Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A multi-center trial of exemestane 25 mg, an oral aromatase irreversible inactivator, was conducted to evaluate its efficacy and safety in 33 postmenopausal patients, and to investigate the pharmacokinetics/serum hormone levels in 16 postmenopausal patients, respectively, with breast cancer and anti-estrogen resistance. Exemestane 25 mg was given once daily for up to 48 weeks (maximum). The objective of this study was to confirm the reproducibility of the results shown in two studies in other countries with similar patients, to investigate the possibility of extrapolating the overseas data to Japanese. The response rate (CR + PR) was 24.2% (8.33%), which exceeded the minimum number (6 cases) required to evaluate efficacy. The response rate in this study was very similar to that observed in the two international open studies. Adverse events (subjective/objective symptoms), in which a causal relationship with exemestane administration could not be excluded, were observed in 26 cases (78.8%). Of these, hot flushes, increased sweating, fatigue, and insomnia occurred in more than 10% of patients, which was similar to that observed in the two international open studies. Abnormal laboratory results occurring in more than 10% of patients, in which a causal relationship with exemestane administration could not be excluded, were as follows: lymphocyte count decrease, alkaline phosphate increase, GOT increase, GPT increase, gamma-GTP increase, triglyceride increase, and inorganic phosphate increase, most of which were either grade 1 or 2. A remarkable decrease in serum hormone concentration was observed only for estrogen. The values of AUC0-infinity at day 1 and AUC0-24 h at day 29 (steady state) were similar, suggesting no accumulative effect of exemestane. These results demonstrate the anti-tumor effect and safety of exemestane in postmenopausal anti-estrogen resistant breast cancer patients. The reproducibility of the results of the two foreign studies was verified in Japanese patients, and it is concluded that the foreign trial data on exemestane can be extrapolated to Japanese.
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PMID:[Late phase II study of exemestane in postmenopausal patients with breast cancer resistant to anti-estrogenic agents]. 1214 2

Until recently, the therapeutic treatment of breast cancer has been dominated by endocrine-based drugs (oestrogen receptor antagonists, aromatase inhibitors etc.) and conventional cytotoxics (doxorubicin, cyclophosphamide, 5-fluorouracil etc.). However, the advent of new generation signal transduction inhibitor drugs targeted against the molecular abnormalities of breast cancer (e.g., the antibody trastuzumab, directed against the cERBB2 receptor) has the promise of providing a new era of more tumour selective therapy. Inhibitors of the enzyme farnesyl transferase (FTIs) are now undergoing early-stage clinical trials, including in patients with advanced breast cancer. Although originally developed as inhibitors of RAS signal transduction pathways, it is now apparent that these drugs are better described as prenylation inhibitors; the addition of a 15-carbon prenyl or farnesyl moiety by farnesyl transferase being critical to the function of a number of proteins, including RAS. At least three FTIs are currently undergoing clinical evaluation; R115777 (tipifarnib, Zarnestra), SCH66336 (lonafarnib, Sarasar) and BMS-214662. In terms of their potential use in the chemotherapeutic treatment of advanced breast cancer, a Phase II trial of R115777 (using either continuous or intermittent twice-daily oral dosing) has demonstrated promising activity (approximately 10% partial response rate). Overall, however, the single agent activity of FTIs in various Phase II trials has been rather modest (as well as the above mentioned breast cancer trial, some responses have been seen in patients with acute and chronic myeloid leukaemias). The main dose-limiting toxicities that have been reported are myelosuppression and fatigue and neurotoxicity (with R115777). Two Phase III trials of R115777 in colorectal (versus placebo) and pancreatic (with gemcitabine versus placebo) cancer have failed to show a survival benefit. It is likely that the future clinical direction of FTIs will be as combination therapy, especially with the taxanes, where synergy has been seen in a variety of preclinical studies.
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PMID:Farnesyl transferase inhibitors in the treatment of breast cancer. 1260 64

Aromatase inhibitors and inactivators are playing an increasing greater role in breast cancer treatment. Exemestane, a highly specific, steroidal aromatase inactivator, is the newest agent in this class. The drug is highly specific, and inhibits the in vivo conversion of androstenedione to oestrone (aromatization) by a mean of 97.9%. Exemestane has shown good efficacy and tolerability in multiple clinical trials among patients with metastatic breast cancer who have failed one or more previous hormonal therapies. Exemestane 25 mg/day slows disease progression and reduces tumour-related signs and symptoms and the drug exhibits a partial lack of cross-resistance with the non-steroidal aromatase inhibitors. Response rates to exemestane of 14% to 29% were observed including patients with visceral metastases, who have historically proven difficult to treat. In a large phase III trial, exemestane was found to be superior to megestrol acetate with respect to time to progression and overall survival. In addition, exemestane is currently under investigation as first-line therapy in metastatic disease and in sequence with tamoxifen in the adjuvant setting. Adverse events include low-grade hot flashes, nausea, and fatigue--mostly of mild to moderate intensity--and treatment-related discontinuations are rare. In conclusion, exemestane represents a novel and interesting drug for the treatment of advanced breast cancer, with exciting prospects for use in adjuvant therapy and, potentially, breast cancer prevention.
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PMID:Exemestane: a review of its clinical efficacy and safety. 1496 85

This paper summarizes the current knowledge concerning the biosynthesis of neurosteroids in the human brain, the enzymes mediating these reactions, their localization, and the putative effects of neurosteroids. The presence of the steroidogenic enzymes cytochrome P450(SCC), aromatase, 5alpha-reductase, 3alpha-hydroxysteroid dehydrogenase, and 17beta-hydroxysteroid dehydrogenase in the human brain has now been firmly established by molecular biological and biochemical studies. Their presence in the cerebral cortex and in the subcortical white matter indicates that various cell types, either neurons or glial cells, are involved in the biosynthesis of neuroactive steroids in the brain. The following functions are attributed to specific neurosteroids: modulation of GABA(A), N-methyl-d-aspartate (NMDA), nicotinic, muscarinic, serotonin (5-HT(3)), kainate, glycine and sigma receptors, neuroprotection and induction of neurite outgrowth, dendritic spines, and synaptogenesis. We still do not know whether and how the steroidogenic enzymes are involved in the pathophysiology of the nervous system. The first clinical investigations in humans produced evidence for an involvement of neuroactive steroids in conditions such as fatigue during pregnancy, premenstrual syndrome, postpartum depression, catamenial epilepsy, and depressive disorders. Further and improved knowledge of the biochemical pathways of neurosteroidogenesis and their actions on the brain may enable new perspectives in the understanding of the physiology of the human brain as well as in the pharmacological treatment of its disturbances.
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PMID:Neurosteroid biosynthesis in the human brain and its clinical implications. 1499 41

Recently, a new non-steroidal aromatase inhibitor, letrozole (Femara tablet 2.5 mg) launched in Japan for the treatment of postmenopausal women with breast cancer. This drug has triazole structure, as similar drug, anastrozole (Arimidex). Currently, this drug has been put on markets in more than 80 countries, in which more than 20 countries have approved the use for the extended adjuvant treatment of early breast cancer. Letrozole is an oral drug given once daily and the first choice for the treatment of patients with steroid receptor positive or receptor-unknown locally advanced or metastatic postmenopausal breast cancer. As for the adverse events, they are mostly mild, including hot flashes, arthritis, miyalgia, and such as nausea, fatigue, anorexia, hyperorexia, edema, headache, vertigo, vomition and others. In the large international breast cancer studies, beneficial results were obtained for the post-surgical endocrine therapy of postmenopausal women with breast cancer, and the similar use of this drug has been approved in Japan.
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PMID:[Introduction of new drug: letrozole, a new non-steroidal aromatase inhibitor for the treatment of postmenopausal women with breast cancer]. 1677 Jan 12

Recently aromatase inhibitors have become a standard care as an adjuvant treatment for many postmenopausal patients with hormone receptor positive early breast cancer. Adjuvant letrozole was made available either immediately postoperative, after 2-3 years of tamoxifen, or as an extended treatment after 5 years of tamoxifen. Between October 2003 and October 2005, we analyzed the subjective tolerance in 185 postoperative early breast cancer patients receiving letrozole outside of a clinical trial. The most prominent toxicity was musculoskeletal pain. In addition hot flushes, increased fatigue, nausea, vomiting, anorexia, mood disturbances, vaginal dryness, hair loss and rash were also recorded. In contrast to the prospective randomized clinical trials, a high drop-out rate of 20% was documented, mainly due to aromatase inhibitor-associated arthralgia syndrome interfering significantly with the daily life of our patients. Although adjuvant aromatase inhibitors have proven to be generally superior to tamoxifen in the adjuvant setting, it is important to focus attention on the tolerance during the adjuvant therapy and to balance this against the potential benefit in individual patients. Alternative options including switching to tamoxifen remain available.
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PMID:Tolerance of adjuvant letrozole outside of clinical trials. 1845 95

Several conditions and drugs induce subclinical hypothyroidism. We report the first case of subclinical hypothyroidism in a 65-year-old woman with breast cancer receiving therapy with the third-generation aromatase inhibitor exemestane 25 mg/day for 2 months. The patient presented with complaints of increasing fatigue and weakness since being commenced on exemestane and was taking no other drugs. There was no past history or family history of thyroid disease. Thyroid function tests prior to breast cancer surgery were normal. Detailed clinical examination and laboratory tests to determine the cause of the patient's increasing fatigue and weakness revealed only subclinical hypothyroidism, that is, an elevated level of thyroid-stimulating hormone (thyrotropin, TSH) only. Ultrasonography revealed a normal thyroid gland. Based on a diagnosis of symptomatic subclinical hypothyroidism, the patient was commenced on levothyroxine sodium 50 microg/day and exemestane was withdrawn. Thyroid dysfunction was restored 4 months after her admission with a significant improvement in symptoms. Levothyroxine sodium was withdrawn 6 months later and no recurrence of thyroid dysfunction occurred during a 1-year follow-up. We believe that the increasing fatigue and weakness in our patient might have been associated either with subclinical hypothyroidism or with administration of exemestane (a known adverse effect of the drug) or both. Further studies are required to investigate how exemestane influences thyroid function.
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PMID:Exemestane-induced subclinical hypothyroidism : a case report. 1878 5

Women with breast cancer have many adverse symptoms, of which some are specific to premenopausal patients. Management of these common symptoms include non-hormonal drugs, such as antidepressants and antiseizure compounds to alleviate hot flushes. Non-oestrogenic vaginal lubricants seem to moderately decrease occurrence of vaginal dryness and dyspareunia. Transdermal testosterone alone has not been shown to improve libido in these women. Options for fertility preservation include cryopreservation of embryos or oocytes before chemotherapy. Exercise is the one evidenced-based intervention shown to positively affect cancer-related fatigue. However, effective prevention and treatments for peripheral neuropathy and paclitaxel acute pain syndrome remain elusive. Weight-bearing exercise helps to maintain bone strength with adequate intake of calcium and vitamin D. Use of bisphosphonates in women taking aromatase inhibitors (combined with ovarian suppression in premenopausal women) to prevent bone fractures has not been substantiated, although it should be considered in women with osteoporosis. No specific drug has been shown to prevent radiation-induced dermatitis alone. Although some effective treatments can counteract symptoms related to cancer or treatments, research is needed to expand evidence-based care in premenopausal survivors of breast cancer.
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PMID:Symptom management in premenopausal patients with breast cancer. 1907 Dec 56

Vitamin D deficiency and insufficiency may contribute to musculoskeletal symptoms and bone loss observed in women taking aromatase inhibitors (AIs). This study was conducted to determine the prevalence of suboptimal vitamin D levels in women initiating adjuvant letrozole for breast cancer and to determine whether supplementation with 50,000 IU of vitamin D3 weekly could reduce musculoskeletal symptoms and fatigue in women who have suboptimal vitamin D levels. Sixty women about to begin an adjuvant AI were enrolled. Baseline 25OHD levels were obtained, and women completed symptom questionnaires. They were then started on letrozole, along with standard dose calcium and vitamin D. Four weeks later, women with baseline 25OHD levels </=40 ng/ml started additional vitamin D3 supplementation at 50,000 IU per week for 12 weeks. 25OHD levels were re-assessed at 4, 10, and 16 weeks; the questionnaires were repeated at weeks 4 and 16. At baseline, 63% of women exhibited vitamin D deficiency (<20 ng/ml) or insufficiency (20-31 ng/ml). 25OHD levels >40 ng/ml were achieved in all 42 subjects who received 12 weeks of supplementation with 50,000 IU vitamin D3 weekly, with no adverse effects. After 16 weeks of letrozole, more women with 25OHD levels >66 ng/ml (median level) reported no disability from joint pain than did women with levels <66 ng/ml (52 vs. 19%; P = 0.026). Vitamin D deficiency and insufficiency are prevalent in post-menopausal women initiating adjuvant AI. Vitamin D3 supplementation with 50,000 IU per week is safe, significantly increases 25OHD levels, and may reduce disability from AI-induced arthralgias.
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PMID:Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer. 1965 44

Endometriosis is defined as the presence of endometrial-like tissue outside the uterus, which induced a chronic inflammatory reaction. The data collected from Italy showed that around 3 million women are affected by endoemtriosis and the condition was predominantly found in women of reproductive age (50% of women were in the 29-39 age range), only 25% of women were asymptomatic. The associated symptoms can create an impact in general physical, mental, and social well-being. Endometriosis is associated with severe dysmenorrhea, deep dyspareunia, chronic pelvic pain, ovulation pain, cyclical, or perimenstrual symptoms, with or without abnormal bleeding, infertility, and chronic fatigue. The annual cost for hospital admission can be estimated to be in a total around 54 million euros. The average time for right diagnosis is around 9 years still today and it follows a long and expensive diagnostic search. Therapies can be useful to relieve and sometimes solve the symptoms, encourage fertility, eliminate endometrial lesions, and restore the anatomy of the pelvis. For medical therapy, several different preparations (oral contraceptives, progestogenics, gestrinone, danazol, and GnRHa) and new options (GnRH antagonists, aromatase inhibitors, estrogen receptor beta agoinist, progesterone receptor modulators, angiogenesis inhibitors, and COX-2 selective inhibitors) are available.
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PMID:Endometriosis in Italy: from cost estimates to new medical treatment. 1990 51


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