The influence of probiotic treatment on sulfasalazine metabolism in rat.

Probiotics are live microorganisms claimed to exert beneficial effects on the host. This study investigated their effect on the metabolism and pharmacokinetics of sulfasalazine (SSZ), a drug whose efficacy depends on metabolism by azoreductase (AR) in the gut microbiota to sulfapyridine (SP) and 5-acetylsalicylic acid (5-ASA). The probiotic strains Lactobacillus acidophilus L10, Bifidobacterium lactis B94 and Streptococcus salivarius K12 possessed AR activity and a corresponding ability to metabolize SSZ. Treatment of male Wistar rats (n = 5) with oral 2 g doses of a mixture of the three probiotics (total dose 1.8 × 109 cfu) every 12 h for 3 days resulted in a significant increase (p < 0.05) in AR activity in ex vivo colon contents with a corresponding increase in SSZ metabolism. Similar probiotic treatment of male Wistar rats (n = 8) followed by an oral 100 mg/kg dose of SSZ produced high plasma levels of SP, but pharmacokinetic parameters of SSZ and SP were not significantly different from control rats given SSZ. These results indicate that probiotic strains possess AR activity and can metabolize SSZ. Treatment with probiotics increases AR activity in the gut microbiota but has no effect on plasma levels of SSZ and SP following a subsequent oral dose of SSZ.

Effect of food on gastrointestinal transit of liquids in cynomolgus monkeys.

We investigated the gastrointestinal transit of liquids, as well as various gastric pH profiles, in fed cynomolgus monkeys. Twelve grams of a biscuit-type solid food were provided 1 h before the test. The acetaminophen method was used to determine the gastric half-emptying time (t(50%)), which provided an estimate of the gastric emptying rate. The gastric emptying rate of liquids was significantly reduced after food intake in monkeys. The mean t(50%) value was 143.5 min and comparable to that of humans after eating. However, there was a large variability in the t(50%) between individual animals as shown by the coefficient of variance of approximately 80%. Next, the median oro-caecal transit time in fed monkeys was determined to be 1.8 h, using the sulfasalazine-sulfapyridine method. There was no significant difference in oro-caecal transit time between unfed and fed monkeys; thus, food intake has no significant effect on the oro-caecal transit time of liquids in either monkeys or humans. However, the oro-caecal transit time in humans is about 2 h longer than that in monkeys. Our experiments using several different foods suggested that the typical human gastric pH profile could not be simulated in fed monkeys.

Dapsone and sulfapyridine.

Dapsone and sulfapyridine are structurally related compounds with anti-microbial and anti-inflammatory effects. Dapsone remains the most important drug for leprosy and is useful in the prophylaxis of Pneumocystis pneumonia in patients with HIV disease. The medical treatment of choice for dermatitis herpetiformis is dapsone; and sulfapyridine also can be used for those patients who are intolerant of dapsone. Other neutrophilic disorders also may respond to these drugs. Toxic side effects of both dapsone and sulfapyridine are mediated through the hydroxylamine metabolite. These include hemolysis, methemoglobinemia, and agranulocytosis. Careful monitoring for possible adverse reactions includes frequently performing complete blood counts and regular blood chemistry profile determinations.

Comparison of the effect of oral sulphasalazine, sulphapyridine and 5-amino-salicylic acid on the in vivo antibody response to oral and systemic antigen.

1. Mice, whose drinking water contained sulphasalazine, sulphapyridine or 5-amino-salicylic acid, received an antigenic challenge by cholera toxin administered either orally or systemically. 2. Sulphasalazine treated mice made less specific antibody of IgA class provided the antigen also was administered orally (P = 0.009 for days 7-28). When the antigen was administered systemically, there was a vigorous anti-cholera toxin antibody response of IgG class, and a lesser IgM but only a weak IgA response. The effect of sulphasalazine in this case was confined to the IgG response, which was significantly suppressed on day 28 (P = 0.008). 3. Sulphapyridine and 5-amino salicylic acid had no significant effect on the anti-cholera toxin (CT) responses of all three classes. 4. It therefore appears that in this model, only sulphasalazine is capable of influencing the humoral immune system, the antibody class affected depending on the route of entry of antigen. This may have implications for conditions such as rheumatoid arthritis and chronic inflammatory bowel disease, for which sulphasalazine has been found useful.

Induction of kinetochore positive and negative micronuclei in mouse bone marrow cells by salicylazosulfapyridine and sulfapyridine.

Salicylazosulfapyridine (SASP) and its major metabolite sulfapyridine (SP) have been shown to induce chromosomal damage in vivo. Both chemicals were tested in the micronucleus (MN)/kinetochore (KC) staining test to gain insight into the question of whether chromosomal breakage, aneuploidy-inducing events, or both were important to the observed production of MN in bone marrow cells of mice. In this test, both SASP and SP were shown to be strong inducers of kinetochore positive (KC+) MN. Although small increases in kinetochore negative (KC-) MN were also observed in SP treated mice, as well as in mice receiving the highest dose of SASP tested, the results suggest that both chemicals induce predominantly aneuploidogenic type damage.

Disposition kinetics and dosage regimen of sulfapyridine in buffalo (Bubalus bubalis).

The disposition kinetics and dosage regimen of sulfapyridine were studied in buffalo calves following a single intravenous dose of 100 mg/kg. Distribution half-life (t1/2 alpha) elimination half-life (t1/2 beta) and Vd (area) was 0.181 +/- 0.008 h, 13.4 +/- 0.52 h and 0.59 +/- 0.03 L kg-1, respectively. Total body clearance, which represents the sum of all clearance processes, and tissue/plasma (T/P) ratio were calculated to be 31.1 +/- 2.28 ml kg-1 h-1 and 2.25 +/- 0.09, respectively. A satisfactory intravenous dosage regimen of sulfapyridine in buffalo would be 104 mg/kg followed by 75 mg/kg at 24 h intervals.

Effect of sulphapyridine on male fertility in the rat.

Male rats administered sulphapyridine (60, 120 and 250 mg/kg) for 60 days demonstrated no change in body weight and testicular weight. However, there was a decrease in the weight of the epididymis. Motility and sperm reserves were reduced and were evident from fewer implantation sites and number of pregnancies. Furthermore, sulphapyridine did not show any effect on the histoarchitecture of the testis or epididymis. Serum levels of testosterone in the treated rats were comparable to their respective controls. Morphological abnormalities as revealed by scanning electron microscopic studies clearly demonstrated the detrimental effects of the drug.

Antifertility effects of sulfapyridine on male hamsters.

Sulfapyridine was administered to mature male golden hamsters either by impregnation in feed pellets, or by subcutaneous injection as a solution in dimethylsulfoxide. The average litter size for control males was 8.3 +/- 3.3 (n = 13) vs. 4.2 +/- 2.7 (n = 11) for sulfapyridine-fed treated animals. Histology of the testis and epididymis was normal and sperm were normal in morphology and motility. Subcutaneous injection of sulfapyridine caused much more dramatic inhibition of male fertility than was achieved by feeding the drug. Sulfapyridine (750 mg/kg body weight in 0.2 ml DMSO) injected subcutaneously for 60 days was effective in reducing testis size and sperm quality. Histology of testes showed spermatogenic arrest at young spermatids. Two classes of animals were found in both sulfapyridine-fed and -injected treatment groups. One class was relatively resistant to the antifertility effects of the drugs. This difference may reflect differing abilities of the animals to convert sulfapyridine to an active form or to excrete its metabolites.

Comparison of the single dose pharmacokinetics of sulphasalazine in rheumatoid arthritis and inflammatory bowel disease.

The pharmacokinetics of sulphasalazine and its principal metabolites in rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) were compared. Patients with RA had a significantly greater concentration of plasma sulphapyridine than patients with IBD (medians 14.0 micrograms/ml and 7.4 micrograms/ml respectively). Patients with RA also tended to maintain a higher plasma sulphapyridine concentration with time, as determined by the area under the curve (AUC), but a lower plasma sulphasalazine AUC than patients with IBD. It is suggested that more sulphasalazine may be presented to the lower bowel for cleavage to sulphapyridine and 5-aminosalicylic acid in patients with RA than in IBD. Patients with RA may also have impaired metabolism of sulphapyridine as a consequence of their disease. Together these factors may contribute to higher peak circulating sulphapyridine concentrations and may be responsible for the higher incidence of side effects of sulphasalazine treatment in patients with RA than in patients with IBD.

Colitis ulcerosa en niños: niveles de salazosulfapiridina y sulfapiridina durante el tratamiento / Ulcerative colitis in children: levels of salicylazosulfapyridine and sulfapyridine during the treatment

La salazosukfapiridina (SASP) tiene una acción efectiva en la colitis ulcerosa (CU), al desdoblarse en el ciego en sulfapiridina (SP) y 5 aminosalicilato (5 ASA), siendo este último el que actúa por contacto sobre la mucosa colónica. El objetivo fué conocer los niveles séricos efectivos de la droga con eventual presencia o no de efectos colaterales, y también verificar fluctuaciones de los mismos en el intervalo de dosificación. Se estudiaron 10 niños de 6 a 16 años con CU, a quienes se les suministraba SASP de 0.50 a 2 gramos por día y cada 12 horas. Los niveles de SASP y SP en sangre se realizaron a las 6 y 12 horas de administrada la droga, y en materia fecal se cuantificó en recolección de 24 horas. Estos dosajes se realizaron por el método de Hansson y Sandberg. Los niveles lasmáticos de SP fueron a las 6 horas de 6.8 a 36.3 microng/ml (x 17.7-9.0 microng/ml) y a las 12 horas de 5.7 a 25.0 microng/ml (x 14.1 -7.2 microng/ml los de SASP fueron de 2.1 a 53.4 microng/ml (x 15.5-15.4microng/ml) a las 6 horas, y 3.9 a 70.7 microng/ml (x 14.0 -20.4 microng/ml) a las 12 horas. La excreción en materia fecal de SASP durante 24 horas fué de 17.4 a 236 mg., observándo-se una correlación significativa (r: 0.88) con la dosis administrada calculada en gramos por metro cuadrado de superficie corporal en 24 horas. Los niveles de SP y SASP no se correlacionaron con la dosis. Los niveles plasmáticos de SASp y SP no tuvieron diferencia significativa entre las 6 y 12 horas. Los niveles de SP no alcanzaron los mínimos ee toxicidad, no detectándose manifestaciones clíncias ni humorales adversas. Estos hallazgos sugieren que conociendo los niveles en plasma de la droga, la dosis puede ser modificada con mayor amplitud

Colitis ulcerosa en niños: niveles de salazosulfapiridina y sulfapiridina durante el tratamiento / Ulcerative colitis in children: levels of salicylazosulfapyridine and sulfapyridine during the treatment

La salazosukfapiridina (SASP) tiene una acción efectiva en la colitis ulcerosa (CU), al desdoblarse en el ciego en sulfapiridina (SP) y 5 aminosalicilato (5 ASA), siendo este último el que actúa por contacto sobre la mucosa colónica. El objetivo fué conocer los niveles séricos efectivos de la droga con eventual presencia o no de efectos colaterales, y también verificar fluctuaciones de los mismos en el intervalo de dosificación. Se estudiaron 10 niños de 6 a 16 años con CU, a quienes se les suministraba SASP de 0.50 a 2 gramos por día y cada 12 horas. Los niveles de SASP y SP en sangre se realizaron a las 6 y 12 horas de administrada la droga, y en materia fecal se cuantificó en recolección de 24 horas. Estos dosajes se realizaron por el método de Hansson y Sandberg. Los niveles lasmáticos de SP fueron a las 6 horas de 6.8 a 36.3 microng/ml (x 17.7-9.0 microng/ml) y a las 12 horas de 5.7 a 25.0 microng/ml (x 14.1 -7.2 microng/ml los de SASP fueron de 2.1 a 53.4 microng/ml (x 15.5-15.4microng/ml) a las 6 horas, y 3.9 a 70.7 microng/ml (x 14.0 -20.4 microng/ml) a las 12 horas. La excreción en materia fecal de SASP durante 24 horas fué de 17.4 a 236 mg., observándo-se una correlación significativa (r: 0.88) con la dosis administrada calculada en gramos por metro cuadrado de superficie corporal en 24 horas. Los niveles de SP y SASP no se correlacionaron con la dosis. Los niveles plasmáticos de SASp y SP no tuvieron diferencia significativa entre las 6 y 12 horas. Los niveles de SP no alcanzaron los mínimos ee toxicidad, no detectándose manifestaciones clíncias ni humorales adversas. Estos hallazgos sugieren que conociendo los niveles en plasma de la droga, la dosis puede ser modificada con mayor amplitud (AU)

[Ulcerative colitis in children. Levels of salicylazosulfapyridine and sulfapyridine during treatment]. / Colitis ulcerosa en niños. Niveles de salazosulfapiridina y sulfapiridina durante el tratamiento.

Salicylazosulfapyridine (SASP) is a drug used in the treatment of ulcerative colitis (UC) owing to the therapeutic action of the 5-aminosalicylic acid produced by the splitting of the molecule in the cecum, which also yields the absorbable compound Sulphapyridine (SP). The aim of our work was to assess the levels of the drug in blood (SASP and SP), to correlate them with undesirable effects in any, to verify their fluctuations in the dosing interval and to investigate the extent of the excretion of the drug in the children who were studied. 10 children (6 to 16 years) with UC, who were treated with SASP (dOsage schedule 0.5-2.0 g/day in a 12 hours interval), were studied. Blood levels of SASP and SP were assessed at 6 and 12 hours after doses, and total fecal excretion of SASP was determines in 24 hs specimens. All the determinations were performed according to Hansson and Sandberg. SP plasma levels were 17.7 +/- 9.0 ug/ml (range 6.8-36.3 ug/ml) at 6 hours after doses. and 14.1 +/- 7.2 ug/ml (range 5.7-25.0 ug/ml) at 12 hours after doses. SASP plasma levels were 15.5 +/- 15.4 ug/ml (range 2.1-53.4 ug/ml) at 6 hours after doses, and 14.0 +/- 20.4 ug/ml (range 3.9-70.7 ug/ml) at 12 hours after doses. The 24 hours fecal excretion was 17.4 to 236 mg. These values were correlated with the given doses (r = 0.88) calculated as SASP g/m2 body surface 24 hs. There was no statistical correlation between doses and SP or SASP levels in this group, and the respective levels of SASP and SP at 6 and 12 hours after doses showed no significative differences.(ABSTRACT TRUNCATED AT 250 WORDS)

Sulphasalazine and sulphapyridine serum levels in children to mothers treated with sulphasalazine during pregnancy and lactation.

Serum concentrations of sulphasalazine and sulphapyridine were measured during the first week of life in 15 children whose mothers had been on sulphasalazine during pregnancy. The serum concentrations of sulphapyridine and sulphasalazine were similar in the children and their mothers at delivery. The elimination rate of the drugs in the newborn children was slow but the concentrations were not so high that a bilirubin displacing effect could be expected. In eight mothers who were breast-feeding and taking sulphasalazine, analyses were done of mothers' serum, breast-milk and serum from their children. The results showed that the amount of sulphasalazine and sulphapyridine transferred to the child via the breast-milk is negligible with regard to the risk of kernicterus. It is concluded that a woman in need of sulphasalazine treatment can continue the medication throughout pregnancy and lactation without risk of development of kernicterus in her child. Only term infants without haemolytic disease were included in the study. Thus our conclusion is not necessarily valid for the prematurely born child or the child with haemolytic disease.