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Some patients with chronic fatigue syndrome say they benefit from taking vitamin supplements. We assessed functional status for the B vitamins pyridoxine, riboflavin and thiamine in 12 vitamin-untreated CFS patients and in 18 healthy controls matched for age and sex. Vitamin-dependent activities--aspartate aminotransferase (AST) for pyridoxine, glutathione reductase (GTR) for riboflavin, transketolase (TK) for thiamine--were measured in erythrocyte haemolysates before and after in-vitro addition of the relevant vitamin. For all three enzymes basal activity (U/g Hb) was lower in CFS patients than in controls: AST 2.84 (SD 0.62) vs 4.61 (1.43), P < 0.001; GTR 6.13 (1.89) vs 7.42 (1.25), P < 0.04; TK 0.50 (0.13) vs 0.60 (0.07), P < 0.04. This was also true of activated values: AST 4.91 (0.54) vs 7.89 (2.11), P < 0.001; GTR 8.29 (1.60) vs 10.0 (1.80), P < 0.001; TK 0.56 (0.19) vs 0.66 (0.08), P < 0.07. The activation ratios, however, did not differ between the groups. These data provide preliminary evidence of reduced functional B vitamin status, particularly of pyridoxine, in CFS patients.

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The contribution of impaired degradative processes to the cellular changes occurring in the brain as a consequence of chronic ethanol exposure was assessed. Male Wistar rats were fed nutritionally adequate liquid diets containing ethanol as 35% of total dietary calories. Controls were pair-fed identical amounts of the same diet in which ethanol was replaced by isocaloric glucose. The results showed that at the end of 3 weeks the activities of neutral protease (nonlysosomal) and cathepsin D (lysosomal) were unaltered. However, there were significant elevations in the activities of the lysosomal enzyme cathepsin B, regardless of whether the activities were expressed relative to wet weight ( p = 0.005), protein (p = 0.006), or DNA (p = 0.045). In addition, we showed that the activities of cathepsin B were not significantly affected by additions of carnosine or acetaldehyde, in vitro. However, neutral protease activities were increased by carnosine additions in vitro. We conclude that selective alterations in brain protease activities may be contributing factors in the genesis of alcoholic brain disorders.

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The toxic effect of acetaldehyde on brain oxidative capacity and dopamine metabolism has been investigated in rat brains after a single intraperitoneal injection of acetaldehyde (5 mmol/kg) and the results compared with those from chronically ethanol fed rats. Acetaldehyde was present in rat brain 120 hr after a single dose of acetaldehyde, confirming that it is able to cross the blood-brain barrier. Brain catalase increased significantly after acetaldehyde or chronic ethanol administration although there were no other significant changes in the total brain activity of superoxide dismutase, glutathione peroxidase or glutathione reductase. Dopamine turnover was increased in both experimental groups. The acute dose of acetaldehyde reduced the ability of the rats to relearn a computer visual discrimination task.

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Etoposide demonstrates incomplete and variable bioavailability after oral dosing, which may be due to its concentration and pH-dependent stability in artificial gastric and intestinal fluids. The use of agents that may influence etoposide stability and, thereby, bioavailability, was investigated in a number of clinical studies. Drugs that influence the rate of gastric emptying, while modulating the time of drug absorption, did not significantly alter the etoposide area under the concentration-time curve (AUC) or bioavailability. Specifically, metoclopramide had little effect on the etoposide absorption profile and did not significantly alter the AUC (AUC with etoposide alone, 68.4 +/- 20.3 micrograms ml-1 h, versus 74.3 +/- 25.9 micrograms ml-1 h with metoclopramide), suggesting that in most patients the drug is already emptied rapidly from the stomach. In contrast, propantheline produced a dramatic effect on etoposide absorption, delaying the time of maximal concentration tmax from 1.1 to 3.5 h (P < 0.01), but again without a significant improvement in drug AUC or bioavailability across the 24-h study period (AUC with etoposide alone 78.3 +/- 19.1 micrograms ml-1 h, versus 88.1 +/- 23.6 micrograms ml-1 h with propantheline). The effect of these drugs on the absorption of oral paracetamol, a drug included in the study as a marker of gastric emptying, was exactly the same as that found for etoposide, with no change in AUC being observed after metoclopramide or propantheline administration but a significant delay in tmax being seen on co-administration with etoposide and propantheline. The co-administration of ethanol or bile salts (agents that significantly improved the stability of etoposide in artificial intestinal fluid) with oral etoposide similarly had no effect on improving the etoposide AUC or reducing the variability in AUC, suggesting that drug stability in vivo was not affected by these agents. In the third study the co-administration of cimetidine had no effect on the pharmacokinetics of oral or i.v. etoposide, despite the previous observation that etoposide stability was markedly improved at pH 3-5 as compared with pH 1 in artificial gastric fluid. This series of studies, designed to investigate factors that improved etoposide stability in laboratory studies, failed to demonstrate any potentially useful improvement in AUC or bioavailability in the clinical setting.

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