PubMed · 3905633
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R A Miller. 1985. Podophyllin.. https://doi.org/10.1111/j.1365-4362.1985.tb05827.x
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The effective action of endothelium-derived nitric oxide (EDNO) is impaired in patients with atherosclerosis. This impairment has been attributed in part to increased vascular oxidative stress. EDNO action is improved by administration of ascorbic acid, a water-soluble antioxidant. Ascorbic acid is a potent free-radical scavenger in plasma, and also regulates intracellular redox state in part by sparing cellular glutathione. We specifically investigated the role of intracellular redox state in EDNO action by examining the effect of L-2-oxo-4-thiazolidine carboxylate (OTC) on EDNO-dependent, flow-mediated dilation in a randomized double-blind placebo-controlled study of patients with angiographically proven coronary artery disease. OTC augments intracellular glutathione by providing substrate cysteine for glutathione synthesis. Brachial artery flow-mediated dilation was examined with high-resolution ultrasound before and after oral administration of 4.5 g of OTC or placebo in 48 subjects with angiographically documented coronary artery disease. Placebo treatment produced no change in flow-mediated dilation (7.0+/-3.9% vs. 7.2+/-3.7%), whereas OTC treatment was associated with a significant improvement in flow-mediated dilation (6.6+/-4.4% vs. 11.0+/-6.3%; P = 0.005). OTC had no effect on arterial dilation to nitroglycerin, systemic blood pressure, heart rate, or reactive hyperemia. These data suggest that augmenting cellular glutathione levels improves EDNO action in human atherosclerosis. Cellular redox state may be an important regulator of EDNO action, and is a potential target for therapy in patients with coronary artery disease.
BACKGROUND: Current equianalgesic reference tables, based largely on single dose studies, give dose ratios of 1:1 to 4:1 for oral morphine to oral methadone, which possibly are inaccurate in patients with cancer pain who are exposed to multiple doses of these opioids. The purpose of this study was to determine the equianalgesic dose ratio between morphine and methadone in patients with cancer pain and to establish whether the dose ratio changes as a function of previous opioid dose. METHODS: A retrospective analysis of consecutive rotations involving morphine and methadone using standard selection criteria identified a total of 20 evaluable rotations (14 from morphine to methadone and 6 from methadone to morphine). Opioid doses and pain intensity levels pre- and postrotation were analyzed. RESULTS: Median dose ratios (lower-upper quartiles) for morphine to methadone and methadone to morphine rotations were 11.36 (range, 5.98-16.27) and 8.25 (range, 4.37-11.3), respectively (P = 0.23). Combining all 20 rotations, a unified median dose ratio of 11.2 (range, 5.06-13.24) was calculated. There was no significant difference in pain intensity levels pre- and postrotation as recorded on a visual analogue scale. Univariate correlational analysis of dose ratio and the level of daily morphine dose prior to rotation revealed a Spearman correlation coefficient of 0.86 (P = 0.0001). In patients receiving >1165 mg per day prior to methadone rotation, a median dose ratio of 16.84 (range, 12.25-87.95) was observed, which was approximately 3 times higher compared with a median dose ratio of 5.42 (range, 2.95-9.09) (P = 0.007) for the 50% of patients receiving lower morphine doses. CONCLUSIONS: The results highlight the general underestimation of methadone potency and the consequent risk of potential life-threatening toxicity. The strongly positive correlation between dose ratio and previous morphine dose suggests the need for a highly individualized and cautious approach when rotating from morphine to methadone in patients with cancer pain.
Oral administration of type II collagen (CII) has been shown to suppress collagen-induced arthritis (CIA) in experimental animals. However, the exact mechanism by which CIA is suppressed following administration of CII remains to be investigated, although it was demonstrated that active suppression by regulatory T cells might be involved in the suppression. Therefore, we have examined whether the inhibitory cytokine IL-4 plays a role in the suppression of CIA, by using an anti-IL-4 mAb (11B11 mAb). Mice were fed daily with CII over a period of 10 days before immunization with CII. 11B11 mAb was i.p. injected 30 min before each oral administration of CII. The results showed that treatment with 11B11 mAb markedly blocked suppression of CIA by the oral Ag. The blockade of suppression of CIA by the anti-IL-4 mAb was associated with the blockade of augmentation of IL-4 secretion in CII-fed mice. The treatment with 11B11 mAb also resulted in the prevention of decreases in anti-CII IgG2a Ab production, DTH responses to CII, proliferation of lymphoid cells to CII, and IFN-gamma secretion in mice given CII orally. Thus, the neutralization of IL-4 by an anti-IL-4 Ab appears to be effective in blocking suppression of CIA by oral administration of CII, suggesting that IL-4 may be critically involved in its suppression.