Estradiol benzoate/estradiol dienanthate/testosterone enanthate benzilic acid hydrazone

Last updated
EB/EDE/TEBH
Combination of
Estradiol benzoate Estrogen
Estradiol dienanthate Estrogen
Testosterone enanthate benzilic acid hydrazone Androgen; Anabolic steroid
Clinical data
Trade names Climacteron, Lactimex, Lactostat, Amenose
Other namesEB/EDE/TEBH
Routes of
administration 		Intramuscular injection
Identifiers
CAS Number
PubChem CID

Estradiol benzoate/estradiol dienanthate/testosterone enanthate benzilic acid hydrazone (EB/EDE/TEBH), sold under the brand names Climacteron, Lactimex, Lactostat, and Amenose, is an injectable combination medication of estradiol benzoate (EB), an estrogen, estradiol dienanthate (EDE), an estrogen, and testosterone enanthate benzilic acid hydrazone (TEBH), an androgen/anabolic steroid, which is used in menopausal hormone therapy for peri- and postmenopausal women and to suppress lactation in postpartum women. [1] [2] [3] [4] [5] [6] [7] Clinical studies have assessed this formulation. [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [1]

Climacteron and Amenose contained 1.0 mg EB, 7.5 mg EDE, and 150 mg TEBH (69 mg free testosterone) and was used to treat menopausal symptoms. [20] [17] [21] They were administered by intramuscular injection typically once every 6 weeks but with a range of every 4 to 8 weeks or less frequently. [20] Climacteron was marketed in Canada in 1961 but was withdrawn in this country in October 2005 due to risk of endometrial hyperplasia and cancer from unopposed estrogen exposure (i.e., no concomitant progestogen) as well as induction of supraphysiological testosterone levels. [1] [22] [23]

Lactimex and Lactostat contained 6 mg EB, 15 mg EDE, and 300 mg TEBH in 2 mL of corn oil and were used to suppress lactation. [2] [3] [24] [25] They were administered as a single intramuscular injection after childbirth or during breastfeeding. [2] They were previously available in Germany and Canada. [2] [25]

Estradiol and testosterone levels following a single intramuscular injection of EB/EDE/TEBH versus 10 mg estradiol valerate have been studied over 28 days. [14] [16]

Androgen replacement therapy formulations and dosages used in women
RouteMedicationMajor brand namesFormDosage
Oral Testosterone undecanoate Andriol, JatenzoCapsule40–80 mg 1x/1–2 days
Methyltestosterone Metandren, EstratestTablet0.5–10 mg/day
Fluoxymesterone HalotestinTablet1–2.5 mg 1x/1–2 days
Normethandrone aGinecosideTablet5 mg/day
Tibolone LivialTablet1.25–2.5 mg/day
Prasterone (DHEA) b–Tablet10–100 mg/day
Sublingual Methyltestosterone MetandrenTablet0.25 mg/day
Transdermal Testosterone IntrinsaPatch150–300 μg/day
AndroGelGel, cream1–10 mg/day
Vaginal Prasterone (DHEA) IntrarosaInsert6.5 mg/day
Injection Testosterone propionate aTestovironOil solution25 mg 1x/1–2 weeks
Testosterone enanthate Delatestryl, Primodian DepotOil solution25–100 mg 1x/4–6 weeks
Testosterone cypionate Depo-Testosterone, Depo-TestadiolOil solution25–100 mg 1x/4–6 weeks
Testosterone isobutyrate aFemandren M, FolivirinAqueous suspension25–50 mg 1x/4–6 weeks
Mixed testosterone esters ClimacteronaOil solution150 mg 1x/4–8 weeks
Omnadren, SustanonOil solution50–100 mg 1x/4–6 weeks
Nandrolone decanoate Deca-DurabolinOil solution25–50 mg 1x/6–12 weeks
Prasterone enanthate aGynodian DepotOil solution200 mg 1x/4–6 weeks
Implant Testosterone TestopelPellet50–100 mg 1x/3–6 months
Notes: Premenopausal women produce about 230 ± 70 μg testosterone per day (6.4 ± 2.0 mg testosterone per 4 weeks), with a range of 130 to 330 μg per day (3.6–9.2 mg per 4 weeks). Footnotes:a = Mostly discontinued or unavailable. b = Over-the-counter. Sources: See template.
Potencies and durations of natural estrogens by intramuscular injection
EstrogenFormDose (mg)Duration by dose (mg)
EPDCICD
Estradiol Aq. soln. ?–<1 d
Oil soln.40–60–1–2 ≈ 1–2 d
Aq. susp. ?3.50.5–2 ≈ 2–7 d; 3.5 ≈ >5 d
Microsph. ?–1 ≈ 30 d
Estradiol benzoate Oil soln.25–35–1.66 ≈ 2–3 d; 5 ≈ 3–6 d
Aq. susp.20–10 ≈ 16–21 d
Emulsion ?–10 ≈ 14–21 d
Estradiol dipropionate Oil soln.25–30–5 ≈ 5–8 d
Estradiol valerate Oil soln.20–3055 ≈ 7–8 d; 10 ≈ 10–14 d;
40 ≈ 14–21 d; 100 ≈ 21–28 d
Estradiol benz. butyrate Oil soln. ?1010 ≈ 21 d
Estradiol cypionate Oil soln.20–30–5 ≈ 11–14 d
Aq. susp. ?55 ≈ 14–24 d
Estradiol enanthate Oil soln. ?5–1010 ≈ 20–30 d
Estradiol dienanthate Oil soln. ?–7.5 ≈ >40 d
Estradiol undecylate Oil soln. ?–10–20 ≈ 40–60 d;
25–50 ≈ 60–120 d
Polyestradiol phosphate Aq. soln.40–60–40 ≈ 30 d; 80 ≈ 60 d;
160 ≈ 120 d
Estrone Oil soln. ?–1–2 ≈ 2–3 d
Aq. susp. ?–0.1–2 ≈ 2–7 d
Estriol Oil soln. ?–1–2 ≈ 1–4 d
Polyestriol phosphate Aq. soln. ?–50 ≈ 30 d; 80 ≈ 60 d
Notes and sources
Notes: All aqueous suspensions are of microcrystalline particle size. Estradiol production during the menstrual cycle is 30–640 µg/d (6.4–8.6 mg total per month or cycle). The vaginal epithelium maturation dosage of estradiol benzoate or estradiol valerate has been reported as 5 to 7 mg/week. An effective ovulation-inhibiting dose of estradiol undecylate is 20–30 mg/month. Sources: See template.

See also

Related Research Articles

<span class="mw-page-title-main">Estradiol valerate</span> Chemical compound

Estradiol valerate (EV), sold for use by mouth under the brand name Progynova and for use by injection under the brand names Delestrogen and Progynon Depot among others, is an estrogen medication. It is used in hormone therapy for menopausal symptoms and low estrogen levels, hormone therapy for transgender people, and in hormonal birth control. It is also used in the treatment of prostate cancer. The medication is taken by mouth or by injection into muscle or fat once every 1 to 4 weeks.

<span class="mw-page-title-main">Norethisterone acetate</span> Chemical compound

Norethisterone acetate (NETA), also known as norethindrone acetate and sold under the brand name Primolut-Nor among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication available in low-dose and high-dose formulations and is used alone or in combination with an estrogen. It is ingested orally.

<span class="mw-page-title-main">Estradiol benzoate</span> Chemical compound

Estradiol benzoate (EB), sold under the brand name Progynon-B among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in women, in hormone therapy for transgender women, and in the treatment of gynecological disorders. It is also used in the treatment of prostate cancer in men. Estradiol benzoate is used in veterinary medicine as well. When used clinically, the medication is given by injection into muscle usually two to three times per week.

<span class="mw-page-title-main">Estradiol cypionate</span> Chemical compound

Estradiol cypionate (EC), sold under the brand name Depo-Estradiol among others, is an estrogen medication which is used in hormone therapy for menopausal symptoms and low estrogen levels in women, in hormone therapy for trans women, and in hormonal birth control for women. It is given by injection into muscle once every 1 to 4 weeks.

<span class="mw-page-title-main">Estradiol enantate</span> Chemical compound

Estradiol enantate, also spelled estradiol enanthate and sold under the brand names Perlutal and Topasel among others, is an estrogen medication which is used in hormonal birth control for women. It is formulated in combination with dihydroxyprogesterone acetophenide, a progestin, and is used specifically as a combined injectable contraceptive. Estradiol enantate is not available for medical use alone. The medication, in combination with DHPA, is given by injection into muscle once a month.

<span class="mw-page-title-main">Estradiol undecylate</span> Chemical compound

Estradiol undecylate, also known as estradiol undecanoate and formerly sold under the brand names Delestrec and Progynon Depot 100 among others, is an estrogen medication which has been used in the treatment of prostate cancer in men. It has also been used as a part of hormone therapy for transgender women. Although estradiol undecylate has been used in the past, it was discontinued and hence is no longer available. The medication has been given by injection into muscle usually once a month.

<span class="mw-page-title-main">Hydroxyprogesterone heptanoate</span> Chemical compound

Hydroxyprogesterone heptanoate (OHPH), also known as hydroxyprogesterone enanthate (OHPE) and sold under the brand names H.O.P., Lutogil A.P., and Lutogyl A.P. among others, is a progestin medication used for progestogenic indications. It has been formulated both alone and in together with estrogens, androgens/anabolic steroids, and other progestogens in several combination preparations. OHPH is given by injection into muscle at regular intervals.

<span class="mw-page-title-main">Estradiol dienantate</span> Chemical compound

Estradiol dienanthate (EDE), sold under the brand names Climacteron among others, is a long-acting estrogen medication which was previously used in menopausal hormone therapy for women and to suppress lactation in women. It was formulated in combination with estradiol benzoate (EB), a short-acting estrogen, and testosterone enanthate benzilic acid hydrazone (TEBH), a long-acting androgen/anabolic steroid. EDE has not been made available for medical use alone. The medication, in combination with EB and TEBH, was given by injection into muscle once or at regular intervals, for instance once every 6 weeks.

<span class="mw-page-title-main">Prasterone enanthate</span> Chemical compound

Prasterone enanthate, also known as dehydroepiandrosterone enanthate (DHEA-E) and sold in combination with estradiol valerate under the brand name Gynodian Depot among others, is a weak androgen, estrogen, and neurosteroid medication which is used as a component of menopausal hormone therapy to treat menopausal symptoms in women. It is available only as an injectable preparation in combination with estradiol valerate. The medication is given by injection into muscle typically once every 4 weeks.

<span class="mw-page-title-main">Testosterone enantate benzilic acid hydrazone</span> Chemical compound

Testosterone enantate benzilic acid hydrazone (TEBH), or testosterone 17β-enantate 3-benzilic acid hydrazone, is a synthetic, injected androgen/anabolic steroid and an androgen ester – specifically, the C17β enantate (heptanoate) ester and C3 benzilic acid hydrazone of testosterone. It was previously marketed in combination with estradiol benzoate and estradiol dienantate under the brand names Climacteron, Lactimex, and Lactostat. Clinical studies have assessed this formulation. TEBH was first described in the scientific literature in 1959. It is a very long-lasting prodrug of testosterone when administered in oil via intramuscular injection.

<span class="mw-page-title-main">Estradiol valerate/prasterone enanthate</span> Combination drug

Estradiol valerate/prasterone enanthate (EV/DHEA-E), sold under the brand name Gynodian Depot among others, is an injectable combination medication of estradiol valerate (EV), an estrogen, and prasterone enanthate (DHEA-E), an androgen, estrogen, and neurosteroid, which is used in menopausal hormone therapy for women. It is provided in the form of 1 mL ampoules containing 4 mg estradiol valerate and 200 mg prasterone enanthate in an oil solution and is administered by intramuscular injection once every 4 to 6 weeks. EV/DHEA-E reportedly has a duration of about 21 days.

<span class="mw-page-title-main">Estradiol benzoate/testosterone isobutyrate</span> Combination drug

Estradiol benzoate/testosterone isobutyrate (EB/TiB), sold under the brand names Femandren M and Folivirin, is an injectable combination medication of estradiol benzoate (EB), an estrogen, and testosterone isobutyrate (TiB), an androgen/anabolic steroid, which is used in menopausal hormone therapy for women. It is provided in the form of 1 mL ampoules containing 2.5 mg estradiol benzoate and 25 mg testosterone isobutyrate in a microcrystalline aqueous suspension and is administered by intramuscular injection once every 4 to 6 weeks. EB/TiB reportedly has a duration of about 14 to 21 days.

<span class="mw-page-title-main">Estradiol benzoate/estradiol phenylpropionate</span> Combination drug

Estradiol benzoate/estradiol phenylpropionate (EB/EPP), sold under the brand name Dimenformon Prolongatum, is an injectable combination formulation of estradiol benzoate (EB), a shorter-acting estrogen, and estradiol phenylpropionate (EPP), a longer-acting estrogen, which has been used in menopausal hormone therapy for women in Europe but appears to no longer be available. It has also been used to suppress lactation in women and has been used in feminizing hormone therapy for transgender women. It has been provided in the form of 1 mL ampoules containing 2.5 mg EB and 10 mg EPP in oil solution and is administered by intramuscular injection at regular intervals.

<span class="mw-page-title-main">Estradiol valerate/testosterone enanthate</span> Combination drug

Estradiol valerate/testosterone enanthate (EV/TE), sold under the brand names Primodian Depot and Ditate among others, is an injectable combination medication of estradiol valerate (EV), an estrogen, and testosterone enanthate (TE), an androgen/anabolic steroid, which is used in menopausal hormone therapy for women. The medication is also used to suppress lactation in postpartum women.

Estradiol benzoate/estradiol phenylpropionate/testosterone propionate/testosterone phenylpropionate/testosterone isocaproate (EB/EPP/TP/TPP/TiC), sold under the brand names Estandron Prolongatum, Lynandron Prolongatum, and Mixogen, was an injectable combination medication of the estrogens estradiol benzoate (EB) and estradiol phenylpropionate (EPP) and the androgens/anabolic steroids testosterone propionate (TP), testosterone phenylpropionate (TPP), and testosterone isocaproate (TiC) which was used in menopausal hormone therapy for women. It was also used to suppress lactation in postpartum women.

Estradiol benzoate/estradiol valerate/norethisterone acetate/testosterone enanthate (EB/EV/NETA/TE), sold under the brand name Ablacton, is an injectable combination medication of estradiol benzoate (EB), an estrogen, estradiol valerate (EV), an estrogen, norethisterone acetate (NETA), a progestin, and testosterone enanthate (TE), an androgen/anabolic steroid, which has been used to suppress lactation in women. It contains 5 mg EB, 8 mg EV, 20 mg NETA, and 180 mg TE in oil solution and is provided in the form of ampoules. It is given as a single intramuscular injection following childbirth. The medication was manufactured by Schering and was previously marketed in Italy and Spain, but is no longer available.

Estrone/progesterone/testosterone (E1/P4/T), sold under the brand name Tristeron or Tristerone, is an injectable combination medication of estrone (E1), an estrogen, progesterone (P4), a progestogen, and testosterone (T), an androgen/anabolic steroid, which was used in the treatment of functional uterine bleeding in women. It contained 6 mg estrone, 50 mg progesterone, and 25 mg testosterone in microcrystalline aqueous suspension and was administered by intramuscular injection. The medication was manufactured by Wyeth and was marketed by 1951. It is no longer available.

Estradiol benzoate/progesterone/testosterone propionate (EB/P4/TP), sold under the brand names Lukestra, Steratrin, Trihormonal, and Trinestryl, is an injectable combination medication of estradiol benzoate (EB), an estrogen, progesterone (P4), a progestogen, and testosterone propionate (TP), an androgen/anabolic steroid. It contained 1 to 3 mg EB, 20 to 25 mg P4, and 25 mg TP, was provided in the form of ampoules, and was administered by intramuscular injection. The medication was introduced by 1949 and was marketed in the United States, the United Kingdom, and Germany among other places. It is no longer available.

References

  1. 1 2 3 Al-Imari L, Wolfman WL (September 2012). "The safety of testosterone therapy in women". Journal of Obstetrics and Gynaecology Canada. 34 (9): 859–865. doi:10.1016/S1701-2163(16)35385-3. PMID   22971455.
  2. 1 2 3 4 Geburtshilfe und Frauenheilkunde: Ergebnisse der Forschung für die Praxis. Georg Thieme Verlag. 1969. p. 387,390. [Kelly and Primose and Dodek found the following androgen-estrogen combination to be particularly effective and well-tolerated: 300 mg 3-benzilic acid hydrazone-testosterone-17-enanthate, 15 mg estradiol di-enanthate, 6 mg estradiol benzoate in 2 ml corn oil. This product is sold in Germany under the name Lactimex and has been clinically examined by us.] [...] Of 1200 postpartum patients one quarter stopped breast feeding for a variety of reasons and received an injection of Lactimex (Protina: Benzil acid hydrazon-testosteron-oenanthat 300 mg, Oestradiol-di-oenanthat 15 mg and Oestradiol-benzoate 6 mg in 1.0 ml of oil). In 76% of cases one injection was sufficient and the remaining 24% required a second injection. A second injection was required rarer if the first injection had been longer after delivery. A higher dosage of Lactimex was not necessary in cases with a preceding medical induction with intraveinous Oxytocin (Orasthin). Mothers who had been treated postpartum with methylergobasin did not as often require a second injection. No localized or generalized adverse reaction to the drug was noticed.
  3. 1 2 Zentralblatt für Gynäkologie. J. A. Barth. 1971. The preparation Lactimex (300 mg 3-benzyl hydrazone-testosterone-17-enanthate + 15 mg estradiol-dienanthate + 6 mg estradiol benzoate in 2 ml corn oil) was injected. [...]
  4. ↑ Ginsburg ES (1999). "Androgen Replacement in Postmenopausal Women". In Seifer DB, Kennard EA (eds.). Menopause. Contemporary Endocrinology. Vol. 18. Humana Press. pp. 209–219. doi:10.1007/978-1-59259-246-3_13. ISBN   978-1-61737-129-5.
  5. ↑ Greenblatt RB, Barfield WE, Jungck EC (January 1962). "The treatment of the menopause". Canadian Medical Association Journal. 86 (3): 113–114. PMC   1848811 . PMID   13901504.
  6. ↑ Seifer DB (27 July 1999). Seifer DB, Kennard EA (eds.). Menopause: Endocrinology and Management. Springer Science & Business Media. pp. 183–. doi:10.1007/978-1-59259-246-3. ISBN   978-1-59259-246-3.
  7. ↑ Hager HH, Kern W, Heinz P, Roth HJ (29 July 2013). Hagers Handbuch der Pharmazeutischen Praxis: Für Apotheker, Arzneimittelhersteller, Ärzte und Medizinalbeamte: Wirkstoffgruppen II Chemikalien und Drogen (A-AL). Springer-Verlag. pp. 157–. ISBN   978-3-662-25655-8.
  8. ↑ Kelly MJ, Primrose T (December 1960). "Evaluation of a new preparation for the suppression of lactation". Canadian Medical Association Journal. 83 (24): 1240–1242. PMC   1938994 . PMID   13752392.
  9. ↑ Schneider J, Macarthur JL, Patrick JW, Burton GV (August 1964). "The Suppression of Lactation: An Objective Study". Obstetrics and Gynecology. 24 (2): 294–297. PMID   14199544.
  10. ↑ Sherwin BB, Gelfand MM (March 1984). "Effects of parenteral administration of estrogen and androgen on plasma hormone levels and hot flushes in the surgical menopause". American Journal of Obstetrics and Gynecology. 148 (5): 552–557. doi:10.1016/0002-9378(84)90746-4. PMID   6367474.
  11. ↑ Sherwin BB, Gelfand MM (January 1985). "Differential symptom response to parenteral estrogen and/or androgen administration in the surgical menopause". American Journal of Obstetrics and Gynecology. 151 (2): 153–160. doi:10.1016/0002-9378(85)90001-8. PMID   3881960.
  12. ↑ Sherwin BB (September 1985). "Changes in sexual behavior as a function of plasma sex steroid levels in post-menopausal women". Maturitas. 7 (3): 225–233. doi:10.1016/0378-5122(85)90044-1. PMID   4079822.
  13. ↑ Sherwin BB, Gelfand MM (1985). "Sex steroids and affect in the surgical menopause: a double-blind, cross-over study". Psychoneuroendocrinology. 10 (3): 325–335. doi:10.1016/0306-4530(85)90009-5. PMID   3903822. S2CID   40861936.
  14. 1 2 3 4 5 Sherwin BB, Gelfand MM, Schucher R, Gabor J (February 1987). "Postmenopausal estrogen and androgen replacement and lipoprotein lipid concentrations". American Journal of Obstetrics and Gynecology. 156 (2): 414–419. doi:10.1016/0002-9378(87)90295-X. PMID   3826177.
  15. 1 2 3 4 Sherwin BB, Gelfand MM (1987). "Individual differences in mood with menopausal replacement therapy: possible role of sex hormone-binding globulin". Journal of Psychosomatic Obstetrics & Gynecology. 6 (2): 121–131. doi:10.3109/01674828709016773. ISSN   0167-482X.
  16. 1 2 Sherwin BB (1988). "Affective changes with estrogen and androgen replacement therapy in surgically menopausal women". Journal of Affective Disorders. 14 (2): 177–187. doi:10.1016/0165-0327(88)90061-4. PMID   2966832.
  17. 1 2 Sherwin BB (1988). "Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women". Psychoneuroendocrinology. 13 (4): 345–357. doi:10.1016/0306-4530(88)90060-1. PMID   3067252. S2CID   24695692.
  18. ↑ Sherwin BB (1994). "The Effect of Sex Steroids on Brain Mechanisms Relating to Mood and Sexuality". Comprehensive Management of Menopause. Clinical Perspectives in Obstetrics and Gynecology. Springer. pp. 327–333. doi:10.1007/978-1-4612-4330-4_31. ISBN   978-1-4612-8737-7. ISSN   0178-0328.
  19. ↑ Sherwin BB (April 2002). "Randomized clinical trials of combined estrogen-androgen preparations: effects on sexual functioning". Fertility and Sterility. 77 (Suppl 4): S49–S54. doi: 10.1016/S0015-0282(02)03002-9 . PMID   12007902.
  20. 1 2 "Climacteron Drug Information, Professional". Drugs.com. Archived from the original on 2 June 2019. Retrieved 2 June 2019.
  21. ↑ Bundesverband der Pharmazeutischen Industrie (Germany) (1974). Rote Liste: Verzeichnis pharmazeutischer Spezialpräparate. Editio Cantor. ISBN   9783871930133. 49035 В Amenose® Rp Ampullen Zus.: 1 Amp. 1 ml enth.: Benzilsäurehydrazid-N-testosteron-hydrazon-17-oenanthat 150 mg, Oestradiol-di-oenanthat 7.5 mg. Oestradiolbenzoat 1 mg in öl-Lösg. Ind.: Androgen-Oestrogen-Gemisch. Gegen Ausfallserscheinungen im Klimakterium und nach Ovarektomie. Osteoporose. Kontraind.: A 90, О 5 Dos.: Durchschnittl. alle 6 Wochen 1 Amp. im. 1 Amp. I ml 6.75 3 Amp 17.40 AP.: 10 Amp.
  22. ↑ Lexchin J (2010). "Drug safety and Health Canada". International Journal of Risk & Safety in Medicine. 22 (1): 41–53. doi:10.3233/JRS-2010-0490.
  23. ↑ "Discontinuation of CLIMACTERON® Injection (estradiol dienanthate ⁄ estradiol benzoate and testosterone enanthate benzilic acid hydrazone injection in corn oil)" (PDF). Sandoz Canada Inc. 23 November 2005. Archived from the original (PDF) on 2013-01-11. Retrieved 2 June 2019.
  24. ↑ Vorherr H (2 December 2012). The Breast: Morphology, Physiology, and Lactation. Elsevier Science. pp. 201–. ISBN   978-0-323-15726-1.
  25. 1 2 Compendium of Pharmaceuticals and Specialties. Canadian Pharmaceutical Association. 1983. ISBN   978-0-919115-04-0. LACTOSTAT [...] Each 2 mL of injectable solution contains testosteorne enanthate benzilic acid hydrazone 300 mg, estradiol dienanthate 15 mg, estradiol benzoate 6 mg, benzyl alcohol 7.5% as preservative, benzyl benzoate 0.75 mg, corn oil q.s. Available in 2 mL ampuls, boxes of 25.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.