metakelfin. Significant difference was recorded on day 2 for sulfalene concentration in blood cells of healthy and P. falciparum cases (t=9.49; P<0.001).
Adult↗
Acetylator phenotype and response of individuals infected with a chloroquine-resistant strain of Plasmodium falciparum to sulfalene and pyrimethamine.
Acetylator phenotype was determined in 33 volunteers who were infected with a chloroquine-resistant strain of Plasmodium falciparum and who received, for cure, 2 g of sulfalene and 50 mg of pyrimethamine. This drug combination did not cure 5 of 14 rapid acetylators and 3 of 19 slow acetylators. This difference is not significant. Plasma levels of non-acetylated sulfalene, acetylated sulfalene, acetylation, and biologic half-life of non-acetylated sulfalene after administration of the combination did not differ importantly between the two groups. Acetylator phenotype does not appear to influence the response to sulfalene and pyrimethamine of individuals infected with chloroquine-resistant falciparum malaria.
Acetylation↗
Host failure in treatment of malaria with sulfalene and pyrimethamine.
An individual infected with a multidrug-resistant strain of Plasmodium falciparum failed to respond to treatment with sulfalene and pyrimethamine. Subinoculation studies showed that parasite resistance to the drug combination was not present. Plasma levels of sulfalene and pyrimethamine in this individual were similar to those of three individuals, subinoculated from him, who were cured by the drug combination. Erythrocyte levels of sulfalene in this individual were similar to those in an individual, subinoculated from him, who was cured by the drug combination. After treatment with the drug combination, in vitro tests showed similar antimalarial activity in the serum of this individual in comparison with the serum of this individual in comparison with the serum of an individual subinoculated from him. The failure of this individual to respond to treatment with sulfalene and pyrimethamine is attributed to an undefined host factor (or factors) that appear(s) to be present in his erythrocytes.
Adult↗
Determination of sulfalene in plasma, red blood cells and whole blood by high-performance liquid chromatography.
A normal phase high-performance liquid chromatographic method using dichloromethane-methanol-perchloric acid (1 M) (96:9:1, v/v) at a flow-rate of 1 ml/min on a Nucleosil 100-7 column (250 x 8 x 4 mm) and UV detection at 254 nm, has been developed to determine the concentration of sulfalene in plasma, red blood cells and whole blood after oral administration of the antimalarial drug metakelfin. The coefficient of variation was 7.1% and the extraction recovery was 82%. Mean concentrations of sulfalene on days 1, 7 and 15 were: 49.56, 10.46 and 2.24 micrograms/ml in plasma, 25.02, 4.34 and 0.84 micrograms/ml in red blood cells and 21.12, 4.44 and 1.00 micrograms/ml in whole blood, respectively. Quinine, chloroquine, desethylchloroquine, mefloquine, primaquine, sulfadoxine, pyrimethamine and dapsone did not interfere in the detection of sulfalene.
Administration, Oral↗
[Effect of sulfalene and furosemide on benzylpenicillin kinetics in rats with aseptic inflammation].
The effect of sulfalen and furosemide on benzylpenicillin kinetics in blood serum, intact tissues and aseptic inflammation foci was studied on rats. It was shown that under the action of sulfalen and furosemide protein binding of benzylpenicillin lowered by 30 per cent. The changes in the antibiotic kinetics after combined use with sulfalen and furosemide were of the same type: markedly increased concentrations in blood serum and tissues and retarded elimination.
Animals↗
[Sulfalene pharmacogenetics. I. The genetic determination of the pharmacokinetic indices].
Genetic determination of pharmacokinetics of sulfalen, a new antibacterial drug, has been studied in 28 twin pairs of Moscow Russian population. In order to determine the degree of heritability of such pharmacokinetic parameters of sulfalen as t 1/2 (half-life); Vd and delta (apparent and specific volumes of distribution) and Co (apparent initial concentration) Holtsinger H-statistics values have been calculated, which are 0.891, 0.866, 0.766 and 0.797 respectively. Possible causes of discrepancies between these values and the coefficients of genetic determination G, calculated by decomposition of general phenotypical dispercion of the parameters via the main equation of quantitative traits of genetics are given (0.913, 0.762, 0.828, 0.856 in that order). The data obtained make it possible to assume that genetic determination t 1/2 of sulfalen is carried out within the system of monogenous interaction (HD = 0.91, HA = 0), that of Vd and Co--within the system of additive-polygenous interaction, while linear and non-linear effects contribute to delta determination (HD = 0.232, HA = 0.596).
Administration, Oral↗
[Effect of acetylsalicylic acid on sulfalene and sulfadimethoxine binding by serum proteins and on their kinetics in rabbits].
The use of sulfalen and sulfadimethoxine in combination with acetylsalicylic acid resulted in the decreased binding of the sulfanilamides by serum proteins, most pronounced with respect to sulfadimethoxine. The decreased binding of the drugs by serum proteins in rabbits was accompanied by decreased elimination of sulfalen and increased excretion of sulfadimethoxine from the host. The different effect of acetylsalicylic acid on the kinetics of sulfalen and sulfadimethoxine in the rabbits was partially due to the unequivalent effect of the decreased binding of the sulfanilamides by the serum proteins on their combined use.
Animals↗
[Pharmacokinetics of sulfalene and sulfamethoxine after combined administration with benzylpenicillin and ampicillin].
The binding of sulfadimethoxine by serum proteins of rabbits did not change in the presence of benzylpenicillin and ampicillin, while the binding of sulfalen increased. The 1.2-2-fold decrease in the proportion of sulfalen not bound by blood proteins was accompanied by its acetylation in rabbits. This in its turn resulted in a decreased rate of the drug elimination. The penicillins did not change the kinetics of sulfadimethoxine in rabbits. When the dose of sulfadimethoxine was increased 2 times, the rate of its elimination in rabbits increased, which is likely to be due to increased acetylation of the drug. This may be associated with the increased level of the free sulfadimethoxine fraction in the blood because of the drug lower binding by serum proteins. When the dose of sulfalen was increased 2 times, its kinetics in rabbits did not change.
Acetylation↗
[Sulfalene kinetics in the blood and cerebrospinal fluid in arachnoiditis].
The kinetics of free sulfalene in the blood and cerebrospinal fluid was studied in patients suffering from chronic arachnoiditis without marked inflammation signs on the part of arachnoid after a single intake of 2 g of the drug. It was found that administration of the drug in this dose once a week is quite justified and that sulfalene penetrates well in the cerebrospinal fluid. Upon administering large doses of the drug its absorption from the gastrointestinal tract declines. Sulfalene is eliminated from the cerebrospinal fluid more slowly than from the blood. High enough drug concentration is maintained in the cerebrospinal fluid for 7 days.
Adolescent↗
[Sulfalene circulation in kidney disease patients].
Examinations of patients suffering from chronic nephritis with the nephrotoxic syndrome and amyloidosis of the kidneys with unchanged glomerular filtration showed that the rate of sulfalen excretion in the patients with the kidney diseases was higher than that in the persons of the control group. The sulfalen elimination rate and the plasmatic clearance in such patients were higher. The higher rate of sulfalen elimination was due to increased excretion of the unchanged drug with urine.
Adult↗
[Effects of sulfalene on the thymus, spleen and adrenals in an experiment].
The effect of sulfalen on the weight and structure of the thymus, spleen and adrenal glands was studied. The findings were compared with the results observed in control rats. It was shown that after administration of sulfalen, the weight of the adrenal glands markedly decreased while their structure did not change. Thymus specimens showed a large number of hypertrophic epitheliocytes, in the medulla which was accompanied by a decrease in its weight.
Adrenal Glands↗
Efficacy of sulfalene and pyrimethamine combination drugs alone and with quinine in treatment of P. falciparum cases in chloroquine resistant areas of north east India.
Studies were carried out in some areas of Assam, Nagaland, West Bengal and Mizoram where chloroquine resistant strains of Plasmodium falciparum were present during 1983 and 1984, to see the efficacy of treatment of P. falciparum cases with SLP alone or with quinine sulphate. The findings have indicated that SLP in the dosage of sulfalene (1000 mg) + Pyrimethamine (50 mg) is suitable for treatment of P. falciparum cases not responding to chloroquine therapy in N.E. India. Treatment with sulfalene (1500 mg) + Pyrimethamine (75 mg) has no advantage over the SLP (1000 + 50) mg. Combination of quinine (1000 mg x 3 days) + SLP (1000 + 50) mg is better with 100 per cent cure rate. In Karhi Anglong district (Manja PHC) of Assam response to these drug combination is however less.
Adolescent↗
[Pharmacokinetics of sulfalene and sulfadimethoxine in chronic pyelonephritis patients].
Accelerated elimination of sulfalen was observed in patients with chronic pyelonephritis, unimpaired glomerular filtration and lowered tubular reabsorption. This was due to lowered sulfalen reabsorption in the kidney tubules. Sulfadimethoxine pharmacokinetics in such patients was not significantly changed.
Absorption↗
[Sulfalene pharmacogenetics. II. The population genetic aspect].
Half-life of sulfalen, a new antibacterial drug, with the biotransformation, performed by means of microsomal acetyltransferase, has been studied in 53 individuals of Moscow Russian population. The absence of sex dimorphism for the trait studied is demonstrated. Distribution of individuals according to values of the pharmacokinetic parameter mentioned within the population is bimodal with the correlation of phenotypic frequencies of "rapid" and "slow" inactivators--72 and 28%. Possible causes of discrepancies between the observed sulfalen inactivator frequencies and similar data on isoniazid are discussed.
Administration, Oral↗
Sulfalene with pyrimethamine and chloroquine with pyrimethamine in single-dose treatment of Plasmodium falciparum infections. A trial in a rural population in northern Nigeria.
A comparative trial was carried out in northern Nigeria of the ability of the drug combinations chloroquine-pyrimethamine and sulfalene-pyrimethamine to clear the peripheral blood stream of asexual forms of P. falciparum within 7 days. The reappearance of asexual P. falciparum forms within the 70-day follow-up period and the occurrence of vomiting during the 2-3 hours following administration of the drugs were also recorded. The purpose of the trial was to choose the more suitable of the two drug combinations for repeated mass administration in the intervention phase of a collaborative field research project in the epidemiology and control of malaria in the African savannah. No differences were observed between the two drug combinations from a parasitological point of view. However, the sulfalene-pyrimethamine combination was found easier to administer and occasioned fewer records of vomiting. It was therefore recommended for use in the project.
Adult↗
Falciparum malaria fully cleared by amodiaquine, pyrimethamine-sulfadoxine and pyrimethamine-sulfalene in areas of chloroquine resistance in Dodoma, Tanzania.
The in vivo response of Plasmodium falciparum to chloroquine, amodiaquine, pyrimethamine-sulfalene (MetakelfinR) and pyrimethamine-sulfadoxine (FansidarR) was assessed in Dodoma in 1988. Asymptomatic schoolchildren with pure P. falciparum infection were given full curative doses of one of the above antimalarials. Daily parasitological follow-ups were made for seven days. Overall successful follow-up cases were 101, 108, 95 and 97 on chloroquine, amodiaquine, MetakelfinR and FansidarR respectively. The overall resistance rate in the area was 28%. Most of the resistant cases were RII type. There was only one case of MetakelfinR resistance. Amodiaquine and FansidarR were fully effective in eliminating asexual parasitaemia from the blood in all the cases during the seven days of follow-up. The results indicate that chloroquine, a commonly used antimalarial in Tanzania, is not as effective as amodiaquine, a less used drug. Although the 'antifols' are still highly effective in Tanzania, their potency could change with continued use. These drugs should, therefore, be protected and used judiciously.
Amodiaquine↗