Pharmacology of cyclosporin A (Sandimmun) and clinical experience in inflammatory bowel diseases.

Pilot studies with cyclosporin A (CsA, Sandimmun) in more than 100 patients with Crohn's disease have shown that CsA was more efficient in chronic active disease than in acute attacks. The onset of effect was rapid, usually within the first month, but most patients relapsed during the weeks following the interruption of CsA treatment. These findings were confirmed by a placebo-controlled study (parallel groups) in 71 patients, in whom the rate of improvement at 3 months was 61% on CsA and 33% on placebo. Promising results have also been reported after short-term use of intravenous CsA in severe acute ulcerative colitis. Further controlled trials are still ongoing in order to ascertain the efficacy of CsA administered according to the current safety guidelines (dose less than or equal to 5 mg/kg/day) for a period of one year in patients with chronic active Crohn's disease.

Efficacy of low-dose cyclosporin A in psoriasis: results of dose-finding studies.

The efficacy of cyclosporin A (CyA) in severe psoriasis was analysed in 457 adult patients included in five European multicentre dose-finding studies. Initial CyA doses were 1.25 mg/kg/day in 33 patients, 2.5-3 mg/kg/day in 285 and 5 mg/kg/day in 139. After 3 months of treatment, the reduction of the Psoriasis Area and Severity Index (PASI) score was 35 +/- 6% with 1.25 mg/kg/day of CyA, 57 +/- 2% with 2.5 mg or 3 mg/kg/day and 86 +/- 2% with 5 mg/kg/day (P less than 0.001). The rates of success, defined by a PASI score reduction greater than or equal to 75% or a score less than or equal to 8, were 24%, 52% and 88%, respectively. There were no differences in age, initial severity or duration of psoriasis. The improvement was maintained for 9 months or more in the majority of patients receiving continuous CyA therapy.

Renal function and blood pressure in psoriatic patients treated with cyclosporin A.

Serum creatinine and blood pressure were measured in patients who had severe psoriasis and who were treated with cyclosporin A (CyA) in initial doses of 1.25 mg (n = 34), 2.5 or 3 mg (n = 314), or 5 (n = 215) mg/kg/day. Of the 563 patients involved, 201 were treated for more than 3 months, and 100 received CyA continuously for 12 months or more. Sixty-eight additional patients were included as controls and received placebo (n = 42) or etretinate (n = 26). At doses of 2.5 and 5 mg/kg/day, CyA induced slight but significant dose-dependent increases in serum creatinine and blood pressure. Creatinine increases of 50% or more over baseline values were detected in 4% of the patients receiving 2.5 mg/kg/day and in 13% of those receiving 5 mg/kg/day. After an initial rise during the first weeks of treatment, mean creatinine level remained stable over 1 year provided that the CyA dose was reduced whenever creatinine levels increased by 30% or more over baseline. The incidence of hypertension was 10.6% and did not vary whether the CyA dose was 2.5 or 5 mg/kg/day. The first elevated blood pressures were recorded early after starting CyA therapy (median: 1 month). However, 3 months after stopping treatment, the increases in creatinine as well as in blood pressure were reversible and the levels did not significantly differ from baseline values.

Clinical trials of cyclosporin in IDDM.

The results of uncontrolled trials in immunomodulation of insulin-dependent diabetes mellitus (IDDM) led to randomized controlled trials in Canada and Europe. In the Canadian open study, the rate of clinical remissions (target control of glycemia maintained with less than or equal to 0.15 U.kg-1.day-1 insulin) was unexpectedly high among 81 subjects who had been treated with cyclosporin for at least 3 mo (mean serum trough levels approximately 125 ng/ml by radioimmunoassay). Subjects entered the study within 14 wk of onset of symptoms and received 6 wk of insulin therapy. The clinical remission rate at 1 yr was 46%; of these patients, 84% were not receiving insulin. An effect on beta-cell function was suggested by recovery of plasma glucagon-stimulated C-peptide levels into the normal range in many patients, with maintenance of levels through 1 yr in patients in remission. On the basis of these findings, the French and Canadian-European study groups conducted randomized double-blind controlled trials of cyclosporin, which confirmed the results of the open studies in terms of clinical remission. The Canadian-European study also demonstrated enhancement of beta-cell function by cyclosporin by 3 mo, which was maintained for 1 yr. In the Canadian open study, most patients relapsed within a few weeks after discontinuation of cyclosporin, indicating the need for longer-term immunomodulatory therapy for maintenance of remission. The nature and degree of structural change in kidney biopsies from patients in these studies are under assessment. The results strongly support the hypothesis that autoimmune mechanisms mediate beta-cell damage in many patients with IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic study of cyclosporin A (Sandimmun) in patients with primary biliary cirrhosis.

The pharmacokinetics of cyclosporin A (CS-A) were studied in 10 patients with primary biliary cirrhosis (PBC) after oral administration in steady state. Mean values for area under the blood concentration-time curve (AUC), time to maximal blood concentration (tmax), maximal blood concentration (Cmax) and elimination half-life (t1/2,z) were similar to results of previous studies in transplant patients. The variation between patients was large. No significant correlations of pharmacokinetic data with biochemical or histological parameters were found. Because of the high variability of pharmacokinetic parameters, patients with PBC treated with CS-A need to be regularly controlled for nephrotoxicity by estimation of serum creatinine and bioavailability (trough blood levels).

Effects of cyclosporine immunosuppression in insulin-dependent diabetes mellitus of recent onset.

Type I diabetes may be an autoimmune disorder, although the evidence is largely circumstantial. The natural history of the disease after diagnosis includes partial remission in most patients, but only about 3 percent achieve transient insulin independence. beta Cell function, as indicated by the plasma concentration of C-peptide, is lost over 6 to 30 months and islet cell antibodies disappeared over 1 to 2 years. This article describes a pilot study in which 41 patients were treated with the immunosuppressive agent cyclosporine for 2 to 12 months. Of 30 patients treated within 6 weeks of diagnosis, 16 became insulin independent with concentrations of plasma C-peptide in the normal range and decreasing titers of islet cell antibodies. Of 11 patients who entered the study 8 to 44 weeks after diagnosis, two achieved this state. These results indicate that a controlled trial of the effects of cyclosporine in type I diabetes should be conducted.

Fluproquazone: analgesic activity in outpatients with non-migrainous headache.

The analgesic activity of 4-(p-fluorophenyl)-1-isopropyl-7-methyl-2(1H)-quinazolinone (fluproquazone) was investigated in three separate controlled studies including 131 outpatients with non-migrainous headache. By means of the patients' self-assessment of pain intensity and pain relief, 25 mg and 50 mg doses were shown to be effective according to some parameters of analgesic effect; a 100-mg dose was more effective, being significantly different from placebo for all parameters of analgesia. Fluproquazone 50 mg was as active as acetylsalicylic acid 1000 mg and slightly less active than a combination of propyphenazone 220 mg and allobarbital 30 mg. Except for the occurrence of vomiting in one patient after fluproquazone 50 mg and 100 mg. the drug was well tolerated.

Antipyretic activity of fluproquazone in man.

A multicentric, double-blind, randomized, parallel-group study was performed in patients with fever of diverse origin to test the tolerance and the antipyretic activity of single oral doses of 4-(p-fluorophenyl)-1-isopropyl-7-methyl-2(1H)-quinazolinone (fluproquazone) (200 mg, n = 18), acetylsalicylic acid (ASA) (1000 mg, n = 22) and placebo (n = 19). Whereas with placebo mean rectal temperature remained constant, a continuous fall was recorded with both active medications over the whole 3-h study period. With fluproquazone normalization of body temperature was nearly reached. Fluproquazone was more effective than placebo (p less than 0.001) and ASA (p less than 0.1), which in turn was more active than placebo (p less than 0.0001). No specific side-effects occurred.

Assessment of analgesics in dental surgery outpatients.

The usefulness of the dental outpatient model for evaluating the efficacy of mild analgesics, first described by Cooper and Beaver, is demonstrated in five separate, double-blind, randomised, single-dose, parallel-group studies. Pain intensity and pain relief were recorded at hourly intervals for 3 h following the administration of aspirin 1000 mg and placebo. In all five studies aspirin was significantly more effective than placebo, with relatively small variability of the response between the studies. The method is simple, reliable and sensitive and complements the inpatient studies of postoperative pain hitherto more frequently used.

Non-migrainous headache for the evaluation of oral analgesics.

1 Eight double-blind, randomized, placebo-controlled, single-dose, cross-over studies were carried out to evaluate the usefulness of testing the acute analgesic effect of drugs in out-patients with non-migrainous headache. 2 The reference compounds were either (1) aspirin, (2) a combination of aminopyrine, caffeine and butalbarbital (Optalidon), and (3) a combination of (2) with dihydroergotamine (Tonopan). 3 The test compounds were (1) proquazone, (2) fluproquazone and (3) and (4), new formulations of Optalidon and Tonopan in which the aminopyrine was replaced by propyphenazone. They were all found to be active. 4 A significant, dose-response relationship was established for aspirin (250, 500 and 1000 mg). 5 It is concluded that the non-migrainous headache model is a practical, reproducible and sensitive method for the investigation of the acute efficacy of analgesics.

Analgesic effect of fluproquazone in postoperative patients.

In 4 double-blind, randomized, stratified, parallel group studies, single oral doses of fluproquazone (75 to 200 mg), a new nonsteroidal anti-inflammatory analgesic, were compared with aspirin (1,000 mg) and placebo in a total of 672 hospitalized patients with moderate or severe pain following episiotomy or other surgical interventions. A dose-dependent effect of fluproquazone which was highly significantly superior to placebo and which resembled the effect of aspirin with respect to onset, degree, and duration was noted in all studies. Fluproquazone, 100 to 150 mg, was found to be approximately equiactive to 1,000 mg of aspirin and better tolerated.