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2-mercaptopropionylglycine

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General Features                  Clinical Study                  Chemical Intervention                 Pharmacological Aspects                 
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CHEMICAL INTERVENTION

Effective dose(experimental): Optimum dose of for protection is 20mg/kg i.p. in mice(it is far below its toxic dose)[1], [2], [3].
MPG 250 mg intravenously has been successfully given to cervical cancer patients[3].
It is mentioned in an article that MPG can be given to man with a dose comparable both to mice and man[3]
Mode of administration: Intraperitoneal[3].
Oral administration[4]is effective in humans[1].
Intravenous administration [5];however Tiopronin serious adverse reactions are more common in intravenous administration, the injection can cause parotid gland swelling, even anaphylactic shock[6].
Intragastric and intraperitoneal modes also offered radioprotection and radiomitigation[7].
Time of administration: Effective when applied both before and 1-5 hrs after irradiation(animal data)[8]
In majority of experiments it is found to be administered before irradiation[49],[50],[51]; however in an clinical evaluation with cervical patients ,significant radioprotection is obtained when MPG is given 15-20 minutes after irradiation[3]
Side Effects: Frequent:
Pain, swelling, tenderness of skin, rash, hives, itching, oral ulcers.
Occasional :
GI upset, taste or smell impairment, bloody or cloudy urine, chills, difficulty in breathing, high blood pressure, hoarseness, joint pain, swelling of feet or lower legs, tenderness of glands.
Rare :
Chest pain; cough; difficulty in chewing, talking, swallowing; double vision; a general feeling of discomfort; illness; weakness; muscle weakness; spitting up blood; swelling of lymph glands[4].
Combinatorial action with other drugs/therapies: Tiopronin is shown to increase the sensitivity of multiple drug resistant human cancer cells lines to certain chemotherapeutic drugs like etoposide, adriamycin[9], [10].
It antagonizes the mitogenic effect of Prolactin on the MCF-7 human breast cancer cell line, at non-toxic concentrations [11].
Pretreatment with either MPG or WR-77913 individually, or in combination could prevent the depletion in liver GSH levels and induction of lipid peroxidation after cyclophosphamide chemotherapy [12]; however in human lymphocytes and in polychromic erythrocytes of mice, it did not offer protection against damage caused by bleomycin and cyclphosphamide [13].
Ascorbic acid and MPG when given together, appearance Ehrlich-Heinz bodies in human venous red cells following in vitro intoxication was retarded [14].
In a study involving 110 patients, the combined application of Yinqin Ginggan Decoction (YQD) with tiopronin achieved good effect in the treatment of Alcohol Liver Disease (ALD) [15].
Studies in animals-
Combination of WR-2721 and 2-mercaptopropionylglycine is seen to be superior to the single-drug treatments in reducing GI injury and increasing survival [2]. This combination was also helpful in mitigating WR-2721 toxicity on mouse bone marrow chromosomes [16], [17]. Combination of these two at different doses as well as at different time of administration influences the overall effect [18]. Administration of 2-MPG after WR-2721 resulted in elevated levels of blood GSH for longer duration in normal and irradiated animals[17].
2-MPG exerts its hepatoprotective activity against isoniazid[19] and Adriamycin[20]induced hepatotoxicity and cardiotoxicity in rats by inhibiting the oxidative toxicity of drug and in Hela and RL♂1 tumor-bearing mice, nullifies the free radicals generated by antitumor drugs - Neocarzinostatin and SMANCS [21].
Cysteamine and MPG in combination is shown to be effective in reducing radiation(lower doses) induced prenatal mortality(decreased percentage of dead and resorbed embryos in mice[22].
Tiopronin alone in Wistar rats [23] as well as its combination with alpha tocopherol in albino gunia pigs showed to slow down the progression of cisplatin induced cochlear damage [24]. In rats, protective effects of tiopronin on cisplatin-induced nephotoxicity is also observed in vitro and in vivo with no reduction in antitumor activity of cisplatin[25], [26].
Complexing of Zn (II) with 2-MPG significantly enhanced its radioprotective activity in mice [27]. MPG with low dose radiation showed apparent radiosensitization of enzyme catalase owing to circumstantial interaction of MPG with Fe++/Fe+++ [28].
In mice MPG treatment in combination with suboptimal doses of AET did not recover leucocytopenia due to whole body gamma irradiation (760R and 1060R) [29] as well as survival of mice also couldn’t be achieved [30] ; in contrast, combined administration of MPG and aminothiols(AET, MEA, cysteine) before irradiation resulted in a synergistic radioprotective effect [8],[31] but when AET was given before irradiation and MPG after, no increase in effectiveness was found[31]; In investigators’ opinion, the contrast in results may be attributed to differences in dose rate, direction of irradiation, strain of animals and some environmental conditions[30].
HT (hydroxytryptophan) + MPG treatments though have failed to prevent the initial 59Fe uptake depression induced by the irradiation, have helped a speedy recovery in the iron uptake[32], the combination offered protection against whole body irradiation(against 10.5Gy but not against 12.5 Gy)[33].
An increase in radioprotection with increasing concentrations of MPG in the presence of EDTA at 266.4 Gy was observed[34].
Gold nanoparticles protected with Tiopronin and functionalized with Tat peptides is shown to be used to target nucleus [35]. Assembly of gold nanoparticles and tiopronin is shown to have cytotoxic effect on cancer cell lines[36].
Protection to mice bone marrow stem cells has been noted after whole body gamma ray exposure by prior treatment with combination of hydroxytryptophan (HT) and B-mercaptopropionylglycine (MPG) as studied by spleen colony forming method[37].
The preventive and therapeutic effects of (±)-tiopronin and (-)-tiopronin on leucopenia induced by cyclophosphamide were found[38].
Tiopronin combined with Vitamin E is found be clinically efficient for the treatment of alcoholic fatty liver disease[39].
MPG could reduce the leucopenia induced by some therapeutic agent like Mitomycin C, Prednisolone, Azathioprine[40].
Protected against genotoxicity induced by Potassium dichromate in mice[41]and also by benzo(a)pyrene in vitro and in vivo[42].
Contraindications: Drastic dietary changes, especially in sodium, should be avoided in cystinuria patients [43]. Fluid intake should be increased to maintain urine pH at a normal range of 6.5-7[4].
Caution is warranted with a history of penicillamine exposure; serious adverse reactions are more likely to occur[44], [4].
It is also contradicted in patients with history of agranulocytosis, aplastic anemia, or thrombocytopenia and hypersensitivity to tiopronin or its components[4].
An acute anti-hypertensive effect of anti-oxidant agent-thiopronine in hypertensive subjects and in both hypertensive and non-hypertensive diabetic patients is reported[45].
In one study, it appeared to be safe to administer tiopronin in patients with slight to moderate renal impairment [46].
A study indicated that Patients treated with tiopronin should be monitored for proteinuria[47]and also for the development of lipid abnormalities[48].
REFERENCES
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13. Formigli LM, Ferrari I, Grisolia CK, Evaluation of genotoxic and cytotoxic potential of thiola (N-2-mercaptopropionylglycine), a medicine used in the treatment of humans contaminated with mercury, Environ Mol Mutagen. 2002; 39(1):18-21.
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20. El-Missiry MA, Othman AI, Amer MA, Abdel-Aziz MA, Attenuation of the Acute Adriamycin-induced Cardiac and Hepatic Oxidative Toxicity by N-(2-Mercaptopropionyl) Glycine in Rats, Free Radic Res. 2001;35(5):575-81.
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22. Sharma P. and Saini MR, Modification of Radiation Induced Prenatal Mortality by Cysteamine, MPG and their Combination in Swiss Albino Mice, Ind. J. Nuc. Med. 2003;18(1 & 2): 12-18.
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