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Granulomatous hepatitis has been associated with many conditions, including chronic ulcerative colitis and sulfonamide therapy. We report a patient with ulcerative colitis in whom hepatic granulomatosis was associated with salicylazosulfapyridine (Azulfidine). Sulfonamides should be considered a possible cause of hepatotoxicity when used therapeutically in inflammatory bowel disease.
In order to elucidate the possibility of the dissociation rate of drugs from plasma proteins presenting a rate limiting step in the elimination of drugs by secretion (renal or biliary) and metabolism, the kinetics of salicylazosulfapyridine (SASP) binding to human serum albumin (HSA) has been investigated by stopped-flow photometry. Equilibrium dialysis showed that HSA has three classes of binding sites for SASP with 0.93, 2.3 and 8.4 sites, respectively, and association constants of 2.1.10(6), 1.4.10(5) and 3.0.10(3) M-1, respectively. The association rate constants for the first and second classes are 4.4.10(6) and 1.5.10(7) M-1 sec.-1, and the dissociation rate constants are 2.1 and 109 sec.-1. At SASP concentrations resulting from the usual therapeutic doses about 83% will bind to the first class binding sites. The dissociation "half time" for this class being 0.34 sec., leads to the conclusion that dissociation rates of this order of magnitude are unlikely to reduce the rate of metabolism or biliary secretion whereas it may reduce renal tubular secretion. Whether this is the case depends on the intrinsic rate constant of secretion.
Effects of the amount and the composition of meals on gastric emptying and small intestinal transit times of a suspension were investigated in beagle dogs using acetaminophen and salicylazosulfapyridine as markers. Gastric emptying time was affected both by the amount and the composition of a meal; it was prolonged proportionally to the amount of a solid meal and varied among the 3 kinds of test meals of the same energy content in the following rank order: lard greater than skimmed milk greater than mashed potatoes. The inter-individual variation of small intestinal transit time in a fed state was smaller than that in a fasted state, whereas the mean transit times in both states were similar. Small intestinal transit time was not affected by the amount of the solid meal. On the other hand, it varied among the 3 kinds of test meals in the following rank order: lard greater than mashed potatoes greater than skimmed milk. It is noteworthy that small intestinal transit time in the beagle dog is approximately 2 h shorter than that in humans both in fasted and fed states.
Gastrointestinal absorption properties of chlorothiazide was investigated in dogs by a double-marker method using acetaminophen and salicylazosulfapyridine as the markers. The mean absorption time of acetaminophen (MATAAP) and the time for first appearance of sulfapyridine in plasma (TFASP) were used for the assessment of gastric emptying and oro-colonic transit times, respectively. Chlorothiazide absorption efficiency was increased by pretreatment with atropine sulfate. There was a good correlation between MATAAP and the extent of bioavailability of chlorothiazide, however, there was no correlation between TFASP and the extent of bioavailability of the drug. These results indicate that chlorothiazide absorption takes place primarily in a limited segment of the upper small intestine, supporting the assumption reported previously. This double-marker method seems to be a useful tool for the investigation of the relationship between drug absorption and its gastrointestinal transit.
The method for the assessment of small intestinal transit time (SITT) in beagle dogs was investigated by using the time for the first appearance of sulfapyridine in the plasma (TFA) after oral administration of salicylazosulfapyridine (SASP). After administration of SASP into the small intestine or the cecum of anesthetized dogs, sulfapyridine (SP) was detected in the plasma only in the latter case. These results indicate that TFA could be an index of arrival time in the cecum, an index of SITT in dogs. A remarkable inter-individual variation of TFA was observed after oral administration of SASP to fasting dogs, and the mean value of TFA was about 3 h. As for intra-individual variation of TFA, both variable and less variable dogs were observed. TFA was prolonged significantly by atropine (0.1 mg/kg, i.v.) and shortened significantly by metoclopramide (0.5 mg/kg, i.v.). As the pharmacological modification of gastrointestinal motility was thus mirrored by TFA, SASP method is considered to be useful for the assessment of SITT in beagle dogs.
Some semen characteristics of eight male patients with clinically inactive ulcerative colitis were investigated. Semen analysis was carried out twice during salicylazosulfapyridine (SASP) treatment and repeated twice after at least 3 months' treatment with mesalazine. The motility variables all showed significant improvement during mesalazine treatment: the graded motility (p less than 0.05), motility in percentage (p less than 0.01), and the penetration in egg white (p less than 0.05). The semen plasma was analyzed for mesalazine and the metabolite Ac-mesalazine during both regimens. There was no difference in the semen plasma concentration of mesalazine during the two regimens, whereas Ac-mesalazine was significantly higher during mesalazine treatment than during SASP treatment, indicating that other SASP metabolites, most likely sulfapyridine, are the agent causing the abnormal sperm characteristics. We suggest that pure mesalazine preparations are a safer alternative in young men with chronic inflammatory bowel disease.
Monocytes (M phi) were simultaneously preincubated with salicylazosulfapyridine (Salazopyrin) (SAZ), 0.78-12.5 mM, and lipopolysaccharide from E. coli, 1 X 10(-9) g/ml. Presence of SAZ resulted in a dose-dependent decrease in the co-stimulatory activity in M phi culture supernatants, corresponding to a 50% reduction by SAZ, 2.0 mM. Co-stimulatory activity was estimated by the mitogen-induced thymocyte proliferation assay (THY assay). The results indicate an inhibitory effect of SAZ in vitro on the production of IL-1 and other possible co-stimulatory factors. This inhibitory effect was not due to decreased M phi viability, production of suppressive substances, or to drug interference with the THY assay. Equimolar preincubations with sulfapyridine, 5-aminosalicylic acid and N-acety-1-5-aminosalicylic acid were without effect on the production of co-stimulatory factors.
OBJECTIVE: To evaluate the therapeutic effect of medicated moxibustion plus administration of salicylazosulfapyridine (SASP) and methotrexate (MTX) for treatment of active ankylosing spondylitis (AS). METHOD: Ninety cases of active AS were randomly assigned to Group A, B and C (N = 30 in each group), and treated respectively with SASP and MTX, acupuncture plus SASP and MTX, and composite sulfur (tablet) moxibustion plus SASP and MTX for 3 successive courses (2 months each course with an interval of 5 days). RESULTS: Improvement in sacroiliitis index, Schober test, occipital wall test, finger-ground distance, as well as the erythrocyte sedimentation rate (ESR) and the content of C-reactive protein (CRP) in Group B and C was far superior to that of Group A (P < 0.01). CONCLUSION: Combined use of western medicine with acupuncture or with medicated moxibustion produces a better therapeutic effect than western medicine given alone.
We examined 122 patients with inflammatory bowel disease treated with salicylazosulfapyridine. Forty-two (34.5%) had adverse effects that led to discontinuation of therapy in 14 (11.5%). In 33 patients the effects appeared to be dose dependent. The plasma sulfapyridine levels in patients exhibiting gastrointestinal side effects were significantly higher than in patients with no adverse effects (41.0 +/- 20.3 and 23.8 +/- 14.8 micrograms/ml respectively, P less than 0.001). Plasma sulfapyridine levels were significantly higher in slow than in fast acetylators (31.5 +/- 17.1 vs. 22.2 +/- 17.1 micrograms/ml). Slow acetylators had three times as many side effects as fast acetylators; however this difference was not statistically significant.
In order to evaluate the efficacy of oral administration of a pharmacological dose of folic or of folinic acid to prevent the folate deficiency in patients with inflammatory bowel disease (IBD) treated with salicylazosulfapyridine (SASP) (1g twice daily at meal times), two groups of 15 patients with IBD received 15 mg/day of folic or folinic acid for one month. In both the groups there were ten patients affected by Crohn's disease and five patients affected by ulcerative colitis. Before starting the treatment, the plasma folate and the red blood cell (RBC) folate concentrations did not statistically differ between the two groups. After one month the mean increase in RBC folate concentration was significantly greater after folinic therapy then after folic acid therapy (910 +/- 383 versus 570 +/- 212 ng/ml; p less than 0.01), while no difference was observed in the mean increase of plasma folate level (19.8 +/- 6.6 versus 18.5 +/- 5.0 ng/ml). It was concluded that: a) both folic and folinic acid could restore and enlarge the body stores of folate in patients with IBD treated with SASP, when administered at the dose of 15 mg daily for one month; b) folinic acid seems to be more efficient in enlarging the body stores of the vitamin than folic acid.
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)
A nursing mother with ulcerative colitis was treated with salicylazosulfapyridine (SASP, Azulfidine). Multiple milk samples were collected over a 2-month period. Maternal plasma, saliva, urine and nursing infant's urine were collected. All fluids were analyzed for SASP and its metabolites. Milk did not contain SASP or its 5-amino salicylate component. Sulfapyridine (SP) and its metabolites were present in milk; the SP level was fairly constant at 3--6 micrograms/ml. The milk/saliva ratio for SP was 0.81; the milk/plasma ratio for SP was 0.60 and 0.63. Assuming an average milk concentration of 5 micrograms/ml of SP, the estimated 24-hour secretion (800 cm3 milk) would be approximately 4 mg or 0.3% of maternal dose of SP in the form of SASP. The levels of SP and metabolites determined in random urine samples from the infant were 3--4 micrograms/ml or a 24-hour excretion of 1.2--1.6 mg (30--40% of the total dose in milk). This exposure did not seem hazardous to this infant.
Four patients with severe chronic radiation enteritis and/or colitis were treated with anti-inflammatory drugs that are used conventionally in the treatment of idiopathic inflammatory bowel disease. Salicylazosulfapyridine (SASP) was used in the treatment of all four patients, while one patient received oral prednisone together with SASP. All four patients were treated and observed for over one year, with follow-up observations now extending to over three years. The four patients showed striking clinical improvement, accompanied by improvement in the radiographic appearance of affected bowel, complete or almost complete in three and incomplete in the fourth patient. The results of this pilot investigation are encouraging and call for wider clinical trials of the same and related drugs in larger groups of patients with chronic radiation enterocolitis, a serious condition that has until now not been successfully treated with drugs.
The toxicokinetics of salicylazosulfapyridine (SASP) and its metabolites were investigated in male and female B6C3F1 mice either following single intravenous (5 mg/kg) or oral (67.5, 675, 1350, and 2700 mg/kg) doses, or following three consecutive daily oral doses (675, 1350, and 2700 mg/kg). Plasma concentrations of SASP and its metabolites were quantified by HPLC. Upon intravenous administration, SASP rapidly disappeared from blood with a mean residence time of 0.45-0.78 hr. The only metabolite of SASP found in plasma after an intravenous dose was sulfapyridine (SP). In both sexes, the absolute oral bioavailability of SASP ranged between 16.6-18.2% at a dose of 67.5 mg/kg, and between 2.6-8.7% at doses of 675-2700 mg/kg. Following oral administration of SASP, both SP and AcSP were identified in plasma. The area under the plasma concentration-time curves (AUC) of SP at all four oral doses were approximately 21- to 32-fold or 5- to 25-fold greater than those of SASP in male or female mice, respectively. The acetylated form of SP and AcSP, produced AUC values higher than SASP but much less than SP. Multiple oral doses with SASP did not alter the temporal patterns of SASP absorption and elimination in comparison to a single dose. However, SP accumulated in both sexes following multiple oral doses. A gender-dependent difference in toxicokinetic profiles for SASP and SP was also observed. Female mice displayed a higher Cmax of SASP and SP than did male mice. Although the volume of distribution of SASP was similar in both sexes, the systemic clearance of SASP in males was about twice that observed in females.(ABSTRACT TRUNCATED AT 250 WORDS)
The time course of free and N4-acetylated sulfapyridine (SP) concentrations in the saliva and whole plasma was determined in a healthy male volunteer after a single 2.0 g oral dose of salicylazosulfapyridine (SASP) as four-500 mg commercial, uncoated tablets. The mean (+/- S.D.) plasma: saliva concentration ratios for free and acetylated SP was 2.04 (+/- 0.24) and 3.12 (+/-0.43), respectively, and were independent of plasma concentration and saliva pH. The elimination half-lives of SP and N4-acetyl SP could be determined from either salivary or plasma concentration-time data. These preliminary results suggest that measurement of saliva concentrations of free and acetylated SP may be a convenient, noninvasive method for monitoring indirectly the plasma concentrations of SP and acetyl SP in patients treated with SASP and for determining acetylator phenotype.
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