Estramustine phosphate

EMP is indicated, in the United States, for the palliative treatment of metastatic and/or progressive prostate cancer, Due to its relatively severe side effects and toxicity, EMP has rarely been used in the treatment of prostate cancer. However, oral EMP is most commonly used at a dose of 560 to 640 mg/day (280–320 mg twice daily). EMP has been used at doses of 240 to 450 mg/day intravenously. In addition, estrogens may offer significant benefits over other means of androgen deprivation therapy, for instance in terms of bone loss and fractures, hot flashes, cognition, and metabolic status. Available forms EMP is or has been available in the form of both capsules (140 mg, 280 mg) for oral administration and aqueous solutions (300 mg) for intravenous injection. ==Contraindications==

EMP is contraindicated when used in children, patients hypersensitive to estrogens or nitrogen mustards, those with peptic ulcer (an ulcer in the digestive tract), those with severely compromised liver function, those with weak heart muscle (also known as myocardial insufficiency) and those with thromboembolic disorders or complications related to fluid retention. ==Side effects==

The side effects of EMP overall have been described as relatively severe. Decreased sexual activity has also been reported in men treated with EMP. The prostate cancer disease state also increases the risk of thromboembolism, and combination with docetaxel may exacerbate the risk of thromboembolism as well. Anticoagulant therapy with medications such as aspirin, warfarin, unfractionated and low-molecular-weight heparin, and vitamin K antagonists can be useful for decreasing the risk of thromboembolism with EMP and other estrogens like diethylstilbestrol and ethinylestradiol. ==Overdose==

There has been no clinical experience with overdose of EMP. Overdose of EMP may result in pronounced manifestations of the known adverse effects of the medication. There is no specific antidote for overdose of EMP. In the event of overdose, gastric lavage should be used to evacuate gastric contents as necessary and treatment should be symptom-based and supportive. In the case of dangerously low counts of red blood cells, white blood cells, or platelets, whole blood may be given as needed. Liver function should be monitored with EMP overdose. After an overdose of EMP, hematological and hepatic parameters should continue to be monitored for at least 6 weeks. EMP has been used at high doses of as much as 1,260 mg/day by the oral route and 240 to 450 mg/day by intravenous injection. == Interactions ==

EMP has been reported to increase the efficacy and toxicity of tricyclic antidepressants like amitriptyline and imipramine. When products containing calcium, aluminium, and/or magnesium, such as dairy products like milk, various foods dietary supplements, and antacids, are consumed concomitantly with EMP, an insoluble chelate complex/phosphate salt between EMP and these metals can be formed, and this can markedly impair the absorption and hence oral bioavailability of EMP. There may be an increased risk of angioedema in those concurrently taking ACE inhibitors. ==Pharmacology==

Pharmacodynamics , the major active cytostatic form of estramustine phosphate. , the major active estrogenic form of estramustine phosphate. EMP, also known as estradiol normustine phosphate, is a combined estrogen ester and nitrogen mustard ester. EMP itself has only very weak affinity for the estrogen receptors. The antigonadotropic and functional antiandrogenic effects of EMP consist of strong suppression of gonadal androgen production and hence circulating levels of androgens such as testosterone; greatly increased levels of sex hormone-binding globulin and hence a decreased fraction of free androgens in the circulation; and direct antiandrogenic actions in prostate cells. The free androgen index with oral EMP has been found to be on average 4.6-fold lower than with orchiectomy. The notion that EMP has relatively weak estrogen activity may have been based on animal research, which found that EMP had 100-fold lower uterotrophic effects than estradiol in rats, and may also not have taken into account the very high doses of EMP used clinically in humans. The mechanism of action of the cytostatic effects of EMP is complex and only partially understood. Because of its tissue selectivity, EMP is said to produce minimal cytostatic effects in healthy tissues, and its tissue selectivity may be responsible for its therapeutic cytostatic efficacy against prostate cancer cells. This side effect is in contrast to most other cytotoxic agents, which instead cause myelosuppression (bone marrow suppression), leukopenia (decreased white blood cell count), and neutropenia (decreased neutrophil count). Antigonadotropic effects EMP at a dosage 280 mg/day has been found to suppress testosterone levels in men into the castrate range (to 30 ng/dL) within 20 days and to the low castrate range (to 10 ng/dL) within 30 days. Estramustine is also partially but considerably oxidized into estromustine by 17β-hydroxysteroid dehydrogenases during the first pass. As such, EMP reaches the circulation as estramustine and estromustine, and the major metabolite of EMP is estromustine. Release of nitrogen mustard gas from normustine via cleavage of the carboxylic acid group has not been demonstrated and does not seem to occur. No unchanged EMP is seen in the circulation with oral administration. ==Chemistry==

EMP, also known as estradiol 3-normustine 17β-phosphate or as estradiol 3-(bis(2-chloroethyl)carbamate) 17β-(dihydrogen phosphate), is a synthetic estrane steroid and a derivative of estradiol. This is in contrast to most other estradiol esters, which are fatty acid esters and lipophilic compounds that are not particularly soluble in water. As a result of these differences in molecular weights, EMP contains about 52%, EMP sodium about 48%, and EMP meglumine about 38% of the amount of estradiol within their structures as does an equal-mass quantity of estradiol. ==History==

EMP was first synthesized in the mid-1960s and was patented in 1967. It was initially developed for the treatment of breast cancer. EMP was originally introduced for use by intravenous injection. Subsequently, an oral formulation was introduced, and the intravenous preparation was almost abandoned in favor of the oral version. ==Society and culture==

Generic names EMP is provided as the sodium salt for oral administration, which has the generic names estramustine phosphate sodium () and estramustine sodium phosphate (, ), and as the meglumine salt for intravenous administration, which has the generic name estramustine phosphate meglumine. The is estramustine phosphate. Canada, and Mexico under the brand name Emcyt, whereas the medication is marketed under the brand name Estracyt in the United Kingdom and elsewhere throughout Europe as well as in Argentina, Chile, and Hong Kong. ==Research==

EMP has been studied in the treatment of other cancers such as glioma and breast cancer. It has been found to slightly improve quality of life in people with glioma during the first 3 months of therapy. == References ==