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.

Distribution of trimethoprim and sulfametopyrazine in the female reproductive tract.

A combination of trimethoprim (TMP) 250 mg and sulfametopyrazine (SMP) 200 mg (dose ratio 5:4) in capsules was administered to ten patients undergoing hysterectomy for uterine leiomyoma. Each patient received a total of 3 of these Kelfiprim capsules: 2 capsules in a single administration 36 hours before surgery and 1 capsule 24 hours later. TMP and SMP concentrations were analyzed in plasma and also in the ovary, Fallopian tube and uterus, removed during surgery. The results indicated that in the reproductive organs of the female genital tract TMP reaches the same concentrations as in plasma. In contrast SMP is 3 to 3.5 times less concentrated in these tissues compared with plasma. At the TMP/SMP ratios obtained in these various organs synergism of the two compounds is reported to be particularly prominent for most bacterial strains. These findings indicate that this TMP-SMP combination may be useful in the treatment of female reproductive tract infections.

[Distribution of sulfanilamides and penicillins in the blood and organs of rats after their combined administration]. / Raspredelenie sul'fanilamidov i penicillinov v krovi i organakh krys pri kombinirovannom primenenii lekarstv.

The use of benzylpenicillin and ampicillin in combination with sulfalen or sulfadimethoxine increased the levels of the penicillins and sulfalen in some organs and tissues of rats. This was accompanied by a rise in the concentration gradients of the drugs. It is concluded that the combined use of the penicillins and sulfanilamides determines their increased penetration from the blood into other organs and tissues of the host.

[Pharmacodynamics of cephaloridine and cephalothin combined with sulfalene in rabbits]. / Farmakokinetika tsefaloridina i tsefalotina u krolikov pri kombinirovannom primenenii s sul'falenom.

The combined use of cephaloridin and cephalothin with sulfalen resulted in decreased binding of the cephalosporins by serum proteins and decreased rate of drug elimination in rabbits. It might be suggested that these two processes were interrelated. The decreased binding of the antibiotics by proteins in rabbits promoted an increase in the volume distribution of the drugs at the expense of a rise in the level of their penetration from the blood into the peripheral tissues.

[Pharmacokinetics of sulfalene and sulfamethoxine after combined administration with benzylpenicillin and ampicillin]. / Farmakokinetika sul'falena i sul'fadimetoksina pri kombinirovannom primenenii s benzilpenitsillinom i ampitsillinom.

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.

Pharmacokinetic study of the new sulfamethopyrazine-trimethoprim combination (kelfiprim) in renal insufficiency.

The combination of trimethoprim (TMP) and sulfamethopyrazine (SMP) has been successfully used to treat chronic urinary tract infections. Since parenchymal involvement associated with renal insufficiency of varying degree is not infrequent in these patients, it was considered important to study the pharmacokinetics of TMP and SMP in a fixed dose combination. Four groups of patients were studied: 1) 4 patients with endogenous creatinine clearance (CLcR) between 80 and 40 ml/min; 2) 3 patients with CLcR between 40 and 10 ml/min; 3) 3 patients on chronic peritoneal dialysis (CAPD); and 4) 3 patients on haemodialysis. A single oral dose of 250 mg TMP and 200 mg SMP was given to each patient. Multiple samples were collected over 9 days and the following pharmacokinetic parameters were calculated: total area under the plasma level curve, slow disposition rate constant beta and the corresponding t1/2 beta, plasma clearance and the apparent volume of distribution. The results show that the two moieties of the TMP-SMP combination behaved differently in uraemic patients as fas as elimination rate was concerned. TMP was eliminated more slowly both in patients with diminished renal function and in those subjected to haemo- or peritoneal dialysis. The reduction in the rate of elimination of TMP was significantly correlated with the degree of renal impairment. The elimination of SMP, however, was not significantly affected by the reduced renal function; indeed a tendency to increase was noted, at least in dialyzed patients.(ABSTRACT TRUNCATED AT 250 WORDS)

[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.

[Sulfalene kinetics in the blood and cerebrospinal fluid in arachnoiditis]. / Kinetika sul'falena v krovi i spinnomozgovoi zhidkosti bol'nykh arakhnoiditom.

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.

[Sulfalene circulation in kidney disease patients]. / Tsirkuliatsiia sul'falena u bol'nykh zabolevaniiami pochek.

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.

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.

[Sulfanilamide absorption and acetylation in rats with experimental hyperlipidemia and cellular regulation of the process of acetylation]. / Vsasyvanie i atsetilirovanie sul'fanilamidov pri éksperimental'noi giperlipidemii u krys i kletochnaia reguliatsiia protsessa atsetilirovaniia.

Experiments on an isolated ileum of the rat with experimental hyperlipidemia have shown the decreased acetylation rate of sulfalen, sulfamonomethoxin and sulfapyridazine. The absorption rate of the free forms of sulfanilamides was increased (significantly for sulfalen and sulfapyridazine). Isadrin (1 . 10(-8) M) and cAMP (1 . 10(-5) M) introduced into the liquid exposed to the mucosa of the rat ileum raised the acetylation rate of sulfamonomethoxin by the ileic wall while anaprilin (1 . 10(-6) M) led to the reduction of both absorption and acetylation of this sulfanilamide. Addition of cAMP to the incubation mixture of mitochondria and microsomes increased the acetylation rate of sulfamonomethoxin.

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.