Studies of the inhibitory activities of tiopronin and mercaptosuccinic acid on glutathione peroxidase and their cytotoxic and antioxidant properties.

Glutathione peroxidase (GPx), an important antioxidative enzmye, can be inhibited by various thiols, including of tiopronin and mercaptosuccinic acid (MSA). Recently, there has been discussion regarding the combination of tiopronin in anticancer therapy to overcome acquired resistance to anticancer drugs. However, thiols are also known to act as antioxidants, which can be contraindicated in cancer chemotherapy. This article focuses on the inhibitory effects of tiopronin and MSA on bovine and human glutathione peroxidase activities, and their effects on the redox status of cancer cells. IC50 values for the inhibition for the bovine erythrocyte enzyme were 356 and 24.7 µM for tiopronin and MSA, respectively, with the corresponding Ki values of 343 µM and 14.6 µM, respectively at pH 7.4 and 25 °C. MSA inhibited human GPx activity in human cancer cell lysates at its IC50 while tiopronin did not. Both compounds were cytotoxic to human cancer cell lines GUMBUS and HL-60, with IC50 values between 42.7 and 149.4 µM. Neither had an effect on cell cycle. Only MSA induced apoptosis in HL-60 cells but not in GUMBUS cells, while tiopronin resulted in no apoptosis in either cell line. Combination studies of the MSA with hydrogen peroxide in living cells enhanced the production of reactive oxygen species in GUMBUS cells while tiopronin acted as antioxidant in HL-60 cells. MSA and tiopronin antagonized the cytotoxic effect of cisplatin, doxorubicin and methotrexate in combination studies. Our findings indicate that the antioxidant properties of both thiols prevail over their GPx inhibitory activity in human cancer cell lines.

Investigating the effect of antioxidant treatment on the protective effect of preconditioning in anesthetized rabbits.

Reactive oxygen and nitrogen species are critical in preconditioning (PC). We sought to determine the effect of N-2-mercaptopropionyl glycine (MPG) on infarct size and on the oxidative status. Rabbits were exposed to 30-minute regional ischemia of the heart, which was followed by 3-hour reperfusion: (1) a control group without further intervention, (2) a PC1 group that was subjected to one cycle of PC, (3) a PC4 group that was subjected to 4 cycles of PC, (4) an MPG group that was treated with MPG for 60 minutes, starting 10 minutes before reperfusion, (5) MPG-PC1, and (6) the MPG-PC4 groups that were treated with the same dose of MPG and with 1 or 4 cycles of PC, respectively. Blood samples were drawn and collected for metabonomic analysis. In another series of experiments, 6 groups respective to the described ones were subjected to 30-minute regional ischemia of the heart and 20 minutes of reperfusion, after which pieces of heart tissue were quickly excised for malondialdehyde, nitrotyrosine, and glutathione content assessment. All PC and MPG groups developed smaller infarct size compared with control (16.5% ± 3.9%, 13.7% ± 3.1%, 18.6% ± 5.0%, 9.7% ± 2.0%, 15.0% ± 2.8% vs. 48.05% ± 7.2%; P < 0.05). MPG did not prevent lipid peroxidation and nitrotyrosine formation but enhanced the glutathione content. PC and MPG induced similar nuclear magnetic resonance changes. Long MPG infusion reduces the infarct size without abolishing the effect of PC, providing novel insights into the activity of MPG in PC.

Nephrotic syndrome occurring during tiopronin treatment for cystinuria.

Cystinuria is an autosomal recessive disorder characterized with abnormal tubular reabsorption of cystine and dibasic amino acids leading to cystine urolithiasis. The classical form is caused by mutations in the SLC3A1 gene (OMIM 220100). The cornerstone of the treatment is high hydration and alkalization of the urine to achieve urine pH between 7.0 and 7.5, at which point, cystine solubility in the urine is optimal. These measures very often fail, and thus addition of sulfhydryl agents like penicillamine and tiopronin (mercaptopropionyl glycine) is recommended. Herein, we report a 3-year-old boy with cystinuria resulting in recurrent nephrolithiasis requiring surgery and extracorporeal shock wave lithotripsy. Nine months after introduction of tiopronin, the boy manifested generalized edema, oliguria, and biochemical indices of nephrotic syndrome. Tiopronin was withdrawn, and the boy was given only supportive treatment. Within 10 days, he entered into clinical and biochemical remission. Pediatricians should be aware of this adverse effect of tiopronin, and therefore, testing of the urine with strips or sulfosalicylic acid at least once weekly at home may be very helpful for early detection of proteinuria.

Protective effects of tiopronin against oxidative stress in severely burned patients.

OBJECTIVE: Tiopronin is an antioxidant. This study investigated the protective effect of tiopronin on oxidative stress in patients with severe burns. METHOD: Patients aged between 16 and 65 years old with >30% body surface area burns admitted to our burn unit from July 2011 to September 2016 were randomly divided into 3 groups: group A treated with tiopronin (15 mg/kg. 24 hrs), group B with vitamin C (792 mg/kg. 24 hrs), the other group with standard treatment (group C). All 3 groups also received standard treatment. Blood superoxide dismutase (SOD), malondialdehyde (MDA), and the biochemical indexes of liver, kidney, and heart were determined before treatment and 24 and 48 hrs after treatment. Samples from 8 normal healthy adult volunteers were also measured. The resuscitation fluid volume requirement for the first 24 hrs was calculated for 3 groups. RESULTS: The serum levels of MDA and the biochemical indexes in severely burned patients were higher than those in healthy volunteers (P<0.01). The serum SOD level of burn patients was lower (P<0.01). After treatment, the levels of SOD increased, the levels of MDA decreased, and the biochemical indexes of heart, liver, and kidney improved; these changes were more obvious in group A and group B compared to group C (P<0.05), and these changes were more obvious in group A compared to group B (P<0.05) at 48 hrs after treatment. There is less resuscitation fluid volume requirement to maintain adequate stable hemodynamic and urine output in the first 24 hrs in group A and group B compared to group C (P<0.05). CONCLUSION: Treatment with tiopronin could exert protective effects against burn-induced oxidative tissue damage and multiple-organ dysfunction, and also could reduce the volume of required fluid resuscitation in severely burned patients.

Effect of increasing doses of cystine-binding thiol drugs on cystine capacity in patients with cystinuria.

Appropriate dosing of cystine-binding thiol drugs in the management of cystinuria has been based on clinical stone activity. When new stones form, the dose is increased. Currently, there is no method of measuring urinary drug levels to guide the titration of therapy. Increasing cystine capacity, a measure of cystine solubility, has been promoted as a method of judging the effects of therapy. In this study, we gave increasing doses of tiopronin or D-penicillamine, depending on the patients' own prescriptions, to ten patients with cystinuria and measured cystine excretion and cystine capacity. The doses were 0, 1, 2, 3 g per day, given in two divided doses, and administered in a random order. Going from 0 to 1 g/day led to an increase in cystine capacity from - 39.1 to 130.4 mg/L (P < 0.009) and decreased 24 h cystine excretion from 1003.9 to 834.8 mg/day (P = 0.039). Increasing the doses from 1 to 2 to 3 g/day had no consistent or significant effect to further increase cystine capacity or decrease cystine excretion. Whether doses higher than 1 g/day have additional clinical benefit is not clear from this study. Limiting doses might be associated with fewer adverse effects without sacrificing the benefit of higher doses if higher doses do not offer clinical importance. However, trials with stone activity as an outcome would be desirable.

Influence of Tiopronin on the Metabolism of Alcohol in Healthy Subjects.

Drug safety- and drug-alcohol interaction studies have mainly been conducted for frequently prescribed drugs with high financial interests. Orphan drugs such as tiopronin (ORPHA25073) are often neglected in terms of clinical research. Tiopronin is a drug that is mainly used for the treatment of cystinuria. In this study, the interaction of tiopronin regarding the metabolism of alcohol (primary objective), and the safety of tiopronin in combination with alcohol was tested in healthy volunteers.In this randomised, double-blind, cross-over study, 13 healthy subjects received 500 mg tiopronin or an identical looking placebo 1 h before the intake of 0.8 g of alcohol per kg of bodyweight. Blood alcohol concentrations were measured over the course of 12 h after consumption. The experiment was repeated 7 days later with the previous placebo group receiving the active drug and vice-versa. Changes in blood alcohol AUC and elimination rate k were analysed using a 2-tailed t-test. Further acetaldehyde concentrations were measured. Additionally, the concentration ability of the subjects was tested and any adverse effects were recorded.There was no significant change in blood alcohol or acetaldehyde concentration. Significant differences in concentration tests refer presumably to learning effects. No serious adverse event occurred. All adverse events were reversible and there was no significant difference in occurrence between drug and placebo group.It was demonstrated that tiopronin does not affect the metabolism of alcohol. Intake of tiopronin in combination with alcohol has no safety implications on healthy subjects.

Delayed ischemic preconditioning activates nuclear-encoded electron-transfer-chain gene expression in parallel with enhanced postanoxic mitochondrial respiratory recovery.

BACKGROUND: Delayed ischemic preconditioning promotes cardioprotection via genomic reprogramming. We hypothesize that molecular regulation of mitochondrial energetics is integral to this cardioprotective program. METHODS AND RESULTS: Preconditioning was induced by use of 3 episodes of 3-minute coronary artery occlusion separated by 5 minutes of reperfusion. Twenty-four hours later, infarct size was reduced by 58% after preconditioning compared with sham-operated controls (P<0.001). Cardiac mitochondria were isolated from sham and preconditioned rat hearts. Mitochondrial respiration and ATP production were similar between the groups; however, preconditioned mitochondria exhibit modest hyperpolarization of the inner mitochondrial membrane potential (> or =22% versus control, P<0.001). After 35-minute anoxia and reoxygenation, preconditioned mitochondria demonstrated a 191+/-12% improvement in ADP-sensitive respiration (P=0.002) with preservation of electron-transfer-chain (ETC) activity versus controls. This augmented mitochondrial recovery was eradicated when preconditioning was abolished by the antioxidant 2-mercaptopropionyl glycine (2-MPG). These biochemical modulations appear to be regulated at the genomic level in that the expression of genes encoding rate-controlling complexes in the ETC was significantly upregulated in preconditioned myocardium, with a concordant induction of steady-state protein levels of cytochrome oxidase, cytochrome c, and adenine nucleotide translocase-1. 2-MPG abolished preconditioning induction of these transcripts. Moreover, transcripts of nuclear regulatory peptides known to orchestrate mitochondrial biogenesis, nuclear respiratory factor-1 and peroxisome-proliferator-activated receptor gamma coactivator 1alpha, were significantly induced in preconditioned myocardium. CONCLUSIONS: Delayed preconditioned mitochondria display increased tolerance against anoxia-reoxygenation in association with modifications in mitochondrial bioenergetics, with concordant genomic induction of a mitochondrial energetic gene regulatory program. This program appears to be mediated by reactive oxygen species signaling.

Adjuvant N-(2-mercaptopropionyl)-glycine in blood cardioplegia does not improve myocardial protection in ischemically damaged hearts.

Oxyradicals potentially limit the myocardial protection provided by blood cardioplegia in ischemically damaged hearts. We tested the hypothesis that the addition to blood cardioplegic solution of a new oxyradical scavenger--N-(2-mercaptopropionyl)-glycine--would result in improved left ventricular performance and oxygen consumption compared to that resulting from the use of blood cardioplegia alone. Gauges and transducer-tipped catheters for left ventricular minor axis ultrasonic dimension were placed in 17 open-chest dogs, and instantaneous left ventricular pressure-diameter data were acquired by computer. The aorta was crossclamped for 30 minutes during total vented bypass to induce ischemic injury. The heart was reoxygenated and protected by multidose, hypothermic blood cardioplegic solution alone (n = 9) or enhanced with 0.0132 mmol N-(2-mercaptopropionyl)-glycine (n = 8) for 1 hour of cardioplegia-induced arrest. Preischemic and postischemic left ventricular performance was measured by slope changes in end-systolic pressure-diameter relations induced by gradual afterload reduction during right heart bypass. When blood cardioplegia alone was used, postischemic left ventricular systolic performance was depressed by 73.2% +/- 10.0% (166.8 +/- 56.1 mm Hg/mm versus 25.1 +/- 7.0 mm Hg/mm). N-(2-mercaptopropionyl)-glycine did not significantly attenuate this functional depression (62.7% +/- 9.0%, 146.6 +/- 67.6 mm Hg/mm versus 33.6 +/- 11.9 mm Hg/mm). The postischemic end-diastolic pressure-diameter relation was shifted to the right, whereas chamber stiffness was increased comparably, with or without N-(2-mercaptopropionyl)-glycine. Postischemic oxygen consumption in the beating working state, calculated from left ventricular blood flow (measured by microspheres) and arterial-coronary sinus oxygen extraction, averaged 7.8 +/- 0.9 ml O2/100 gm/min with blood cardioplegia alone and 7.5 +/- 1.0 ml O2/100 gm/min with N-(2-mercaptopropionyl)-glycine, and was unchanged from paired preischemic values in both groups. We conclude (1) that N-(2-mercaptopropionyl)-glycine added to blood cardioplegic solution in the dose and delivery regimen tested did not improve ventricular systolic and diastolic performance compared with blood cardioplegia alone and (2) that postischemic oxygen consumption may not parallel the extent of left ventricular functional recovery.

Studies on prolonged acute regional ischemia. V. Metabolic support of remote myocardium during left ventricular power failure.

This study tests the hypothesis that metabolic support of remote "nonischemic" myocardium during acute infarction will reverse the trend toward cardiogenic shock. Thirty-seven dogs underwent ligation of the left anterior descending coronary artery and 50% stenosis of the circumflex coronary artery. Irreversible ventricular fibrillation developed in 11 of them. The 26 survivors were observed for up to 6 hours; global and regional left ventricular function (cardiac index, stroke work index, ultrasonic crystals) and regional blood flow (radioactive microspheres) were measured. After 2 hours, eight dogs received an intravenous infusion of glutamate/aspartate, glucose-insulin-potassium, coenzyme Q10, and 2-mercapto-propionyl-glycine for 4 hours. Five dogs received the mannitol infusion to raise serum osmolarity 30 mOsm. Four additional dogs received the intravenous substrate infusions over 4 hours without undergoing ischemia. The substrate infusion for 4 hours caused no change in regional or global cardiac function in the four control dogs. Three of nine untreated dogs died of cardiogenic shock, and progressive left ventricular power failure occurred in the six others (40% decrease in cardiac index, 50% decrease in stroke work index, p less than 0.05) because of persistent dyskinesia in the left anterior descending region (-40% of systolic shortening, p less than 0.05) and hypocontractility in the circumflex region (48% of control systolic shortening, p less than 0.05), despite normal transmural blood flow in the posterior left ventricular wall (76 ml/100 gm/min). In contrast, in treated dogs, hypercontractility recovered in the circumflex segment (138% of systolic shortening) and stroke work index rose to control levels (91%) without a change in regional blood flow. Mannitol infusion did not improve hemodynamics or avoid the development of progressive left ventricular power failure. We conclude that cardiogenic shock after myocardial infarction is due, in large part, to impaired ability of "nonischemic" myocardium to maintain hypercontractility. This limitation can be prevented by metabolic support of viable muscle, and the data imply that intravenous substrate infusions may be helpful before definitive treatment (i.e., coronary artery bypass grafting) is undertaken.

Radioprotective effect of combinations of WR-2721 and mercaptopropionylglycine on mouse bone marrow chromosomes.

The radioprotective and toxic effects of low to moderate doses of S-2-(3-aminopropylamino)ethyl phosphorothioic acid (WR-2721) and its combination with mercaptopropionylglycine (MPG, 20 mg/kg body wt) on the chromosomes of the bone marrow cells of Swiss albino mice were studied at 24 h and 14 days postirradiation. Significant protection against radiation-induced chromosome aberrations was observed with 50 mg/kg WR-2721. The protection increased with the dose of the drug administered, and the degree of protection per unit dose increment was more pronounced at lower than at higher doses. A combination of WR-2721 and MPG given before exposure resulted in a significantly greater number of normal metaphases at 24 h postirradiation compared to the respective single-drug treatment groups. On Day 14 postirradiation, when the presence of WR-2721 resulted in an increase in the frequency of aberrant cells, combination with MPG helped to reduce this value markedly, especially at WR-2721 doses below 200 mg/kg. On the basis of these results it is suggested that 150 mg/kg WR-2721 may be considered an optimum dose for combination with MPG for protection of chromosomes of bone marrow cells when repeated drug administrations are not needed. Changes in the level of glutathione (GSH) in the blood were studied at different times following the administration of 150 mg/kg WR-2721 and its combination with MPG (20 mg/kg) before sham irradiation or exposure to 4.5 Gy 60Co gamma rays. The results showed that WR-2721 elevated blood GSH levels significantly above normal values by the time radiation was delivered, while MPG did not. Glutathione appears to have an important role in the action of WR-2721, while protection by MPG may not be mediated through GSH. Injection of MPG after WR-2721 helps to maintain the higher GSH level for a longer duration compared to treatment with WR-2721 alone. It is possible that MPG delays the metabolism of GSH.

Changes in body temperature and metabolic rate following microinjection of Met-enkephalinamide in the preoptic/anterior hypothalamus of rats.

The effects of Met-enkephalinamide (MET-ENKamide) on brain temperature (Tb) and metabolic rate (MR) were assessed following direct administration into the preoptic/anterior hypothalamus (PO/AH) of freely moving rats. Bilateral microinjections of saline or MET-ENKamide (1-25 micrograms/microliter) were delivered through cannula guide tubes previously implanted in nine animals. Thiorphan, an enkephalinase inhibitor, was microinjected into the PO/AH of two of the animals. All injections were made remotely at an ambient temperature of 22 +/- 1 degree C in a volume of 1 microliter. Measurements of Tb (via a brain-dwelling thermistor) and MR were recorded continuously. The ability of naloxone to antagonize the effects of MET-ENKamide was investigated by fashioning a double-barreled injection cannula to fit within each guide tube; 1 microliter of saline or naloxone (1-10 micrograms) was delivered bilaterally into the PO/AH followed by 1 microliter of MET-ENKamide (25 micrograms) 5-10 min later. PO/AH administration of MET-ENKamide (1-25 micrograms) produced dose-dependent increases in Tb preceded by dose-dependent increases in MR, with a characteristic time course of approximately 30 min. Naloxone antagonized the rise in Tb and MR, either partially or completely, depending on dose. When administered alone, naloxone had no effect on Tb or MR. Microinjection of thiorphan (10 micrograms) into the PO/AH evoked increases in Tb and MR that were similar to those responses induced by MET-ENKamide. These results support a role for endogenous Met-enkephalin in the regulation of Tb in the rat.

"Two-route chemotherapy" using high-dose intra-arterial neocarzinostatin and systemic tiopronin, its antidote, for rat limb tumor.

We studied the effect of "two-route chemotherapy" (TRC) with intra-arterial (IA) neocarzinostatin (NCS) and IV N-(2-mercaptopropionyl)-glycine (tiopronin), its antidote, on rat limb tumors. Chemotherapy experiments were carried out on day 9 after the inoculation of 10(6) syngeneic transitional carcinoma cells into the hind limb in female Wistar King A rats. In the group given TRC, 3500 units/kg NCS and 800 mg/kg tiopronin were given via the femoral artery and the femoral vein, respectively. The antitumor effect was evaluated by the tumor weight on day 12 after the treatment. Compared with the weight of tumors in untreated controls, TRC reduced tumor weight to one-tenth, while 700 units/kg IA NCS alone reduced tumor weight to one-third and 700 units/kg systemic NCS alone reduced tumor weight to three-fourths of the control weight. In the group given TRC, WBC and nucleated bone marrow cells were completely protected and loss of body weight was slight.

Naloxone-insensitive potentiation of neurotensin hypothermic effect by the enkephalinase inhibitor thiorphan.

The hypothermic effect of neurotensin (0.1 microgram) injected i.c.v. in mice is potentiated by the enkephalinase inhibitor thiorphan (10 micrograms, i.c.v.). This potentiation is not reversed by systemic naloxone. The hypothermic effect of neurotensin is not modified by the amino-peptidase inhibitor bestatin (50 micrograms, i.c.v.) nor by the angiotensin-converting enzyme inhibitor captopril (50 micrograms, i.c.v.). These data indicate the involvement of enkephalinase in the inactivation of neurotensin, at least when it is injected i.c.v.

Electroacupuncture and morphine analgesia potentiated by bestatin and thiorphan administered to the nucleus accumbens of the rabbit.

The endogenous opioid peptide enkephalin (EK) is known to be degraded mainly by two enzymes, the dipeptidyl carboxypeptidase 'enkephalinase' and aminopeptidase. Microinjection of the enkephalinase inhibitor thiorphan or the aminopeptidase inhibitor bestatin into the nucleus accumbens of the rabbit produced a dose-dependent analgesic effect. This analgesic effect was totally reversed by the narcotic antagonist naloxone or by antibodies against [Met5]enkephalin (MEK) administered to the same site. Antibodies against [Leu5]enkephalin were not effective. Moreover, microinjection of thiorphan or bestatin into the nucleus accumbens resulted in a marked potentiation of the aftereffect of electroacupuncture (EA) produced analgesia, as well as the analgesia induced by a small dose of morphine. It is concluded that the analgesic effect elicited by EA and morphine is mediated, at least in part, by MEK-like immunoreactive substance(s) in the nucleus accumbens.

Delayed onset and decreased incidence of diabetes in BB rats fed free radical scavengers.

We tested the hypothesis that free radicals play a role in the selective destruction of pancreatic beta-cells in BB/Wor rats. Diabetes-prone BB rats of both sexes and 40 days of age were divided into three groups. The control group was fed ad libitum Purina rat chow powder, while the experimental group was fed ad libitum the rat chow powder blended with a mixture of four known free radical scavengers: allopurinol, mercaptopropionylglycine, dimethylthiourea and Vitamin E. A third group was pair-fed 10 g chow powder/rat/day, since in earlier experiments we observed that rats on the experimental diet consumed only about 10 g/rat/day. All rats were studied up to age 120 days. Body weight and food intake were measured daily. Urine was tested for glucose beginning at age 60 days. When glucosuria appeared, blood glucose and urinary ketones were measured. Body weight gain in the experimental and pair-fed groups was similar, but lower than the control group. Life table analysis of the data showed a decreased and a delayed onset of diabetes in the rats fed free radical scavengers. Thus, the results of this study demonstrated that calorie restriction and the related impaired growth did not affect the incidence of diabetes in the BB rat. In addition, the results suggested a role for free radicals in the spontaneous destruction of pancreatic beta-cells in the BB rat.

Origin of the stimulation of food intake by oral administration of enkephalinase inhibitors in sheep.

The influence of two enkephalinase inhibitors (thiorphan and acetorphan) orally, parenterally and centrally administered on food intake was tested in hay-fed ewes. When orally administered at a dose of 1 mg/kg, acetorphan, but not thiorphan, produced a biphasic increase in food intake corresponding to a 17.0% increase of daily food intake. Similarly thiorphan (0.1 mg X kg-1) IV administered increased by 19.3% the daily food intake; in contrast acetorphan IV administered produced a early (0-2 h) decrease followed by a late increase in hay consumption without significant (P greater than 0.05) change in the daily food intake. When ICV administered (10 micrograms X kg-1) thiorphan but not acetorphan at the same dose depressed the early (0-2 h) and daily food intake by 43.2% and 25.4% respectively. Pretreatment with naltrexone (0.1 mg X kg-1 IV) blocked the increased food intake induced by oral acetorphan or IV acetorphan and thiorphan but did not affect the anorectic effects of ICV thiorphan. We conclude that enkephalinase inhibitors like thiorphan and acetorphan increase daily food intake in sheep probably by increasing enkephalin levels in peripheral tissues.

Long-term outcome with gold thiosulphate and tiopronin in 200 rheumatoid patients.

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.

2-Mercaptopropionylglycine affords enhanced radioprotection after a liposome encapsulation.

Use of radioprotective drugs in radiotherapy is desirable to protect normal tissues. 2-mercaptopropionylglycine (MPG) has shown promising results in experimental radioprotection. In this report, a liposome drug delivery system for MPG has been used in Swiss albino mice exposed to 1 to 8 Gy whole body Gamma-irradiation to test whether or not this modality enhances the MPG afforded radioprotection. A statistically significant, dose dependent enhancement of protection by liposome encapsulated MPG (LEM) was observed. LEM, as compared to free MPG, improved the viabilities of spleen and bone marrow cells by factors between 1.11 and 2.23 for different doses of radiation.

Effects of 2-mercaptopropionylglycine on the development of X-ray-induced cataract in rats.

The effect of 2-mercaptopropionylglycine on the development of cataract induced by a single dose of X-ray (10 Gy) was investigated in rats. Intraperitoneal injection of 20 mg/kg, three times weekly starting 1 day after irradiation delayed the development of X-ray-induced cataracts significantly. The amounts of non-protein SH groups, malondialdehyde and the Na+/K+ ratio, in the lenses of rats post-treated with the drug were significantly maintained at normal levels even at 27 weeks after irradiation. On the other hand, a single administration of 250 mg/kg of the compound, 30 min prior to irradiation had no effect on cataract progression induced by X-ray.

Cystinuria in the dog: clinical studies during 14 years of medical treatment.

The purpose of this study was to summarize 14 years of clinical experience with medical treatment of 88 cystinuric dogs. Of special interest was evaluation of recurrence rate of cystine uroliths and adverse effects during long-term tiopronin treatment. Twenty-six different breeds were recognized, and the most common breeds were Dachshunds, Tibetan Spaniels, and Basset Hounds. In 76 of 88 treated dogs (86%), re-formation of cystine uroliths was prevented. Recurrence rate of cystine uroliths changed from 7 months before to 18 months during tiopronin treatment. On 28 occasions, bladder stones were found, and in about 60% of the dogs, the uroliths dissolved. Quantitative measurement of the urinary excretion of cystine showed a significantly (P < .03) higher excretion of cystine in dogs with recurrent urolith formation than in dogs with only 1 urolith episode. Another finding was a significant (P = .02) decrease in urinary cystine excretion in older (>5 years) than in younger (<5 years) dogs. Adverse effects were found in 11 dogs, and the most severe signs were aggressiveness and myopathy. All signs disappeared when tiopronin treatment was stopped. In conclusion, this study emphasizes the importance of an individual strategy for lifelong treatment of cystinuria. In addition to increasing water intake, chemical modification of the cysteine molecule into a more soluble form by means of tiopronin is useful. In dogs with re-formed cystine uroliths, dissolution may be induced by increasing the tiopronin dosage to 40 mg/kg body weight per day. In dogs with a low urolith recurrence rate and low urinary cystine excretion, the tiopronin dosage may be decreased or treatment discontinued.