Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Terconazole: Difference between pages

{{short description|Chemical compound}}

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| IUPAC_name = 1-[4-[ [(2''S'',4''S'')-2-(2,4-Dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-propan-2-yl-piperazine

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| C=26 | H=31 | Cl=2 | N=5 | O=3

'''Terconazole''' is an [[antifungal]] drug used to treat [[vaginal yeast infection]]. It comes as a lotion or a suppository and disrupts the biosynthesis of fats in a yeast cell. It has a relatively broad spectrum compared to azole compounds but not triazole compounds. Testing shows that it is a suitable compound for prophylaxis for those that suffer from chronic vulvovaginal candidiasis.

==Medical uses==

Terconazole is approved to treat vulvovaginal candidiasis (vaginal thrush). It works as a broad spectrum antifungal and has shown to be an effective first-line treatment against other ''Candida'' species.<ref>{{cite journal | vauthors = Tolman EL, Isaacson DM, Rosenthale ME, McGuire JL, Van Cutsem J, Borgers M, Van den Bossche H | title = Anticandidal activities of terconazole, a broad-spectrum antimycotic | journal = Antimicrobial Agents and Chemotherapy | volume = 29 | issue = 6 | pages = 986–991 | date = June 1986 | pmid = 3729366 | pmc = 180489 | doi = 10.1128/aac.29.6.986 }}</ref> It also shows effectiveness against dermatomycoses in animal models.<ref>{{cite journal | vauthors = Sood G, Nyirjesy P, Weitz MV, Chatwani A | title = Terconazole cream for non-Candida albicans fungal vaginitis: results of a retrospective analysis | journal = Infectious Diseases in Obstetrics and Gynecology | volume = 8 | issue = 5–6 | pages = 240–243 | date = 2000 | pmid = 11220485 | pmc = 1784691 | doi = 10.1155/S1064744900000351 | doi-access = free }}</ref>

A review found that short-term rates for intravaginally administered azole treatments shows cure in 80% of cases in a short term follow-up and 66% over long term follow-up.<ref>{{cite journal | vauthors = Denison HJ, Worswick J, Bond CM, Grimshaw JM, Mayhew A, Gnani Ramadoss S, Robertson C, Schaafsma ME, Watson MC | title = Oral versus intra-vaginal imidazole and triazole anti-fungal treatment of uncomplicated vulvovaginal candidiasis (thrush) | journal = The Cochrane Database of Systematic Reviews | volume = 2020 | issue = 8 | pages = CD002845 | date = August 2020 | pmid = 32845024 | pmc = 8095055 | doi = 10.1002/14651858.CD002845.pub3 }}</ref> In a double-blind study by Slavin in 1992, terconazole showed a 75% mycological cure over a short-term period (7–14 days) and 100% mycological cure over a long-term period (28–34 days). This study focused on the drug as an 80&nbsp;mg vaginal suppository, taken three times overnight by 10 women.<ref>{{cite journal | vauthors = Slavin MB, Benrubi GI, Parker R, Griffin CR, Magee MJ | title = Single dose oral fluconazole vs intravaginal terconazole in treatment of Candida vaginitis. Comparison and pilot study | journal = The Journal of the Florida Medical Association | volume = 79 | issue = 10 | pages = 693–696 | date = October 1992 | pmid = 1460451 }}</ref> In another placebo-controlled, double blind study by Schmidt et al., the efficacy of different concentrations of terconazole creams were tested. Cream was applied for three days to 24 women between the ages of 18 and 60. The results showed 0.8% terconazole mycologic cure rates were 83.3% within 1–3 days of starting treatment, 83.3% within 8–11 days of treatment and 58.3% within 30–35 days of treatment.<ref name="Schmidt">{{cite journal | vauthors = Schmitt C, Sobel J, Meriwether C | title = Comparison of 0.8% and 1.6% terconazole cream in severe vulvovaginal candidiasis | journal = Obstetrics and Gynecology | volume = 76 | issue = 3 Pt 1 | pages = 414–416 | date = September 1990 | pmid = 2381618 }}</ref> The suppository is more effective after a long-term follow-up than terconazole as a cream or other intravaginal treatments.<ref>{{cite book| veditors = Maibach HI, Farage MA |title=The Vulva: Anatomy, Physiology and Pathology|date=2006|publisher=Informa Healthcare USA, Inc.|location=New York|isbn=978-0-8493-3608-9|pages=128–129|edition=1st|chapter=Vulvar Therapies: Evidence vs. Testimony. Fungal: Candidiasis.}}</ref>

==Side effects==

The most common side effects of terconazole include [[headache]]s, vulvar/vaginal irritation, [[rash]], [[itch]]ing, burning or discomfort.<ref>{{cite web| vauthors = Workowski KA, Berman S |title=Sexually Transmitted Diseases Treatment Guidelines, 2010. Vol. 59. No. RR-12.|url=https://www.cdc.gov/mmwr/pdf/rr/rr5912.pdf|website=USA Centers for Disease Control and Prevention|publisher=Office of Surveillance, Epidemiology, and Laboratory Services, Centers for Disease Control and Prevention (CDC), U.S. Department of Health and Human Services, Atlanta, GA 30333|access-date=10 July 2015|date=December 17, 2010}}</ref> Other side effects may include abdominal pain or cramps, [[dysmenorrhea]], [[chills]], [[fever]] and allergic reactions. Flu-like symptoms have been recorded in those that take suppositories greater than 160&nbsp;mg.<ref name="Schmidt" /> May cause birth defects if used in the first trimester.<ref>{{cite journal| vauthors = Faro S, Apuzzio J, Bohannon N, Elliott K, Martens MG, Mou SM, Phillips-Smith LE, Soper DE, Strayer A, Young RL |title=Treatment Considerations in Vulvovaginal Candidiasis|journal=The Female Patient|date=March 1997|volume=22|issue=1|pages=1–17}}</ref>

Terconazole is not considered hazardous when handled under normal conditions. It is generally non-flammable and non-carcinogenic. Generally is non-toxic, however, can emit toxic fumes when dust is set alight. Can cause respiratory distress as dust.<ref>{{cite book| vauthors = Mancano MA, Gallagher JC |title=Frequently Prescribed Medications: Drugs You Need to Know|date=2013|publisher=Jones & Bartlett Learning|location=Burlington, MA |isbn=978-1-4496-9884-3|page=312|edition=2nd}}</ref> Can be absorbed by embryo within the first trimester of pregnancy and cause birth defects. Cross inhibition shows that there may be some toxicity.<ref>{{cite web|author1=Melbourne Sexual Health Centre|title=Vaginal thrush|url=http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/Thrush|website=Better Health Channer|publisher=State Government of Victoria|access-date=10 July 2015|archive-date=5 October 2015|archive-url=https://web.archive.org/web/20151005181502/http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/Thrush|url-status=dead}}</ref>

== Interactions ==

Terconazole may interact with the spermicide [[nonoxynol-9]]. A precipitate is formed upon combination of both drugs. Terconazole may weaken latex-based [[condom]]s.<ref>{{cite book| veditors = Grayson ML, Crowe SM, McCarthy JS, Mills J, Mouton JW, Norrby SR, Paterson DL, Pfaller MA |title=Kucers' the Use of Antibiotics Sixth Edition: a Clinical Review of Antibacterial, Antifungal, Antiparasitic, and Antiviral Drugs |date=2010 |publisher=CRC Press. Taylor & Francis Group |location=Boca Raton, FL |isbn=978-0340927670 |pages=1933–5 |edition=6th}}</ref>

==Chemistry==

Terconazole is a triazole [[ketal]] with broad-spectrum antifungal/antimycotic tendencies.{{cn|date=December 2022}}

Terconazole synthesis synologous with ketoconazole except for the fact that triazole and not imidazole heterocyclic ring is used, and that isopropyl group instead of acetamide.

[[File:Terconazole synthesis.svg|thumb|center|701px|Terconazole synthesis: {{US patent|4144346}} {{US patent|4223036}} <ref>{{cite journal | vauthors = Heeres J, Hendrickx R, Van Cutsem J | title = Antimycotic azoles. 6. Synthesis and antifungal properties of terconazole, a novel triazole ketal | journal = Journal of Medicinal Chemistry | volume = 26 | issue = 4 | pages = 611–613 | date = April 1983 | pmid = 6834396 | doi = 10.1021/jm00358a032 }}</ref> {{Cite patent|country=DE|number=2804096}}]]

Terconazole has the chemical formula C₂₆H₃₁Cl₂N₅O₃. The chemical name for terconazole is 1-<nowiki/>{[(2''S'',4''S'')-2-(2,4-dichlorophenyl)-4-<nowiki/>{[''p''-(4-isopropyl-1-piperazinyl)phenoxy]methyl}-1,3-dioxolan-2-yl]methyl}-1''H''-1,2,4-triazole. Terconazole has a melting point of 126.3&nbsp;°C (259.34&nbsp;°F). The molecular weight of terconazole is 532.462 g/mol. Terconazole is synthesized using two chemical compounds: ''cis''-[2(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl] methyl benzoate and the sodium salt of triazole, created by mixing [[triazole]] with [[sodium hydride]]. These are put in a solution and catalyzed using [[dimethyl sulfate]] at 1300&nbsp;°C (2372&nbsp;°F) to give many different types of triazole derivatives.<ref name="Cauwenbergh" /> These are purified using alcohol and [[chromatography]]. Terconazole is non-reactive except when exposed to strong oxidizing agents or strong bases due to the nitrogen attached to the triazole ring. It has been found to be photosensitive.<ref>{{cite journal | vauthors = Fromtling RA | title = Overview of medically important antifungal azole derivatives | journal = Clinical Microbiology Reviews | volume = 1 | issue = 2 | pages = 187–217 | date = April 1988 | pmid = 3069196 | pmc = 358042 | doi = 10.1128/CMR.1.2.187 }}</ref>

==Mechanism of action==

Terconazole binds to the heme iron component on the [[cytochrome P450]] enzyme [[lanosterol]] of fungi, also known as [[CYP3A4]]. The gene ERG11 controls lanosterol creation.<ref>{{cite book | vauthors = Yoshida Y | chapter = Cytochrome P450 of Fungi: Primary Target for Azole Antifungal Agents | title = Current Topics in Medical Mycology | volume = 2 | pages = 388–418 | year = 1988 | pmid = 3288361 | doi = 10.1007/978-1-4612-3730-3_11 | isbn = 978-1-4612-8323-2 }}</ref> Lanosterol is found within the yeast plasma membrane. It is a class of methylsterol. Within a normal yeast cell, lanosterol is demethylated using 14α-demethylation.<ref>{{cite journal | vauthors = Isaacson DM, Tolman EL, Tobia AJ, Rosenthale ME, McGuire JL, Vanden Bossche H, Janssen PA | title = Selective inhibition of 14 alpha-desmethyl sterol synthesis in Candida albicans by terconazole, a new triazole antimycotic | journal = The Journal of Antimicrobial Chemotherapy | volume = 21 | issue = 3 | pages = 333–343 | date = March 1988 | pmid = 3129389 | doi = 10.1093/jac/21.3.333 }}</ref> This process creates [[zymosterol]]: a major constituent in the ergosterol biosynthesis pathway for the creation of cell membrane constituents in yeast. This structure provides the membrane with fluidity.<ref>{{cite web|title=C-4 Methylsterol Oxidase Activity|url=http://www.yeastgenome.org/go/GO:0000254/overview|website=Saccharomyces Genome Database|publisher=Stanford University, Stanford, CA 94305|access-date=10 July 2015}}</ref> This occurs by transforming lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-β-ol. This stops respiration by prohibiting reduction of [[Nicotinamide adenine dinucleotide|NADH]] to NAD. This stops biosynthesis of cell membrane products as well as transport and catabolism. Eventually, membrane fluidity and activity of membrane bound enzymes become depleted. It has also been shown to inhibit morphologic change of yeast as well as cell adherence and is directly toxic to yeast. Terconazole targets fungi specifically since humans do not use lanosterol in this pathway. This process does not affect all fungi such as ''[[Pneumocystis jirovecii]]'', which lacks lanosterol.<ref>{{cite journal | vauthors = Sobel JD |title=Mini Review. Candida Vaginitis|journal=Infectious Diseases in Clinical Practice |date=1994 |volume=3 |issue=5 |pages=334–339 |doi=10.1097/00019048-199409000-00002 |s2cid=220575082 |doi-access=free }}</ref>

==Metabolism==

Absorption of terconazole is 5–8% in patients that have had a hysterectomy and 12–16% in other patients. In those that administered 0.8% terconazole, plasma concentrations of the drug remained quite low with the peak plasma concentration being 0.006 mcg at 6.6 hours. Those metabolism rates show similar results in pregnant vulvovaginal candidiasis, non-pregnant vulvovaginal candidiasis and healthy women. The half-life of terconazole in blood is recorded to be around 6.9 hours over a range of 4–11.3 hours). Radioactivity of plasma terconazole is low compared to terconazole at 0.6%. Excretion of radioactivity is via two routes, renal (32–53%) and fecal (47–52%). Metabolism is extensive and is highly protein bound (94.9%) with the degree of binding being independent of drug concentration.<ref>{{cite journal | vauthors = Sheehan DJ, Hitchcock CA, Sibley CM | title = Current and emerging azole antifungal agents | journal = Clinical Microbiology Reviews | volume = 12 | issue = 1 | pages = 40–79 | date = January 1999 | pmid = 9880474 | pmc = 88906 | doi = 10.1128/cmr.12.1.40 }}</ref>

==History==

In 1940, the first commercial antifungal drug, called [[amphotericin B]], was available on the market, replacing rare and expensive treatments. It was effective in its function but was very toxic and only used for serious infections. The drug was infused into the bloodstream and could cause kidney damage and other side effects. The first azole compounds to replace this treatment were synthesized in the late 1960s and early 1970s and administered to humans under strict care. These compounds were imidazoles, a molecule containing two non-adjacent nitrogen atoms in a 5 membered ring. The first oral antimycotic imidazole, called [[ketoconazole]], was available on the market in 1981. Triazole based drugs came shortly after and quickly gained popularity due to its broader spectrum of antifungal activity and less toxicity.<ref>{{cite journal | vauthors = Maertens JA | title = History of the development of azole derivatives | journal = Clinical Microbiology and Infection | volume = 10 | issue = Suppl 1 | pages = 1–10 | date = March 2004 | pmid = 14748798 | doi = 10.1111/j.1470-9465.2004.00841.x | doi-access = free }}</ref> Terconazole was the first triazole-based antifungal drug synthesized for human use. [[Janssen Pharmaceutica]] developed it in 1983.<ref>{{cite journal | vauthors = Heeres J, Hendrickx R, Van Cutsem J | title = Antimycotic azoles. 6. Synthesis and antifungal properties of terconazole, a novel triazole ketal | journal = Journal of Medicinal Chemistry | volume = 26 | issue = 4 | pages = 611–613 | date = April 1983 | pmid = 6834396 | doi = 10.1021/jm00358a032 }}</ref> Previously, all triazole based drugs targeted fungal infections related to plants from ''Candida'' species. Since creation, terconazole has been superseded by second-generation triazoles due to their even broader spectrum and higher activity levels against resistant pathogens like ''Aspergillus spp.''<ref name="Cauwenbergh">{{cite journal | vauthors = Cauwenbergh G, Vanden Bossche H | title = Terconazole. Pharmacology of a new antimycotic agent | journal = The Journal of Reproductive Medicine | volume = 34 | issue = 8 Suppl | pages = 588–592 | date = August 1989 | pmid = 2677363 }}</ref> It is still used as a treatment in cases of resistance to other drugs.{{cn|date=December 2022}}

==Available forms==

Terconazole is a white, odourless powder. It can be purchased commercially in the following forms:

* Terconazole 0.4% cream 5 g applied intravaginally once a day for 7 days;

* Terconazole 0.8% cream 5 g applied intravaginally once a day for 3 days;

* Terconazole 80&nbsp;mg vaginal suppository used once daily for 3 days.<ref>{{cite book|author1=Mosby| veditors = White K, Watrous J |title=Mosby's Drug Reference for Health Professions|date=2012|publisher=Elsevier|location=St. Louis, Missouri|isbn=978-0-323-09574-7|pages=1558–1559|edition=3rd|chapter=Terconazole}}</ref>

== References ==

{{Reflist}}

== External links ==

* [https://www.nlm.nih.gov/medlineplus/druginfo/meds/a688022.html Information about terconazole from the United States Government]

{{Gynecological anti-infectives and antiseptics}}

{{Antifungals}}

{{Xenobiotic-sensing receptor modulators}}

[[Category:Dioxolanes]]

[[Category:Lanosterol 14α-demethylase inhibitors]]

[[Category:Phenol ethers]]

[[Category:Piperazines]]

[[Category:Triazole antifungals]]

[[Category:Isopropyl compounds]]

[[Category:Chloroarenes]]

[[Category:Phenylethanolamine ethers]]