Influence of intestinal transit time on azo-reduction of salicylazosulphapyridine (Salazopyrin).

During a normal and an accelerated intestinal transit, in seven healthy volunteers, the recoveries of salicylazosulphapyridine (SASP) and its split products sulphapyridine (SP) and 5-aminosalicylic acid (5-ASA) were determined in urine and faeces. The azo-reduction of SASP and consequently the recovery of 5-ASA in the faeces was found to be substantially decreased during an accelerated intestinal transit. In addition, in 18 patients with inflammatory disease of the colon during maintenance therapy of SASP it could be demonstrated that the serum SP levels were related to the diarrhoeal state and did not correlate with disease activity. As recent studies have reported that 5-ASA is possibly the active therapeutic moiety of SASP, the ineffectiveness of SASP therapy in patients with active colitis may be ascribed to the reduced azo reduction of SASP as the result of profuse diarrhoea.     

Retrospective study of salazosulfapyridine in eight patients with rheumatoid arthritis on hemodialysis

Abstract

Objective. We examined the pharmacokinetics (PK) of salazosulfapyridine (SASP) and its metabolite, sulfapyridine (SP), as well as the influence of hemodialysis (HD), and investigated the utility of consecutive administration of SASP in rheumatoid arthritis patients undergoing HD.

Methods. The PK of salazosulfapyridine and SP in serum samples from 8 patients was determined using high-performance liquid chromatography.

Results. When SASP 500 mg was administered, the area under curve for serum concentration of SASP was similar to that seen with normal subjects in the Phase I study. The maximum serum concentration of SP was significantly higher than that in normal subjects, but was far from the danger level. SASP was not dialyzed, whereas on average 62% of SP was dialyzed. Following 5 consecutive days of administration of SASP, serum levels of SASP and SP on day 5 were rather higher than those on day 1, although both remained within the safe range. SASP administration from four months to three years in seven subjects resulted in four American College of Rheumatology 20 improvement criteria (57.1%), with one developing a rash.

Conclusions. If SASP is initiated at a low dosage (≤ 500 mg) and increased up to 1000 mg under careful monitoring, it is safe for HD patients.     

Hemolysis During Salicylazosulfapyridine Therapy

In 36 unselected patients with ulcerative colitis or Crohn's disease taking 4.5-6 gm. salicylazosulfapyridine per day the incidence of hemolysis and its relation to the serum level of salicylazosulfapyridine (Salazopyrin, Azulfidline, SASP), free sulfapyridine (SP) and acetyl sulfapyridine (ac-SP) was investigated. In 19 patients hemolysis was present. Serum levels of free SP were significantly higher in these patients (P less than 0.001). All patients with a serum SP level higher than 37 microgram./ml. had hemolysis as compared to only four of 21 patients with a serum SP level below 37 microgram./ml. Four patients had evidence of hemolytic anemia. In these patients the serum SP level was higher than 55 microgram./ml. Eighteen of the 19 patients with hemolysis were slow acetylators while six of the 17 patients without hemolysis belonged to the slow acetylator phenotype.     

The metabolism of salicylazosulphapyridine in ulcerative colitis: II The relationship between metabolites and the progress of the disease studied in outpatients

Serum concentrations of salicylazosulphapyridine (SASP), sulphapyridine (SP), and 5-aminosalicylic acid (5-ASA) were measured in 64 outpatients with ulcerative colitis. About 90% of the patients in remission had serum total SP concentrations above 20 μg/ml. Seven patients, however, had active disease despite a serum total SP concentration > 20 μg/ml. The SASP and the individual SP metabolites did not show any correlation with the disease state. Three g per day seems to be the most effective dose. Plain and enteric-coated tablets produced similar concentrations at equivalent dosage. Side effects due to SASP were frequent in patients who had a total SP concentration > 50 μg/ml of serum.     

Placental transfer of sulphasalazine and sulphapyridine and some of its metabolites

In eleven pregnant patients with ulcerative colitis or Crohn's disease who were treated with sulphasalazine (SASP) the serum concentrations of SASP and sulphapyridine (SP) were measured at delivery. The concentrations of SASP and SP were almost identical in the cord serum and the maternal serum. In seven of the women the same concentrations were measured at a later occasion when they were not pregnant. The serum SASP concentration remained the same, but the SP concentration was higher in the non-pregnant women. This probably reflects the different degree of protein binding of SASP and SP, respectively, and the change of distribution volume that occurs in pregnancy. In the newborn the concentrations of SASP and SP were 4.6 +/- 3.1 microgram/ml and 18.2 +/- 8.7 microgram/ml, respectively. Current studies have shown that neither SASP nor SP in these concentrations causes significant displacement of bilirubin from albumin. Thus, SASP can be given to the pregnant patient up to delivery without risks for the newborn full-term infant.     

Placental Transfer of Sulphasalazine and Sulphapyridine and Some of Its Metabolites

In eleven pregnant patients with ulcerative colitis or Crohn's disease who were treated with sulphasalazine (SASP) the scrum concentrations of SASP and sulphapyridine (SP) were measured at delivery. The concentrations of SASP and SP were almost identical in the cord serum and the maternal serum. In seven of the women the same concentrations were measured at a later occasion when they were not pregnant. The serum SASP concentration remained the same, but the SP concentration was higher in the non-pregnant women. This probably reflects the different degree of protein binding of SASP and SP, respectively, and the change of distribution volume that occurs in pregnancy. In the newborn the concentrations of SASP and SP were 4.6 ± 3.1 μg/ml and 18.2 ± 8.7 μg/ml, respectively. Current studies have shown that neither SASP nor SP in these concentrations causes significant displacement of bilirubin from albumin. Thus, SASP can be given to the pregnant patient up to delivery without risks for the newborn full-term infant.     

Effects of dialysis on the pharmacokinetics of salazosulfapyridine

There was no standard or report for the treatment of rheumatoid arthritis (RA) patients on hemodialysis with Salazosulfapyridine (SASP). We examined the pharmacokinetics of SASP and its metabolites in RA patient on hemodialysis. Hemodialysis was started 2 h after administration of SASP at a dose of 250 or 500 mg. Blood samples were took 8 times during the observation period. The concentration of SASP and its metabolites (SP, Ac-SP) in blood sample were measured. There was no difference for the concentration of SASP before and after hemodialysis. Results showed SASP was nondialyzable, but SP and AC-SP were dialyzable. At a dose of 500 mg, AUC0-∞ of SASP and SP were higher than healthy volunteer. Therapy with SASP for hemodialysis RA should be started at a lower dose for adverse event risk.     

The metabolism of salicylazosulphapyridine in ulcerative colitis: I The relationship between metabolites and the response to treatment in inpatients

The metabolism of salicylazosulphapyridine was studied in 16 patients with ulcerative colitis admitted to hospital. The acetylator phenotype was determined on admission. The mean serum concentration (mug/ml) (at steady state eight +/- two days in patients responding to treatment) of SASP, total SP, and 5-ASA were 18.7 +/- 12.8; 53.7 +/- 23.1; and 1 +/- 0.9 for slow acetylators and 17.6 +/- 7.1; 31 +/- 9.0 and 1 +/- 0.9 for fast acetylators respectively. Twenty-four hour urinary excretion of SASP, total SP, and 5-ASA were 4.6% +/- 3.1; 52% +/- 9.6 and 22.3 +/- 6.7% of the administered dose respectively.Serum total SP concentration of 20 to 50 mug/ml appeared to coincide with clinical improvement in the absence of any side effects related to salicylazosulphapyridine. No such relationship could be shown with serum SASP, individual metabolites, or 5-aminosalicyclic acid.     

Discordant hypothyroxinemia and hypertriiodothyroninemia in treated patients with hyperthyroid Graves' disease

Hypothyroxinemia and hypertriiodothyroninemia may occur in the course of antithyroid drug or 131I treatment for hyperthyroid Graves' disease. To determine the frequency of combined high serum T3 and low serum T4 concentrations during such treatment and to assess the clinical significance of its recognition, we reviewed 60 patients treated for hyperthyroid Graves' disease with antithyroid drugs (n = 43) or radioactive iodine (n = 17). Six of these patients (10%) were found to have high serum T3 and low serum T4 concentrations during therapy. Four were receiving antithyroid drugs, and 2 had received radioactive iodine. At the time this abnormality occurred, 4 patients were euthyroid, 1 was hypothyroid, and 1 was hyperthyroid. The serum TSH concentration was increased in 2, at the upper limit of normal in 1, and undetectable in 3 patients. In 2 clinically euthyroid patients, these biochemical findings resolved spontaneously. After discontinuation or reduction in the dose of antithyroid drug, clinical and chemical euthyroidism was restored in 2 additional patients with previously elevated TSH levels. In 2 patients, both of whom previously had undetectable serum TSH levels, clinical hyperthyroidism persisted or recurred, and additional therapy was required. No patient developed permanent hypothyroidism during the period of follow-up (1-22 months). An additional 19 of the 60 patients (32%) had an elevated serum T3 level with a normal serum T4 concentration during the course of follow-up. Among these 19 patients, the magnitude of serum T3 elevation was not different between clinically euthyroid (n = 13) and hyperthyroid (n = 6) patients. We conclude that discordance of serum T4 and T3 concentrations is frequently encountered in patients with hyperthyroid Graves' disease during or after therapy. In such patients, the low serum T4 level does not predict hypothyroidism, nor does a high serum T3 level predict hyperthyroidism. Furthermore, the serum T3 concentration in these patients correlates poorly with their clinical thyroid status.     

Pharmacokinetics of digoxin and digitoxin in patients undergoing hemodialysis

The pharmacokinetics of digoxin and digitoxin in patients undergoing long-term hemodialysis were examined to determine which is the preferred cardiac glycoside in this patient population.Absorption curves from 0 to 24 hours after an oral dose of digitoxin were similar in dlalyzed patients and in control patients. Serum glycoside concentrations after an oral dose of digoxin were higher in dialyzed patients than in control patients, significantly so from 2 to 24 hours, reflecting the absence of the predominantly renal route of excretion of digoxin.When nine dialyzed patients were placed on a maintenance dose of digoxin, 0.125 mg 5 days a week, serum levels plateaued at 30 days at a mean concentration (± SE) of 0.84 ± 0.05 ng/ml. Maintenance therapy with 0.1 mg digitoxin 5 days a week resulted in stabilization of serum levels within 30 days at a mean concentration of 19 ± 1 ng/ml. Variability in the serum glycoside concentrations was determined after stabilization of levels during 2 to 19 week follow-up periods with each drug. Variability in serum levels was somewhat increased during maintenance therapy with digitoxin. On the basis of the pharmacokinetic data obtained in this study, no clear cut preference for one glycoside over the other could be established.     

The effect of auranofin and sulphasalazine therapy on circulating levels of interleukin 6 in rheumatoid arthritis patients

Summary Serum levels of interleukin 6 (IL-6), primarily a macrophage derived cytokine and soluble interleukin 2 receptor (sIL-2R), a marker of lymphocyte activation are elevated in rheumatoid arthritis (RA). We have found that the second line drugs auranofin (AUR) and sulphasalazine (SASP) do not significantly alter circulating levels of sIL-2R implying that these durgs do not influence lymphocyte activity. The effect of AUR and SASP on IL-6 is not established. In RA patients we have investigated the effect of these second line agents on serum II-6 levels.Using the B9 bioassay, serum IL-6 was sequentially measured at 0 and 12 weeks in RA patients treated with auranofin (n=26) or sulphasalazine (n=20). Clinical and laboratory indices of disease activity were also assessed. In patients receiving either AUR or SASP, serum IL-6 was significantly reduced. This reduction was parallelled by improvement in clinical indices of disease activity. AUR and SASP significantly reduce serum IL-6 levels in RA patients receiving these treatments. Combining one of these agents with a drug that also influences sIL-2R may be a more rational approach to combining second line therapy in RA.     

The treatment of rheumatoid arthritis with low dose pulse methotrexate--comparative study with other disease modifying antirheumatic drugs]

Low dose pulse methotrexate (MTX, 5-7.5mg/week) was administered to fifty one patients with severe and active rheumatoid arthritis (RA) who did not respond to the various disease modifying antirheumatic drugs (DMARDs). The follow-up period ranged from 2 to 30 months. As to efficacy rate and probability of patients continuing therapy, the results of MTX were compared with those of the other DMARDs (131 cases of bucillamine (BU), 163 of D-penicillamine (DP), 98 of salazopyrin (SASP), 126 of auranofin (AF), 55 of lobenzarit (CCA)). The patients treated with MTX showed remarkable improvement within 1 or 2 months in Lansbury's index items, CRP, immunoglobulin levels and rheumatoid factor values. But OKT4/8 ratio remained unchanged throughout the study period. As to the adverse reactions due to MTX an elevation of serum transaminase occurred most frequently (41.2%). MTX treatment was, however, tolerable to the most cases with its transient discontinuance or its dose reduction. The efficacy rate of MTX (71.4%) was the best among above mentioned DMARDs at the end of 6 months treatment. After treatment of 24 months, the probability of still taking MTX (70.1%) proved to be about the same with that of DP and better than that of BU, SASP, AF and CCA. In conclusion low dose pulse MTX turned out to be effective in the treatment of severe and active rheumatoid arthritis.     

Appropriate Replacement Dose of Thyroxine in Primary Hypothyroidism

ABSTRACT An ultrasensitive thyrotropin (TSH) assay was used to determine how many of 65 patients with primary hypothyroidism on thyroxine (T₄) replacement therapy had suppressed serum TSH. In 13 patients (20%) TSH levels ≤0.1 mlU/l were found, indicating an overdose of thyroxine. After correction of the dose, 48 patients had normal TSH values. Their mean dose of thyroxine was 119 μg/24 hours, and the appropriate replacement dose tended to decline with advancing age. The serum level of thyroid hormones during replacement therapy with thyroxine very imperfectly reflected serum TSH values. It is concluded that overdose of thyroxine is common when suppressed serum TSH is used as an end point. Biochemical follow-up of replacement therapy with thyroxine in primary hypothyroidism therefore requires the use of an ultrasensitive TSH assay in order to detect such suppression. Serum levels of thyroxine or triiodothyronine (T₃) during thyroxine therapy are poor indicators of pituitary TSH secretion and are therefore not useful as parameters of adequate thyroxine dosage.     

Gynecomastia after chemotherapy for lymphoma

Although development of gynecomastia in a patient with cancer may indicate persistence or regrowth of a tumor, we studied three patients with lymphoma in whom development of gynecomastia during or after chemotherapy did not portend a poor outcome. In all patients, serum testosterone levels were normal, serum luteinizing hormone (LH) levels were high-normal or elevated, and serum follicle-stimulating hormone (FSH) levels were clearly elevated. The serum estradiol level of one patient was elevated at the onset of gynecomastia, but it fell to normal as the gynecomastia resolved spontaneously over a three-month period during which the patient received no chemotherapy. In a second patient, gynecomastia resolved over a period of eight months while the patient continued on maintenance chemotherapy, and he remains clinically well in remission 21/2 years after onset of gynecomastia. In the third patient, gynecomastia developed while the patient was in complete remission and off of all therapy, and it remained unchanged for the duration of a 21/2-year remission without therapy. Gynecomastia after chemotherapy for lymphoma is not an ominous prognostic sign and does not necessarily indicate the need for alteration of the treatment regimen.     

A study to determine the active moiety of sulphasalazine in rheumatoid arthritis

Thirty patients with active rheumatoid arthritis (RA) participated in an open study of 6 months' treatment with either 5-aminosalicylic acid (5-ASA) or sulphapyridine (SP), the two moieties of sulphasalazine (SASP). Patients were assessed at regular intervals using clinical and biochemical tests designed to detect specific antirheumatic activity. Patients taking SP showed significant improvement in disease activity, but those taking 5-ASA did not improve, despite the fact that high serum concentrations of 5-ASA and acetyl 5-ASA were achieved. These results suggest that SP is the active moiety of SASP. Its possible mode of action is discussed. Nausea was a frequent problem in patients taking SP. Unless this can be overcome, SP is unlikely to offer any therapeutic advantages over SASP in the treatment of RA.     

Low serum vitamin B12 levels in an outpatient HIV-infected population

A retrospective review was conducted on serum vitamin B12 levels in an HIV-infected outpatient cohort, many of whom received antiretroviral therapy. B12 levels were obtained at most staging visits (every six months) and when clinically indicated. For each serum B12 level, laboratory values and clinical symptoms were recorded. Thirty-two patients (32/251 or 13%) had at least one low B12 level (<211pg/mL) during the course of their HIV infection. Within two years of their initial HIV presentation, 6/57 patients had a low serum B12. Using multiple linear regression analysis, a higher serum B12 level was significantly associated with higher folate levels, African-American race, and lower mean corpuscular volume. B12 levels increased significantly after initiating antiretroviral therapy (416 vs 535 pg/mL, P=0.04). In conclusion, low serum B12 levels occur commonly among HIV-infected patients, even at early stages without overt symptoms of B12 deficiency. Antiretroviral therapy may increase serum B12 levels.     

Real-life outcome of anti-tumor necrosis factor α in the ambulatory treatment of ulcerative colitis

AIM:To evaluate the outcome of anti-tumor necrosis factor alpha(anti-TNFα) therapy in outpatients with ulcerative colitis at a tertiary referral center.METHODS:All patients with a confirmed diagnosis of ulcerative colitis undergoing therapy with infliximab and/or adalimumab at the outpatient clinic for inflammatory bowel diseases at the University Hospital Heidelberg between January 2011 and February 2014 were retrospectively enrolled.Patients with a followup period of less than 6 mo from start of anti-TNFα therapy were excluded.Medical records of all eligible individuals were carefully reviewed.Steroid-free clinical remission of a duration of at least 3 mo,colectomy rate,duration of anti-TNFα therapy,need for anti-TNFα dose escalation,and the occurrence of adverse events were evaluated as the main outcome parameters.RESULTS:Seventy-two patients were included(35 treated with infliximab,17 with adalimumab,20 with both consecutively).Median follow-up was 27 mo(range:6-87 mo).Steroid-free clinical remission was achieved by 22.2% of the patients(median duration:21 mo until end of follow-up; range:3-66 mo).Patients attaining steroid-free clinical remission displayed lower hemoglobin and albumin blood levels at the start of treatment than those who did not achieve remission.The overall colectomy rate was 20.8%.Nearly 50% of the patients underwent anti-TNFα dose escalation during the follow-up period.For both the infliximab and the adalimumab treated patients,non-response to anti-TNFα therapy was the major reason for treatment discontinuation.18.2% of the infliximab-treated patients and 13.5% of the adalimumab-treated patients had to discontinue their therapy due to adverse events.CONCLUSION:Real-life remission rates of ulcerative colitis under anti-TNFα are overall low,but some patients have a clear long-term benefit.     

Fluctuation patterns of HCV-RNA serum level in patients with chronic hepatitis C

The serum level of hepatitis C virus (HCV)-RNA is clinically important as a predictor of the response to interferon (IFN) therapy in patients with chronic hepatitis C. If serum HCV-RNA levels fluctuate during follow-up, and IFN therapy is begun at the time of a low HCV-RNA level, the IFN therapy may be more effective. We evaluated the fluctuation of HCV-RNA serum levels for 2 years in 212 patients with chronic hepatitis C, untreated with IFN who had HCV genotype 1b and an HCV-RNA level of 10 Meq/ml or more at first consultation. The HCV-RNA level was measured monthly for 2 years with an HCV branched DNA probe assay (b DNA probe assay). We classified HCV-RNA patterns into three types by the ratio of maximum HCV-RNA level (a) to minimum HCV-RNA level (b). In pattern 1 (constant type, 151 patients; 71.2%) the a/b ratio was 1–5. In pattern 2 (slight fluctuation type, 46 patients; 21.7%) the a/b ratio was 5–10. In pattern 3 (severe fluctuation type, 15 patients; 7.1%), the a/b ratio was 10 or more. Next, we evaluated the factors associated with the three patterns. Acute exacerbation of chronic hepatitis was regarded as an increase in serum alanine aminotransferase (ALT) level to more than 250 IU/l. The incidence of acute exacerbation for a 2-year follow-up was 13.9% (21/151) in pattern 1, 19.6% (9/46) in pattern 2, and 53.3% (8/15) in pattern 3. Multivariate analysis showed that acute exacerbation was the most important factor in the manifestation pattern 3. In conclusion, we found that: (1) about 70% of patients had a constant HCV-RNA levels for 2 years. (2) A few patients had severe fluctuation of serum HCV-RNA level after acute exacerbation of chronic hepatitis. Received: July 23, 1999 / Accepted: September 24, 1999     

Deflazacort for long-term maintenance of remission in type I autoimmune hepatitis.

OBJECTIVE: most patients with autoimmune hepatitis require long-term treatment, but up to 80% of them will develop collateral effects. The aim of this study was to evaluate the efficacy of deflazacort, an oxazolinic derivative of prednisolone with fewer effects on bone and glucose metabolism, in the maintenance of remission of type I autoimmune hepatitis in patients treated previously with conventional immunosuppressive therapy. METHODS: fifteen patients with type I autoimmune hepatitis were included. All patients had been treated previously with prednisone with or without azathioprine until biochemical remission was obtained and the dose could be reduced. Prednisone was then discontinued and deflazacort was started at a dose adjusted to a ratio of 5 mg prednisone per 7.5 mg deflazacort. The biochemical activity (serum ALT and IgG levels) of liver disease was monitored during a follow-up period of 25.8 +/- 7. 7 months. RESULTS: prednisone therapy was followed by a statistically significant decrease in serum ALT (0P: 386 +/- 345 U/L vs 2M 80 +/- 22 U/L, p < 0.02) and IgG (0P 3029 +/- 1934 mg/dL vs 2M 2064 +/- 933 mg/dL, p < 0.05), from the second month of treatment. After changing to deflazacort no alterations in ALT and IgG serum levels were detected except for a mild, transient increase in serum IgG during the first 3 months. During follow-up, 94% of the patients had normal or slightly increased (less than 50% above normal) ALT levels. The titers of ANA and ASMA remained the same in 82% of the patients, decreased in 12%, and increased in the remaining 6%. During follow-up no patient developed arterial hypertension, diabetes mellitus, or changes in visual acuity. Eight patients, all women, complained of dorsolumbar pain which was not related to osteoporosis. CONCLUSIONS: deflazacort seems to be useful in maintaining remission of autoimmune hepatitis during a prolonged period of follow-up. Future studies should include a histological evaluation of the patients and a prospective comparative analysis of side-effects.