Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0600142 (hot flushes)
 1,242 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vorozole is a triazole derivative which binds to the cytochrome P450 moiety of aromatase, thus causing reversible inhibition of the enzyme. Plasma estradiol levels are reduced by about 90% in postmenopausal women treated with vorozole. Phase II clinical studies found vorozole to be an effective agent for the treatment of postmenopausal women with advanced breast cancer, achieving objective responses in up to 35% of patients. In 2 large phase III studies, vorozole 2.5 mg/day demonstrated favourable clinical efficacy compared with aminoglutethimide and megestrol. Vorozole improved patients' quality of life to a greater extent than aminoglutethimide. Clinical trials to date indicate that the tolerability of vorozole is better than that of aminoglutethimide. Vorozole also appears to be at least as well tolerated as megestrol (although inappropriate bodyweight gain is more common in megestrol recipients). The most common adverse events with vorozole are hot flushes, and nausea, which are generally mild in severity.
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PMID:Vorozole. 930 82

Microsomal cytochrome P450 (CYP 450) enzyme aromatase belongs to CYP 19 super family. It is involved in the conversion of androgens to estrogens. In postmenopausal women the main sites of aromatisation are skin, adipose tissue and breast. Aromatase localized in breast tumor produces sufficient estrogen for its proliferation. Hence it is an important target for the treatment of hormone dependent breast cancer in postmenopausal women. There are mainly two types of aromatase inhibitors, one is steroidal another is nonsteroidal type. The first and second generation aromatase inhibitors encounter the undesirable drug- drug interactions besides being not very specific and plagued with pharmacokinetic problems. Third generation aromatase inhibitors developed recently are more potent and specific with a greater capacity to annihilate circulating estrogen levels. These agents have satisfactory pharmacokinetic profiles and are devoid of major drug-drug interactions. Third generation aromatase inhibitors became drugs of choice for both first and second line treatment of advanced breast cancer. Aromatase inhibitors can also be used for neoadjuvant therapy of breast cancer in which they have achieved better therapeutic efficacy than tamoxifen. Early results of ATAC (Armidex Tamoxifen Alone or Combination) trial suggest that anastrozole is superior to tamoxifen in adjuvant setting for disease free survival, particularly in receptor positive patients, and in reducing the incidence of contralateral breast cancer. Therapeutic potential of aromatase inhibitors stretches beyond the postmenopausal breast cancer treatment as they also play a role in the treatment of estrogen dependent benign and malignant conditions such as gynaecomastia, prostate cancer, fibroadenomata and the induction of ovulation. By virtue of their ability to reduce estrogen levels they pose problems like demineralization of bone, hot flushes and anti-implantation effects.
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PMID:Aromatase inhibitors: a new paradigm in breast cancer treatment. 1557 17

Letrozole is a highly selective, nonsteroidal, third-generation aromatase inhibitor approved for first-line and extended adjuvant therapy in postmenopausal women with hormone-responsive, early-stage breast cancer. Binding of letrozole to the haeme component of the cytochrome P450 subunit of aromatase inhibits estrogen biosynthesis throughout the body. As first-line adjuvant therapy in approximate, equals 8000 postmenopausal women with hormone-responsive, early-stage breast cancer, once-daily letrozole 2.5mg significantly prolonged disease-free survival (DFS; primary endpoint) and reduced the risk of relapse at distant sites relative to once-daily tamoxifen 20mg in the ongoing Breast International Group 1-98, double-blind, multinational trial. The median duration of follow-up for this primary core analysis was 25.8 months. Extended adjuvant therapy with once-daily letrozole 2.5mg significantly prolonged DFS relative to placebo treatment at a median follow-up of 30 months (primary endpoint) in the MA-17 trial in approximate, equals 5000 postmenopausal women who were disease free after 4.5-6 years of tamoxifen therapy for hormone-responsive, early-stage breast cancer. Letrozole treatment for up to 5 years was generally well tolerated in this clinical setting. As first-line treatment, relative to tamoxifen, letrozole was associated with a significantly lower incidence of venous thromboembolitic events, vaginal bleeding, hot flushes and night sweating, whereas the incidence of cardiac failure, bone fractures and arthralgia was higher in letrozole recipients.
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PMID:Letrozole : in postmenopausal hormone-responsive early-stage breast cancer. 1652 26

Tamoxifen has a key role in the management of women with hormone receptor (HR) positive breast cancer. It is the endocrine treatment of choice in premenopausal women with HR positive breast cancer and is also clinically indicated in significant numbers of post-menopausal women who have relative contraindications to aromatase inhibitors. Tamoxifen is a pro-drug that is metabolised to its active metabolites by the cytochrome P450 (CYP) enzymes including CYP2D6, CYP3A, CYP2B6, and CYP2C19. The CYP genes are polymorphic resulting in variable enzyme activity. Retrospective clinical data suggests that specific single nucleotide polymorphisms (SNPs) of CYP2D6 can lead to null or reduced enzyme activity resulting in worse outcomes for those individuals when treated with tamoxifen for HR positive breast cancer. There is however a lack of robust prospective clinical data on this subject. Commercial tests are now available for the genotyping of CYP2D6 with the aim of individualisation of tamoxifen therapy for patients with HR positive breast cancer. Selective serotonin reuptake inhibitor antidepressant drugs such as paroxetine and fluoxetine have also been used to manage tamoxifen induced hot flushes. These drugs potently inhibit the metabolism of tamoxifen by CYP2D6 and thus potentially may lessen the efficacy of tamoxifen. The genetic variations in other enzymes involved in tamoxifen metabolism (CYP3A, CYP2B6, CYP2C19) do not appear to cause any meaningful difference in the efficacy of tamoxifen. This review article will summarize the available published breast cancer data on the interaction between the relevant SNPs for CYP2D6, CYP3A, CYP2B6, and CYP2C19 and the efficacy of tamoxifen, their role in individualisation of hormonal therapy and the role of the commercially available genotyping kits.
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PMID:Tamoxifen, cytochrome P450 genes and breast cancer clinical outcomes. 2118 24

Tamoxifen, an oestrogen antagonist, is the standard hormone treatment for breast cancer. It is extensively transformed into its active metabolites by the cytochrome P450 enzyme system, especially into endoxifen by isoenzyme CYP 2D6. Co-administration of tamoxifen with isoenzyme CYP 2D6 inhibitors reduces this metabolism. Selective serotonin reuptake inhibitor (SSRI) antidepressants inhibit isoenzyme CYP 2D6. Paroxetine and fluoxetine reduce the plasma concentration of endoxifen by about 50%. Two epidemiological studies involving about 3700 women have shown a link between the use of SSRI antidepressants and an increased frequency of breast cancer recurrence. Other studies, with a lower level of evidence, were less convincing. Studies of other isoenzyme CYP 2D6 inhibitors showed no increase in the risk of breast cancer recurrence, but they lacked statistical power. It is better to avoid prescribing isoenzyme CYP 2D6 inhibitors to women treated with tamoxifen for breast cancer, especially SSRI antidepressants such as paroxetine and fluoxetine. Depression does not always require antidepressant drug therapy, and antidepressants have no proven preventive impact on hot flushes linked to the menopause. If in certain cases, an antidepressant is considered necessary, it may be advisable to replace tamoxifen with anastrozole.
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PMID:Tamoxifen and CYP 2D6 inhibitors: caution. 2175 53

During the menopausal transition and early postmenopause, participants in the Seattle Midlife Women's Health Study (SMWHS) experienced one of the three symptom severity clusters identified through latent class analysis: severe hot flashes with moderate sleep, mood, cognitive, and pain symptoms (high-severity hot flash); low-severity hot flashes with moderate levels of all other symptom groups (moderate severity); and low levels of all symptom groups (low severity). In an effort to determine whether gene polymorphisms were associated with these symptom severity classes, we tested associations between gene polymorphisms in the estrogen synthesis pathways (cytochrome P450 19 [CYP 19] and 17 beta hydroxysteroid dehydrogenase [ 17HSDB1]) and the three symptom severity clusters. SMWHS participants ( N = 137) recorded symptoms monthly in diaries and provided buccal smears for genotyping. Multilevel latent class analysis with multinomial regression was used to determine associations between gene polymorphisms and symptom severity clusters. Only the 17HSDB1 polymorphisms ( rs615942 and rs592389) were associated significantly with the high-severity hot flash cluster versus the low-severity symptom cluster. None of the polymorphisms was associated with the moderate-severity cluster versus the low-severity symptom cluster. Findings of associations of the 17HSDB1 polymorphisms with the high-severity hot flash symptom cluster are consistent with those of an association between 17HSDB1 polymorphisms and hot flashes in the Study of Women and Health Across the Nation population and our previous findings of associations between these polymorphisms with greater estrone levels.
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PMID:Polymorphisms in Estrogen Synthesis Genes and Symptom Clusters During the Menopausal Transition and Early Postmenopause: Observations From the Seattle Midlife Women's Health Study. 2933 60