Action of Bacopa monnieri to antagonize cisplatin-induced emesis in Suncus murinus (house musk shrew).

Bacopa monnieri (BM, family Scrophulariaceae) is used in several traditional systems of medicine for the management of epilepsy, depression, neuropathic pain, sleep disorders and memory deficits. The present study investigated the potential of BM methanol (BM-MetFr) and BM n-butanol fractions (BM-ButFr) to reduce chemotherapy-induced emesis in Suncus murinus (house musk shrew). Cisplatin (30 mg/kg, i.p.) reliably induced retching and/or vomiting over a 2 day period. BM-MetFr (10-40 mg/kg, s.c.) and BM-ButFr (5-20 mg/kg, s.c.) antagonized the retching and/or vomiting response by ∼59.4% (p < 0.05) and 78.9% (p < 0.05), respectively, while the 5-HT3 receptor antagonist, palonosetron (0.5 mg/kg, s.c.), reduced the response by ∼71% (p < 0.05). The free radical scavenger/antioxidant, N-(2-mercaptopropionyl)-glycine (30-300 mg/kg, s.c.) reduced the retching and/or vomiting response occurring on day one non-significantly by 44% (p > 0.05). In conclusion, the n-butanol fractions of BM have anti-emetic activity comparable with palonosetron and MPG. BM may be useful alone or in combination with other anti-emetic drugs for the treatment of chemotherapy-induced emesis in man.

Synthetic and natural antioxidants attenuate cisplatin-induced vomiting.

BACKGROUND: Synthetic and natural antioxidants including Bacopa monnieri (L.) Pennell (Scrophulariaceae) which also possess anti-dopaminergic properties, have been proposed to be useful for emetogenic chemotherapy. In this study, synthetic [N-(2-mercaptopropionyl) glycine (MPG), vitamin C (Vit-C)] and natural [grape seed proanthocyanidin (GP), B. monnieri n-butanolic fraction (BM-ButFr)] antioxidants and their combinations were evaluated against cisplatin-induced emesis in pigeons during a 24 h observation period. METHODS: Emesis was induced using cisplatin (7.0 mg/kg, i.v). MPG (10, 20, 30 mg/kg), Vit-C (100, 200, 300 mg/kg), GP (50, 100, 150 mg/kg) and BM-ButFr (5, 10, 20 mg/kg) and their combinations were administered i.m., 15 min before cisplatin administration. The number of vomiting bouts, retching, emetic latency and % weight loss were recorded to assess antiemetic potential. Antioxidant activity was evaluated by the DPPH free radical scavenging assay (FRSA). RESULTS: Significant attenuation of vomiting bouts, retching, % weight loss along with an increase in latency was produced by all the antioxidants and their combinations compared to cisplatin alone and this is the first report of this activity of GP in pigeons. Low EC50 values in the FRSA for MPG (67.66 µg/mL), Vit-C (69.42 µg/mL), GP (6.498 µg/mL) and BM-ButFr (55.61 µg/mL) compared to BHT standard (98.17 µg/mL) demonstrated their radical scavenging capacity. Correlation between the antioxidant activity and antiemetic efficacy disclosed a high degree of correlation for the tested antioxidants. CONCLUSION: The selected synthetic and natural antioxidants and their combinations were able to attenuate cisplatin-induced vomiting, which correlated with their potent in vitro antioxidant activity.

Prospective analysis of tiopronin in prevention of sorafenib and antiviral therapy inducing liver toxicity in advanced hepatitis B virus-related hepatocellular carcinoma.

Hepatotoxicity induced by sorafenib and antiviral therapy is a limitation for its continuation treatment for patients with advanced hepatitis B virus-related hepatocellular carcinoma (HCC). This prospective study determined the efficacy of tiopronin in hepatotoxicity prevention of HBV-related HCC treatment. Eighty-two patients (median age, 50 years; 71 % male) of advanced HCC treated with sorafenib and antiviral therapy were included, of whom 40 were given the supplementation of tiopronin. The primary endpoint was liver function which was checked before the treatment and every week during the therapy. Besides, course discontinuations, dose reductions, HBV DNA levels and treatment efficacy were evaluated. Patient characteristics and liver function were comparable (p > 0.05). The proportion of abnormal liver function was significantly lower in tiopronin group than in control group including alanine transaminase (ALT, p = 0.035), aspartate aminotransferase (AST, p = 0.041), total bilirubin (TBIL, p = 0.021) and albumin (ALB, p = 0.001). Rates of course discontinuations (p = 0.024) and dose reductions (p = 0.046) were significantly lower in tiopronin groups, and disease control rate (p = 0.036) was higher. No difference was found in HBV DNA level. Multivariate regression analysis showed that sorafenib (OR 7.837; 95 % CI 3.845-15.333; p = 0.004), antiviral therapy (OR 3.871; 95 % CI 1.572-9.569; p = 0.044) and hepatoprotective drug (OR 3.007; 95 % CI 1.321-6.308; p = 0.046) played important roles in clinical outcome. Tiopronin tends to prevent the HCC patients from the treatment-induced hepatotoxicity, enhance patients' tolerance to sorafenib and antiviral therapy and even improve the cancer treatment efficacy.

The role of tiopronin for the prevention of chemotherapy-related liver toxicity in advanced colorectal cancer patients treated with mFOLFOX7: a prospective analysis.

AIMS AND BACKGROUND: Chemotherapy-related hepatotoxicity is a limitation for the continuation of chemotherapy in patients with advanced colorectal cancer (CRC). This prospective study determined the efficacy of tiopronin infusion in chemotherapy-induced hepatoxicity. METHODS AND STUDY DESIGN: One hundred and fifty patients having advanced CRC treated with first-line palliative chemotherapy were included, of whom 86 were treated with mFOLFOX7 plus supplementation of tiopronin and 64 were treated with the same regimen without tiopronin. Aspartate aminotransferase (AST), alanine transaminase (ALT), lactate dehydrogenase (LDH), total bilirubin (TBIL), gamma-glutamyl transferase (γ-GT), alkaline phosphatase (ALP), and albumin (ALB) were recorded before treatment and during every therapy cycle. In addition, course discontinuations, dose reductions, and chemotherapy efficacy were evaluated. RESULTS: The age and gender of the two groups were comparable (P >0.05). The proportions of abnormal mean ALT (P = 0.042), AST (P = 0.045), TBIL (P = 0.044) and ALB (P = 0.043) were significantly lower in the tiopronin group than the control group. Course discontinuations (P = 0.002), dose reductions (P = 0.005) and efficacy (P = 0.012) were significantly different between the two groups. Multivariate logistic regression analysis showed that the hepatoprotective drug played an important role in clinical outcome (OR = 6.837; 95% CI, 1.845 to 25.333; P = 0.004). CONCLUSIONS: Tiopronin tends to decrease the incidence of chemotherapy-induced hepatoxicity, enhance patients' tolerance to mFOLFOX7 treatment, and even benefit the efficacy of chemotherapy.

The protective role of thiola and soybean seeds against the genotoxicity induced by potassium dichromate in mice.

The genotoxic potential of potassium dichromate (K(2)Cr(2)O(7)) was evaluated in vivo in mice using different mutagenic end points. Chromosomal aberrations in bone-marrow and spermatocytes as well as sperm abnormalities in the tested mice were determined. The doses used were 3, 6, 12 mg K(2)Cr(2)O(7)kg(-1) body weight which correspond to 1/16, 1/8, 1/4 the experimental LD(50), respectively. The protective roles of i.p. injection with thiola (a synthetic sulfhydryl compound) at 20 mg kg(-1) body weight and feeding treatment with soybean seeds (30% of the diet) were also studied. For chromosomal aberration analysis, subacute treatment for a period of 3 weeks were performed. All the tested doses of K(2)Cr(2)O(7) induced a statistically significant increase in the percentage of chromosomal aberrations in both somatic and germ cells with dose and time relationships. The percentage of the induced chromosomal aberrations was significantly minimized in all groups of mice i.p. treated with thiola or fed soybean seeds during the period of treatment. Potassium dichromate also induced a significant increase (P<0.01) in the percentage of abnormal sperms at the doses 6 and 12 mg kg(-1) body weight. Such percentage reached 7.52+/-0.45, 5.50+/-0.53 and 4.28+/-0.45 in mice treated with the highest tested dose of K(2)Cr(2)O(7), K(2)Cr(2)O(7) and thiola; K(2)Cr(2)O(7) and soybean, respectively compared with 2.14+/-0.33 for the control. In conclusion, the results demonstrate the genotoxic effect of potassium dichromate in mice. The results also confirm the protective role of thiola and soybean seeds against the genotoxicity of potassium dichromate.

A comparative study of radioprotection by Ocimum flavonoids and synthetic aminothiol protectors in the mouse.

The radioprotective effects of two flavonoids, orientin (Ot) and vicenin (Vc), obtained from the leaves of Ocimum sanctum, and the synthetic compounds WR-2721 and MPG (2-mercaptopropionyl glycine) have been compared by examining chromosome aberration in cells of bone marrow in irradiated mice. Healthy adult Swiss mice were injected intraperitoneally (i.p.) with 50 micrograms kg-1 body weight of Ot or Vc; 20 mg kg-1 of MPG; 150 mg kg-1 of WR-2721 or double distilled water (DDW). They were exposed to whole body irradiation of 2.0 Gy gamma radiation 30 min later. After 24 h, chromosomal aberrations were studied in the bone marrow of the femur by routine metaphase preparation after colchicine treatment. Radiation (2 Gy) increased the number of aberrant cells from less than 1% in controls to almost 20%. Pre-treatment with all the protective compounds resulted in a significant reduction in the percentage of aberrant metaphases as well as in the different types of aberration scored. Vc produced the maximum reduction in percent aberrant cells while MPG was the least effective; Ot and WR-2721 showed an almost similar effect. However, WR-2721 was the most effective against reduction of complex an almost similar effect. However, WR-2721 was the most effective against reduction of complex aberrations, followed by Vc. Neither flavonoids had any systemic toxicity, even at 200 mg kg-1 body weight. Considering the low dose needed for protection and the high margin between the effective and toxic doses, the ocimum flavonoids may be promising for human radiation protection.

Studies of hypoxemic/reoxygenation injury: with aortic clamping. X. Exogenous antioxidants to avoid nullification of the cardioprotective effects of blood cardioplegia.

This study tests the hypothesis that reoxygenation of cyanotic immature hearts when starting cardiopulmonary bypass produces an "unintended" reoxygenation injury that (1) nullifies the cardioprotective effects of blood cardioplegia and (2) is avoidable by adding antioxidants N-(2-mercaptopropionyl)-glycine plus catalase to the cardiopulmonary bypass prime. Twenty immature piglets (2 to 3 weeks) underwent 30 minutes of aortic clamping with a blood cardioplegic solution that was hypocalcemic, alkalotic, hyperosmolar, and enriched with glutamate and aspartate during 1 hour of cardiopulmonary bypass. Of these, six piglets did not undergo hypoxemia (blood cardioplegic control) and 14 others remained hypoxemic (oxygen tension about 25 mm Hg) for up to 2 hours by lowering ventilator fraction of inspired oxygen before reoxygenation on cardiopulmonary bypass. The primary solution of the cardiopulmonary bypass circuit was unchanged in eight piglets (no treatment) and supplemented with the antioxidants N-(2-mercaptopropionyl)-glycine (80 mg/kg) and catalase (5 mg/kg) in six others (N-(2-mercaptopropionyl)-glycine and catalase). Myocardial function (end-systolic elastance), lipid peroxidation (myocardial conjugated diene production), and antioxidant reserve capacity were evaluated. Blood cardioplegic arrest produced no biochemical or functional changes in nonhypoxemic control piglets. Reoxygenation caused an approximate 10-fold increase in conjugated production that persisted throughout cardiopulmonary bypass, lowered antioxidant reserve capacity 86% +/- 12%, and produced profound myocardial dysfunction, because end-systolic elastance recovered only 21% +/- 2%. Supplementation of the cardiopulmonary bypass prime with N-(2-mercaptopropionyl)-glycine and catalase reduced lipid peroxidation, restored antioxidant reserve capacity, and allowed near complete functional recovery (80% +/- 8%).** Lipid peroxidation (conjugated diene) production was lower during warm blood cardioplegic reperfusion than during induction in all reoxygenated hearts, which suggests that blood cardioplegia did not injure reoxygenated myocardium. We conclude that reoxygenation of the hypoxemic immature heart causes cardiac functional and antioxidant damage that nullifies the cardioprotective effects of blood cardioplegia that can be avoided by supplementation of the cardiopulmonary bypass prime with antioxidants (*p < 0.05 vs blood cardioplegic control; **p < 0.05 vs reoxygenation).

[The use of MPG in preventing the post-reperfusion injury of an epigastric island flap: an experimental study in rats]. / O uso de MPG na proteção da lesão pósreperfusão do retalho epigástrico em ilha: estudo experimental em rato.

The objective of this work was to study the protective effects of the free radical scavenger N2-mercaptopropionylglycine used in a rat model of reperfusion of epigastric island flaps submitted to transient occlusion of their vascular pedicles. In one group the epigastic vein of the flap was occluded for 5 hours. In the second group the epigastric artery was occluded for 21 hours and in the third group both the epigastric vein and artery were occluded for 8 hours. The scavenger or equivalent volume of saline solution was injected 10 minutes before the vascular occlusion and 10 minutes before declamping. The flap viability was assessed on the seventh day after flap reperfusion. In the three types of vascular occlusion a significant, and differential, increase of the areas of flap survival was observed. The protective effect of N2-mercaptopropionylglycine in reperfusion injuries was demonstrated.

Naloxone-reversible antidiarrheal effects of enkephalinase inhibitors.

Thiorphan and acetorphan, two potent inhibitors of enkephalinase (EC 3.4.24.11 membrane-metalloendopeptidase) significantly reduced the castor oil-induced diarrhea in rats when administered intravenously (or orally, for acetorphan) but not when administered intracerebroventricularly. These effects were more marked during the 90 min period following the castor oil challenge but were still significant up to 4-8 h after the latter. Acetorphan was about 6 times more potent than thiorphan. The antidiarrheal activity of both compounds was completely prevented in rats receiving naloxone subcutaneously but not intracerebroventricularly (in the case of thiorphan). In contrast to loperamide, a peripherally acting opiate receptor agonist, the enkephalinase inhibitors did not significantly reduce gastrointestinal transit as measured in the charcoal meal test. The antidiarrheal activity of enkephalinase inhibitors therefore seems attributable to protection of endogenous opioids, presumably outside the brain, and to reduction of intestinal secretion rather than transit.

N-2-mercaptopropionylglycine improves recovery of myocardial function after reversible regional ischemia.

Myocardial reperfusion after reversible regional ischemia is known to result in delayed recovery of contractile function, but the mechanism responsible for this phenomenon remains unclear. We examined the ability of N-2-mercaptopropionylglycine, a synthetic thiol compound with oxygen free radical scavenging properties, to attenuate postischemic dysfunction in open chest dogs undergoing a 15 minute occlusion of the left anterior descending coronary artery followed by 4 hours of reperfusion. Treated animals received an infusion of N-2-mercaptopropionylglycine (50 mg/kg per h) for 4 hours starting 15 minutes before coronary occlusion. Collateral flow, as determined with radioactive microspheres after 10 minutes of ischemia, was 0.07 +/- 0.01 ml/min per g (mean +/- SE) in both control (n = 20) and treated (n = 13) groups. The occluded vascular bed, as determined by postmortem perfusion, averaged 26.1 +/- 1.2% of the weight of the left ventricle in control and 29.6 +/- 1.3% in treated animals. Systolic wall thickening (an index of regional function) was assessed with an epicardial pulsed Doppler probe. The two groups exhibited comparable systolic thickening under baseline conditions and similar degrees of dyskinesia during ischemia. Nevertheless, recovery of function (expressed as percent of baseline) was considerably greater in the treated dogs at 1 hour (44.6 versus 12.8%, p = 0.05), 2 hours (64.0 versus 31.6%, p less than 0.02), 3 hours (77.1 versus 36.7%, p less than 0.01) and 4 hours of reperfusion (75.0 versus 40.0%, p less than 0.05). Thus, N-2-mercaptopropionylglycine produced a significant and sustained improvement in recovery of contractile function after a brief episode of regional myocardial ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

[Cystine stone therapy with mercapto-propyonyl-glycine (MPG) (Thiola) (author's transl)]. / Cystinsteintherapie mit Mercaptopropyonylglycin (MPG) (Thiola)

Six patients with recurrent cystine stones and cystinuria were treated with MPG. Three patients were treated for 3 years and 3 patients for 6 months. A relatively high dosage resulted in a reduction of the cytinuria. Since MPG has almost no side effects it represents a valuable aid in the treatment of cystine stones.