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Acrodermatitis enteropathica, a heritable disease of zinc deficiency, was formerly amenable to treatment only with dihaloquinolinol drugs. A few cases of optic atrophy were reported in surviving patients and were proposed as examples of ocular drug toxicity, principally because of the association between iodochlorhydroxyquin and subacute myelo-optic neuropathy (SMON) in Japan. An alternate hypothesis is now offered: that the optic atrophy was secondary to the zinc deficiency, which is consistent with diverse evidence cited from the literature. Therefore, it would seem worthwhile to investigate zinc in cases of disk pallor described as idiopathic or drug associated, and to investigate visual function in cases of severe malnourishment.

Oral contraceptives are combinations of estrogens and progestogens or, in the case of the mini-pills, progestogens alone. With specific test procedures in laboratory animals or human subjects, it is possible to assign potency evaluations to the components relative to the progestational, estrogenic, or antiestrogenic activities of the progestogen or to the estrogenic potencies of the estrogenic component. It might even be possible to quantify the synergistic effects of the estrogen on the progestational agent. Unfortunately, however, it is impossible now to amalgamate such assay results into single estimates of the potencies of the combinations (either the combination products per se or the combination tablets of sequential products). For example, an over-all estrogenic potency of a combination preparation would involve the integration of contributions form the estrogen itself plus the estrogenic products of metabolism of the progestogen minus the antagonistic effect of the progestational agent, if any. These factors cannot now be quantified independently, much less merged into a single figure of clinical significance. Further, even if it were possible to produce such an estimate, it is unlikely that the evaluation would be meaningful in relation to any putative side effect or adverse reaction, i.e., the alleged thrombogenic effects of oral contraceptives cannot currently be related directly to any measure of potency that will allow prediction of these clinical conditions from laboratory models. Any evaluation of the potential of a given contraceptive to produce a specific side effect will depend upon data generated with specific regard to that adverse reaction and the individual product in question.

In 1980, an FDA advisory committee found inconclusive the evidence that the safety of oral contraceptives was related to their steroid content. In 1988, another FDA advisory committee examining the same evidence concluded that there is a trend to suggest such a relationship. The present review critically examines the published evidence and concludes that there is no scientific support for the suggestion that higher-dose oral contraceptives are less safe. Nevertheless, such products are no longer being made available in the United States.

Five male human subjects were administered repeated oral doses of ethanol approximately four hours apart and were examined for venous ethanol levels during the third and fourth hours after each dose. Estimates of the slopes of the apparently linear ethanol disappearance curves exhibited statistically significant variation along a 24-hour time scale within 4 of the 5 subjects, as well as among individuals. Prior findings on one of the subjects were confirmed. It is proposed in general that pharmacokinetic parameters may vary in accord with the physiologic circadian phase at the time of drug challenge.

The low-calorie sweetening agent, aspartame, is broken down in the small intestine into three moieties: aspartic acid, methanol and phenylalanine. Acute loading studies have been performed in human beings who received up to six times the 99th percentile of the projected daily intake (6 X 34 = 200 mg/kg). No evidence of risk to the fetus was developed. Aspartate does not readily cross the placenta. Small elevations of blood methanol following such abuse doses of aspartame did not lead to measurable increases of blood formic acid, which is the product responsible for the acidosis and ocular toxicity in methanol poisoning. Phenylalanine is concentrated on the fetal side of the placenta. Aspartame in abuse doses up to 200 mg/kg in normal subjects, or to 100 mg/kg in PKU heterozygotes, did not raise blood phenylalanine levels to the range generally accepted to be associated with mental retardation in the offspring. It is concluded that, under foreseeable conditions of use, aspartame poses no risk for use in pregnancy.

A recent report by Pike et al. from the U. S. A. concluded on the basis of epidemiologic evidence that an increased risk of breast cancer was manifested by young women who had used combination oral contraceptives (OC) with a high "potency" of progestogen over a prolonged period. This conclusion is criticized in the present article, centering on three cardinal defects in the Pike study: (1) The assigned potencies of OC's are fiction and were derived from out-dated delay-of-menses data; (2) Well-known risk factors for breast cancer were ignored; (3) The method assumed no error of recall of OC brand, dose and duration of use occurring many years before telephone interviews. Noting that others have not been able to confirm these findings, it is concluded that there is no scientific basis for accepting the suggestion of Pike et al.

A male human subject administered single, oral doses of ethanol was examined repeatedly for venous ethanol levels. Four separate trials, begun at 03.00, 09.00, 15.00, and 21.00 h, on different days yielded four different estimates of the slope of the apparently linear ethanol disappearance curve. The slopes appeared to exhibit circadian rhythmicity. In a second study of the same subject, the slope was estimated 7 times over a period of 26 h following repeated oral doses. These slopes also appeared to vary in a daily fashion. These preliminary results suggest that pharmacokinetic parameters may not be invariable with time of day.

Pelvic inflammatory disease (PID) was recorded for 365 of 10,760 women using the Cu-7 for up to 48 months during clinical investigations in the United States. This involved a total exposure of 242,169 woman-months, or some 20,000 woman-years. The overall incidence of PID was 18 cases/1000 woman-years. Incidence was inversely related to age and to duration of use. It was statistically significantly greater in parous subjects than in nulliparous, after stratifying for age. The estimated rates in this study do not differ markedly from those in most other prospective investigations.

When single oral doses of ethanol were given to human subjects at different circadian stages on different days, the blood cortisol levels displayed the expected circadian variation and were not significantly affected by the ethanol challenges. When the ethanol was administered repeatedly in a single 24-h experiment, the cortisol levels were variably elevated by these challenges, primarily in the afternoon hours; however, the circadian excursions did not appear to be blocked or markedly phase-shifted. The phase relationships of circadian blood cortisol levels and previously reported blood ethanol decay rates showed individual subject variation. They tended to occur in phase in two of five subjects and out of phase in the remaining three. It is concluded that cortisol clearance rates following ethanol doses are not independent of the circadian stage but are not necessarily synchronous with those for ethanol clearance.

Pharmacokinetic parameters are generally assumed to be invariate with the time of day, although circadian variation of drug metabolism and drug response is known. As proposed, chronopharmacokinetics considers the implications of the chronovariability of pharmacokinetic parameters. In order to investigate chronovariation in the rate of disappearance of a substance from the approximate a linear course until very low blood levels are attained. As a background for such studies, the literature on the chronopharmacologyof ethanol and the pharmacokinetics of ethanolemia is reviewed. Theoretical considerations are presented for chronovariation of elimination constants for hypothetical drugs following exponential and zero-order models. In describing these cases, the substitution of a sinusoidal function for the rate-constants in pharmacokinetic differential equations is proposed and graphed herin for the first time. It is concluded that: 1)rhythmicity within elimination curves can only be determined by repetion of the experiment at different times of the diel period; 2)the expectation that a rate-constant estimated at one time of the day may be valid for another part of the day carries with it an unknown risk. No pharmacokinetic analysis can be considered definitive unless chronopharmacokinetic variation of parameters is considered.