Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new premarin research articles will be listed here shortly after becoming available to us.
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Medical research on premarin
Am J Obstet Gynecol. 2008 May 22;
Cline JM, Botts S, Lees CJ, Brommage R
OBJECTIVE: The purpose of this study was to assess the effects of lasofoxifene on the reproductive system in ovariectomized nonhuman primates. STUDY DESIGN: This was a 2-year, randomized study. Adult female macaques (Macaca fascicularis) were assigned randomly into 5 groups: ovariectomized, placebo-treated controls (n = 22); sham-ovariectomized, placebo-treated controls (n = 24); ovariectomized animals given 0.021 mg Premarin kg/d (conjugated equine estrogen; n = 25); lasofoxifene at 1.0 mg/kg/d (n = 23); or lasofoxifene at 5.0 mg/kg/d (n = 25). Outcomes included organ weights and histopathologic findings. RESULTS: Lasofoxifene did not increase uterine weight or endometrial thickness and did not change mammary, vaginal, or cervical histologic condition. Mild endometrial fibrosis and cystic change were seen in lasofoxifene-treated animals, in contrast to significant uterine weight increases and endometrial hyperplasia induced by conjugated equine estrogen. CONCLUSION: Lasofoxifene did not increase uterine weight and produced minor histologic uterine changes at the doses that were given and had no effect on the breast, vagina, or cervix.
PREMARIN CAN ACT VIA ESTROGEN RECEPTORS TO RESCUE MICE FROM HEATSTROKE-INDUCED LETHALITY.
Shock. 2008 May 13;
Shen KH, Lin CH, Chang HK, Chen WC, Chen SH
The present study was conducted to assess whether Premarin, a water-soluble estrogen sulfate, can act via estrogen receptors (ERs) to rescue mice from heat-induced lethality. Unanesthetized, unrestrained mice were exposed to ambient temperature of 42.4 degrees C to induce heatstroke (HS). Another group of mice was exposed to room temperature (24 degrees C) and used as normothermic controls. They were given isotonic sodium chloride solution, Premarin (0.1 - 1.0 mg/kg of body weight, i.p.), or Premarin (1 mg/kg of body weight, i.p.) plus the nonselective ER antagonist ICI 182, 780 (0.25 mg/kg of body weight, i.p.) 1 h after the termination of heat stress. Their physiologic and biochemical parameters were continuously monitored. Mice that survived on day 4 of heat treatment were considered survivors. When the vehicle-treated mice underwent heat, the fraction survival and core temperature at +4 h of body heating were found to be 0 of 12 and 34.4 degrees C +/- 3 degrees C, respectively. Administration of Premarin (1 mg/kg) 1 h after the cessation of heat stress rescued the mice from heat-induced death (fraction survival, 12/12) and reduced the hypothermia (core temperature, 37.3 degrees C). The beneficial effects of Premarin in ameliorating lethality and hypothermia can be abolished by simultaneous administration of ICI 182, 780. Both IL-10 (an anti-inflammatory cytokine) and estradiol in the serum were increased significantly in heat-stressed mice administered Premarin compared with vehicle-treated HS group. Heat-induced apoptosis, as indicated by terminal deoxynucleotidyl-transferase-mediated alphaUDP-biotin nick end-labeling staining, in the spleen, liver, and kidney were significantly reduced by Premarin. The increased levels of cellular ischemia (e.g., glutamate, lactate-to-pyruvate ratio, and nitrite) and damage (e.g., glycerol) markers and iNOS expression in the hypothalamus during HS were decreased significantly by Premarin therapy. The levels of proinflammatory cytokines (e.g., IL-1beta and TNF-alpha) and renal and hepatic dysfunction markers in plasma that are up-regulated in heat stressed mice were significantly lower in Premarin-administered mice. The data indicate that Premarin may act via ERs to rescue mice form HS-induced lethality.
Microbes Infect. 2008 May; 10(6): 620-7
Dahn A, Saunders S, Hammond JA, Carter D, Kirjavainen P, Anukam K, Reid G
The aim of the study was to investigate gene expression profiles of post-menopausal women receiving Premarin estrogen replacement therapy (ERT), compared to controls, and to examine any correlations between the bacterial vaginosis (BV) status of the subjects. Based upon an expected finding of a 50-60% difference between gene expression of host antimicrobials with alpha=0.05 (2-sided), beta=0.20 the calculation of 7 subjects per group, led to a sample size of 10 subjects receiving Premarin estrogen replacement therapy and 10 healthy, age-matched controls. Vaginal samples were collected at a single timepoint and processed for RNA recovery and Affymetrix array analysis, as well as Nugent scoring and denaturing gradient gel electrophoresis to identify bacteria. Lactobacillus iners was the most commonly detected species in the normal flora and this was confirmed with L. iners-specific PCR method. Vaginal swabs from 6 Premarin and 8 control vaginal samples provided a non-invasive means to analyze human gene expression. There was no significant up-regulation of cancer-associated gene expression in subject receiving Premarin ERT, but some evidence that the potentially protective innate immunity was reduced in patients with BV. Of those with a normal flora, there was a 2-fold down-regulation of carcinoma associated forkhead box A1 gene expression. BV was associated with 7-fold down-regulation of host antimicrobial colony stimulating factor, -9.83-fold for IL-1alpha, -8.33 for IL-1beta and -3.63 for IL-6. This is the first study to use gene arrays to correlate changes in host expression response to estrogen replacement therapy and BV.
[Diagnosis and treatment of 17alpha-hydroxylase deficiency: a case report and literature review.]
Beijing Da Xue Xue Bao. 2008 Apr 18; 40(2): 221-2
Zhang L, Wang HN, Hong TP
A 16-year-old "female" patient presented as hypertension, hypokalemia, male pseudohermaphroditism, lowered gonadal steroids and cortisol, elevated adrenocorticotropic hormone and pituitary gonadotropin, and 46 XY karyotype. The patient was diagnosed as 17alpha-hydroxylase deficiency, a rare case of congenital adrenal hyperplasia. "She" chose to remain female appearance and social gender after negotiation with the parents. Cryptorj chidism of both inguinal canals was surgically removed for preventing canceration. After the surgery, a very small daily dose of dexamethasone (0.187 5 mg at bedtime) was enough to control hypertension and hypokalemia, and the therapy of conjugated estrogens (Premarin) was given to promote the development of female characters. After 6 months of treatment, normotension and normokalemia remained, and pubarche and mammogenesis emerged.
Bazedoxifene: Bazedoxifene Acetate, TSE 424, TSE-424, WAY 140424.
Drugs R D. 2008; 9(3): 191-6
Bazedoxifene is a third-generation selective estrogen receptor modulator (SERM) that is being developed by Ligand Pharmaceuticals in collaboration with Wyeth. The agent has effects on bone and cardiovascular tissue, but does not affect breast or uterine tissue. Bazedoxifene is in clinical development as a monotherapy for the prevention and treatment of postmenopausal osteoperosis, and in combination with conjugated estrogens for the treatment of menopausal symptoms and prevention of postmenopausal osteoporosis.American Home Products changed its name and the names of its subsidiaries Wyeth-Ayerst and Wyeth Lederle to Wyeth in March 2002.Wyeth and Ligand entered into a discovery research collaboration for bazedoxifene in September 1994. Under the agreement, Wyeth has worldwide development rights to the compound and is solely responsible for its clinical development. In exchange, Ligand is entitled to milestone and royalty payments associated with development and commercialization achievements.Ligand entered into an agreement with Royalty Pharma in March 2002 whereby Royalty Pharma purchased the rights to a share of Ligand's entitlement to milestone and royalty payments. Under the agreement, Ligand received $US6 million from Royalty Pharma in exchange for a 0.25% stake in net sales of three SERM products (lasofoxifene, bazedoxifene and bazedoxifene/Premarin((R))) for a period of 10 years. Subsequently, Ligand and Royalty Pharma further amended their existing royalty agreement for three SERM products in November 2004. Under the revised agreement, Royalty Pharma would purchase an additional 1.625% of the SERM products' net sales for $US32.5 million, which represents an acceleration of the previous option timetable and an increase in the royalty amount as well as aggregate purchase price. Consequently, Royalty Pharma increased its rights to a total of 3.0125% of net sales of each SERM product for 10 years following first commercial sale of each product and has no further options. Ligand retains an approximately equal portion of lasofoxifene and other SERM's net sales going forward and for periods that could exceed 10 years. The royalty rates owed to Royalty Pharma for the royalties just purchased could be reduced by one-third if product sales exceed certain thresholds. Payments from the royalty purchase are non-refundable, regardless of whether the products ever become successfully launched or not. Milestone payments owed by Ligand's partners as products achieve development and regulatory targets would be paid to Ligand as earned, and are not included in this amended agreement. The US FDA issued a second approvable for bazedoxifene in December 2007, after Wyeth submitted additional study reports from two completed clinical studies for the prevention of postmenopausal osteoporosis. The study reports provided data from two studies conducted in Asia and will form part of a complete response to safety and efficacy issues raised in an initial approvable letter issued by the FDA in April 2007. Prior to approval of the NDA, the FDA must also analyse final safety and efficacy data from a completed phase III trial, and complete an acceptable establishment evaluation on the manufacturing facilities for bazedoxifene. In January 2008, Wyeth stated that the FDA expects to convene an Advisory Committee meeting in July 2008 to review both the treatment and prevention of osteoporosis indications for bazedoxifene. While the second approvable letter issued by the FDA expressed concerns about the incidence of stroke and venous thrombotic events, Wyeth has reported that no additional studies would be needed. Initial filing of the NDA in June 2006 triggered a milestone payment from Wyeth to Ligand.A 2-year, randomized, phase III trial (study 300) has been conducted to compare bazedoxifene (10, 20 and 40 mg) and raloxifene (60 mg) in 1583 patients for the prevention of osteoporosis. Data presented in September 2007 demonstrated that bazedoxifene treatment prevented bone loss, reduced bone turnover, and was generally well tolerated in postmenopausal women with normal or low bone mineral density.Wyeth submitted an NDA to the FDA in July 2007 to gain marketing approval for bazedoxifene as a treatment for postmenopausal osteoporosis. In January 2008, Wyeth stated that the FDA expects to convene an Advisory Committee meeting in July 2008 to review both the treatment and prevention of osteoporosis indications for bazedoxifene.Wyeth has completed a phase III trial comparing bazedoxifene with raloxifene and placebo in 7492 patients with moderate-to-severe postmenopausal osteoporosis. The three-year, randomized, double-blind study commenced in October 2001, and was conducted at sites in the US. Data presented in September 2007 indicated that bazedoxifene showed significant risk reduction for new vertebral fractures, compared with placebo.In addition, Wyeth conducted a phase II trial in Japan to investigate bazedoxifene dose-response in 375 patients with postmenopausal osteoporosis. The randomized, double-blind, placebo-controlled, parallel assignment study commenced in August 2003 and is no longer recruiting patients.The patent covering bazedoxifene will expire in 2017 with the potential for extension.
Successful Use of Balloon Ablation to Treat Menorrhagia Complicating Aplastic Anemia.
Gynecol Obstet Invest. 2008 Apr 29; 66(2): 123-126
Kim N, Donohue T, Sloand E, Stratton P
Background: Aplastic anemia (AA) complicated by menorrhagia is treated with transfusion and hormonal therapy. When bleeding is life-threatening, balloon endometrial ablation can safely be used to treat menorrhagia in selected patients. Case: A 56-year-old postmenopausal woman was diagnosed with AA after several weeks of menorrhagia and pancytopenia. She became heavily alloimmunized after extensive platelet transfusion. During treatment with antithymocyte globulin, vaginal bleeding increased and the platelet count fell to 1,000/mul on supportive measures. After bleeding stopped with use of intravenous Premarin, she was examined in the operating room. There, a clot was removed and appeared to be a uterine caste; hemostasis continued. Transvaginal ultrasound revealed a normal endometrial contour and thin endometrium; endometrial histology was benign. After she completed antithymocyte globulin and her platelet count could be maintained over 30,000/mul with matched platelets, endometrial ablation was performed without any complications. Conclusion: Thermal balloon endometrial ablation is an effective alternative to hysterectomy for women with persistent menorrhagia and AA when supportive measures fail. Prior to endometrial ablation, evaluation should ensure normal endometrial contour and histology, and that sufficient blood products are available to maintain platelet counts above 30,000/mul during the healing process.
Conformational properties of equilenin-DNA adducts: stereoisomer and base effects.
Chem Res Toxicol. 2008 May; 21(5): 1064-73
Ding S, Shapiro R, Cai Y, Geacintov NE, Broyde S
Equilin and equilenin, components of the hormone replacement therapy drug Premarin, can be metabolized to the catechol 4-hydroxyequilenin (4-OHEN). The quinoids produced by 4-OHEN oxidation react with dC, dA, and dG to form unusual stable cyclic adducts, which have been found in human breast tumor tissue. Four stereoisomeric adducts have been identified for each base. These 12 Premarin-derived adducts provide a unique opportunity for analyzing effects of stereochemistry and base damage on DNA structure and consequently its function. Our computational studies have shown that these adducts, with obstructed Watson-Crick hydrogen-bond edges and near-perpendicular ring systems, have limited conformational flexibility and near-mirror-image conformations in stereoisomer pairs. The dC and dA adducts can adopt major- and minor-groove positions in the double helix, but the dG adducts are positioned only in the major groove. In all cases, opposite orientations of the equilenin rings with respect to the 5' --> 3' direction of the damaged strand are found in stereoisomer pairs derived from the same base, and no Watson-Crick pairing is possible. However, detailed structural properties in DNA duplexes are distinct for each stereoisomer of each damaged base. These differences may underlie observed differential stereoisomer and base-dependent mutagenicities and repair susceptibilities of these adducts.
J Natl Cancer Inst. 2008 Apr 16; 100(8): 563-71
Rohan TE, Negassa A, Chlebowski RT, Habel L, McTiernan A, Ginsberg M, Wassertheil-Smoller S, Page DL
BACKGROUND: Estrogens stimulate proliferation of breast epithelium and may therefore increase the risk of benign proliferative breast disease, a condition that is associated with increased risk of breast cancer. We tested the effect of conjugated equine estrogen (CEE) on risk of benign proliferative breast disease in the Women's Health Initiative (WHI) randomized controlled trial. METHODS: In the WHI CEE trial, 10,739 postmenopausal women were randomly assigned to 0.625 mg/d of CEE or to placebo. Baseline and annual breast examinations and mammograms were required. We identified women in the trial who reported breast biopsies that were free of cancer, obtained the associated histological sections, and subjected them to standardized central review. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: A total of 232 incident cases of benign proliferative breast disease were ascertained during follow-up (average duration, 6.9 years), with 155 in the CEE group and 77 in the placebo group. Use of CEE was associated with a more than two-fold increase in the risk of benign proliferative breast disease (HR = 2.11, 95% CI = 1.58 to 2.81). For benign proliferative breast disease without atypia, the HR was 2.34 (95% CI = 1.71 to 3.20), whereas for atypical hyperplasia, it was 1.12 (95% CI = 0.53 to 2.40). Risk varied little by levels of baseline characteristics. CONCLUSION: Use of 0.625 mg/d of CEE was associated with a statistically significant increased risk of benign proliferative breast disease.
Estrogen plus progestin therapy and breast cancer in recently postmenopausal women.
Am J Epidemiol. 2008 May 15; 167(10): 1207-16
Prentice RL, Chlebowski RT, Stefanick ML, Manson JE, Pettinger M, Hendrix SL, Hubbell FA, Kooperberg C, Kuller LH, Lane DS, McTiernan A, Jo O'Sullivan M, Rossouw JE, Anderson GL
The Women's Health Initiative trial found a modestly increased risk of invasive breast cancer with daily 0.625-mg conjugated equine estrogens plus 2.5-mg medroxyprogesterone acetate, with most evidence among women who had previously received postmenopausal hormone therapy. In comparison, observational studies mostly report a larger risk increase. To explain these patterns, the authors examined the effects of this regimen in relation to both prior hormone therapy and time from menopause to first use of postmenopausal hormone therapy ("gap time") in the Women's Health Initiative trial and in a corresponding subset of the Women's Health Initiative observational study. Postmenopausal women with a uterus enrolled at 40 US clinical centers during 1993-1998. The authors found that hazard ratios agreed between the two cohorts at a specified gap time and time from hormone therapy initiation. Combined trial and observational study data support an adverse effect on breast cancer risk. Women who initiate use soon after menopause, and continue for many years, appear to be at particularly high risk. For example, for a woman who starts soon after menopause and adheres to this regimen, estimated hazard ratios are 1.64 (95% confidence interval: 1.00, 2.68) over a 5-year period of use and 2.19 (95% confidence interval: 1.56, 3.08) over a 10-year period of use.
Dr J. B. Collip and the development of Premarin.
J Obstet Gynaecol Can. 2008 Mar; 30(3): 244-7
Kinch RA,