The measurement of free radical reactions in humans. Some thoughts for future experimentation

The question as to whether free radical reactions are a major cause of tissue injury in human disease, or merely an accompaniment to such injury, is very difficult to answer because of lack of adequate experimental techniques. New techniques that are becoming available are discussed, with specific reference to their use in humans.     

Antioxidant defence mechanisms: From the beginning to the end (of the beginning)

When life first evolved on Earth, there was little oxygen in the atmosphere. Evolution of antioxidant defences must have been closely associated with the evolution of photosynthesis and of O₂-dependent electron transport mechanisms. Studies with mice lacking antioxidant defences confirm the important roles of MnSOD and transferrin in maintaining health, but show that glutathione peroxidase (GPX) and CuZnSOD are not essential for everyday life (at least in mice). Superoxide can be cytotoxic by several mechanisms: one is the formation of hydroxyl radicals. There is good evidence that OH^· formation occurs in vivo. Other important antioxidants may include thioredoxin, and selenoproteins other than GPX. Nitric oxide may be an important antioxidant in the vascular system. Diet-derived antioxidants are important in maintaining human health, but recent studies employing “biomarkers” of oxidative DNA damage are questioning the “antioxidant” roles of β-carotene and ascorbate. An important area of future research will be elucidation of the reasons why levels of steady-state oxidative damage to DNA and lipids vary so much between individuals, and their predictive value for the later development of human disease.     

Prevalence of potentially inappropriate long term prescribing in general practice in the United Kingdom, 1980-95: systematic literature review.

OBJECTIVE: To determine the prevalence of potentially inappropriate long term prescribing in general practice in the United Kingdom. DESIGN: Review of 62 studies of the appropriateness of prescribing identified from seven electronic databases, from reference lists, and by hand searching of journals. A nominal group of 10 experts helped to define the appropriateness of prescribing. SETTING: General practice in the United Kingdom. MAIN OUTCOME MEASURES: Prevalences of 19 indicators of inappropriate long term prescribing representing five dimensions: indication, choice of drug, drug administration, communication, and review. RESULTS: Prevalences of potentially inappropriate prescribing varied by indicator and chronic condition, but drug dosages outside the therapeutic range consistently recorded the highest rates. The lowest rates were generally associated with indicators of the choice of the drug, except cost minimisation. Communication is studied less frequently than other dimensions of prescribing appropriateness. CONCLUSIONS: The evidence base to support allegations of widespread inappropriate prescribing in general practice is unsound. Although inappropriate prescribing has occurred, the scale of the problem is unknown because of limitations associated with selection of a standard, publication bias, and uncertainty about the context of prescribing decisions. Opportunities for cost savings and effectiveness gains are thus unclear. Indicators applicable to individual patients could yield evidence of prescribing appropriateness.     

Biologically relevant metal ion-dependent hydroxyl radical generation. An update.

Transition metal ions, especially iron, appear to be important mediators of oxidative damage in vivo. Iron(II) reacts with H2O2 to give more-reactive radicals. On the basis of ESR spin-trapping data with DMPO, supported by aromatic hydroxylation studies and patterns of DNA base modification, it is concluded that hydroxyl radical (OH.) is likely to be the major damaging species formed in Fenton Systems under biologically-relevant conditions (which include iron concentrations no higher than the micromolar range). Although reactive oxo-iron species (such as ferryl and perferryl) may also be important, direct chemical evidence for their formation and identity in biologically relevant Fenton systems is currently lacking. Studies at alkaline pH values show that iron(IV) and iron(V) species are highly oxidizing under those reaction conditions, with a pattern of reactivity different from that of OH..