Closed-chamber inhalation pharmacokinetic studies with hexamethyldisiloxane in the rat

Gas uptake methods together with physiologically based pharmacokinetic (PBPK) modeling have been used to assess metabolic parameters and oral absorption rates for a wide variety of volatile organic compounds. We applied these techniques to study the in vivo metabolism of hexamethyldisiloxane (HMDS), a volatile siloxane with low blood/air (partition coefficient PB approximately 1.00) and high fat/blood partitioning (partition coefficient PF approximately 300). In contrast to other classes of metabolized volatiles, metabolic parameters could only be estimated from closed-chamber results with confidence by evaluating both closed-chamber disappearance curves and constant concentration inhalation studies. The constant-concentration inhalation results refine the estimate of the blood/air partition coefficient and constrain model structure for storage of the lipophilic compound in blood and tissues. The gas uptake results, from Fischer 344 rats (male, 8-9 wk old) exposed to initial HMDS air concentrations from 500 to 5000 ppm, were modeled with a 5-tissue PBPK model. Excellent fits were obtained with diffusion-limited uptake of HMDS in fat and a lipid storage pool in the blood. Metabolism, restricted to the liver, was described as a single saturable process (V(max) = 113.6 micro mol/h/kg; K(m) = 42.6 micro mol/L) and was affected by inhibitors (diethyldithiocarbamate) or inducers (phenobarbital) of cytochrome P-450s. Exhalation kinetics of HMDS after oral/intraperitoneal administration showed low bioavailability and significant lag times, also quite different from results of other classes of volatile hydrocarbons. In general, estimates of metabolic clearance by gas uptake studies were improved by simultaneous examination of time-course results from constant concentration inhalation studies. This conclusion is likely to hold for any volatile lipophilic compound with low blood/air partitioning.     

Treatment of sleep disturbance in alcohol recovery: a national survey of addiction medicine physicians

Sleep disturbance is common among patients in recovery from alcoholism and can precipitate relapse. Though sleep complaints are commonly managed with medication, little is known about their management among recovering alcoholic patients. We performed a postal survey of a self-weighted, random systematic sample of 503 members of the American Society of Addiction Medicine (ASAM) to examine addiction medicine physicians' medical management of sleep disturbance among patients in early recovery from alcoholism. After 3 mailings, 311 (62%) responded. Of responents, 64% have offered pharmacological treatment to an insomniac, alcoholic patient in the first 3 months after detoxification, but only 22% offered medication to more than half of such patients. Trazodone was the preferred therapy, chosen first by 38% of respondents, followed by other sedating antidepressants (12%), and antihistamines (12%). The mean duration of therapy for trazodone and other sedating antidepressants exceeded one month. Experts in addiction medicine appear reluctant to prescribe medication to sleep-disturbed patients in early recovery from alcoholism. When they do prescribe, trazodone, other sedating antidepressants and antihistamines are favored, despite limited evidence for or against this indication. Although the treatment of disordered sleep among alcoholic patients in early recovery may have merit to prevent relapse, controlled studies of these sleep agents are needed.     

Tumor cell hypoxia and the hypoxia-response signaling system as a target for prostate cancer therapy

The accumulation of cancerous cells within a growing prostate tumor can deprive them of adequate vascular support. Without this support, the affected tumor cells become hypoxic, a condition that is usually unfavorable for the further growth and survival of eukaryotic cells. Mammalian cells, however, have the ability of responding to a hypoxic environment by activating a "hypoxia-response" signaling system. Ultimately, this signaling system upregulates the expression of a network of gene products that increase the propensity of the cell to survive even in this adverse environment. With increasing evidence that hypoxia and an activated hypoxia-response signaling system can influence progression (via increased angiogenic propensity and apoptotic resistance) and the therapeutic responsiveness of prostate cancer cells, this review will examine the concept of targeting hypoxia or the hypoxia-response system of prostate tumor cells as a means to suppress prostate tumor progression and metastasis or perhaps even as a means for eliminating prostate tumors in advanced prostate cancer patients.     

Vitamin A metabolism in the retinal pigment epithelium: genes,mutations, and diseases

Mutations in the genes necessary for the metabolism of vitamin A (all-trans retinol) and cycling of retinoids between the photoreceptors and retinal pigment epithelium (RPE) (the visual cycle) have recently emerged as an important class of genetic defects responsible for retinal dystrophies and dysfunctions. Research into the causes and treatment of diseases resulting from defects in retinal vitamin A metabolism is currently the subject of intense interest, since disorders affecting the RPE are, in principle, more accessible to therapeutic intervention than those affecting the proteins of photoreceptor cells. This chapter presents an overview of the visual cycle, as well as the function of the RPE genes involved in the conversion of vitamin A to 11-cis retinal, the chromophore of the visual pigments. The identification of disease-causing mutations in this group of genes is described as well as the associated phenotypes that range from stationary night blindness to childhood-onset severe visual handicap. Consideration is also given to alternative genetic paradigms potentially relevant to defects in vitamin A metabolism, including a discussion of the relationship of this pathway to age-related macular degeneration, a non-Mendelian disease of late onset. Finally, progress and prospects for targeted therapeutic intervention in vitamin A metabolism are presented, including retinoid and gene replacement therapy. On the basis of early successes in animal models, and plans underway for Phase I/II clinical trials, it is hoped that the near future will bring effective therapies for many retinal dystrophy patients with defects in vitamin A metabolism.     

Apoptosis in male germ cells in response to cyclin A1-deficiency and cell cycle arrest

Male mice homozygous for a mutated allele of the cyclin A1 gene (Ccna1) are sterile due to a block in cell cycle progression before the first meiotic division. Meiosis arrest in Ccna1(-/-) spermatocytes is associated with desynapsis abnormalities, lowered MPF activity, and apoptosis as evidenced by TUNEL-positive staining. With time, adult testicular tubules exhibit severe degeneration: some tubules in the older animals are almost devoid of germ cells at various stages of spermatogenesis. The mechanisms by which the cells sense the cell cycle arrest and the regulation of the decision to undergo cell death are under investigation.