Acrylamide (AM), used in the manufacture of polyacrylamide and grouting agents, is produced during the cooking of foods. Workplace exposure to AM can occur through the dermal and inhalation routes. The objectives of this study were to evaluate the metabolism of AM in humans following oral administration, to compare hemoglobin adduct formation on oral and dermal administration, and to measure hormone levels. The health of the people exposed under controlled conditions was continually monitored. Prior to conducting exposures in humans, a low-dose study was conducted in rats administered 3 mg/kg (1,2,3-13C3) AM by gavage. The study protocol was reviewed and approved by Institute Review Boards both at RTI, which performed the sample analysis, and the clinical research center conducting the study. (1,2,3-13C3) AM was administered in an aqueous solution orally (single dose of 0.5, 1.0, or 3.0 mg/kg) or dermally (three daily doses of 3.0 mg/kg) to sterile male volunteers. Urine samples (3 mg/kg oral dose) were analyzed for AM metabolites using 13C NMR spectroscopy. Approximately 86% of the urinary metabolites were derived from GSH conjugation and excreted as N-acetyl-S-(3-amino-3-oxopropyl)cysteine and its S-oxide. Glycidamide, glyceramide, and low levels of N-acetyl-S-(3-amino-2-hydroxy-3-oxopropyl)cysteine were detected in urine. On oral administration, a linear dose response was observed for N-(2-carbamoylethyl)valine (AAVal) and N-(2-carbamoyl-2-hydroxyethyl)valine (GAVal) in hemoglobin. Dermal administration resulted in lower levels of AAVal and GAVal. This study indicated that humans metabolize AM via glycidamide to a lesser extent than rodents, and dermal uptake was approximately 6.6% of that observed with oral uptake.

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The purpose of this study was to determine which specific structures within the medial preoptic-anterior hypothalamic area are necessary to maintain cyclic ovulation in the rat, and to define the deficit(s) in the feedback regulation of gonadotropin secretion associated with lesions that result in anovulation. Large (∼1.1 mm dia.) or small (∼0.7 mm dia.) electrolytic lesions were placed in several loci within preoptic, anterior hypothalamic and suprachiasmatic areas in regularly cycling adult female rats. Large lesions which included the suprachiasmatic nuclei (SCN) induced an anovulatory condition characterized by persistent vaginal cornification and polyfollicular ovaries (persistent estrus). Large or small lesions which included the medial preoptic nucleus (MPN), a small periventricular column of cells located immediately caudal to the organum vasculosum of the lamina terminalis (OVLT), also induced persistent estrus. Lesions placed elsewhere within the medial preoptic-anterior hypothalamic area never induced persistent estrus but were frequently associated with repeated periods of prolonged diestrus separated by brief periods of vaginal cornification. These prolonged diestrous intervals appeared to be related to spontaneous luteal activation following ovulation rather than impaired folliculogenesis. LH and FSH surges induced by sequential administration of estradiol benzoate and progesterone (P) were completely abolished only by lesions which included the MPN. Small lesions involving only the MPN and OVLT or the MPN and caudally adjacent loci in the suprachiasmatic region were as effective in this respect as larger lesions encompassing most of the preoptic-suprachiasmatic region from the diagonal band of Broca to the rostral pole of the SCN. On the other hand, P-induced gonadotropin surges were never completely blocked by SCN lesions, although the magnitude of the surge was highly variable and frequently attenuated compared to controls. It is concluded that both the MPN and SCN are required for the long-term maintenance of spontaneous cyclic ovulation in the rat. However, the characteristically dissimilar deficits in P-induced gonadotropin release associated with lesions of one or the other of these structures indicate that these nuclei may play different roles in the regulation of gonadotropin surges. It is suggested that neural elements indispensable for phasic gonadotropin release are located within and/or immediately adjacent to the MPN. The SCN may influence phasic gonadotropin release indirectly, by regulating circadian rhythms which govern the responsiveness of other neural elements to hormonal stimuli.

Raltegravir is an HIV integrase inhibitor that is metabolized through glucuronidation by uridine diphosphate glucuronosyltransferase 1A1, and its use is anticipated in combination with atazanavir (a uridine diphosphate glucuronosyltransferase 1A1 inhibitor). Two pharmacokinetic studies of healthy subjects assessed the effect of multiple-dose atazanavir or ritonavir-boosted atazanavir on raltegravir levels in plasma. Atazanavir and atazanavir plus ritonavir modestly increase plasma levels of raltegravir.

Very small electrolytic lesions were made over the anterior or posterior portion of the optic chiasm in mature female rats showing normal estrous cycles. Lesions over the posterior portion of chiasm destroyed the suprachiasmatic nucleus of the hypothalamus (SCN) while the anterior lesions destroyed a small neural structure, here designated as the medial preoptic nucleus (MPN). Both lesions were effective in inducing persistent vaginal estrus, but when animals were ovariectomized and treated with exogenous and progesterone it was found that lesions including the MPN alone, but not the SCN alone, eliminated the positive feedback effects of this steroid regimen on LH release.