Phase II study of Disulfiram and Cisplatin in Refractory Germ Cell Tumors. The GCT-SK-006 phase II trial.

BACKGROUND: Multiple relapsed/refractory germ cell tumor (GCT) patients have extremely poor prognosis. Cisplatin resistant testicular GCTs overexpress aldehyde-dehydrogenase (ALDH) isoforms and inhibition of ALDH activity by disulfiram is associated with reconstitution of cisplatin sensitivity in vitro as well as in animal model. This study aimed to determine the efficacy and toxicity of ALDH inhibitor disulfiram in combination with cisplatin in patients with multiple relapsed/refractory GCTs. METHODS: Disulfiram was administered at a dose of 400 mg daily until progression or unacceptable toxicity, cisplatin was administered at dose 50 mg/m2 day 1 and 2, every 3 weeks. Twelve evaluable patients had to be enrolled into the first cohort, and if 0 of 12 patients had treatment response, the study was to be terminated. The results of the first stage of the trial are presented in this report. RESULTS: Twelve patients with multiple relapsed/refractory GCTs were enrolled in the phase II study from May 2019 to September 2021. Median number of treatment cycles was 2 (range 1-6). None of patients achieved objective response to treatment, therefore the study was terminated in first stage. Median progression-free survival was 1.4 months, 95% CI (0.7-1.5 months), and median overall survival was 2.9 months 95% CI (1.5-4.7 months). Disease stabilization for at least 3 months was observed in 2 (16.7%) patients. Treatment was well tolerated, however, 5 (41.7%) of patients experienced grade 3/4 fatigue, 4 (33.3%) thrombocytopenia, 3 (25.0%) anemia, while 2 (16.7%) experienced neutropenia, nausea and infection. CONCLUSIONS: This study failed to achieve its primary endpoint and our data suggest limited efficacy of disulfiram in restoring sensitivity to cisplatin in multiple relapsed/refractory GCTs.

Role of oxidative stress, adiponectin and endoglin in the pathophysiology of erectile dysfunction in diabetic and non-diabetic men.

Erectile dysfunction (ED) and diabetes mellitus (DM) share common pathophysiological risk factors including endothelial dysfunction which together with hyperglycemia contribute to the increased oxidative/glycooxidative stress. A reduced NO concentration is insufficient for relaxation processes in the penis. Chronic inflammation and endoglin are involved in the regulation of endothelial function. Adiponectin from the adipose tissue has anti-inflammatory effects. Our study aimed to investigate the relation between erectile function in patients with and without DM and the oxidative stress, hormone adiponectin, and endothelial dysfunction marker endoglin. Men (n=32) with ED evaluated by the International Index of Erectile function (IIEF-5) questionnaire (17 without DM (NDM); 15 with type 2 diabetes mellitus (DM)) and 31 controls were included. Advanced glycation end products (AGEs), 8-isoprostanes (8-isoP), protein carbonyls, antioxidant capacity, adiponectin and endoglin were determined in the blood. DM patients compared to NDM patients and controls, had increased levels of glucose, C-reactive protein, triacylglycerols, 8-isoP, AGEs, endoglin and BMI. IIEF-5 score, NO and adiponectin levels were decreased. We are the first to find out that endoglin shows a negative correlation with erectile function in NDM, but not in DM patients. Endoglin can be considered as endothelial dysfunction marker in nondiabetic men suffering from ED.

Probiotics and vitamin C for the prevention of respiratory tract infections in children attending preschool: a randomised controlled pilot study.

BACKGROUND: This pilot study investigates the efficacy of a probiotic consortium (Lab4) in combination with vitamin C on the prevention of respiratory tract infections in children attending preschool facilities. SUBJECTS/METHODS: In a double-blind, randomised, placebo-controlled pilot study with children aged 3-6 years, 57 received 1.25 × 10(10) colony-forming units of Lactobacillus acidophilus CUL21 (NCIMB 30156), Lactobacillus acidophilus CUL60 (NCIMB 30157), Bifidobacterium bifidum CUL20 (NCIMB 30153) and Bifidobacterium animalis subsp. lactis CUL34 (NCIMB 30172) plus 50 mg vitamin C or a placebo daily for 6 months. RESULTS: Significant reductions in the incidence rate of upper respiratory tract infection (URTI; 33%, P=0.002), the number of days with URTI symptoms (mean difference: -21.0, 95% confidence interval (CI):-35.9, -6.0, P=0.006) and the incidence rate of absence from preschool (30%, P=0.007) were observed in the active group compared with the placebo. The number of days of use of antibiotics, painkillers, cough medicine or nasal sprays was lower in the active group and reached significance for use of cough medicine (mean difference: -6.6, 95% CI: -12.9, -0.3, P=0.040). No significant differences were observed in the incidence rate ratio or duration of lower respiratory tract infection or in the levels of plasma cytokines, salivary immunoglobulin A or urinary metabolites. CONCLUSIONS: Supplementation with a probiotic/vitamin C combination may be beneficial in the prevention and management of URTIs.

Effect of natural polyphenols (Pycnogenol) on oxidative stress markers in children suffering from Crohn's disease--a pilot study.

Crohn's disease (CD) is a nonspecific, chronic inflammatory disease of the gastrointestinal tract. It is supposed that in etiopathogenesis oxidative stress (OS) plays a role. However, its precise role in the active and non-active states of disease is not known yet. We conducted a pilot study focusing on the relationship between OS of CD in remission and the possibility to influence clinical parameters and markers of OS by polyphenolic extract, Pycnogenol® (Pyc). Compared to 15 healthy controls 15 pediatric CD patients (all were in remission according to their disease activity index - PCDAI) had reduced the activity of Cu/Zn-superoxide dismutase (SOD) and increased the oxidative damage to proteins. We found negative correlations between markers of inflammation (calprotectin, CRP) as well as between PCDAI and total antioxidant capacity (TAC). Activities of antioxidant enzymes, SOD, and glutathione peroxidase (GPX) negatively correlated with calprotectin and PCDAI. Pyc (2 mg/kg) positively influenced the parameters of OS in CD patients after 10 weeks of administration.

The effect of selected membrane active substances on erythrocyte deformability.

Aminoguanidine improved the erythrocyte filterability by 4%, pyridoxyliden-aminoguanidine by 11% and pyridoxal by 13% in healthy subjects. In diabetic patients the aminoguanidine effect on erythrocyte filterability was improved by 7%, PAG effect by 9% and pyridoxal effect by 15% in comparison to the control group. The other investigated haematological variables in both groups were within the range of the physiological standard. All of the tested substances demonstrated a mild protective influence on erythrocyte elasticity both in healthy subjects and diabetic patients. Significant elasticity improvement was obtained only by pyridoxal (p<0.01) in patients with diabetes mellitus. (Fig. 4, Ref. 18.).

Fluidising effect of resorcylidene aminoguanidine on sarcolemmal membranes in streptozotocin-diabetic rats: blunted adaptation of diabetic myocardium to Ca2+ overload.

The "remodelling" of cardiac sarcolemma in diabetes is believed to underlie the reduced sensitivity of diabetic hearts due to their overload with extracellular calcium. Along with a non-enzymatic glycosylation and the free radical-derived glycoxidation of sarcolemmal proteins there is ongoing reduction in cardiomyocyte membrane fluidity, the modulator of cardiac sarcolemmal functioning. Aminoguanidine derivatives, that inhibit glycation and glycoxidation, might suppress myocardium "remodelling" occurring in diabetic heart. To verify this hypothesis, we studied physical parameters of cardiac sarcolemma from the streptozotocin-induced diabetic rats (45 mg.kg(-1) i.m.) treated with resorcylidene aminoguanidine (RAG, 4 or 8 mg.kg(-1) i.m.). The treatment with RAG not only completely abolished protein glycation and a generation of free oxygen species (p < 0.001) in treated diabetic animals, but also considerably attenuated the decrease in sarcolemmal membrane fluidity (p < 0.001). In diabetic animals the "normalization" of the sarcolemmal membrane fluidity was accompanied by the vastly increased susceptibility of diabetic hearts to be overload with external calcium. We concluded that the decreased fluidity of the sarcolemmal membrane, apparently linked to the excessive glycation of sarcolemmal membrane proteins, might be intimately connected with the adaptation mechanism(s) that are likely to develop in diabetic heart to protect it against the overload with external calcium.

[Effect of vitamin C and E on nonenzymatic glycation and physico- chemical properties of isolated erythrocyte membranes in diabetic patients]. / Vplyv vitamínu C a E na neenzýmovú glykáciu a fyzikálno-chemické vlastnosti izolovaných membrán erytrocytov u diabetických pacientov.

Non-enzymatic glycation, accompanied by the formation of free radicals, represents a serious problem in diabetes mellitus. It is supposed to be the cause of the development of long-term diabetic complications. The aim of this work was to estimate the effect of treatment with vitamin C (1 g per day) and E (600 mg per day) on selected biochemical parameters as well as to determine the physicochemical state of erythrocyte membranes in diabetics. The paper also compares the physicochemical state of diabetic and control erythrocyte membranes. The changes in the values of glycaemia, glycated haemoglobin, and fructosamine were insignificant after three months of treatment. This points out that the doses used could be low or that the patient compliance was poor. An anionic fluorescent probe merocyanine 540 (MC540) was used to monitor possible changes in the physicochemical properties of isolated diabetic erythrocyte membranes. Significantly higher affinity of MC540 monomers to the membrane in diabetics treated with vitamin E was observed, which can be the result of the antioxidative effect of the vitamin (p < 0.02). A comparison of absorption spectra of MC540 in diabetic and control membranes revealed significant changes in the position of the bands and in their absorbances (p < 0.01 and less). They result from substantial alterations in the structure, surface charge, and the fluidity of erythrocyte membranes in diabetes mellitus. (Tab. 2, Fig. 3, Ref. 22.)

Antioxidant systems in polymorphonuclear leucocytes of Type 2 diabetes mellitus.

AIMS: To examine the effect of Type 2 diabetes mellitus (DM) on enzymes of importance for oxygen-dependent killing of microorganisms by leucocytes. METHODS: Twenty patients with Type 2 DM and 20 nondiabetic controls provided blood samples for analysis. RESULTS: The superoxide dismutase (SOD) activity was lower by 41% in polymorphonuclear leucocytes (PMNL) from patients with Type 2 DM than in controls (3.42+/-0.32 U/mg of protein vs. 5.79+/-0.71 U/mg of protein, P<0.005). Glutathione peroxidase (GSHPx) and glutathione reductase (GR) activities of Type 2 DM patients were 73.04% and 81.12% of control values (0.84+/-0.07 nkat/mg of protein vs. 1.15+/-0.10 nkat/mg of protein, P<0.003, and 2.02+/-0.12 nkat/mg of protein vs. 2.49+/-0.16 nkat/mg of protein, P < 0.023, respectively). The catalase activity showed no significant difference. A significant increase (141.37% of control) in the concentration of thiobarbituric acid reactive products was observed (9.91+/-0.78 miromol/l vs. 7.01+/-0.47 micromol/l, P<0.003). A positive correlation between thiobarbituric acid reactive products and glucose, glycated haemoglobin and fructosamine in the serum of diabetic patients was observed. CONCLUSION: These findings may explain some of the mechanisms underlying the increased susceptibility to certain infection in patients with Type 2 DM.