Pro-oxidant activity and methionine metabolism in chronic alcohol abusers: relationship to alcohol withdrawal and folate administration.

AIM: The aim of this study was to investigate whether alcohol withdrawal and folate administration could play a role on redox balance and metionine metabolism in heavy drinkers. METHODS: The derivatives of reactive oxygen metabolites (d-ROMs), homocysteine, total thiols, vitamin B12 and folate were evaluated in a selected group of 40 consecutive chronic alcohol abusers by comparison with 44 healthy moderate drinkers, as controls. RESULTS: Before alcohol withdrawal, d-ROMs were significantly higher (p<0.0001) in heavy drinkers than in controls: 368.5 (254.8-718.6) U.CARR vs 245 (200.7-360) U.CARR, respectively, median with range. Plasma homocysteine were significantly higher in alcoholics than in moderate drinkers (p<0.0001): 18 (9.5-82.2) micromol/L vs 9.1 (4.9-19.6) micromol/L, respectively. Heavy drinkers also exhibited higher serum thiols than moderate drinkers (p<0.003): 605.8 (448.2-717.7) micromol/L vs 554.8 (508.3-658.4) micromol/L, respectively. The patients showed lower plasma folate than controls (p<0.0001): 4.1 (1.9-9.7) ng/mL vs 8.8 (5.0-8.4) ng/mL, respectively, but similar vitamin B12 levels: 487 (299-786) pg/mL 621 (243-894) pg/mL. A negative correlation between homocysteine and folate was observed before withdrawal in alcoholics (r=-0.4546, p<0.038). Both serum thiols (549.7 micromol/L, range 402.4-616.6 micromol/L) and homocysteinemia (6.6 micromol/L, range 2.9-18.5 micromol/L) were significantly decreased (p<0.0001 and p<0.022, respectively) after a week of alcohol withdrawal and folate administration. CONCLUSION: Our findings show that both enhanced pro-oxidant activity and a derangement of methionine metabolism can be observed in heavy drinkers before alcohol withdrawal and folate administration. Furthermore, folate seems to be a strong determinant of both plasma homocysteine and thiol concentrations.

Modifications of apoptosis-related protein levels in lymphocytes of patients with Parkinson's disease. The effect of dopaminergic treatment.

In this study, we investigated whether changes in the regulatory mechanisms of apoptosis and oxidative stress may be detected, peripherally, in patients with Parkinson's disease (PD). For this purpose, we measured caspase-3 activity, Bcl-2 concentrations, peripheral benzodiazepine receptor (PBR) expression and Cu/Zn superoxide dismutase (SOD) concentrations in lymphocytes of untreated PD patients, patients treated only with L-Dopa or with L-Dopa and dopamine agonists and healthy volunteers. Caspase-3 activity was significantly increased in all PD patient groups. Patients treated with L-Dopa and dopamine agonists showed the lowest values of Bcl-2, coupled with the highest density of PBRs, while increased levels of Cu/Zn SOD were found in the group under monotherapy with L-Dopa. We also found, in PD patients, clear, negative correlations between Bcl-2 levels and both duration and severity of the disease. Our findings point to the existence of changes in the regulatory mechanisms of apoptosis in PD patients -- observable outside the central nervous system -- which seem to be modulated by the pharmacological treatment with dopaminergic agents.

Effects of dopaminergic stimulation on peripheral markers of apoptosis: relevance to Parkinson's disease.

We investigated the effects of dopaminergic stimulation on anti-apoptotic protein Bcl-2, pro-apoptotic enzyme caspase- 3, and anti-oxidant/anti-apoptotic enzyme Cu/Zn superoxide dismutase (SOD) in human lymphocytes exposed to dopamine (DA). The same determinations were also carried out in parkinsonian patients treated with L-dopa. Caspase-3 activity and Cu/Zn SOD levels tended to increase when lymphocytes were exposed to low or intermediate doses of DA, while a decrease was observed, particularly in caspase-3 activity, with the higher DA dose. Bcl-2 levels were unaffected. In patients, we observed a negative correlation between Cu/Zn SOD levels and daily intake of L-dopa, which also tended to be negatively correlated with caspase-3 activity, but not with Bcl- 2. Our results show that dopaminergic stimulation is associated with complex changes in regulatory proteins of apoptosis.

Modifications of plasma and platelet levels of L-DOPA and its direct metabolites during treatment with tolcapone or entacapone in patients with Parkinson's disease.

We compared--retrospectively--the effects of a 3-month therapy with catechol- O-methyltransferase (COMT) inhibitors tolcapone (100 mg, t.i.d.) and entacapone (200 mg, t.i.d.), on L-DOPA metabolism in two groups of parkinsonian patients with motor fluctuations. Plasma and platelets concentrations of L-DOPA and its direct metabolites, dopamine and 3- O-methyldopa (3-OMD), were measured before starting treatment, after two weeks and at the end of treatment. Patients treated with tolcapone showed significant increases in plasma and platelet L-DOPA levels and marked reduction of plasma and platelet 3-OMD levels, both at short- and long-term. Entacapone did not modify L-DOPA levels, while inducing a less marked reduction of plasma and platelet 3-OMD concentrations, with respect to tolcapone, at both time points. Both drugs were similarly effective in increasing plasma and platelet levels of dopamine. These results confirm the different profiles of activity of the two drugs, with tolcapone proving more effective on both the intra- and extra-cellular levels of L-DOPA and 3-OMD.

Peripheral markers of apoptosis in Parkinson's disease: the effect of dopaminergic drugs.

In this study, we measured the lymphocyte levels of proteins involved in apoptosis regulation, such as Bcl-2, the peripheral benzodiazepine receptor (PBR), caspase-3, and Cu/Zn superoxide dismutase (Cu/Zn SOD), in patients with Parkinson's disease (PD), either untreated or under therapy with dopaminergic agents (l-Dopa alone or l-dopa + dopamine agonists) and in healthy volunteers. All PD groups showed increased activity of caspase-3, compared to controls, particularly those under treatment only with l-Dopa. In this latter group, the increase in caspase-3 activity was also paralleled by an increase in the concentration of Cu/Zn SOD. In addition, patients taking l-Dopa + dopamine agonists showed marked decrease in Bcl-2 levels and increased PBR expression, which seems in keeping with the hypothesis that PBR may be functionally related to Bcl-2. In conclusion, we found clear modifications in the levels of proteins involved in the control of apoptosis in lymphocytes of PD patients. These changes were disease related but also modulated by the pharmacological treatment, which confirms the potential role of apoptosis in PD pathogenesis and the modulatory influence of dopaminergic agents.

Pancreatic enzyme replacement therapy in post-pancreatectomy patients.

The occurrence of malnutrition and maldigestion was studied in nine patients who underwent pancreatoduodenectomy and sclerosis of the residual pancreatic stump with neoprene. The operation causes a complete loss of exocrine pancreatic function, but spares islet cell function. Upon discharge from the hospital, patients received pancreatin powder as a dietary enzyme supplement (18,000 lipase U/meal). Patients were again hospitalized 2 y after surgery for evaluation of nutritional status and digestive function (hospital checkup). Nutritional status was evaluated by measuring serum albumin, total iron binding capacity, and total lymphocytes. Digestive function was assessed by the D-xylose tolerance test and determination of fecal fat excretion. Patients were then discharged with pancrelipase enteric-coated microspheres (ECM) as a dietary enzyme supplement (16,050 lipase U/meal). Malnutrition, defined as the occurrence of at least two abnormal nutritional parameters, was observed in three patients at the time of the hospital checkup. Upon reevaluation of nutritional status after 6 mo on pancrelipase ECM, all patients were well nourished. The mean body weight, which had been 52.8 Kg immediately after surgery, increased to 54.9 Kg at the time of the hospital checkup (p less than 0.01) and to 58.0 Kg after six months of pancrelipase ECM therapy (p less than 0.05). At the hospital checkup, the D-xylose test was normal in all patients and steatorrhea had decreased from a mean of 32.8 g/d without enzyme supplementation to 16.7 g/d with pancrelipase therapy (16,050 lipase U/meal). The complete loss of exocrine pancreatic function following surgery was well tolerated. In fact, when patients were on pancrelipase therapy, much of the original body weight was recovered and the biochemical indices of malnutrition were normalized.

Correction of malnutrition and maldigestion with enzyme supplementation in patients with surgical suppression of exocrine pancreatic function.

We studied the occurrence and extent of malnutrition and maldigestion in 13 patients who underwent pancreatoduodenectomy (PD) and injection of Neoprene (polychloroprene) (NI) into the duct of Wirsung, which results in sclerosis of hte acinar pancreatic tissue, but spares the endocrine function. At discharge, patients under took an enzyme supplementation regimen with pancreatin (18, 00 United States Pharmacopoeia units of lipase per meal). Patients were rehospitalized 24.9 months after PD plus NI to undergo nutritional and metabolic evaluation (hospital control). Nutritional status was evaluated by measuring the serum albumin level, total iron binding capacity and total lymphocyte count. Digestive function was assessed by the D-xylose tolerance test and determination of fecal fat excretion. Patients were then discharged with pancrelipase, enteric-coated microspheres (ECM) supplementation (16,050 United States Pharmacopoeia units of lipase per meal). Malnutrition, defined as the occurrence of at least two abnormal nutritional parameters, was observed in six patients at hospital control. After six months on pancrelipase ECM, the nutritional status was re-evaluated in nine patients (three previously malnourished) who were all well nourished. The mean body weight was 84.7 per cent of usual body weight at discharge after PD plus NI and raised to 88.0 per cent at the hospital control (p less than 0.01) and to 93.7 per cent )p less than 0.05) after six months on pancrelipase ECM. At hospital control, results from the D-xylose test were normal in all patients, and steatorrhea dropped from 33.6 grams per day without enzyme supplementation to 15.3 grams per day with pancrelipase ECM (16,050 United States Pharmacopoeia units of lipase per meal). Steatorrhea was incompletely but satisfactorily corrected by pancrelipase ECM. On supplementation therapy with pancrelipase ECM, patients recover a good deal of the body weight and normalize the biochemical indices of malnutrition.