Simultaneous quantitative analysis of the antimalarials pyrimethamine and sulfamethoxypyrazine in plasma samples using liquid chromatography/tandem mass spectrometry.

The work presented here deals with the development of a quantitative tool for the simultaneous determination of sulfamethoxypyrazine (sulfalene)/pyrimethamine in plasma. The chromatography used only takes 12.5 min, allowing a fast sample turnover time. Relative standard deviation of retention times was never above 3.48% (n = 66). Adequate sample clean-up was achieved by a simple and relatively fast liquid/liquid extraction. In this way, ionisation suppression effects, typical for more simple sample clean-up procedures, could be avoided resulting in absolute plasma effects of maximum -17.1% for sulfalene, -16.1 for the internal standard (IS), and 12% for pyrimethamine. For both pyrimethamine and sulfalene, quadratic calibration curves from 0.00101 to 0.807 microg/mL for pyrimethamine and from 0.271 to 216 microg/mL for sulfalene gave the best fit. Mean coefficients of determination (R2) were 0.9951 (n = 6, CV% 0.39) for pyrimethamine and 0.9942 (n = 6, CV% 0.13) for sulfalene. Precision was below 9.35% for pyrimethamine and 13.9% for sulfalene. Inaccuracy remained below 15% at all cases. The optimised method was used for a time-course study of the sulfalene/pyrimethamine combination concentration in plasma of patients treated with Co-Arinate, a new curative antimalaria-medicine.

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).

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.

[Interactions of sulfanilamides, penicillins and acetylsalicylic acid in serum protein binding]. / Vzaimodeistvie sul'fanilamidov, penitsillinov i atsetilsalitsilovoi kisloty pri sviazyvanii ikh syvorotochnymi belkami.

Combined use of sulfalen and sulfadimethoxine with benzylpenicillin and ampicillin resulted in increased binding of sulfalen to serum proteins of man. Acetylsalicylic acid promoted a decrease in the sulfanilamide binding to the serum proteins. The observed changes in the sulfanilamide binding to proteins of human blood serum were due to increased or decreased affinity of the drugs to the protein molecules.

A single dose of sulfametopyrazine versus 7 days of ampicillin in acute on chronic bronchitis.

Forty-two patients with acute on chronic bronchitis received in double-blind fashion either a single dose of 2 g of sulfametopyrazine or ampicillin 250 mg thrice daily for 7 days. There were no significant differences between treatments in the number of patients achieving white sputum, the time to do so, or the incidence of pathogens at the end of treatment. Blood levels of sulfametopyrazine between 8 and 24 hours and on the seventh day were likely to result in sputum concentration adequate to kill Haemophilus influenzae.

[Effect of acetylsalicylic acid on sulfalene and sulfadimethoxine binding by serum proteins and on their kinetics in rabbits]. / O vliianii atsetilsalitsilovoi kisloty na sviazyvanie sul'falena i sul'fadimetoksina syvorotochnymi belkami i na ikh kinetiku u krolikov.

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.

[Characteristics of the distribution of long-acting sulfanilamides in purulent pyelonephritis in rats]. / Osobennosti raspredeleniia dlitel'no deistvuiushchikh sul'fanilamidov pri sinegnoinom pielonefrite u krys.

Distribution of sulfalen, sulfadimethoxine and sulfamethoxypyridazine in the blood and organs of rats and binding of the drugs to the blood serum proteins of the animals with experimental P. aeruginosa pyelonephritis were studied. It was shown that in rats with P. aeruginosa pyelonephritis the levels of long-acting sulfanilamides in the blood and organs were lower, while the levels of their penetration through the histohematic barriers were higher, which was partially due to the decreased binding of sulfanilamides to blood proteins.

[Pharmacokinetics of penicillins following combined administration with sulfanilamides]. / Farmakokinetika penitsillinov pri kombinirovannom primenenii s sul'fanilamidami.

Combined use of benzylpenicillin or ampicillin with sulfalen or sulfadimethoxine resulted in a decreased binding of the antibiotics to the blood serum proteins and slower elimination of penicillins from the experimental rabbits. It is quite possible that the decreased levels of the antibiotic binding to the proteins caused their slower elimination rates, which was realized by increasing the volume of the drug distribution mainly at the expense of the peripheral compartment and decreased excretion with the urine.

Serum and saliva levels of a trimethoprim-sulfamethopyrazine combination in man.

A combination of trimethoprim (TMP) and sulfamethopyrazine (SMP) was administered to six healthy volunteers for 8 days, according to the proposed therapeutic repeated dose schedule. The weak base TMP (pKa = 7.3) and the weak acid SMP (pKa = 6.1) were measured simultaneously in serum and saliva, both under normal conditions and after stimulation of saliva flow. The flow of saliva was stimulated by chewing plastic material in order to obtain saliva at a pH close to the normal plasma pH of 7.4. This procedure excluded pH-dependent distribution effects. Under these experimental conditions a highly significant correlation was observed between the serum and saliva concentrations of both drugs, with very small inter- and intraindividual variations. Substantial agreement was found between the saliva:serum concentration ratio and the fractions of both drugs not bound to plasma protein. Some discrepancies were noted, probably due to minor shifts in saliva pH during the collection period.

[Sulfalene pharmacogenetics. I. The genetic determination of the pharmacokinetic indices]. / Farmakogenetika sul'falena. Soobshchenie I. Geneticheskaia determinatsiia farmakokineticheskikh pokazatelei.

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).

[Sulfalene pharmacogenetics. II. The population genetic aspect]. / Farmakogenetika sul'falena. Soobshchenie II. Populiatsionno--geneticheskii aspekt.

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.