piperidines and Leiomyoma

Uterine leiomyomas are a common disorder resulting in significant morbidity for women and substantial economic impact on the health care system. Current therapies include conservative surgery, hysterectomy, and hormonal therapy. Conservative surgical therapy often fails because of recurrence, and hysterectomy dramatically limits reproductive options. Radiologic therapies are associated with considerable risk of morbidity and mortality and are not likely to be compatible with reproduction. Hormonal therapies such as gonadotropin-releasing hormone (GnRH) analogues or progestins with or without estrogen are utilized by many patients, but long-term use of either is often responsible for unacceptable morbidity and hormonal therapies are not compatible with reproduction. Newer hormonal alternatives such as progesterone antagonists and selective agonists as well as "add-back" estrogen therapy in addition to GnRH analogues have been developed and show promise. However, no hormonal therapy that significantly alters estrogen and progesterone production or function is likely to be compatible with reproduction. Thus, it is important to develop novel nonhormonal therapies for medical treatment of leiomyomas. Other laboratories have evaluated pirfenidone, halofuginone, heparin, and interferon-alpha (IFN-alpha). Recent work in our laboratory suggests potential use of two additional classes of compounds, thiazolidinediones and tocopherol analogs. The rationale, evidence, and potential for the use of each of these compounds in the treatment of leiomyomas are discussed.

Topics: Bexarotene; Female; Heparin; Humans; Interferon-alpha; Leiomyoma; ortho-Aminobenzoates; Piperidines; Pyridones; Quinazolines; Quinazolinones; Reproduction; Tetrahydronaphthalenes; Thiazolidinediones; Tocopherols; Uterine Neoplasms

The purpose of this study was to investigate the safety and efficacy of alvimopan, a novel peripherally acting mu-opioid receptor antagonist, in patients who undergo simple total abdominal hysterectomy.. Women (n = 519) were randomized (4:1) to receive alvimopan 12 mg (n = 413) or placebo (n = 106) > or = 2 hours before the operation then twice daily for 7 days (hospital and home). Adverse events were monitored up to 30 days after the last dose of study drug was administered. Efficacy was assessed for 7 postoperative days.. Overall, the most common adverse events were nausea, vomiting, and constipation; < 5% of patients discontinued use because of adverse events. Alvimopan significantly accelerated the time to first bowel movement (hazard ratio, 2.33; P <.001). Average time to first bowel movement was reduced by 22 hours, with more frequent bowel movement and better bowel movement quality found in the treatment cohort.. Alvimopan has a safety profile that is similar to that of placebo and provides significantly improved lower gastrointestinal recovery in women who undergo simple total abdominal hysterectomy.

Topics: Adult; Analgesics, Opioid; Defecation; Double-Blind Method; Female; Gastrointestinal Motility; Humans; Hysterectomy; Leiomyoma; Middle Aged; Pain Measurement; Piperidines; Postoperative Nausea and Vomiting; Postoperative Period; Recovery of Function; Uterine Neoplasms

Does halofuginone (HF) inhibit the growth of human uterine leiomyoma cells in a mouse xenograft model?. HF suppresses the growth of human uterine leiomyoma cells in a mouse xenograft model through inhibiting cell proliferation and inducing apoptosis.. Uterine leiomyomas are the most common benign tumors of the female reproductive tract. HF can suppress the growth of human uterine leiomyoma cells in vitro. The mouse xenograft model reflects the characteristics of human leiomyomas.. Primary leiomyoma smooth muscle cells from eight patients were xenografted under the renal capsule of adult, ovariectomized NOD-scid IL2Rγ(null) mice (NSG). Mice were treated with two different doses of HF or vehicle for 4 weeks with six to eight mice per group.. Mouse body weight measurements and immunohistochemical analysis of body organs were carried out to assess the safety of HF treatment. Xenografted tumors were measured and analyzed for cellular and molecular changes induced by HF. Ovarian steroid hormone receptors were evaluated for possible modulation by HF.. Treatment of mice carrying human UL xenografts with HF at 0.25 or 0.50 mg/kg body weight for 4 weeks resulted in a 35-40% (P < 0.05) reduction in tumor volume. The HF-induced volume reduction was accompanied by increased apoptosis and decreased cell proliferation. In contrast, there was no significant change in the collagen content either at the transcript or protein level between UL xenografts in control and HF groups. HF treatment did not change the expression level of ovarian steroid hormone receptors. No adverse pathological effects were observed in other tissues from mice undergoing treatment at these doses.. While this study did test the effects of HF on human leiomyoma cells in an in vivo model, HF was administered to mice whose tolerance and metabolism of the drug may differ from that in humans. Also, the longer term effects of HF treatment are yet unclear.. The results of this study showing the effectiveness of HF in reducing UL tumor growth by interfering with the main cellular processes regulating cell proliferation and apoptosis are in agreement with previous studies on the effects of HF on other fibrotic diseases. HF can be considered as a candidate for reducing the size of leiomyomas, particularly prior to surgery.. This project was funded by NIH PO1HD057877 and R01 HD064402. Authors report no competing interests.

Topics: Animals; Antineoplastic Agents; Apoptosis; Body Weight; Cell Proliferation; Female; Humans; Immunohistochemistry; Leiomyoma; Mice, Inbred NOD; Mice, SCID; Piperidines; Quinazolinones; Uterine Neoplasms; Xenograft Model Antitumor Assays

The purpose of this study was to examine the hemodynamics and bispectral index score during lower abdominal surgery under balanced anesthesia with the two different combination doses of desflurane and remifentanil.. Twenty patients undergoing total hysterectomy were allocated into two groups; 1) 10 patients received 4.5% end-tidal concentration of desflurane combined with remifentanil 0.125 μg x kg(-1) x min(-1) (H group) and 2) 10 patients received 3.0% end-tidal concentration of desflurane combined with remifentanil 0.2 μg x kg(-1) X min(-1) (L group). Mean arterial pressure (MAP), heart rate (HR) and BIS were recorded 5 times (on admission to operating room, immediately before surgery, 5 minutes after the skin incision, at the moment of uterine extraction and during retroperitoneal closure).. MAP and HR during surgery did not increase compared with those on admission to operating room, and BIS was unchanged throughout the study in both two groups.. The patients could be anesthetized adequately during lower abdominal surgery under balanced anesthesia with the two different combination doses of desflurane and remifentanil.

Topics: Anesthetics, Inhalation; Anesthetics, Intravenous; Balanced Anesthesia; Desflurane; Female; Humans; Hysterectomy; Isoflurane; Leiomyoma; Piperidines; Remifentanil

Dysregulated cyclin-dependent kinases (CDKs) are considered a potential target for cancer therapy. Flavopiridol is a potent CDK inhibitor. In this study, the antiproliferative effect of the flavonoid compound flavopiridol and its mechanism in human uterine leiomyoma cells were investigated. The present study focused on the effect of flavopiridol in cell proliferation and cell cycle progression in primary cultured human uterine leiomyoma cells. Cell viability and cell proliferation assays were conducted. Flow cytometry was performed to determine the effect of flavopiridol on cell cycle. The expression of cell cycle regulatory-related proteins was evaluated by Western blotting. Cell viability and proliferation of uterine leiomyoma cells were significantly reduced by flavopiridol treatment in a dose-dependent manner. Flow cytometry results showed that flavopiridol induced G1 phase arrest. Flavopiridol-induced growth inhibition in uterine leiomyoma cells was associated with increased expression of p21(cip/wafl) and p27(kip1) in a dose-dependent manner. Downregulation of CDK2/4 and Cyclin A with a concomitant increase in dephosphorylation of retinoblastoma was observed. This study demonstrates that flavopiridol inhibits cell proliferation by initiating G1 cell cycle arrest in human uterine leiomyoma. We also found that flavopiridol is effective in inhibiting xenografted human uterine leiomyoma growth. These results indicate that flavopiridol could prove to be a promising chemopreventive and therapeutic agent for human uterine leiomyoma.

Topics: Adult; Animals; Antineoplastic Agents; Cell Survival; Dose-Response Relationship, Drug; Female; Flavonoids; Humans; Leiomyoma; Mice; Mice, Knockout; Middle Aged; Piperidines; Treatment Outcome; Tumor Cells, Cultured; Uterine Neoplasms; Xenograft Model Antitumor Assays

We report a case of first-degree atrioventricular (A-V) block progressing to second-degree (Wenckebach-type) A-V block after administration of indigo carmine in a patient undergoing hysterectomy under general anesthesia. We believe that the onset of Wenckebach-type A-V block may have been induced by one or more of three factors: 1) preoperative first-degree A-V block, 2) the anesthetics used (propofol and remifentanil), and 3) administration of indigo carmine.

Topics: Adult; Anesthesia, General; Atrioventricular Block; Coloring Agents; Disease Progression; Electrocardiography; Female; Humans; Hysterectomy; Indigo Carmine; Intraoperative Complications; Leiomyoma; Piperidines; Propofol; Remifentanil; Ureter; Uterine Neoplasms; Vagus Nerve

Uterine leiomyomas, or fibroids, are the most frequent gynecological tumors in premenopausal women with as many as 65% of women becoming clinically symptomatic. Uterine fibroids are benign myometrial tumors that produce large quantities of extracellular matrix proteins. Despite its high morbidity, the molecular basis underlying the development of uterine leiomyomas is not well understood. Domestic hens of Gallus gallus domesticus develop oviductal leiomyomas similar to those found in humans. We investigated the natural history of chicken leiomyomas, in vivo expression of protein biomarkers, and in vitro expression of ovarian steroid receptors. Based on the analysis of 263 hens, tumor prevalence, tumor number per hen, and tumor size increased as the hens aged. Immunohistochemistry for alpha-smooth muscle actin (SMA) and desmin confirmed the smooth muscle phenotype of the chicken leiomyomas. Intense collagen expression was detected in these oviductal leiomyomas by Mason's trichrome, and the tumors also showed increased expression of TGFB3 and collagen type I mRNAs. Consistent with human leiomyomas, chicken fibroids displayed increased BCL2 and estrogen (E) and progesterone (P) receptor expression. Chicken leiomyomas were dissociated for in vitro culture. Cells from explants were positive for SMA, desmin, and E and P receptors until the fourth passage. These cells also displayed a response similar to human cells when challenged with halofuginone, an antifibrotic agent. Our findings indicate that the chicken is an excellent complementary model for studies involving the pathophysiology of human uterine leiomyomas.

Topics: Aging; Animals; Antineoplastic Agents; Chickens; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Humans; Leiomyoma; Oviducts; Piperidines; Poultry Diseases; Prevalence; Primary Cell Culture; Quinazolinones; Tumor Cells, Cultured; Uterine Neoplasms

To investigate the effects of the antifibrotic drug halofuginone on extracellular matrix production, cell proliferation, and apoptosis of cultured myometrial and leiomyoma smooth muscle cells.. Comparative and controlled experimental research study.. University research laboratory.. Leiomyoma and myometrial tissues were obtained from eight different patients at the time of elective hysterectomy.. The effects of halofuginone on cell proliferation were assessed by tritiated thymidine uptake assays and cell count assays. Effects on TGFbeta1, collagen type I, and collagen type III mRNA levels were assessed by quantitative real-time polymerase chain reaction. Effects on apoptosis were assayed using a chemiluminescent assay to measure changes in caspase 3 and 7.. Halofuginone inhibited cell proliferation of both leiomyoma and autologous myometrial cells in a dose-dependent manner by inhibiting DNA synthesis within 24 hours and later inducing apoptosis (as measured by increased caspase 3/7) by 48-72 hours. Halofuginone also significantly reduced collagen type I (alpha1) and collagen type III (alpha1) mRNA levels, as well as the profibrotic factor TGFbeta1 mRNA levels in both cell types.. These results provide evidence to support the use of the antifibrotic drug halofuginone as a novel drug treatment for uterine leiomyomas.

Topics: Apoptosis; Cell Proliferation; Collagen Type I; Collagen Type III; Female; Fibrosis; Growth Inhibitors; Humans; Leiomyoma; Myocytes, Smooth Muscle; Myometrium; Piperidines; Quinazolinones; Transforming Growth Factor beta; Tumor Cells, Cultured; Uterine Neoplasms

The design of a novel selective estrogen receptor modulator (SERM) for the potential treatment of uterine leiomyoma is described. 16 (LY2066948-HCl) binds with high affinity to estrogen receptors alpha and beta (ERalpha and ERbeta, respectively) and is a potent uterine antagonist with minimal effects on the ovaries as determined by serum biomarkers and histologic evaluation.

Topics: Animals; Binding Sites; Biological Availability; Cell Line; Cell Proliferation; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Humans; Leiomyoma; Mammary Glands, Animal; Models, Molecular; Naphthalenes; Organ Size; Ovary; Piperidines; Rats; Rats, Sprague-Dawley; Selective Estrogen Receptor Modulators; Structure-Activity Relationship; Uterine Neoplasms; Uterus

Leiomyomas (fibroids) are benign smooth-muscle cell (SMC) tumors of the uterus and are the most common pelvic tumors in women. These tumors occur primarily during the reproductive years and are the most common indication for hysterectomy in women. Unfortunately the only effective treatments for leiomyomas and the associated abnormal uterine bleeding are surgical, involving either hysterectomy, myomectomy, or hysteroscopic removal of the tumors. The goal of this paper is to discuss recent research findings that support the idea of using therapeutic compounds that block the actions of specific growth factors as therapeutic agents for treatment of leiomyomas and abnormal uterine bleeding. Most of the studies were carried out using cell cultures of leiomyoma or myometrial SMCs. Primary cultures of SMCs provide a system for investigation of the roles of growth factors and their receptors in proliferation of normal myometrial and leiomyoma SMCs. Several growth factors have been shown to be present and to have regulatory roles in the proliferation of uterine SMCs. Bioassay and Western blotting of fast protein liquid chromatography fractions of tissue extracts identified platelet-derived growth factor, heparin-binding epidermal growth factor, hepatoma-derived growth factor, and basic fibroblast growth factor in normal myometrium and fibroid tumors. The presence of heparin-binding growth factors suggests a possible focus for therapeutic agents. RG13577 (a heparinlike compound) and halofuginone (an alkyloid) reversibly inhibited DNA synthesis of normal myometrial and leiomyoma cells without toxic effects. Pirfenidone, a known antifibrotic drug, inhibited DNA synthesis and synthesis of collagen type I mRNA in normal and fibroid cells, and decreased collagen type III mRNA only in normal myometrial cells. Another hopeful therapeutic candidate, interferon-Alpha, significantly inhibited growth factor-stimulated proliferation in both normal and leiomyoma cells. These results suggest that future nonsurgical treatments for leiomyomas may include compounds that block the actions of specific growth factors that regulate proliferation and collagen production by uterine SMCs.

Topics: Antineoplastic Agents; Blotting, Western; Chromatography, Liquid; Female; Growth Inhibitors; Growth Substances; Humans; Hysterectomy; Hysteroscopy; Immunohistochemistry; Interferon-alpha; Leiomyoma; Phenoxyacetates; Piperidines; Polymers; Protein Synthesis Inhibitors; Pyridones; Quinazolines; Quinazolinones; Receptors, Growth Factor; Uterine Neoplasms

The distribution of mRNAs for endothelinA and B (ET(A) and ET(B)) receptors and their binding properties was studied in human nonpregnant and pregnant term myometrium and in uterine leiomyomas. ET(A)- and ET(B)-receptors functionally coupled to phospholipase C (PLC) coexisted in myometrial tissues, but only the functional ET(A)-receptor subtype was detected in leiomyomas. ET(A)-receptor mRNA and three other spliced variants were distributed in all tissue studied. We reported an increase in the proportion of ET(A)-receptors coupled to PLC in term pregnant myometrium when compared to nonpregnant tissue. These results suggest that upregulation of the myometrial ET(A)-receptors may account for or contribute to the control of normal development and growth of human myometrium during pregnancy. They also support a pathological role for the endothelin-1 (ET-1)/ET(A)-receptor system in leiomyoma development.

Topics: Azepines; Endothelin-1; Female; Humans; Indoles; Leiomyoma; Myometrium; Oligopeptides; Piperidines; Pregnancy; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; RNA, Messenger; Uterine Neoplasms

Chronic exposure of oophorectomized guinea pigs to 17beta-estradiol causes leiomyoma formation. Our aims were to determine whether these leiomyomas can become estradiol independent after exposure to estradiol and if raloxifene inhibits leiomyoma growth when given concomitantly with estradiol.. To induce leiomyoma development, 6 oophorectomized animals received two estradiol implants for 140 days. Next, the estradiol implants were replaced with empty implants in 3 animals, whereas the other 3 received 2 new estradiol implants and raloxifene given per os 10 mg/kg per day for 60 days. Tumor size was monitored biweekly by ultrasonography.. On estradiol removal, abdominal wall leiomyomas regressed within 15 to 30 days; when estradiol implants were reintroduced, leiomyomas redeveloped. Within 30 days on raloxifene, all abdominal leiomyomas (n = 9) regressed as determined by ultrasonography and verified at laparotomy. Serum raloxifene and estradiol levels were 432 +/- 46 pg/mL and 78 +/- 13 pg/mL (mean +/- SEM, n = 3), respectively, after 60 days of treatment.. Leiomyomas did not become estradiol independent, even after long exposure to estradiol; ultrasonography allowed frequent, noninvasive assessment of leiomyoma size, and raloxifene rapidly regressed leiomyomas in this animal model.

Topics: Animals; Estradiol; Estrogen Antagonists; Female; Guinea Pigs; Leiomyoma; Ovariectomy; Piperidines; Raloxifene Hydrochloride; Ultrasonography; Uterine Neoplasms

Uterine leiomyoma is the most frequent gynecologic neoplasm in women. By using a panel of cell lines derived from spontaneous Eker rat leiomyomas, we examined the estrogen-responsive phenotype of these tumor cells. Leiomyoma-derived ELT cell lines proliferated in response to estrogen, and estrogen-induced cell proliferation could be inhibited by the estrogen antagonist ICI 182780 and the selective estrogen-receptor modulators (SERMs) raloxifene and tamoxifen. In addition to inhibiting cell growth, these antagonists also inhibited estrogen-induced increases in progesterone-receptor expression. These data indicate that SERMs such as raloxifene and tamoxifen act as estrogen antagonists in uterine myometrial cells and suggest that this class of compounds may be effective for treatment of this important gynecologic neoplasm.

Topics: Animals; Cell Division; Estradiol; Estrogen Antagonists; Female; Fulvestrant; Leiomyoma; Phenotype; Piperidines; Raloxifene Hydrochloride; Rats; Receptors, Estrogen; Tamoxifen; Tumor Cells, Cultured; Uterine Neoplasms