Hypertension and Acute Mountain Sickness in Himalayan Trekkers in Nepal: An Observational Cohort Study.

Introduction: A history of preexisting hypertension is common in people participating in mountain activities; however, the relationship between blood pressure (BP), preexisting hypertension, and acute mountain sickness (AMS) is not well studied. We sought to determine these relationships among trekkers in the Everest region of Nepal.

Methods: This was a prospective observational cohort study of a convenience sample of adult, nonpregnant volunteers trekking in the Everest Base Camp region in Nepal.

Novel Selective Agents for the Degradation of Androgen Receptor Variants to Treat Castration-Resistant Prostate Cancer.

Androgen receptor (AR) mediates the growth of prostate cancer throughout its course of development, including in abnormal splice variants (AR-SV)-driven advanced stage castration-resistant disease. AR stabilization by androgens makes it distinct from other steroid receptors, which are typically ubiquitinated and degraded by proteasomes after ligand binding. Thus, targeting AR in advanced prostate cancer requires the development of agents that can sustainably degrade variant isoforms for effective therapy.

Androgen receptor antagonists: a patent review (2008-2011).

Introduction: Androgen receptor (AR) antagonists are predominantly used as chemical castration to treat prostate cancer (i.e., in conjunction with androgen deprivation therapy (ADT)).

Combination therapy of antiandrogen and XIAP inhibitor for treating advanced prostate cancer.

Purpose: Overexpression of the androgen receptor (AR) and anti-apoptotic genes including X-linked inhibitor of apoptosis protein (XIAP) provide tumors with a proliferative advantage. Therefore, our objective was to determine whether novel antiandrogen (CBDIV17) and XIAP inhibitor based combination therapy can treat advanced prostate cancer.

Methods: CBDIV17 and embelin-6g were synthesized and their effect on cell proliferation, apoptosis, cell cycle and AR and XIAP gene silencing determined.

Unexpected binding orientation of bulky-B-ring anti-androgens and implications for future drug targets.

Several new androgen receptor antagonists were synthesized and found to have varying activities across typically anti-androgen resistant mutants (Thr877 → Ala and Trp741 → Leu) and markedly improved potency over previously reported pan-antagonists. X-ray crystallography of a new anti-androgen in an androgen receptor mutant (Thr877 → Ala) shows that the receptor can accommodate the added bulk presented by phenyl to naphthyl substitution, casting doubt on previous reports of predicted binding orientation and the causes of antagonism in bulky-B-ring antagonists.

Biotransformation of a novel antimitotic agent, I-387, by mouse, rat, dog, monkey, and human liver microsomes and in vivo pharmacokinetics in mice.

3-(1H-Indol-2-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone (I-387) is a novel indole compound with antitubulin action and potent antitumor activity in various preclinical models. I-387 avoids drug resistance mediated by P-glycoprotein and showed less neurotoxicity than vinca alkaloids during in vivo studies. We examined the pharmacokinetics and metabolism of I-387 in mice as a component of our preclinical development of this compound and continued interest in structure-activity relationships for antitubulin agents.

I-387, a novel antimitotic indole, displays a potent in vitro and in vivo antitumor activity with less neurotoxicity.

(3-(1H-indol-2-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone (I-387) is a novel synthetic compound that inhibits tubulin action and exhibits potent antitumor activity in various preclinical models. I-387 inhibited the in vitro growth of several human cancer cell lines with IC₅₀ values in the range of 15 to 39 nmol/L. Nanomolar concentrations of the compound induced apoptosis and caused phosphorylation of the antiapoptotic protein Bcl-2.

Nonsteroidal selective androgen receptor modulators enhance female sexual motivation.

Women experience a decline in estrogen and androgen levels after natural or surgically induced menopause, effects that are associated with a loss of sexual desire and bone mineral density. Studies in our laboratories have shown the beneficial effects of selective androgen receptor modulators (SARMs) in the treatment of osteoporosis and muscle wasting in animal models. A series of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-propionamide analogs was synthesized to evaluate the effects of B-ring substitutions on in vitro and in vivo pharmacologic activity, especially female sexual motivation.

A novel bis-indole destabilizes microtubules and displays potent in vitro and in vivo antitumor activity in prostate cancer.

Purpose: Microtubules are one of the most useful subcellular targets in chemotherapy. We identified a novel indole, (3-(1H-indol-2-yl)phenyl)(1H-indol-2-yl)methanone (15), that inhibits tubulin action and exhibits potent antitumor activity in various preclinical models.

Methods: In vitro cancer cell growth inhibition was measured by SRB or MTT assay in human cancer cell lines.

Tricarbon-yl(2-methyl-2-η-phenyl-1,3-dioxolane)chromium(0).

The structure of the title compound, [Cr(C(10)H(12)O(2))(CO)(3)], is presented. The distorted piano-stool geometry features an off-center Cr(CO)(3) fragment which reduces contact with the dioxolane ring. The dioxolane ring, in twisted conformation, is syn-oriented towards the Cr(CO)(3) moiety.

Micellar delivery of bicalutamide and embelin for treating prostate cancer.

Purpose: To examine the effect of bicalutamide and embelin on the growth of prostate cancer cells in vitro and in vivo

Methods: Cell viability was determined by MTT assay. Micelles were fabricated with polyethylene glycol-b-polylactic acid (PEG-PLA) copolymer and characterized in terms of particle size, micellar solubilization and drug loading, followed by evaluation in nude mice bearing LNCaP xenografts.

Results: Embelin induced caspase 3 and 9 activation in LNCaP and C4-2 cells by decreasing XIAP expression and was more potent than bicalutamide in killing prostate tumor cells irrespective of their androgen status.

Development of ultrafast photochromic organometallics and photoinduced linkage isomerization of arene chromium carbonyl derivatives.

We review recent studies of processes relevant to photoinduced linkage isomerization of organometallic systems with the goal of preparing organometallics with an efficient and ultrafast photochromic response. The organometallic system thus corresponds to two linkage isomers with different electronic environments that are responsible for different optical properties. Much of this work has focused on examining processes following irradiation of cyclopentadienyl manganese tricarbonyl derivatives (compounds 3-21) including solvent coordination, thermal relaxation, solvent displacement by tethered functional groups (chelation), dissociation of tethered functional groups, and linkage isomerization.

Solvent and structural effects on ultrafast chelation dynamics of arene chromium tricarbonyl sulfide derivatives.

The chelation dynamics of three new [Cr{eta6-C6H5C(O)R}(CO)3] complexes, 1 [R = CH2(SCH3)], 2 [R = CH(SCH3)2], and 3 [R = C(SCH3)3], has been investigated on the picosecond to millisecond time scales by UV pump/IR probe transient absorption spectroscopy following photodissociation of CO in room temperature n-heptane, tetrahydrofuran (THF), and acetonitrile. In n-heptane, UV irradiation of 1, 2, or 3 dissociates CO to initially yield a Cr-S chelate (in which the pendant sulfide moiety is coordinated to the metal center) and a transient Cr-heptane solvate in approximately 1:2, 1:2, and 2:1 ratios, respectively. The Cr-heptane solvate is unstable and converts to the Cr-S chelate within 30 ns in each case.