Angelique® [Drospirenone, Estradiol]
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The preparation Angelica contains 17β-estradiol, in its chemical and biological properties identical to estradiol produced in the human body, and a synthetic progestogen, drospirenone. 17β-estradiol provides hormone replacement therapy during and after the menopausal period. the additional inclusion of drospirenone allows you to control bleeding and prevents the development of estrogen-induced endometrial hyperplasia.
Effect of estradiol
Inhibition of ovarian function, accompanied by a decrease in the production of estrogens and progestogens in the body, determines the climacteric syndrome, characterized by vasomotor and organic symptoms. To eliminate these disorders hormone replacement therapy (HRT) is prescribed.
Estradiol is the most effective of all physiological estrogens and has the highest affinity for estrogen receptors. The target organs that are affected by estrogen include the uterus, hypothalamus, pituitary gland, vagina, mammary glands, bones (namely, osteoclast cells).
Other effects of estrogen include a decrease in blood insulin and glucose concentrations, local vasoactive effects mediated by receptors, and an effect on vascular muscle that is independent of receptors. Estrogen receptors have been identified in the heart and coronary arteries.
Oral administration of natural estrogens has a positive effect in some cases of hypercholesterolemia, providing the maximum metabolic effect of the liver on lipids.
After one year of therapy with Angelik, the average changes in HDL cholesterol concentration were insignificant. With the simultaneous use of 1 mg of drospirenone, a slight increase in these indicators by 1.1% was determined; when using 2 and 3 mg of drospirenone, this indicator decreased by 1.6 and 3.4%, respectively. The concentration of LDL cholesterol in serum decreased on average by 11 (1 mg of drospirenone), 14 (2 mg of drospirenone) and 13% (3 mg of drospirenone) compared with a 9% decrease after 1 year of monotherapy with 1 mg of estradiol.
It is likely that combination drugs with drospirenone weaken the increase in the concentration of TG due to monotherapy with 1 mg of estradiol. After one year of treatment, 1 mg of estradiol in patients TG concentrations on average exceeded the initial level by about 18, compared with average growth, 9 (1 mg of drospirenone), 5 (2 mg of drospirenone) and 4% with a combination of 1 mg of estradiol with drospirenone .
Therapy with Angelik for 2 years leads to an increase in the mineral density of bone tissue throughout the body, in the lumbar spine and pelvic bones by approximately 3-5%. Prolonged HRT reduces the risk of peripheral bone fractures in women in the postmenopausal period.
HRT also has a positive effect on the collagen content in the skin, skin density and can delay the formation of wrinkles.
Depending on the dose, estrogen monotherapy stimulates mitotic activity and proliferation of the endometrium, which leads to an increase in the number of cases of endometrial hyperplasia and an increased risk of developing endometrial carcinoma. To prevent endometrial hyperplasia, estrogen must be combined with any progestogen.
The effect of drospirenone
The pharmacodynamic properties of drospirenone are similar to the action of natural progesterone.
Drospirenone is a strong progestogen that has a central inhibitory effect on the hypothalamus-pituitary-gonadal system. In women of childbearing age, drospirenone provides a contraceptive effect; monotherapy with drospirenone inhibits the process of ovulation. The minimum dose of drospirenone necessary to inhibit ovulation is 2 mg / day. Complete transformation of the endometrium under the influence of estrogen is achieved at doses of 4–6 mg / day for 10 days (40–60 mg per cycle).
Angelique is a combined preparation for continuous HRT, which helps to avoid regular withdrawal bleeding that occurs with cyclic or phase HRT. Bleeding and spotting, "spotting" in the first months of treatment are quite frequent, but over time their number decreases. While taking Angelik (2 mg drospirenone), the percentage of cases of amenorrhea quickly increased to 81% already in the 6th cycle, then to 86% in the 12th cycle and up to 91% in the 24th cycle.
After 12 months of therapy with Angelic, 72–82% of women noted endometrial atrophy. The combination of the components of the drug Angelik effectively inhibits the development of endometrial hyperplasia caused by estrogen. In clinical studies in women who received different doses of the active substance of the drug, endometrial hyperplasia was not detected.
Drospirenone has a competing antagonistic effect of aldosterone. The antihypertensive effect is most pronounced in women with hypertension with increasing doses of drospirenone. After 12 weeks of treatment, 1 mg of estradiol / 3 mg of drospirenone average BP decreased (systolic / diastolic by 14–8 mm Hg, compared with 6–3 mm Hg compared with placebo). No corresponding changes in blood pressure are expected in women with normal blood pressure.
When using Angelik, the average body weight decreased during the 12 months of treatment by 1.1–1.2 kg (2 mg of drospirenone daily), while patients receiving estradiol monotherapy noted an increase in body weight by 0.5 kg.
During a clinical study in women receiving drospirenone in combination with estradiol, a lower incidence of peripheral edema was determined compared with patients receiving estradiol monotherapy.
Like natural progesterones, drospirenone has antiandrogenic properties.
Effect on carbohydrate metabolism
Drospirenone does not have glucocorticoid and antiglucocorticoid activity and does not affect glucose tolerance and insulin resistance. When using Angelica, glucose tolerance does not change.
Angelique has a positive effect on health and quality of life. According to the survey, the beneficial effect of the drug Angelik significantly exceeded the effect compared with estradiol monotherapy. This high rate is attributable mainly to improved somatic symptoms, decreased severity of anxiety / fear, and cognitive impairment.
According to numerous studies, when using a combination of conjugated equin estrogens with medroxyprogesterone acetate, it is assumed that the incidence of colon cancer in women receiving HRT is reduced. With monotherapy with conjugated equin estrogens, there was no decrease in the risk of developing this pathology.
After oral administration, drospirenone is rapidly and almost completely absorbed. As indicated in the table below, the maximum concentration of a substance in blood serum is reached approximately 1 hour after single and multiple oral administration of Angelic. The pharmacokinetic characteristics of drospirenone depend on the dose received within 1–4 mg. Bioavailability is 76–85% and does not depend on food intake.
|Pharmacokinetic parameter||Angelique 1 mg (drospirenone)||Angelique 2 mg * (drospirenone)||Angelique 3 mg * (drospirenone)|
|Maximum concentration, single dose (ng / ml)||11,6||21,9||32,2|
|Maximum concentration, equilibrium concentration, (ng / ml)||17,6||35,9||54,1|
|Area under the curve (AUC, 0–24 h), single dose, (ng / ml)||82,1||161||240|
|Area under the curve (AUC, 0–24 h), equilibrium concentration, (ng / ml)||194||408||623|
* Data for Angelik-2 mg and Angelik-3 mg were calculated by interpolating the studied doses of 1 mg of drospirenone + 1 mg of estradiol and 4 mg of drospirenone + 1 mg of estradiol.
After oral administration, the concentration of drospirenone in the blood serum decreases over two phases with an average final half-life of about 35–39 hours. Drospirenone binds to serum albumin, does not bind to sex steroid-binding globulin (SHBG), and corticoids-binding globulin (GSK, CBG). In the form of a free steroid, only 3-5% of the total concentration of drospirenone is present in the blood serum. The average apparent volume of distribution of drospirenone is 3.7–4.2 l / kg.
After oral administration, drospirenone is significantly metabolized. The main plasma metabolites are the acid form of drospirenone, obtained by opening the lactone ring, as well as 4,5 dihydro-drospirenone - 3-sulfate. Both metabolites are formed without the participation of the P450-dependent system. According to in vitro studies, drospirenone is slightly metabolized by cytochrome P450 3A4.
The total clearance of drospirenone from serum is 1.2–1.5 ml / min / kg. Only very small amounts of drospirenone are excreted unchanged. Drospirenone metabolites are excreted in the feces and urine in a ratio of about 1.2: 1.4. The elimination half-life of metabolites with urine and feces is up to 40 hours.
The table above shows the maximum equilibrium concentrations (AUC) of drospirenone in blood serum achieved during treatment. AUC is reached after approximately 10 days of daily intake of Angelique.
After oral administration, estradiol is rapidly and completely absorbed. During absorption and first passage through the liver, estradiol is significantly metabolized, which reduces the absolute bioavailability of e