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Pemphigus foliaceus and proteinuria occurred in a patient with cystinuria treated with alpha-mercaptopropionylglycine. This drug is similar to D-penicillamine in structure and function, and it is being used in patients who are unable to tolerate D-penicillamine. Although side effects of D-penicillamine are common, no major adverse reactions have been reported previously with alpha-mercaptopropionylglycine. Pemphigus foliaceus and proteinuria occurring during therapy with alpha-mercaptopropionylglycine and D-penicillamine are discussed.

Effects of oral administration of tiopronin (2-mercaptopropionylglycine) on acute liver damage induced in rats by intraperitoneal administration of carbon tetrachloride (CCl4) were investigated. Tiopronin suppressed increase in serum transaminase activity, accumulation of liver triglyceride and decrease of liver glucose-6-phosphatase activity induced by CCl4. CCl4 induced a significant decrease of nonprotein thiol (NPSH) in the liver 24 hr after administration, but this decrease did not result in an increase of nonprotein disulfide in the liver. Tiopronin suppressed the decrease in NPSH induced by CCl4, but did not influence NPSH in normal rats 24 hr after administration. In addition to these biochemical findings, it was also noted that tiopronin prevented necrosis and decrease of glycogen in liver, as determined histologically. Other compounds such as cystamine, cysteine and glutathione proved to have a preventive effect on CCl4-induced liver damage as in the case of tiopronin. It was revealed that such preventive effect correlated to some extent with NPSH content in liver as well as serum transaminase activity and histological findings.

The influences of methylene blue (MB), thionine, ascorbic acid (ASA), sodium thiosulfate (STS), N-(2-mercaptopropionyl)-glycine (MPG) and reduced glutathione (GSH) on methemoglobin-(MHb)-emia and sulf-hemoglobin (SHb)-emia induced by 4-chloroaniline (4-Cl-A) i.p. were studied. Preventive or therapeutic effect on MHb-emia and preventive effect on SHb-emia in mice: MHb formation was inhibited by MB i.p. whether it was administered simultaneously with or after 4-Cl-A, but SHb formation was increased. Similar effects were seen with thionine. Both compounds proved to have MHb and SHb forming activities. STS or MPG, if administered i.p. simultaneously with 4-Cl-A, inhibited formation of MHb, but exerted no effect on delayed SHb formation. However, if administered i.p. or i.v. 120 minutes after 4-Cl-A when the peak of MHb formation had passed, there was a preventive effect on delayed SHb formation. GSH inhibited MHb formation and prevented SHb formation only when it was administered i.v. 120 minutes after 4-Cl-A. ASA did not inhibit MHb formation when it was administered either i.p. or i.v., but showed a preventive effect on SHb formation, if administered 120 minutes after 4-Cl-A. Combined i.v. administration of the corresponding doses to the clinical ones of MB and ASA 120 minutes after 4-Cl-A showed a therapeutic effect on MHb-emia and a preventive effect on SHb-emia. However, at higher dose levels, MB masked the preventive effect of ASA on SHb-emia. Therapeutic effect on SHb-emia in mice and rats: None of MB, STS, GSH and ASA proved to have any therapeutic effects for established SHb-emia. On the basis of these results, significance of clinical usage of drugs in the treatment of chemically induced MHb-emia and SHb-emia is discussed.

The effectiveness of alpha-MPG management was evaluated in terms of changes in the liver cell depuration fraction in patients who presented reduced a levels. There was a marked improvement occasionally to the point of normalisation, in patients with toxic hepatosis. Variations were less significant in cirrhosis, especially in patients with a very low liver metabolism flow. No conclusions could be draw in the case of subjects with chronic heaptitis of various aetiology, since their DF was normal under basal conditions. It seems reasonable to suppose that further improvements are obtainable from prolonged administration of the drug.

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.

We report 2 cases of cystinuria in which a nephrotic syndrome developed during treatment with alpha-mercaptopropionylglycine. This syndrome resolved after withdrawal of the drug and it did not recur when the alpha-mercaptopropionylglycine was given again in lower doses. The hypothesis is made that the nephrotic syndrome was dose-related. The alpha-mercaptopropionylglycine must be used in doses less than 50 mg./kg per day with regular monitoring of 24-hour urinary protein in cystinuric children.

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.

Contents of high energy phosphates in the isolated perfused rat heart were followed during ischemia and reperfusion using 31P NMR spectroscopy. Application of 2-mercaptopropionylglycine resulted in significantly higher content of ATP in the reperfusion phase whereas during ischemia no differences between control and therapy hearts were found. Analysis of postischemic mitochondrial function reveals that improved ATP level is paralleled by an increased respiratory control index and a reduced ATPase activity. It is suggested that 2-mercaptopropionylglycine may cause increase of high energy phosphates during reperfusion by improving mitochondrial oxidative phosphorylation.

7 children, 20 months to 11 years old, with cystinuria and renal calculi were studied. Surgical treatment and alpha-mercaptopropionylglycine (MPG) gave satisfactory results in 5 children. The causes of the recurrences in the other 2 children are discussed. MPG therapy is effective but can cause a nephrotic syndrome at a dose of more than 50 mg/kg/day. A cystinuria of less than 200 mg/day cannot always be considered safe in children. The alkalinization and dilution of urine remain extremely important in the treatment of cystinuria.

Sixteen patients with cystinuria have been treated with Thiola for 0.5-4 years. Only two of the patients had recurrence of stones because of initial inadequate dose. The excretion of free cystine and the mixed Thiola-cysteine disulphide in the urine has been measured on an automatic amino acid analyser. Thiola has less side effects than D-penicillamine with respect to bone marrow, kidney, liver, gastrointestinal tract and skin. No chelating properties on urinary excretion of copper and zinc were observed during Thiola treatment. We conclude that successful treatment will depend on determining an individual dose of Thiola for every patient and from monitoring free cystine and Thiola-cysteine disulphide in the urine.

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.

Oxygen radicals may have an important role in the shock process. Several studies showed that stimulated polymorphological granulocytes altered biological membranes to a varying degree, especially in the pulmonary circulation. It could be demonstrated on isolated mitochondria that substances of the thiol group carrying SH-groups are capable of counteracting this damaging influence of toxic O2-metabolites. Furthermore the use of the thiol reagents was associated with an improvement in the mitochondrial energy situation (adenosine triphosphate increase). A total of 12 dogs were included into the study. Using standardised conditions haemorrhagic shock was induced by controlled bleeding. After reaching a mean blood pressure of 40 mmHg and a stabilisation of this stage, alternatively either 250 mg of alpha-mercaptopropionylglycine (therapy group T) or an equivalent volume of physiologic saline (controls K) were administered at random. In the dogs on controlled respiration the effect of the above-mentioned substance upon the haemodynamic of the total organism was monitored by means of continuous measuring of the arterial pressure by a Swan-Ganz catheter. Furthermore the acid-base balance, the electrolytes sodium, potassium and calcium were analyzed. Whereas the sodium and potassium values as well as the acid-base balance did not show any difference between both groups, the haemodynamic parameters partly showed very distinct differences, however, without being statistically significant in most cases. The administration of the thiol reagent (group T) led to a reduction in mean arterial pressure, heart rate, peripheral resistance and rate-pressure product. As far as the survival rate at the end of the study was concerned, no difference between the control and therapy group was seen.(ABSTRACT TRUNCATED AT 250 WORDS)

Cystinuria is an inherited disorder of amino acid transport affecting the epithelial cells of the renal tubules and the gastro-intestinal tract. Treatment consists of the prophylaxis of recurrent urolithiasis, which is the clinical manifestation of the disease. Long-term treatment with alpha-mercapto-propionyl-glycine (MPG; Thiola) promises to be successful. 3 cytinuric patients with recurrent urolithiasis underwent treatment over a period of 6 months. Therapy was controlled by regular follow-up investigations of the urinary excretion and serum levels of cystine and di-basic amino acids. The results did not indicate any permanent decrease in cystine excretion. No recurrence of renal calculi was observed. The possibility is discussed of a direkt mechanism of action of the drug on the metabolism of the involved amino acids.

The "Urocystin Test" has been used as a screening procedure for the diagnosis of the incidence of cystinuria in Ioannina District (Northwest Greece). From the 210 investigated urine samples, eight were positive and four of them were also L-cystine stone formers. All positive cases belong to two cystinuric families. The pedigree in village "Kato-Lapsista" is a genetic type of a "completely recessive cystinuria" while the other one in "Marmara" is the type of an "incompletely recessive cystinuria". All patients with L-cystine urolithiasis, except one child, were treated with the drug Thiola.

The isolated perfused working rat heart model of cardiopulmonary bypass and ischaemic cardiac arrest has been used to investigate whether addition of various organic anti-oxidants to the St Thomas' Hospital cardioplegic solution can enhance the recovery of function of the rat myocardium after normothermic (37 degrees C) global ischaemic arrest. Five anti-oxidants were studied: (i) ascorbate (1.0 and 10.0 mmol.litre-1), (ii) methionine (1.0 and 10.0 mmol.litre-1), (iii) reduced glutathione (1.0 and 10.0 mmol.litre-1), (iv) dimethylthiourea (0.1, 1.0, 10.0 and 50.0 mmol.litre-1), (v) N-2-mercaptopropionyl glycine (0.1, 1.0 and 10.0 mmol.litre-1). The recovery of aortic flow in control hearts which were free of anti-oxidant was 50.7(SEM 0.5)%; ascorbate (1.0 or 10.0 mmol.litre-1) improved this recovery to 72.1(1.7) and 70.2(0.3)% respectively; methionine (1.0 and 10.0 mmol.litre-1) improved the recovery to 74.1(5.7)% and 67.7(1.7)%, respectively; reduced glutathione (1.0 and 10.0 mmol.litre-1) improved the recovery to 66.7(1.4)% and 74.0(1.7)% respectively. In further studies, the addition of dimethylthiourea (0.1, 1.0 and 10.0 mmol.litre-1) to the cardioplegic solution failed to improve recovery of aortic flow [47.3(8.0), 24.6(7.3), 48.0(7.7)% respectively] when compared to its anti-oxidant free control value of 40.4(6.1)% and at a concentration of 50.0 mmol.litre-1 a very poor recovery of aortic flow of 7.7(4.8)% was observed. Mercaptopropionyl glycine (0.1, 1.0 and 10.0 mmol.litre-1) also failed to improve the recovery of aortic flow [34.7(1.6), 34.7(7.7) and 25.6(5.4)% respectively.2+ Since biological membranes are highly permeable to dimethylthiourea and mercaptopropionyl glycine, it is possible that they accumulate in the intracellular compartment.(ABSTRACT TRUNCATED AT 250 WORDS)

We have compared 2-mercaptopropionylglycine (MPG) with D-penicillamine in its capacity to reduce the urinary excretion of cystine by patients with cystinuria. Satisfactory ion-exchange chromatographic methods for the measurement of urinary MPG, D-penicillamine, cystine and the cysteine-disulfides of the two drugs have been developed, and we have established the time course of the excretion of these substances after oral intake of each drug. MPG was found to be approximately one and a half times as effective as D-penicillamine, both in reducing urinary excretion of free cystine and in the amounts of mixed disulfide which appeared in the urine.

In the basic treatment of 25 cases of classic or ARA defined rheumatoid arthritis, Tiopronin (alpha-mercaptopropionylglycine) was used for one year. The results obtained showed its therapeutic efficacy, as proven by the remission or improvement in humoral indexes of phlogosis and the suspension or dose reduction of steroid drugs and/or FANS in a high percentage of treated patients (84%). Nephrotic syndrome (1:25) and ageusia (1:25) were the most important side effects. These are common to the other sulfhydryl drugs and probably connected with a particular genetic predisposition in rheumatoid patients.

The effects of 60 min pretreatment with the enkephalinase inhibitor acetorphan were assessed on naloxone-precipitated (2.5 mg/kg IP) abstinence in chronically morphinized rats. In addition, the antinociceptive activity of the compound was investigated in mice. Intraperitoneal injection (50 mg/kg) in rats attenuated some aspects of the opioid withdrawal syndrome such as burrowing, wet dog shakes, squeal on touch hostility, tachypnoea, ptosis and rough hair, whereas jumping and escape behaviour were significantly increased in acetorphan-treated animals. No effect was observed on withdrawal hypothermia or acute weight loss. Similarly, chronic dosing with acetorphan after withdrawal produced no significant effect on body weight. Acetorphan (50 mg/kg IP) failed to produce any antinociceptive activity in the mouse tail immersion test, but potentiated the antinociceptive effect of D-Ala2-D-Leu5-enkephalin. These results are discussed in terms of acetorphan crossing the blood-brain barrier before being hydrolysed to thiorphan, thus yielding opioid withdrawal relieving effects.

The results of using alpha-mercapto-propionyl-glycine treatment (500 mg i.v. pro die for a time varying from one to four months) in a group of 25 patients suffering from aregenerative enteropathy with differing aetiopathogenesis are reported and compared with 29 control patients, i.e. patients suffering from the same situation and not treated with the drug. Morphological (by optical and electronic microscope) and functional (absorption of oleic acid, xylose and B12) study of the small intestine showed up the effectiveness of alpha-mercapto-propionyl-glycine on the trophism of small intestine mucosa, by way of normalization of intestinal cytokinetics, in aregenerative enteropathies due to special physiopathological situations (gastroresection) or to drugs (cytostatics, etc.) inhibiting enterocytic regeneration.

Some parameters (serum antioxidant activity, -SH groups, ceruloplasmin, copper) involved in the mechanisms of defence against oxygen free radicals were investigated in 25 rheumatoid patients and in 15 control subjects, matched for sex and age. When comparing the results obtained in the two groups, there is in rheumatoid arthritis a marked increase in the serum-specific antioxidant activity, related to ceruloplasmin, ESR, haemoglobin and Ritchie's index and a net decrease in the -SH groups inversely related to Ritchie's index and to ceruloplasmin. On analysing the sensitivity of the various parameters in discriminating between rheumatoid and healthy subjects, it is found that the -SH groups are the most sensitive, followed by the specific antioxidant activity, copper content, and ceruloplasmin. The evaluation of the same parameters in a group of 14 rheumatoid patients before and after 6 months of therapy with an antioxidant drug, viz. Tiopronin, confirms their usefulness in providing information regarding response to the treatment and on the recovery from the disease.

Two hundred rheumatoid patients were prospectively studied over a five-year period. One hundred and three received tiopronin (T) and 97 were treated with gold thiosulphate (GTS). At the end of the five-year period, similar percentages of patients dropped out because of lack of efficacy or because of major toxicities. Likewise, the percentages of patients still receiving the original drug in the two drug regimens at the 5th year of follow-up were 27.8% (GTS) vs. 25.2% (T), respectively.

Two sisters with hereditary glutathione synthetase deficiency (5-oxoprolinuria) were investigated. Assays of erythrocyte enzyme levels in relatives revealed additional clinically healthy carriers. The girls had chronic metabolic acidosis, which was corrected by substitution with bicarbonate. They had an increased rate of hemolysis which was well compensated. Their granulocyte function was normal when tested in vitro. In both girls mental retardation developed progressively without additional clinical neurological symptoms. Their electroretinograms were abnormal indicating disturbed retinal electrophysiological function. Therapeutic trials were performed with oral administration of glutathione (Tathion), mercaptopropionylglycine (Thiola) and vitamin E. None of these compounds had an effect on the urinary excretion of 5-oxoproline, acid-base balance, pathological electroretinograms or the clinical condition. Initially, Thiola therapy increased the low levels of glutathione in patient erythrocytes but after several months of treatment the concentration of glutathione declined to pretreatment levels. There was no indication that orally administered glutathione, mercaptopropionylglycine or vitamin E had a beneficial effect in the doses used. Nevertheless, vitamin E administration has been continued in addition to the correction of acidosis with sodium bicarbonate.

The synthesis of triethylphosphine gold complex with the alpha-mercaptopropionylglycine ethyl ester (compound 3) is reported. The new compound shows an antiinflammatory and antiarthritic activity superior to auranofin.

At the beginning of the four chapters on phenomena, analysis, pathophysiology and therapy of cystinuria the essentials of the published literature are summarized. The frequency of cystinuria is in the order of 1:10,000. Besides the cystine lithiasis occurring in nine tenths of all cystinuria patients neurological diseases may also be observed. All commonly applied methods to analyze cystine detect the sum of cystine and cysteine. Cystinuria is characterized by a higher cystine excretion, up to the 100-fold of the normal. Also the concentrations of lysine, arginine and ornithine in the urine of cystinuria patients are elevated, caused by intestinal and renal transport defects. Inevitable damage of renal parenchyma by multiple operations can drastically be reduced by the therapy with D-penicillamine or alpha-mercaptopropionylglycine. The disadvantages of that formation of soluble asymmetric disulfides are the side effects, such as nausea, gastric difficulties and dermatosis, occurring in up to 50% of the patients. Using the especially developed method with HPLC separation and electrochemical detector with a mercury electrode, cystine and cysteine are analyzed simultaneously. In the urine of healthy persons the molar concentration of cysteine is in the same order as cystine. But in cystinuria the cysteine concentration in urine is about a thousand times less than that of cystine. These results are evidence that a shifted redox-equilibrium of cystine-cysteine is also typical of cystinuria. The molar cysteine percentage of cysteine in healthy persons is increased from 30 to 50% by oral ascorbic acid administration. Therefore a vitamin C therapy for cystinuria is developed. 31 cystinuria patients who receive 5 g of vitamin C a day show a decrease in the cystine concentration of about 40%. Up to now, no side effects have been observed. The most obvious sign of the positive effect of the proposed vitamin C therapy for cystinuria is the missing cystine sediment in fresh urine.