WS 12

Neuroendocrine effects of Hypericum extract WS 5570 in 12 healthy male volunteers.[Pubmed:11518061]

Pharmacopsychiatry. 2001 Jul;34 Suppl 1:S127-33.

In the present study, the effects of acute p.o. administration of placebo at 300 mg and 600 mg of WS 5570 Hypericum perforatum extract on cortisol (COR), growth hormone (GH) and prolactin (PRL) secretion were examined in twelve physically and mentally healthy subjects. WS 5570 is a hyperforin containing extract of St. John's Wort which has been proven effective in mild to moderate depression. After inserting an i.v. catheter, blood samples were drawn one hour prior to the administration of WS 5570 or placebo, at the time of application and up to five hours after application in 30-minute intervals. Plasma concentrations of COR, GH, and PRL were determined in each blood sample by double-antibody RIA methods. No PRL stimulation could be observed after placebo or after WS 5570 (300, 600 mg). A small but statistically significant elevation in GH AUC values occurred after 300 mg of WS 5570. After 600 mg of WS 5570, a clear-cut COR stimulation was observed, occurring from 30 up to 90 minutes after the application. In this period of time (from t = 30 min to t = 90 min), the mean COR concentrations were significantly higher after 600 mg of WS 5570 compared to placebo. 300 mg of WS 5570 did not show any effects on COR secretion. We propose that the Hypericum extract WS 5570 is able to influence central neurotransmitters, thereby causing COR stimulation in a dose-dependent manner.

Menthol derivative WS-12 selectively activates transient receptor potential melastatin-8 (TRPM8) ion channels.[Pubmed:18930858]

Pak J Pharm Sci. 2008 Oct;21(4):370-8.

Transient receptor potential melastatin-8 (TRPM8), a cationic ion channel is involved in detection of normal cooling-sensation in mammals. TRPM8 activation by cooling or chemical agonists have been shown to produce profound, mechanistically novel analgesia in chronic pain states such as neuropathic pain in rodents. Known TRPM8 agonists such as menthol and icilin have a relatively low potency and cross-activate nociceptors like TRPA1; thus bearing a limited therapeutic usefulness. For that reason, characterising ligands, which selectively activate TRPM8, presents a clinical need. Using Xenopus laevis oocytes as expression system, we evaluated WS-12, a menthol derivative, for its potential interaction with all six thermo-sensitive TRP ion channels. Oocytes were injected with cRNA of gene of interest and incubated for 3-5 days (at 16 degrees C) before testing for functional characterisation of the recombinant ion channels. Oocytes were superfused with the test and standard substances respectively. Responses were measured by two-electrode voltage clamp technique and the amplitudes of evoked currents were compared with baseline values. WS-12 robustly activated TRPM8 in low micromolar concentrations (EC50 12+/-5 microM) thereby displaying a higher potency and efficacy compared to menthol (EC50 196+/-22 microM). Any of the other described thermo-sensitive TRP ion channel including TRPV1, TRPV2, TRPV3, TRPV4 and TRPA1 were not activated at a concentration (1 mM) optimally effective for TRPM8 responses; a characteristic which is in sharp contrast to menthol as it activates TRPA1 and TRPV3 in addition to TRPM8. Unlike icilin (75% reduction; p<0.001, n=6), WS-12 does not induce tachyphylaxis (4+/-2.3% increase in responses; p<0.08, n=6) of TRPM8 mediated currents to repeated exposure of 1 mM doses. In addition, acidosis or variations in extracellular calcium have no influence on potency/efficacy of WS-12 for TRPM8. The selectivity profile of WS-12, its several-fold higher potency and around two-fold increase in efficacy compared to menthol warrants its potential utility for therapy in chronic neuropathic pain states and as a diagnostic probe in prostate cancer.

Development of a 12-Item Abbreviated Three-Dimensional Wisdom Scale (3D-WS-12): Item Selection and Psychometric Properties.[Pubmed:26209513]

Assessment. 2017 Jan;24(1):71-82.

Wisdom has been reported to be associated with better mental health and quality of life among older adults. Over the past decades, there has been considerable growth in empirical research on wisdom, including the development of standardized measures. The 39-item Three-Dimensional Wisdom Scale (3D-WS) is a useful assessment tool, given its rigorous development and good psychometric properties. However, the measure's length can prohibit use. In this article, we used a sample of 1,546 community-dwelling adults aged 21 to 100 years (M = 66 years) from the Successful AGing Evaluation (SAGE) study to develop an abbreviated 12-item version of the 3D-WS: the 3D-WS-12. Balancing concerns for measurement precision, internal structure, and content validity, factor analytic methods and expert judgment were used to identify a subset of 12-items for the 3D-WS-12. Results suggest that the 3D-WS-12 can provide efficient and valid assessments of Wisdom within the context of epidemiological surveys.

Prospects for prostate cancer imaging and therapy using high-affinity TRPM8 activators.[Pubmed:16949669]

Cell Calcium. 2007 Mar;41(3):285-94.

One of the best-studied temperature-gated channels is transient receptor potential melastatin 8 (TRPM8), which is activated by cold and cooling agents, such as menthol. Besides inducing a cooling sensation in sensory neurons, TRPM8 channel activation also plays a major role in physiopathology. Indeed, TRPMP8 expression increases in early stages of prostate cancer and its involvement in prostate cell apoptosis has recently been demonstrated. Thus, as TRPM8 is a tumor marker with significant potential use in diagnosis, as well as a target for cancer therapy, there is a need for new TRPM8-specific ligands. In this study, we investigated the action of "WS" compounds on TRPM8 channels. We compared the affinity of these molecules to that of menthol and icilin. This enabled us to identify new TRPM8 agonists. The menthol analog with the highest affinity, WS-12, had an EC(50) value about 2000 times lower than that of menthol and is, therefore, the highest-affinity TRPM8 ligand known to date. Finally, incorporating a fluorine atom in the WS-12 retained 75% of the activity of the parent compound. The high affinity of this new TRPM8 ligand and the possibility of incorporating a radiohalogen could thus be useful for diagnosis, monitoring and, perhaps, even therapy of prostate cancer.

Characterisation of TRPM8 as a pharmacophore receptor.[Pubmed:17517434]

Cell Calcium. 2007 Dec;42(6):618-28.

Some proteins of the transient receptor potential (TRP) family form temperature sensitive ion channels. One member of the melastatin (M) group, namely TRPM8 is activated by cold and cooling compounds such as menthol and icilin, and its gene is up-regulated in prostate cancer and other malignancies. Here we characterise the effects of the carboxamides WS-12, CPS-113, CPS-369, the carboxylic acid WS-30 and the phosphine oxide WS-148 by Ca2+ imaging experiments and whole-cell patch-clamp recordings on TRPM8 expressing human embryonic kidney (HEK), lymph node prostate cancer (LNCaP) and dorsal root ganglia (DRG) cells. The cooling compounds introduced in this study, show a dose-dependent and reversible activation of TRPM8 with EC50 values in the nM to low microM range. The carboxamide WS-12 is most potent in activating TRPM8. It is selective, since other TRP proteins are not stimulated at muM concentrations and its efficacy with respect to TRPM8 is similar to the one of icilin. In summary, the compounds described in this study represent new tools to dissect TRPM8 functions and may serve as chemical leads for the development of additional TRPM8 agonists and novel antagonists. Such compounds may be beneficial for preventing noxious cold perception. They could also be useful in diagnosis and treatment of most common cancers in which the TRPM8 gene is up-regulated in comparison to the corresponding normal tissue.