piperidines and Hot-Flashes

The selective estrogen receptor modulators (SERMs) are substances with estrogenic/anti-estrogen effect that act differently depending on the tissue and composition. Since the discovery that tamoxifen and raloxifene (RLX) had a breast cancer preventive effect, the search for the perfect SERM has been the goal. The evidence that tamoxifen significantly increased the risk of endometrial cancer as compared to placebo made this tissue the center of interest in developing new SERMs. Thus, ospemifen, arzoxifene, lasofoxifene (LFX) and bazedoxifene (BZA) appeared as third-generation SERMs but only BZA reached the stage of clinical use. Both experimental and clinical data available on the effects of RLX or third-generation SERMs reaching clinical stage (LFX and BZA) show either neutrality or anti-estrogenic effects at endometrial level. BZA has shown to be equivalent to vehicle in several experimental conditions and acts as anti-estrogen in models were estrogens (conjugated equine estrogens [CEE] or E2) were co-administered. In a 7 years pivotal study the incidence of endometrial adenocarcinoma has been significantly lower in the BZA than in the placebo group. Moreover, in a clinical trial to evaluate the ability of a combination of BZA and CEE to prevent hot flushes in symptomatic postmenopausal women, doses of 20mg or higher of BZA have significantly decreased the risk of presenting endometrial hyperplasia when co-administered with either 0.650 or 0.450mg of CEE.

Topics: Adenocarcinoma; Animals; Breast Neoplasms; Clinical Trials as Topic; Double-Blind Method; Drug Evaluation, Preclinical; Endometrial Neoplasms; Endometrium; Estradiol; Estrogen Replacement Therapy; Estrogens, Conjugated (USP); Female; Hot Flashes; Humans; Indoles; Menopause; Multicenter Studies as Topic; Organ Specificity; Osteoporosis, Postmenopausal; Piperidines; Pyrrolidines; Rats; Selective Estrogen Receptor Modulators; Tamoxifen; Tetrahydronaphthalenes; Thiophenes; Thromboembolism

Arzoxifene increased bone mineral density and decreased bone turnover to a significantly greater extent than raloxifene. The hot flush incidence was lower with arzoxifene than raloxifene.. To assess the effect of arzoxifene versus raloxifene on change in lumbar spine (LS) bone mineral density (BMD) in postmenopausal women with osteoporosis.. In this 12-month study (NEXT trial), participants were randomly assigned to arzoxifene 20 mg/day (N = 158) or raloxifene 60 mg/day (N = 162). All received daily calcium and vitamin D. Change in LS BMD was assessed by DXA. Secondary objectives included assessment of femoral neck (FN) and total hip BMD, serum bone turnover markers, and safety.. Treatment groups were similar at baseline (mean age 63 years, mean LS BMD T-score -2.9). At 12 months, the increase in LS BMD with arzoxifene was greater than with raloxifene (+2.75% vs. +1.66%), as was FN and total hip BMD (P < 0.05). For LS and FN, this effect was also evident at 6 months. Arzoxifene reduced bone turnover to a greater extent than raloxifene at 3, 6, and 12 months (P < 0.05). The proportion of women reporting ≥ 1 adverse event did not differ between treatment groups, nor did vaginal bleeding. No cases of endometrial polyps, hyperplasia, or cancer were reported. Nasopharyngitis and bronchitis were reported more frequently with arzoxifene versus raloxifene (10.1% vs. 2.5%, and 5.1% vs. 0%, respectively) and new/worsening hot flushes were reported less frequently with arzoxifene (7.0% vs. 16.7%) (P < 0.05).. Arzoxifene increased BMD and suppressed bone turnover to a greater extent than raloxifene and resulted in a lower incidence of new/worsening hot flushes. Based on subsequent findings from a fracture outcome study, this difference did not translate into improved fracture efficacy.

Topics: Absorptiometry, Photon; Aged; Bone Density; Bone Density Conservation Agents; Bone Remodeling; Double-Blind Method; Female; Femur Neck; Hip Joint; Hot Flashes; Humans; Lumbar Vertebrae; Middle Aged; Osteoporosis, Postmenopausal; Piperidines; Raloxifene Hydrochloride; Thiophenes; Treatment Outcome

We evaluated the tolerability, adverse events profile, pharmacokinetics, and pharmacodynamics of CHF 4227, a new selective oestrogen receptor modulator (SERM), in healthy postmenopausal women.. Two phase I studies were conducted according to a double-bind, placebo-controlled design. Subjects were randomized to receive six single (5-400 mg) or five multiple oral doses of CHF 4227 for 28 days (5-100 mg).. No vaginal bleeding and no changes in either endometrial thickness or the placenta protein 14 marker were found after 4 weeks of treatment. The compound did not induce negative effects on the fibrinolytic system. After 28 days of treatment, CHF 4227 decreased both total and LDL cholesterol concentrations (maximum decreases from baseline of 17.4% (95% CI 7.0, 27.7) and 27.6% (95% CI 9.0, 46.3), respectively). Decreases in both serum and urinary type-I C-terminal collagen telopeptide were also observed producing maximum changes of 40.6% (95% CI 29.5, 51.7), and 41.7% (95% CI 20.3, 56.8), respectively. CHF4227 (5 and 10 mg) induced near maximal oestrogen-like effects on bone markers and serum lipids without causing hot flushes. The pharmacokinetics of CHF 4227 were characterized by a slow absorption, a long elimination half-life (31-42 h after single administration) and dose linearity with respect to C(max) and AUC up to 100 mg.. CHF 4227 is a well-tolerated SERM when administered once daily for 28 days. It is potentially active on bone resorption and serum lipids, without affecting the endometrium and without worsening hot flushes. CHF 4227 is a promising agent for the treatment of several conditions in postmenopausal women.

Topics: Benzopyrans; Bone Resorption; Dose-Response Relationship, Drug; Double-Blind Method; Endometrium; Female; France; Hot Flashes; Humans; Lipids; Piperidines; Postmenopause; Selective Estrogen Receptor Modulators

To assess the incidence of adverse events in postmenopausal women treated with raloxifene compared with placebo, hormone replacement therapy (HRT), or unopposed estrogen.. Common treatment groups were pooled across eight randomized, parallel clinical trials (6-30 months' duration) of raloxifene to create the following three databases: placebo-controlled, HRT-controlled, and estrogen-controlled databases. Incidence and severity of all treatment-emergent adverse events, defined as events that first occurred or worsened during treatment, were compared among groups in each of the databases.. Discontinuation rates overall, and those related to adverse events, were not significantly different between treatment groups in any database. There was no significant difference in incidence of vaginal bleeding or breast discomfort between women treated with raloxifene (60 mg/d) or placebo. Both of these events were reported more frequently in women receiving HRT or estrogen. Vaginal bleeding was responsible for significantly more discontinuations from the HRT groups compared with the raloxifene group. Hot flashes was the only event common to all three databases that was significantly increased in the raloxifene group, but this event did not increase the discontinuation rates. The incidence of leg cramps was greater in raloxifene-treated women compared with placebo-treated women in the placebo-controlled database, but did not cause any discontinuations of therapy. Raloxifene had no effect on the incidence of vaginal symptoms or central nervous system events.. Raloxifene had an adverse event profile distinct from HRT and unopposed estrogen and was well tolerated by postmenopausal women.

Topics: Adult; Aged; Breast Diseases; Estrogen Antagonists; Estrogen Replacement Therapy; Female; Hot Flashes; Humans; Incidence; Middle Aged; Pain; Piperidines; Postmenopause; Raloxifene Hydrochloride; Uterine Hemorrhage

Long-term estrogen therapy can reduce the risk of osteoporotic fracture and cardiovascular disease in postmenopausal women. At present, however, these beneficial effects are not separable from undesirable stimulation of breast and endometrial tissues.. We studied the effect of raloxifene, a nonsteroidal benzothiophene, on bone mineral density, serum lipid concentrations, and endometrial thickness in 601 postmenopausal women. The women were randomly assigned to receive 30, 60, or 150 mg of raloxifene or placebo daily for 24 months.. The women receiving each dose of raloxifene had significant increases from base-line values in bone mineral density of the lumbar spine, hip, and total body, whereas those receiving placebo had decreases in bone mineral density. For example, at 24 months, the mean (+/-SE) difference in the change in bone mineral density between the women receiving 60 mg of raloxifene per day and those receiving placebo was 2.4+/-0.4 percent for the lumbar spine, 2.4+/-0.4 percent for the total hip, and 2.0+/-0.4 percent for the total body (P<0.001 for all comparisons). Serum concentrations of total cholesterol and low-density lipoprotein cholesterol decreased in all the raloxifene groups, whereas serum concentrations of high-density lipoprotein cholesterol and triglycerides did not change. Endometrial thickness was similar in the raloxifene and placebo groups at all times during the study. The proportion of women receiving raloxifene who reported hot flashes or vaginal bleeding was not different from that of the women receiving placebo.. Daily therapy with raloxifene increases bone mineral density, lowers serum concentrations of total and low-density lipoprotein cholesterol, and does not stimulate the endometrium.

Topics: Bone Density; Cholesterol; Cholesterol, LDL; Double-Blind Method; Endometrium; Estrogen Antagonists; Female; Hip Joint; Hot Flashes; Humans; Lumbar Vertebrae; Middle Aged; Osteocalcin; Osteoporosis, Postmenopausal; Piperidines; Postmenopause; Raloxifene Hydrochloride

In our studies of the development of a novel class of selective estrogen receptor modulators, (+)-3-[4-(1-piperidinoethoxy)phenyl]spiro[indene-1,1'-indane]-5,5'-diol hydrochloride (1) was found to be an estrogen receptor ligand with beneficial effects in rat models for human hot flush. Moreover, 1 was found to have beneficial effects on lipid and bone metabolism while maintaining marginal effects on the uterus and breasts. These findings suggest that 1 would provide a new treatment for hot flush.

Topics: Animals; Bone Density; Breast Neoplasms; Cholesterol; Drug Evaluation, Preclinical; Estradiol; Female; Hot Flashes; Indans; Male; Morphine Dependence; Naloxone; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Skin Temperature; Spiro Compounds; Stereoisomerism; Tumor Cells, Cultured; Uterus