Let’s know about Hydroxyprogesterone Caproate. Hydroxyprogesterone caproate ( OHPC ), sold under the brand names Proluton and Makena among others, is a progestin drug which is used to prevent preterm birth in pregnant women with a history of the condition and to treat gynecological disorders . It is also used in combination with estrogens for various indications (brand names Gravibinon and Primosyston ) and long-acting injectable birth control.(brand name).Sugar injection No. 1 ). [11] It is not used by mouth and is instead given by injection into muscle or fat , usually once per week to once per month depending on indication.
OHPC is generally well tolerated and causes few side effects. [1] Injection site pain and swelling are the most common side effects of OHPC. [1] The drug may increase the risk of gestational diabetes when used in pregnant women. [1] [12] OHPC is a progestin or synthetic progestogen, and therefore an agonist of the progesterone receptor, a biological target of progestogens such as progesterone. [12] It has some antimineralocorticoid activity and no other significant hormonal activity. [13] [14] [15] [16] [17] The drug shows several differences from natural progesterone.
OHPC was discovered in 1953 and was introduced for medical use in 1954 or 1955. [19] It was marketed in the United States under the Delalutin brand and throughout Europe under the Proluton brand name. [20] The drug was discontinued in the United States in 1999. [21] However, OHPC was later reintroduced in the United States under the Makena brand name in 2011 for the treatment of premature birth. [22] Because of the very high price, a pricing dispute arose in this country. [22] OHPC was previously available at low cost from compounding pharmacies in the United States, but was banned in 2016.
medical use
preterm birth
The use of OHPC in pregnancy to prevent premature birth in women with a history of premature labor between 20 weeks and 36 weeks and 6 days is supported by Society of Maternal Fetal Medicine Clinic guidelines, which were introduced in May 2012 at Level I and III was presented as evidence, a Level A recommendation [26]Level I evidence refers to an appropriately conducted randomized controlled trial, and Level III evidence is endorsed by expert opinion, while a Level A recommendation acknowledges that the recommendation has been made on the basis of good and consistent scientific evidence. OHPC 250 mg IM weekly is recommended starting at 16-20 weeks up to 36 weeks. In these women, if transvaginal ultrasound reduces cervical length to <25 mm at <24 weeks, cervical cerclage may be offered. The 2013 study is based on the recommendation of the guideline, [27]There was a significant reduction in neonatal morbidity, including lower rates of necrotizing enterocolitis (0 in the treatment group versus 4 in the control), intraventricular hemorrhage (4 in the treatment group). compared to 8 in controls for a relative risk of 0.25), and the need for supplemental oxygen (14% in the treatment group versus 24% in placebo for a relative risk of 0.42). In addition, 463 women were included in this study, 310 of whom received the injection. Of these women, 9 had infants with congenital malformations (2%), but no consistent pattern and no internal organ involvement.
OHPC is currently (as of June 2014) pregnancy category B, meaning there is no evidence of fetal risk with the use of this drug during pregnancy. Although this is now the recommendation, it has not always been so. A review by Mark Keirs of Flinders University concluded that there was a lack of information about potential harms. [28] Three clinical studies in singleton pregnancies at 250 mg/week of intramuscular OHPC showed an increased tendency for pregnancy loss due to miscarriage compared to placebo. [29] [30] [27]One of them, a large 2003 National Institutes of Health (NIH) study, looked at the effects of OHPC injections in women at risk of repeated preterm birth and found that the treated group experienced preterm birth. in 37% versus 55% in controls. [27] A follow-up study of offspring showed no evidence that OHPC affected children in the first years of life. [31] Based on these NIH data, OHPC was approved by the Food and Drug Administration (FDA) in 2011 as a drug to reduce the risk of premature birth in selected women at risk.
The FDA expressed concerns about abortion at a 2006 advisory committee meeting; The committee voted unanimously that further studies are needed to evaluate the potential association of OHPC with an increased risk of second-trimester miscarriage and stillbirth. [32] A toxicology study in rhesus monkeys resulted in the death of all rhesus fetuses exposed to 1 and 10 times the equivalent human dose of OHPC. [33] As of 2008 , OHPC was a category D progestin according to the FDA (that is, there is evidence of fetal harm). There is speculation that the castor oil in the OHPC formulation may not be beneficial for pregnancy. [34] [35]Of note, the above mentioned NEJM study by Meyers et al. Comparison of the effect of OHPC (with castor oil component) as a placebo with castor oil injection.
A study published in February 2016 in The Lancet states the following along with other findings: [36]
OPPTIMUM strongly suggests that the efficacy of progesterone in improving outcomes is either nonexistent or weak. Given the heterogeneity of preterm Labor syndrome we cannot exclude benefits in specific phenotypic or genotypic subgroups of women at risk. However, the subgroups of women who may benefit do not appear to be readily identifiable by current selection strategies, including cervical length measurement and fibronectin testing. Reassuringly, our study shows that progesterone is safe for those who wish to take it for preterm birth prophylaxis. The overall rate of maternal or infant adverse events was similar in the progesterone and placebo groups. With the exception of higher rates of renal, gastrointestinal and respiratory complications in childhood in the progesterone groups, There were some differences in the incidence of adverse secondary outcomes in the two groups. Importantly, the absolute rate of these complications was low.Follow-up of other infants exposed to vaginal progesterone in utero will be helpful in determining whether the increased rate of certain renal, gastrointestinal and respiratory complications is a true effect or a variant error.
Journal reviewer Richard Lehmann, Senior Research Fellow in the Department of Primary Health Care at the University of Oxford, made the following noteworthy comment on the OPPTIMUM study: “That’s it. This story is over, and no one needs to use vaginal progesterone again. No. Prevent premature birth.” [37]
A Cochrane review on progestogens to prevent preterm birth concluded that there was little evidence that vaginal or intramuscular progesterone helped reduce the risk of preterm birth in women with multiple pregnancies. [38]
gynecological disorders
OHPC is used in the treatment of threatened miscarriage, gynecological disorders such as dysmenorrhea, premenstrual syndrome, fibrocystic breast disease, adenosis and breast pain. [9] In addition, OHPC is used in the treatment of endometrial cancer and has been found to be significantly effective in prolonging life in both premenopausal and postmenopausal women with the disease. [39] The drug was widely used for such indications in the 1950s to 1970s, but OHPC has recently received the most attention in the prevention of premature birth. [9]
birth control
OHPC is available in some countries as a once-monthly combined injectable contraceptive in combination with estradiol valerate. [11] [40]
other uses
OHPC has been used as a component of menopausal hormone therapy in women. [41] [42]
OHPC has been used to treat benign prostatic hyperplasia in men, although the evidence for effectiveness is marginal and uncertain. [43] It has also been used to treat prostate cancer, at a dose of 1,500 mg twice per week. [44] [45] [46] [47] The mechanism of action of OHPC in these uses is the suppression of testicular androgen production through suppression of luteinizing hormone secretion, a consequence of the progestogenic and antigonadotropic activity of OHPC. [43] However, symptoms of hypogonadism can develop when OHPC is used for this indication, with two-thirds of men reportedly experiencing impotence. [48]
OHPC has been used as a component of feminine hormone therapy for transgender women. [49] [50] [51] [52] [53] Because of micronization, bioidentical progestogens are more commonly used.
Available Forms
Single-use pack of Proluton Depot (OHPC). Castor oil and benzyl benzoate solution contains 1-mL ampoules of 250 mg/mL hydroxyprogesterone caproate (250 mg total) as well as 21 G needles and disposable syringes and is indicated for use by intramuscular injection.
OHPC is available alone as ampoules and vials of 125 and 250 mg/mL oil solution for intramuscular injection (brand names Proluton, Makena). [54] [55] It is also available alone as a 250 mg/mL autoinjector for use by subcutaneous injection (brand name Makena). [3]
OHPC 250 mg/mL is available as vials and vials of OHPC in combination with estradiol valerate and 5 mg/mL estradiol valerate oil solution for intramuscular injection (brand name Gravibinon, Sugar Injection No. 1). [56] [57] [58] [59 ] The drug is available as ampoules of 125–250 mg OHPC in combination with estradiol benzoate and as 10 mg estradiol benzoate in oil solution for intramuscular injection (brand name Primosyston ) Too. [60] [61] [62] [63] [64] : 1045In addition, OHPC is marketed in combination with estradiol dipropionate as 50 mg/mL OHPC and 1 mg/mL estradiol dipropionate (brand name EP Hormone). depot) in Japan. [65] [66]
Difference
Contraindications to OHPC include previous or current thrombosis or thromboembolic disease, known or suspected breast cancer, previous or current history of other hormone-sensitive cancers, abnormal vaginal bleeding unrelated to pregnancy, cholestatic jaundice of pregnancy, liver tumors or active liver disease, and Uncontrolled hypertension. [3] Some relative contraindications also exist for OHPC. [3]
Side effects
OHPC is generally well tolerated and causes relatively few side effects. [1] Injection site pain, soreness, swelling, itching, bruising, and lump-like reactions are the most common side effects of OHPC. [1] Although unlike large doses of progesterone, which produce moderate to severe such reactions, OHPC is relatively free of injection site reactions. [67] Side effects of OHPC that occurred in greater than or equal to 2% of users included injection site pain (34.8%), injection site swelling (17.1%), urticaria (12.3%), pruritus. (7.7%), the injection site is involved. Pruritus (5.8%), nausea (5.8%), injection site nodules (4.5%), and diarrhea (2.3%). [3]Miscarriage (2.4% vs 0%), stillbirth (2.0% vs 1.3%), admission to preterm labor (16.0% vs 13.8%), preeclampsia or gestational hypertension (8. There were numerically increased rates relative to controls for 8%), gestational diabetes (5.6% versus 4.6%), [1] [12] and oligohydramnios (3.6% versus 1.6%). 3%) has been observed in clinical trials in which it was given to pregnant women to prevent premature birth. [3]
more than enough
There have been no reports of overdose of OHPC. [3] In the event of an overdose, treatment should be based on symptoms. [3] OHPC has been studied in humans by intramuscular injection at high doses of 2,000 to 5,000 mg per week without safety concerns. [7] [17] [68] [69]
Conversation
OHPC is unlikely to affect most cytochrome P450 enzymes at therapeutic concentrations. [3] Drug interaction studies have not been conducted with OHPC. [3]
medicine
pharmacodynamics
OHPC has progestogenic activity, some antimineralocorticoid activity, and no other significant hormonal activity. [13] [8] [14] [15] [68]
| compound | HPR-A | HPR-B | rbpr | rbgr | rber |
|---|---|---|---|---|---|
| progesterone | 100 | 100 | 100 | <1 | <1 |
| 17α-hydroxyprogesterone | 1 | 1 | 3 | 1 | <1 |
| Hydroxyprogesterone caproate | 26 | 30 | 28 | 4 | <1 |
| Hydroxyprogesterone Acetate | 38 | 46 | 115 | 3 | ? |
| Note: Values are percentages (%). The reference ligands (100%) were progesterone for the PR, dexamethasone for the GR and estradiol for the ER. Source: View template. |
| compound | Form | Dosage for Specific Uses (mg) [C] | DOA [D] | ||
|---|---|---|---|---|---|
| TFD [E] | POICD [F] | CICD [G] | |||
| algestone acetophenide | Oil soln. | – | – | 75-150 | 14-32D |
| gestoneorone caproate | Oil soln. | 25-50 | – | – | 8-13 d |
| Hydroxyprogest. Acetate [H] | AQ. Doubt | 350 | – | – | 9-16 d |
| Hydroxyprogest. caproate | Oil soln. | २५०-५०० [i] | – | 250-500 | 5-21 days |
| Medroxyprog. acetate | AQ. Doubt | 50-100– | १५० | 25 | 14-50+ D |
| megestrol acetate | AQ. Doubt | – | – | 25 | >14 d |
| norethisterone enanthate | Oil soln. | 100-200 | 200 | 50 | 11-52D |
| progesterone | Oil soln. | 200 [i] | – | – | 2-6 d |
| AQ. solan | ? | – | – | 1-2 d | |
| AQ. Doubt | 50-200– | – | – | 7-14 d | |
| Notes and Sources:^ Source: [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [ 80] [81] [82] [83] [84] [85 ] ] [86] [87] [88] [89]^ All given by intramuscular or subcutaneous injection.^ Progesterone production during the luteal phase is ~25 (15-50) mg/day. The OID is 250 to 500 mg/month of OHPC.^ Duration of action in days.^ Usually given for 14 days.^ Dosage is usually given every two to three months.^ Usually applied once monthly.^ Never marketed or approved by this route.^ a b In divided doses ( 2 × 125 or 250 mg for OHPC, 10 × 20 mg for P4 ). |
progestogenic activity
OHPC, also known as 17α-hydroxyprogesterone caproate, is closer to progesterone in terms of structure and pharmacology than most other progestins, and is essentially a pure progestogen – that is, a progestin of the progesterone receptor (PR). Selective agonists with minimal or no other. hormonal activity. [16] [17] However, OHPC has improved pharmacokinetics compared to progesterone, namely a much longer duration with intramuscular injection in oil solution. [9] [90 ] [61] [91]
Administered by intramuscular injection, the endometrial transformation dosage of OHPC is 250 to 500 mg per cycle, and the weekly replacement dose of OHPC is 250 mg, while the effective dose of OHPC in the Menstrual Delay Trial (Greenblatt) is 25 mg per week. [61] [ 91] [ 92] An effective ovulation-inhibiting dose of OHPC is 500 mg per month by intramuscular injection. [58] [93] [94] However, the dosage of OHPC is 250 mg once a month in combined injectable contraceptives, and this combination is similarly effective for inhibition of ovulation. [58] [94]For comparison, doses of medroxyprogesterone acetate (MPA; 6α-methyl-17α-hydroxyprogesterone acetate), a close analogue of OHPC, are used by intramuscular injection in microcrystalline aqueous suspension in combined injectable contraceptives once a month. , is 25 mg. [58] [93] It has also been noted that given by intramuscular injection, 250 mg of OHPC in oil solution is equivalent to the progestogenic potential of 50 mg of medroxyprogesterone acetate in a microcrystalline aqueous suspension. [95] Although the elimination half-life of intramuscular OHPC in oil solution in non-pregnant women is approximately 8 days, [7] [8]The elimination half-life of intramuscular medroxyprogesterone acetate in microcrystalline aqueous suspension in women is approximately 50 days. , [96] OHPC is also somewhat less potent than the more closely related ester hydroxyprogesterone acetate (OHPA; 17α-hydroxyprogesterone acetate). [97]
17α-Hydroxyprogesterone (OHP) has weak progestogenic activity, but C17α esterification results in high progestogenic activity. [64] Among a variety of different esters, the caproate (hexanoate) ester was found to have the strongest progestogenic activity, and has served as the basis for the development of OHPC, as well as other caproate progestogen esters such as gestanoate caproate. [64] OHPC is a much more potent progestogen than 17α-hydroxyprogesterone, but does not have as high affinity for PR as progesterone. [97] OHPCs have approximately 26% and 30% of the progesterone affinity for human PR-A and PR-B, respectively. [1] [97] activating these receptors and in vitroThe drug was no more effective than progesterone in eliciting related gene expression. [1] [97]
Antigonadotropic effect
Due to the activation of the PR, OHPC has antigonadotropic effects, or produces suppression of the hypothalamic–pituitary–gonadal axis, [98] [99] and can significantly suppress gonadotropin secretion and gonadal sex hormone production at sufficiently high doses. Is . [47] One study found that OHPC by intramuscular injection at a dose of 200 mg twice weekly for the first two weeks and then 200 mg once weekly for 12 weeks reduced estrogen, luteinizing hormone, or follicle-stimulating hormone. did not significantly affect urinary excretion. in men with benign prostatic hyperplasia. [100]In another study that used an unspecified dose of intramuscular OHPC, testosterone secretion was evaluated in one individual and ranged from 4.2 mg/day to 2.0 mg/day (or approximately 52%) in 6 less than a week’s treatment was found. , whereas the secretion of luteinizing hormone remained unchanged in man. [16] Yet another study found that 3,000 mg/week of OHPC by intramuscular injection reduced testosterone levels from 640 ng/dL to 320–370 ng/dL (42–50%) in a man with prostate cancer. , which was similar to testosterone suppression with cyproterone acetate or chlormadinone acetate. [101] Gestonorone caproate, a progestin closely related to OHPC, with approximately 5 to 10-fold greater potency in humans, [102] [103]It was found to suppress testosterone levels by up to 75% in men at a dose of 400 mg/week. with prostate cancer. [104] [105] For comparison, orchiectomy reduced testosterone levels by 91%. [104] In general, progestins are able to maximally suppress testosterone levels by about 70 to 80%. [106] [107] [108] [104] [105] The antigonadotropic effect of OHPC and therefore its testosterone suppression is the basis for the use of OHPC in the treatment of benign prostatic hyperplasia and prostate cancer in men. [43] [44] [46] [47] Suppression of luteinizing hormone levels by OHPC has also been observed in females.[109] [103]
glucocorticoid activity
OHPC is said to have no glucocorticoid activity. [17] Accordingly, OHPC by intramuscular injection has not been found to alter cortisol levels in humans, even with very high doses. [7] This is relevant because drugs with significant glucocorticoid activity suppress cortisol levels by causing increased negative feedback on the hypothalamic–pituitary–adrenal axis. [54] [110] [111] OHPC has been studied in humans by intramuscular injection at high doses of up to 5,000 mg per week, with observed safety and glucocorticoid effects. [7] [69]Although the drug interacts with the glucocorticoid receptor; It has approximately 4% of the affinity of dexamethasone for the rabbit glucocorticoid receptor. [1] [97] But it acts as a partial agonist of the receptor and is no more effective than progesterone in activating the receptor and eliciting related gene expression in vitro . [1] [97] [112]
other activities
As a pure progestogen, OHPC has no androgenic, antiandrogenic, estrogenic or glucocorticoid activity. [16] [17] [113] The absence of androgenic and antiandrogenic activity with OHPC is in contrast to most other 17α-hydroxyprogesterone-derived progestins. [90] [113] Because of its lack of androgenic properties similar to progesterone, OHPC has no teratogenic effect on the fetus, making it safe for use during pregnancy. [17] Although OHPC has been described as a pure progestogen, there is evidence that it possesses some antimineralocorticoid activity similar to progesterone and 17α-hydroxyprogesterone. [14] [114][15] These include clinically significant diuretic effects and reversal of estrogen-induced fluid retention and edema. [114] Unlike progesterone, OHPC and its metabolites are not expected to interact with non-genomic receptors such as membrane progesterone receptors or the GABA A receptor. [18] Accordingly, OHPC is not believed to possess the neurosteroid activities of progesterone or its associated sedative effects. [18]
With regard to cytochrome P450 enzymes, OHPC has no effect on CYP1A, CYP2D6, CYP2C9, or CYP3A4, but is a minor inducer of CYP2C19. [9]
difference with progesterone
There are pharmacodynamic differences between progesterone and OHPC, which may have implications for obstetric use. [12] [18] These include: [12] [18]
- Decreased myometrial activity with progesterone in vitro but no effect or increased myometrial activity with OHPC [115]
- Prevention of cervical ripening with progesterone but unknown effect with OHPC
- A non-significant increased rate of stillbirths and miscarriages with OHPC (in one study)
- Possible increased risk of gestational diabetes with OHPC (increased in two studies, no difference in one study) but no such effect with progesterone
- Significantly increased risk of perinatal adverse effects such as fetal loss and premature labor in multiple pregnancies with OHPC (in two studies)
Differences in the metabolism of progesterone and of OHPC and differences in the formation and activities of the metabolites may be responsible for or involved in these observed biological and pharmacological differences. [18] Progesterone is metabolized in various tissues by 5α- and 5β-reductases, 3α- and 3β-hydroxysteroid dehydrogenases, and 20α- and 20β-hydroxysteroid dehydrogenases. [18] [116] In target tissues, particularly the cervix and myometrium, these enzymes regulate local progesterone concentrations and can activate or deactivate progesterone signaling. [18]In addition, these enzymes catalyze the formation of metabolites of progesterone such as 5β-dihydroprogesterone and allopregnanolone, which signal through their own non-genomic receptors such as membrane progesterone receptors and the GABA A receptor and have their own important effects in pregnancy. There are. , [115] [117] [118] For example, 5b-dihydroprogesterone has been found to play an important role in suppressing myometrial activity, whereas allopregnanolone has potent sedative and anesthetic effects in the mother, and especially in the fetus, Involved in the development of the nervous system. , [18] [117] [118] [119] [ 120]Unlike progesterone, OHPC is not metabolized by conventional steroid-transforming enzymes and is instead metabolized exclusively through oxidation at the caproate side chain by cytochrome P450 enzymes. [18] As such, it is not believed that progesterone has the same tissue-specific activation and inactivation patterns nor the same non-genomic actions that progesterone and its metabolites have. [18]
Further clinical research is expected to provide additional data to help clarify the issue of safety with OHPC. [12] In any case, it is recommended by the American College of Obstetricians and Gynecologists that pregnant women treated with OHPC receive counseling about its risks and benefits. [12]
pharmacokinetics
| Parameters | single thing | twins |
|---|---|---|
| C max (ng/ml) | 22.6 (15.8–27.4) | 17.3 (12-27) |
| Mean C (0-t) (ng/ml) | 16.8 (12.8-22.7) | 12.3 (8.4-18.7) |
| Sea Trough (ng/ml) | 14.1 (10-18.1) | 11.2 (4.8–16.3) |
| AUC 0-t (ng/ml/day) | 117.3 (89.9–159.1) | 86.1 (59–131) |
| T 1/2 (day) | 16.2 (10.6–21.0) | १० (६-१६) |
| T max (days) | 1.0 (1-3) | १.२ (१-२) |
| V d / f (×10 3 ) (L) | 56 (25.2-69.6) | १६.९ (९.१-२४.५) |
| Cl/f (×10 3 ) (L) | २.१ (१.५-२.७) | १.२ (०.९-१.७) |
| Footnote: A = OHPC 250 mg by intramuscular injection once per week. Source: [9] [121] [122] |
absorption
In animals, the bioavailability of OHPC with intramuscular injection is approximately 100%, but its oral bioavailability is very low, at less than 3%. [4] In women, 70 mg/day oral OHPC has similar endometrial potency to 70 mg/day oral OHPA and 2.5 mg/day oral medroxyprogesterone acetate, indicating that oral OHPC and OHPA have similar endometrial potency to medroxyprogesterone via oral About 30 times less potency than acetate. Administration. [123] Studies on progestogenic endometrial changes with oral OHPC in women are mixed, however, one found weak effects with 100 mg/day while the other found that doses of 250 to 1,000 mg produced no effect. [124] [125]As a result of its low oral potency, OHPC has not been used by the oral route and has instead been administered by intramuscular injection. [4] However, a new oral formulation of OHPC (developmental code name LPCN-1107) is under development and has been found to be effective, although in clinical studies it has required twice a day administration. [126] [127] [128]
A depot effect occurs when OHPC is injected intramuscularly or subcutaneously, such that the drug has a prolonged duration of action. [2] [9] After a single intramuscular injection of 1,000 mg OHPC in five women with endometrial cancer, the peak level of OHPC was 27.8 ± 5.3 ng/mL and the time to peak concentration was 4.6 ± 1. It was .7 (3-7) days. [7] [129] After administration of 1,000 mg OHPC continuously for 13 weeks, the Trough level of OHPC was 60.0 ± 14 ng/mL. [7] [129] The pharmacokinetics of 250 mg OHPC by intramuscular injection once a week have also been studied in pregnant women with singleton and multiple (twin and triple) gestation. [9] [121] [122]Steady levels of the drug are achieved within 4 to 12 weeks in pregnant women. [1] The duration of clinical biological effect of OHPC by intramuscular injection in women has also been studied. [130] A single intramuscular injection of 65 to 500 mg OHPC in an oil solution has been found to last for a period of 5 to 21 days in terms of effects on utero and body temperature in women. [130]
OHPC has been found to possess similar pharmacokinetics, including peak levels, time to peak levels, area-under-the-curve levels (i.e., total exposure), and elimination half-lives, with administration via intramuscular injection or subcutaneous autoinjection. [2] However, there was a higher incidence of injection site pain with subcutaneous autoinjection compared to intramuscular injection (37.3% vs. 8.2%). [2]
Distribution
OHPC is extensively bound to plasma proteins, including albumin. [1] Unlike progesterone and 17α-hydroxyprogesterone, OHPC has a very low affinity for corticosteroid-binding globulin (less than 0.01% of cortisol). [5] Progesterone and 17α-hydroxyprogesterone have low affinity for sex hormone-binding globulin, and for this reason, only a very small fraction of them (less than 0.5%) are bound to this protein in the circulation. [6]
metabolism
It appears that OHPC is primarily metabolized by the cytochrome P450 enzymes CYP3A4 and CYP3A5. [1] It can also be metabolized by CYP3A7 in the fetal liver and placenta. [1] Unlike progesterone, OHPC is not metabolized by conventional steroid-conversion enzymes and does not form similar metabolites. [18] OHPC is metabolized by reduction, hydroxylation, and conjugation, including glucuronidation, sulfation, and acetylation. [18] The caproate ester is not cleaved during OHPC metabolism, so 17α-hydroxyprogesterone is not formed from OHPC. [18] [97] As such, OHPC is not a prodrug of 17α-hydroxyprogesterone, nor is progesterone. [18] [97]
The elimination half-life of OHPC has been found to be 7.8 days when given by intramuscular injection in an oil-based formulation to non-pregnant women. [7] [8] Its total duration is reported to be 10 to 14 days, which is much longer than the duration (2 to 3 days) of intramuscularly administered progesterone in an oil formulation. [131] In pregnant women, the elimination half-life of OHPC appears to be longer, approximately 16 or 17 days. [1] [9] However, in pregnant women with twins rather than singles, the elimination half-life of OHPC was found to be shorter, at 10 days. [9] It has been detected in pregnant women up to 44 days after the last dose of OHPC. [9]
be fired
OHPC is eliminated 50% in feces and 30% in urine when given by intramuscular injection to pregnant women. [1] Both free steroids and conjugates are excreted through these routes, with the conjugates being more prominent in the feces. [1]
animal treatment
The pharmacokinetics of OHPC has been studied in various ungulates, including cattle, buffalo, sheep and goats. [132]
time-concentration curve
OHPC levels during one month after the last dose after continuous therapy with 250 mg per week OHPC by intramuscular injection in pregnant women with singleton gestation.
chemistry
After knowing about Hydroxyprogesterone caproate you will now learn about chemistry. OHPC, also known as 17α-hydroxyprogesterone caproate or 17α-hydroxypregn-4-ene-3,20-dione 17α-hexanoate, is a synthetic pregnancy steroid and a derivative of progesterone. [20] [133] It is derived specifically from the ester of 17α-hydroxyprogesterone with a hexanoate (caproate) at the C17α position. [20] [133]OHPC-like analogues include other 17α-hydroxyprogesterone derivatives such as algestone acetophenide (dihydroxyprogesterone acetophenide), chlormadinone acetate, cyproterone acetate, hydroxyprogesterone acetate, hydroxyprogesterone heptanoate, medroxyprogesterone acetate, and caprogesterone (caprogesterone acetate, caprogesterone acetate, caprogesterone acetate, and caprogesterone acetate. caproate), medroxyprogesterone caproate, megestrol caproate, and methenmadinone caproate.
synthesis
The chemical synthesis of OHPC has been described. [134] [135] [136] : 6
history
After knowing about Hydroxyprogesterone caproate you will now learn about history. Along with hydroxyprogesterone acetate, OHPC was developed by Carl Junkman of Schering AG in 1953 and first reported by him in the medical literature in 1954. [137] [138] [139] [ 140] [141] It was reportedly first marketed in Japan in 1954 or 1955, [19] and was later introduced as Delalutin in the United States 1956 [9] [142] Because of its much longer duration than parenteral progesterone, OHPC was largely replaced by progesterone in clinical practice by 1975 [ 143]After decades of use, the manufacturer, Squibb, voluntarily withdrew the Delalutin product in the United States in 1999. [21] Renewed interest in OHPC in the United States increased with a large NIH-sponsored study in 2003, which found that OHPC selectively reduced the risk of premature birth in at-risk pregnant women. [27] With follow-up data showing no evidence of harmful effects on offspring, the FDA approved the drug, as sponsored by the KV drug, Makena , as an orphan drug in February 2011 in women before premature birth 37 weeks gestation with a single fetus that has had at least one prior preterm birth to reduce the risk of miscarriage. [22] [144]
society and culture
common name
Hydroxyprogesterone caproate is the common name for OHPC and its INN , USN , BANM and JAN , while hydroxyprogesterone hexanoate was its former BANM .
OHPC is often mislabeled and confused as progesterone and 17α-hydroxyprogesterone. [145] It should also not be confused with hydroxyprogesterone acetate, hydroxyprogesterone heptanoate, or medroxyprogesterone acetate. [133]
brand names
OHPC is marketed worldwide under a variety of brand names including Proluton , Proluton Depot , and Makena (US), among many others. [20] [40] [133] It was formerly marketed under other brand names including Delalutin , Prodrox , and Hyalutin , but these formulations have since been discontinued. [20] [133] also known as estradiol valerate [56] [57] [58] [59 ]and is marketed under the brand names Gravibinon and Injection No. 1 (or Chinese Injection No. 1). Primosiston in combination with estradiol benzoate. [60] [61] [62] [63] [64]
availability
OHPC is marketed in the United States and throughout Europe, Asia, and Central and South America. [20] [40] [146] It is not specifically available in Canada, the United Kingdom, New Zealand or South Africa, and only veterinary formulations are available in Australia. [20] [40] [146] OHPC is marketed in combination with estradiol valerate as a combined injectable contraceptive in several countries, including South America, Mexico, Japan, and China. [20] [40] [146] It has also been marketed in some countries as an injectable preparation in combination with estradiol benzoate. [60] [61] [62] [63] [64]
price dispute
With the designation of OHPC as an orphan drug by the FDA and the approval of Makena in 2011, the price of OHPC in the United States was going to increase from about US$15 to US$1500 . Dosage, or US$300 to between US $25,000 and US$30,000 for a typical one-month treatment . [22] This was a nearly 100-fold increase in cost with “minimal additional clinical benefit”, and the pricing strategy was strongly criticized. [22] The FDA later announced that the compounding pharmacy would sell OHPC for approximately US$10 to US$20 without fear of legal retribution.may continue to sell at its normal price per dose. [22] [23] KV Pharmaceutical also opted to reduce the price of Makena to US$ 690 per dose. [22] [147] OHPC remained available at low cost from compounding pharmacies until the end of 2016, after which the FDA published new guidance documents prohibiting compounding pharmacies from selling products that “essentially” substitute commercially available pharmaceutical products. copies from”. [24] [25]
Research
Cyclic therapy with 150 mg OHPC by intramuscular injection was found to be effective in the treatment of 76 women with persistent, treatment-refractory acne in a preliminary study, with 84% responding to therapy and experiencing “good to excellent” improvement. in symptoms. [131] [148]
OHPC by Schering was studied as a progestogen-only injectable contraceptive at doses of 250 to 500 mg once a month by intramuscular injection, but produced poor cycle control at these doses and was never marketed went. [149] [150]
OHPC by itself has been found to have little or no effect in the treatment of breast cancer in women. [64] [151] [152] [153] In contrast, a combination of estradiol valerate and OHPC has been found to be effective in the treatment of breast cancer in women. [64] [114] [154] Preliminary research based on limited clinical data suggests that the breast-cancer response rate with the combination of estradiol valerate and OHPC appears to be higher than with estrogen alone (35% vs 50%). it occurs. [64]However, later research using the related but more potent progestin gestoneurone caproate found that the combination of estradiol valerate and gestanorone caproate had effectiveness that was not significantly different from estrogen alone in the treatment of breast cancer in women. [155]
A new oral formulation of OHPC (developmental code name LPCN-1107) is being developed for the prevention of preterm labor. [126] [127] As of September 2017, it is in a phase II or phase III clinical trial for this indication.
