Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Toremifene is an antiestrogen that binds strongly to estrogen receptors (ER). A total of 19 previously treated postmenopausal women with metastatic breast cancer whose performance status was good and whose ER status was positive or unknown were studied to determine the maximum tolerated dose of toremifene. Cohorts of patients received 200, 300, or 400 mg/m2 p.o. daily until relapse or unacceptable toxicity had occurred. Nausea, vomiting, and dizziness were dose-related. Three of five patients receiving 400 mg/m2 experienced moderate or severe vomiting and another developed reversible disorientation and hallucinations. Mild sweating, peripheral edema, vaginal discharge, and hot flushes were encountered at all doses. Reversible corneal pigmentation was identified in seven cases but was not of clinical importance. The pharmacokinetics of toremifene was studied weekly and in detail on day 42 using a high-performance liquid chromatographic (HPLC) assay that identified the parent compound and three active metabolites, N-desmethyltoremifene, (deaminohydroxy)toremifene, and didemethyltoremifene. Steady state was achieved at 1-3 weeks. The toremifene area under the curve and the maximal concentration were dose-dependent at high doses. The recommended phase II dose is 300 mg/m2 p.o. daily.
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PMID:Phase I clinical and pharmacokinetics study of high-dose toremifene in postmenopausal patients with advanced breast cancer. 138 61

A phase I multicenter evaluation of a novel antiestrogen, toremifene, was undertaken in postmenopausal women with various advanced difficult-to-treat malignancies. One hundred and seven women were treated at one of six dosage levels (10, 20, 40, 60, 200, or 400 mg/d orally) for at least 8 weeks. Weekly evaluations for toxicity were conducted. The most common side effects were nausea (31%), vomiting (12%), and hot flashes (29%). Five patients were removed from the study for possible adverse reactions: three patients experienced hypercalcemia; one experienced tremulousness, fatigue, and inability to think clearly; and one had vaginal bleeding. Twelve patients died while on study, 11 with disease progression and one with a pulmonary embolus. Sex hormone-binding globulin (SHBG) levels increased and there was a modest decline in serum antithrombin III levels. Four of 48 assessable patients had partial responses: three with breast cancer and one with endometrial cancer. Toremifene was generally well tolerated at the doses tested.
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PMID:Phase I study of toremifene in patients with advanced cancer. 183 8

Toremifene was given within the dose range of 3-680 mg as a single dose or on five consecutive days to 72 postmenopausal volunteers. Blood samples for clinical chemistry were taken hourly up to 7 h and 1, 2, 3, 7, 10 and 15 days after the last dose of toremifene. The concentrations of serum bilirubin, creatinine, amylase, free thyroxine, cortisol, prolactin, electrolytes and blood glucose remained unchanged at all dose levels. A statistically significant decrease was observed in liver enzymes (ASAT, ALAT, ALP) at the dose levels of 220-680 mg, whereas gamma-GT remained unchanged. A decrease in the concentration of LH and FSH was observed at the dose levels of 46 mg or higher and 220 mg or higher, respectively. These hormonal changes including the increase of SHBG at the dose levels of 220-680 mg and the decrease of antithrombin III (220-680 mg) may be attributed to a weak estrogen-like effect of toremifene. Side effects were minimal: pulse rate, blood pressure and ECG remained unchanged during the test period. Only two patients on 680 mg dose suffered from nausea and vertigo, and one of them discontinued the medication.
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PMID:Effect of toremifene on clinical chemistry, hematology and hormone levels at different doses in healthy postmenopausal volunteers: phase I study. 214 36

Toremifene is a triphenylethylene derivative structurally and pharmacologically similar to tamoxifen. This Phase I trial assessed the safety, pharmacokinetics, anti-estrogenic, and estrogenic effects of toremifene at six dose levels (10, 20, 40, 60, 200, and 400 mg/day). The most common side-effects associated with therapy included gastrointestinal (nausea/vomiting 43%), anti-estrogenic (hot flashes 29%), and CNS (dizziness/vertigo 12%). Three patients with bone metastases from breast cancer developed hypercalcemia. At doses greater than or equal to 40 mg/day a decline in LH and FSH occurred which was not statistically significant. At all doses tested SHBG rose during therapy. A dose dependent estrogenic blockade was seen on the vaginal epithelium following challenge with transdermal estradiol. Steady-state concentrations of toremifene were reached within 4 weeks, and at doses greater than or equal to 60 mg/day ranged from 879-3445 ng/ml. The half-life was found to be 5 days, and at three weeks following discontinuation of treatment concentrations greater than 24 ng/ml were detected. The N-desmethyl and 4-hydroxy metabolites achieved steady state levels within 4 weeks and had half-lives of 6 and 5 days respectively. Partial responses were seen in 4 patients, 3 with breast cancer treated at 200 mg/day and 1 with endometrial cancer treated at 400 mg/day.
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PMID:Phase I study of the tolerance and pharmacokinetics of toremifene in patients with cancer. 214 80

Toremifene (Fareston) is a triphenylethylene derivative structurally similar to tamoxifen (Nolvadex) that was selected for development based on its in vitro activity against breast cancer and its lesser uterotrophic effect than tamoxifen in rat models. In phase I and II studies conducted in several countries, toremifene was well tolerated over a wide range of doses (10 to 680 mg/d). The major side effects were hot flashes, nausea, and vomiting. Toremifene's excretion half-life is 5 days. It produces a modest decline in serum levels of luteinizing hormone, follicle-stimulating hormone, and antithrombin III, as well as an increase in sex hormone-binding globulin levels. In studies in which toremifene was used as first-line therapy in patients with estrogen receptor (ER)-positive or ER-unknown tumors, response rates to doses of 40 to 60 mg/day ranged from 30% to 54%. In two larger studies of patients who had proved refractory to tamoxifen therapy, toremifene produced an objective response rate of 4% to 5%. When patients with stable disease were added to those with objective responses, 27% to 28% of patients were considered to derive clinical benefit from toremifene. The dose range chosen for further study was 40 to 60 mg/d.
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PMID:Phase I and II studies of toremifene. 916 2

To compare the efficacy and safety of high doses (200 or 240 mg/d) of toremifene (Fareston) to standard doses (20 or 40 mg/d) of tamoxifen (Nolvadex) in postmenopausal women with estrogen receptor (ER)-positive or ER-unknown advanced breast cancer, we pooled data from two randomized, three-arm clinical trials. Of the 733 patients included in the overview, 369 were randomized to high-dose toremifene and 364, to tamoxifen. At median follow-up of 19 months, disease had progressed in over 70% of the patients. Response rates were 25.2% in the high-dose toremifene arm and 19.8% in the tamoxifen arm (P = .087). The two treatments appeared to be statistically equivalent with respect to risk for disease progression and survival. Reversible SGOT elevation was observed in 26 tamoxifen-treated patients vs 64 high-dose toremifene recipients (P < .001) and nausea in 33 vs 50 patients (P = .085). Reversible corneal keratopathy was diagnosed in two patients on tamoxifen and eight on high-dose toremifene (P = .061). Treatment had to be discontinued in 17.3% of patients in the high-dose toremifene arm and 20.1% in the tamoxifen arm. Discontinuation due to toxicity was rare, and toxicity did not differ significantly between the treatments. Toremifene, in doses up to 240 mg/d, is an effective, safe treatment for postmenopausal women with ER-positive/unknown advanced breast cancer.
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PMID:High-dose toremifene vs tamoxifen in postmenopausal advanced breast cancer. 916 4

Toremifene is a chlorinated tamoxifen analogue that is indicated for the treatment of postmenopausal hormone-dependent breast cancer. It competes with estradiol for estrogen receptors and has growth-inhibitory effects on MCF-7 breast cancer cells. At concentrations < 10(-6) mol/L, this growth inhibition can be reversed by estradiol, but at higher concentrations toremifene is cytotoxic. In dimethylbenzanthracene (DMBA)-induced mammary cancer in rats, toremifene has been shown to decrease the number of new tumours and to inhibit the growth of existing tumours. Toremifene causes growth inhibition by suppressing mitosis and inducing apoptosis. The mechanism by which these events occur may involve the induction of transforming growth factor-beta 1 and inhibition of insulin-like growth factor-1 (mecasermin). Toremifene is primarily an antiestrogen, but it has some estrogen agonist properties in postmenopausal women. The latter are reflected by the fall in luteinising hormone and follicle-stimulating hormone levels and the rise in sex hormone-binding globulin levels that are associated with its use in most women. After estrogen priming, toremifene 68mg administered orally has been found to exert a similar antiestrogenic effect on the vaginal epithelium in postmenopausal women as tamoxifen 60mg. The half-life of toremifene in plasma is 5 days, and the drug is > 99% bound to plasma proteins. The main metabolites of toremifene are N-demethyl-toremifene and deaminohydroxy-toremifene. Altered liver, but not kidney, function affects the pharmacokinetics of toremifene. Toremifene 60mg daily is as effective as tamoxifen 20mg daily in the treatment of postmenopausal hormone-dependent breast cancer, producing a response in about 50% of patients. Soft tissue and visceral metastases respond better to toremifene than bone metastases. Most of the adverse effects of toremifene are related to its activity at estrogen receptors and include hot flashes, vaginal discharge and nausea. Although toremifene decreases antithrombin III levels slightly, the incidence of thromboembolic complications is low. Thus far, no carcinogenic effects have been noted in humans, and preclinical data are mostly reassuring. Toremifene has favourable effects on serum lipids, and thus has potential in preventing coronary heart disease. Although toremifene is somewhat more expensive to use than tamoxifen, toremifene is an effective and well tolerated alternative to tamoxifen in the treatment of postmenopausal women with hormone-dependent breast cancer. No formal pharmacoeconomic comparisons of toremifene and tamoxifen have yet been published. Toremifene is potentially safer than tamoxifen in relation to carcinogenic effects and effects on serum lipids.
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PMID:Toremifene in postmenopausal breast cancer. Efficacy, safety and cost. 934 56