Biomedical subjects

T Kensler

Publications and source records attributed to T Kensler.

3 recordsLinked to original sources

PubMed1998

Nefazodone and REM sleep: how do antidepressant drugs decrease REM sleep?

In previous uncontrolled studies, nefazodone, a new antidepressant drug, increased REM sleep or had no effect on REM sleep. We report a double-blind, placebo-controlled, parallel group study on effects of nefazodone (N) on polysomnographic sleep variables in healthy human volunteers. Nefazodone was administered for 16 consecutive days, and nocturnal sleep, as well as multiple sleep latency test (MSLT), was monitored before, during, and after N administration. We found that N had no effect on any measured REM sleep variable including REM sleep duration, REM density, and nocturnal REM sleep distribution. Nefazodone also had no significant effect on nocturnal total sleep time or NREM variables, but increased daytime alertness measured by the MSLT. Since N is a potent serotonin reuptake blocker, the present findings that N had no effect on REM sleep cast doubt on the hypothesis that antidepressant drugs decrease REM sleep by increasing serotonergic neurotransmission. A review of other relevant work also casts doubt on this hypothesis.

Adolescent↗

PubMed1995

Role of reactive intermediates in tumor promotion and progression.

Many tumor promoters, including the phorbol esters, do not require biotransformation to stimulate cell growth. By contrast, some promoters, notably organic peroxides and hydroperoxides, must be metabolized to reactive intermediates to trigger signal transduction pathways for mitogenesis. These intermediates can be both free radicals and electrophiles. For example, skin tumor promoters such as tert-butyl hydroperoxide, cumene hydroperoxide, dicumyl peroxide and benzoyl peroxide undergo metal-dependent activation in keratinocytes to form alkoxyl, alkyl and aryl radicals as determined by spin trapping and electron paramagnetic resonance spectroscopy. These radicals can participate in substitution, addition or hydrogen-abstraction reactions leading to protein oxidation or alkylation, lipid peroxidation and/or DNA damage. Scavenger studies indicate that these macromolecular interactions mediate the cytotoxic and mitogenic effects of these peroxides. In some instances radicals can undergo further oxidation to electrophiles. The promoting activity of butylated hydroxytoluene hydroperoxide is mediated by a quinone methide, an electrophile formed through a phenoxyl radical intermediate. In this instance, covalent interaction of the quinone methide with sulfhydryl groups or other nucleophiles in the target cell appears to transmit the molecular signal for cell division and replication. Like the phorbol esters, peroxides and hydroperoxides lead to a genetic reprogramming manifest by the induction of immediate early response genes such as c-jun and late response genes such as ornithine decarboxylase, suggesting convergence in the molecular signalling processes among different classes of promoters.

Animals↗

PubMed1992

Mechanisms of chemoprotection by oltipraz.

1,2-Dithiole-3-thiones are five-membered cyclic sulfur-containing compounds with antioxidant, chemotherapeutic, radioprotective and cancer chemoprotective properties. One substituted dithiolethione, oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione], originally developed as an antischistosomal agent, has recently been observed to protect against chemically induced carcinogenesis in lung, trachea, forestomach, colon, breast, skin, liver and urinary bladder in rodents. The induction of electrophilic detoxication enzymes, which result in diminished carcinogen-DNA adduct formation and reduced cytotoxicity, appears to be an important component of the anticarcinogenic action of oltipraz and other dithiolethiones. Phase I trials of oltipraz are presently underway in the United States. Subsequent trials might be most appropriately targeted towards individuals at high risk for occupational or environmental exposures to genotoxic carcinogens.

Animals↗