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Background: D-penicillamine-induced muscle disorders are well-known, tiopronine-induced disorders are less often reported., Case Report: A 62-year-old patient, given tiopronine for rheumatoid arthritis, developed severe polymyositis with characteristic clinical and pathology features. The course was favorable after tiopronine withdrawal and substitution with methotrexate., Discussion: Clinicians should be aware of the side-effects of tiopronine, particularly muscle disorders, and implement careful surveillance to achieve early diagnosis and appropriate therapy.

Myasthenia gravis (MG) is a well known side-effect of D-Penicillamine used in the treatment of rheumatoid polyarthritis. Tiopronin is another drug available in France, which can also induce MG. Drug-induced MG are characterized by frequent involvement of facial and oropharyngeal muscles. Moreover, the generalization is scarce and the outcome always quite good. No thymoma is present, anti-acetylcholine receptors antibodies are often highly positive. Furthermore, some HLA phenotypes are most frequently found among patients with drug-induced MG suggesting a genetic predisposition. This observation underlines the interest of careful management of patients treated by tiopronin.

From 1987 to 1990, 719 subjects (385 males and 334 females) were screened, by means of urocystin-kit, for cystinuria and cystine lithiasis, in Epirus district (North-West Greece). The positive results were confirmed by chromatographic analysis of urine amino acids and laboratory tests. Forty patients, belonging to six cystinuric families, were identified. These patients were excreting 3.1 +/- 1.7 mmol/24 h of cystine in urine. All patients were treated by per os administration of alpha-MPG in daily doses of 400-1,200 mg/24 h). We therefore report the results of a 4 +/- 2 year follow-up of these patients. We conclude that treatment with alpha-MPG is very effective with minimal side effects in patients suffering from cystinuria or cystine urinary calculi.

Thiopronin is a second line drug for rheumatoid arthritis with proven efficacy in controlled trials versus a placebo, D-penicillamine, or gold salts. This 4-month study was aimed mainly at comparing the efficacy and safety of two thiopronin regimens, i.e., 1 g/d for 2 weeks followed by 1.5 g/d (regimen A) versus 0.5 g/d for 1 month, 0.750 g/d during the second month, then 1 g/d (regimen B). Because earlier investigations have suggested a role for copper in the activity of D-penicillamine, a secondary goal of this study was to evaluate whether the clinical effects of thiopronin were related to changes in serum copper and ceruloplasmin levels. Among the 61 included patients, 32 received regimen A and 29 regimen B. The primary efficacy criterion was the physician's overall efficacy assessment. Efficacy was rated good or excellent in 65.5% of regimen A patients and 55.6% of regimen B patients. Eighteen of the 32 regimen A patients and 23 of the 29 regimen B patients experienced at least one adverse event (p = 0.055). Failure to tolerate the drug required withdrawal in 12 of the 32 regimen A patients (37.5%) versus 11 of the 29 regimen B patients (37.9%). Declines in serum copper and ceruloplasmin levels were not correlated with treatment efficacy or tolerance. These findings, together with previously reported data, suggest that treatment should be initiated in a dosage of 1 g/day and that thiopronin-related adverse events are not dose-dependent.

Sixteen rheumatoid arthritis patients were serologically examined, before and after a 2-month treatment with tiopronine (TP). The titer of agglutinating rheumatoid factor (RF) as well as the level of non-agglutinating RF were significantly reduced in serum and synovial fluid (SF). The functional affinity of the remaining RF was attenuated in serum (p less than 0.01) and SF (p less than 0.05). Conversely, the proportion of asialylated IgG was enhanced in serum (p less than 0.05) and SF (p less than 0.05). These findings would suggest that TP might restore the efficacity of sialyl transferase at the B lymphocyte level.

Fifteen patients with rheumatoid arthritis were treated with tiopronine, and an immunological check-up carried out before the onset and after a two-month treatment. The latex test titres decreased, and there was a significant fall in the levels of IgA-containing circulating immune complexes, in parallel with a depletion of plasma complement breakdown products. Patients displayed a decrease in CD8+T cells and in CD4+Leu 8-T cells and a high proportion of activated T lymphocytes. This returned to normal after treatment. Treatment with TP led also to a reduction of adherence and chemotaxis of polymorphonuclear cells.

One hundred and forty patients with classic or definite rheumatoid polyarthritis were treated with N2 mercapto-propionly-glycine: thiopronine (Acadione) at an average dose of 1 g per day over a mean duration of 11.7 months + 10.7 months. The retrospective study of these cases, followed between 1980 and 1988 by the same medical team, permits to evaluate the long-term tolerance of the product. Adverse reaction, always subsiding were observed in 55 p. cent of the patients, requiring discontinuation of the treatment in 40 p. cent of the cases. These side effects occur in 3/4 of the cases, during the first 6 months of the treatment. The intolerance mainly affect skin and mucosae: 46 cases (32.8 p. cent) resulting in 32 instances (22.8 p. cent) discontinuation of the treatment because of stomatitis, pruritus, various types of erythema, pemphigus (1 case). Fourteen patients presented a renal failure (10 p. cent) requiring in 8 instances (5.7 p. cent) discontinuation of the thiopronine because of nephrotic syndrome (3 case) and proteinuria (5 cases). Haematological disorders were observed in 13 instances (9.2 p. cent), justifying, in 10 instances (7.1 p. cent) discontinuation of the treatment because of thrombopenia or leucothrombopenia. The other side effects observed are the following: digestive disorders 15 cases (10.7 p. cent) requiring discontinuation of the treatment in 3 instances (2.1 p. cent), agueusia in 6 instances (4.2 p. cent) requiring discontinuation of the treatment in one case; miscellaneous disorders 13.5 p. cent for which the responsibility of thiopronine is not precisely established (especially hepatic cholostasis, muscle disorders), requiring discontinuation the the treatment in 1.4 p. cent of the cases.(ABSTRACT TRUNCATED AT 250 WORDS)

A study of patients with rheumatoid arthritis permitted us to note the interest of tiopronine (sulfhydryl compound of the d-penicillamine type) in the basic treatment of rheumatoid arthritis. The dose of the drug was on average, 1 gram daily, which, in one series of patients, was administered at the start of treatment and in another series, with an increase of dosage of 250 mg every 20 days. The results, judged by the reduction of the Ritchie and Lee index, of the E.R.S. and the steroid and non-steroid anti-inflammatory requirements, are good (very good and good) in 47% of cases. These patients were in an advanced stage of the disease and there had been numerous therapeutic failures. Side effects similar to those observed during treatment with D-penicillamine were present in 38% of cases, and in 31% required stopping treatment. It is likely that the frequency of stopping treatment for side effects was definitely exaggerated. The place of this new drug in the basic treatment of rheumatoid arthritis requires further study by a double blind test with D-penicillamine, and this is at present in progress.

The authors report the first results of the use of mercaptopropionyl-glycine (M.P.G.) in the solubilising and preventive treatment of cystine lithiasis. This substance results in the formation of a soluble cystine M.P.G. complex. It increases the solubility of cystine much more than D-penicillinamine. Twenty one cases of cystinuric cystine lithiasis were treated in this way, combined with forced diuresis, alkalinisation of the urine and uricolytic treatment. In 4 of their 21 patients, calculi disappeared completely, whilst in another 3 they decreased in size. Recurrence of lithiasis was avoided in 20 patients out of 21. These impressive results are similar to those in the brief literature concerned with the substance. Toxicity is virtually nil and its efficacy make this the drug par excellence for cystine lithiasis.

Prophylactic measures or dissolution by medical therapy was used to treat bladder cystine stones in 14 children over about a 10-year period. All patients received alpha-MPG (alpha-mercaptopropionylglycine) except one child allergic to alpha-MPG who was treated with DNP (D-penicillamine). In 10 patients the treatment was administered 11 times to dissolve the stones, with resulting total dissolution in 6 cases, partial removal in one case. Two patients are still under treatment and 2 cases failed to respond. Among the 12 patients receiving preventive therapy, only 2 cases were reported as developing recurrences, due in fact to irregular taking of medication. Lytic treatment proceeded without any particular problems, and results were more than satisfactory, but for preventive therapy the difficulty resides in its application and duration when confronted with the serious and frequent danger of a relapse.

2 mercapto propionyl glycine (tiopronine) has, like D-penicillamine, a thiol radicle; it is a powerful chelating agent of heavy metals. This analogy suggests that it may be used in rheumatoid arthritis. A preliminary double blind study lasting four months comparing 1g./day in 20 patients and a placebo in 10 patients showed slight (non significant) efficacy concerning all parameters. An open study using 1.5 g. daily is being carried out in 32 patients, and we note a beneficial effect on the morning stiffness, the joint index, the functional index, the prehension strength, the E.S.R., and the joint swelling. The side effects are similar to those of D-penicillamine: loss of taste, proteinuria, mucous ulceration, which required stopping treatment. The therapeutic effect within 4 months and was maintained for 18 months in the 15 patients under treatment. A new double blind trial comparing placebo and tiopronine at a dose of 1.5 g. daily is in progress.

The authors review the theoretical bases for the treatment of systemic scleroderma (SS) by D-penicillamine (DP). They then present a review of the papers published over the last 20 years on the subject. Although Rodnan's team has conducted studies against a control series and the majority of published works have concluded on the effectiveness of this treatment, there has not been any randomised prospective study, to date, to clearly demonstrate this effectiveness. The authors report a series of 14 patients with SS treated for a mean of 2 years with 900 mg/day of DP. DP seemed to be effective on the cutaneous lesions in 12 of the patients treated at a maximum of 3 years after the frank onset of the disease. Treatment failed in 2 patients who were only treated late in the disease. Objective results were obtained on the pulmonary lesion, but they are more difficult to interpret. 5 patients had to interrupt DP treatment because of intolerance. Tiopronine was tried in 4 of these patients with 3 interpretables follow-ups. This agent was well tolerated and effective in 2 of these 3 patients.

A long-term survey of 268 patients.--Tiopronin (Acadione) is a new long-term treatment of rheumatoid arthritis. To define the tolerance and the therapeutic maintenance, the data for 268 patients with rheumatoid arthritis who started a treatment with Tiopronine from January 1979 to December 1986 have been reviewed in December 1987. Tiopronin was started after a mean duration of rheumatoid arthritis of 14.1 +/- 8.2 years, at a mean daily dosage of 1.2 +/- 0.2 grammes. The efficacy of tiopronin was considered very good or good in 67 p. cent of the patients. Adverses effects led to stop the treatment in 27.7 p. cent of the patients: these adverses effects were similar to those observed with D-Penicillamine, but no crossed intolerance was noticed between tiopronin and D-Penicillamine. At the 72nd month of follow-up, tiopronin remained effective and well-tolerated in 40 p. cent of the patients. The efficacy and the high rate of prolonged therapeutic maintenance make tiopronin a new major long-term treatment of rheumatoid arthritis.

We report on a case of cystinuria in an adult woman without any familial or self stone-forming history. The first symptom appeared at 43 years, as an acute renal colic caused by an obstructing ureteral calculous. Hence, this case differs from the majority in its isolated form of presentation and its uncommon age of incidence. Two clinic aspects of cystinuria are emphasized: the precocity of recurrence or stone growth without treatment, and the success obtained frequently in relapses prevention with prophylactic measures (dietary patterns, urine alkalinisation), and continued medical therapy.

This article summarizes the authors' experience and data from the literature regarding acadione, a medication like D-penicillamine with a thiol radical, in the treatment of rheumatoid arthritis. Two control studies versus placebo and two control trial versus D-penicillamine prove the effectiveness of the treatment and demonstrate a similar activity between 1 g of acadione and 600 mg of D-penicillamine. The side-effects of acadione are similar of those of D-penicillamine, essentially rash, toxic dermatitis, agueusia, proteinuria, which disappear upon discontinuation of the treatment. The fact that the patient exhibited a side effect with D-penicillamine, increases, the risk with acadione, but this is not systematic, which is the main advantage of this product.

This study concerns 69 patients with rheumatoid arthritis (RA) and having received successively D-penicillamine (DP) then, after a mean period of 2 years, tiopronin (TP) at a daily dose of 1,500 mg. TP demonstrated an as frequent, as marked, and as prolonged effectiveness as that of DP. 28 patients are still under TP treatment, with a mean length of treatment of 43.7 months. The rate of effectiveness of TP was similar, whether or not the response to DP was favorable: 64.1 and 64.3 p. cent respectively; 72.4 p. cent of the 29 cases which did not respond to DP, responded favorably to TP. The manifestations of intolerance to TP were similar in nature (including the first reported case of obstructive bronchiolitis) and frequency to those observed with DP. There were only a few manifestations of crossed intolerance: the rate of TP discontinuation because of intolerance was the same, whether the DP was well tolerated (29.6%) or discontinued because of poor tolerance (30%). The same undesirable effect was only observed in 4 cases: one case of pemphigus, another case of toxic dermatitis, 2 proteinurias. This study confirms that TP represents a new, major long-term treatment of RA and demonstrates that this very product is an excellent take over medication.

This article summarises the authors' experience and the data of the literature concerning Tiopronine, a drug with a thiol function like D-penicillamine, in the treatment of rheumatoid arthritis. Two controlled trials versus placebo and two controlled trials versus D-penicillamine demonstrated the effectiveness of treatment and the identical action of 1 g of Tiopronine and 600 mg of D-penicillamine. The side effects of Tiopronine are very similar to those of D-penicillamine: essentially rash, toxiderma, aguestia, proteinuria, which resolve when treatment is stopped. Patients with a past history of side effects with D-penicillamine have an increased risk of developing side effects with Tiopronine, but this risk is not systematic, which constitutes the principal value of this drug.