Terconazole

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Terconazole
Terconazole structure.svg
Clinical data
Trade names Terazol
AHFS/Drugs.com Monograph
MedlinePlus a688022
ATC code
Pharmacokinetic data
Protein binding 94.9%
Identifiers
  • 1-[4-[ [(2S,4S)-2-(2,4-Dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-propan-2-yl-piperazine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.061.573 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C26H31Cl2N5O3
Molar mass 532.47 g·mol−1
3D model (JSmol)
  • Clc1ccc(c(Cl)c1)[C@@]4(O[C@@H](COc3ccc(N2CCN(C(C)C)CC2)cc3)CO4)Cn5ncnc5
  • InChI=1S/C26H31Cl2N5O3/c1-19(2)31-9-11-32(12-10-31)21-4-6-22(7-5-21)34-14-23-15-35-26(36-23,16-33-18-29-17-30-33)24-8-3-20(27)13-25(24)28/h3-8,13,17-19,23H,9-12,14-16H2,1-2H3/t23-,26-/m0/s1 Yes check.svgY
  • Key:BLSQLHNBWJLIBQ-OZXSUGGESA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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.

Contents

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. [1] It also shows effectiveness against dermatomycoses in animal models. [2]

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. [3] 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 mg vaginal suppository, taken three times overnight by 10 women. [4] 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. [5] The suppository is more effective after a long-term follow-up than terconazole as a cream or other intravaginal treatments. [6]

Side effects

The most common side effects of terconazole include headaches, vulvar/vaginal irritation, rash, itching, burning or discomfort. [7] 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 mg. [5] May cause birth defects if used in the first trimester. [8]

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. [9] Can be absorbed by embryo within the first trimester of pregnancy and cause birth defects. Cross inhibition shows that there may be some toxicity. [10]

Interactions

Terconazole may interact with the spermicide nonoxynol-9. A precipitate is formed upon combination of both drugs. Terconazole may weaken latex-based condoms. [11]

Chemistry

Terconazole is a triazole ketal with broad-spectrum antifungal/antimycotic tendencies.[ citation needed ]

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.

Terconazole synthesis: U.S. patent 4,144,346 U.S. patent 4,223,036 .mw-parser-output .citation{word-wrap:break-word}.mw-parser-output .citation:target{background-color:rgba(0,127,255,0.133)} DE 2804096 Terconazole synthesis.svg
Terconazole synthesis: U.S. patent 4,144,346 U.S. patent 4,223,036 DE 2804096  

Terconazole has the chemical formula C26H31Cl2N5O3. The chemical name for terconazole is 1-{[(2S,4S)-2-(2,4-dichlorophenyl)-4-{[p-(4-isopropyl-1-piperazinyl)phenoxy]methyl}-1,3-dioxolan-2-yl]methyl}-1H-1,2,4-triazole. Terconazole has a melting point of 126.3 °C (259.34 °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 °C (2372 °F) to give many different types of triazole derivatives. [13] 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. [14]

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. [15] 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. [16] 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. [17] This occurs by transforming lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-β-ol. This stops respiration by prohibiting reduction of 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. [18]

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. [19]

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. [20] Terconazole was the first triazole-based antifungal drug synthesized for human use. Janssen Pharmaceutica developed it in 1983. [21] 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. [13] It is still used as a treatment in cases of resistance to other drugs.[ citation needed ]

Available forms

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

Related Research Articles

<span class="mw-page-title-main">Candidiasis</span> Fungal infection due to any type of Candida

Candidiasis is a fungal infection due to any species of the genus Candida. When it affects the mouth, in some countries it is commonly called thrush. Signs and symptoms include white patches on the tongue or other areas of the mouth and throat. Other symptoms may include soreness and problems swallowing. When it affects the vagina, it may be referred to as a yeast infection or thrush. Signs and symptoms include genital itching, burning, and sometimes a white "cottage cheese-like" discharge from the vagina. Yeast infections of the penis are less common and typically present with an itchy rash. Very rarely, yeast infections may become invasive, spreading to other parts of the body. This may result in fevers, among other symptoms, depending on the parts involved.

Vaginitis, also known as vulvovaginitis, is inflammation of the vagina and vulva. Symptoms may include itching, burning, pain, discharge, and a bad smell. Certain types of vaginitis may result in complications during pregnancy.

<span class="mw-page-title-main">Antifungal</span> Pharmaceutical fungicide or fungistatic used to treat and prevent mycosis

An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as cryptococcal meningitis, and others. Such drugs are usually obtained by a doctor's prescription, but a few are available over the counter (OTC). The evolution of antifungal resistance is a growing threat to health globally.

<span class="mw-page-title-main">Ketoconazole</span> Antifungal chemical compound

Ketoconazole, sold under the brand name Nizoral among others, is an antiandrogen, antifungal, and antiglucocorticoid medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous candidiasis, pityriasis versicolor, dandruff, and seborrheic dermatitis. Taken by mouth it is a less preferred option and only recommended for severe infections when other agents cannot be used. Other uses include treatment of excessive male-patterned hair growth in women and Cushing's syndrome.

<span class="mw-page-title-main">Fluconazole</span> Antifungal medication

Fluconazole is an antifungal medication used for a number of fungal infections. This includes candidiasis, blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, dermatophytosis, and tinea versicolor. It is also used to prevent candidiasis in those who are at high risk such as following organ transplantation, low birth weight babies, and those with low blood neutrophil counts. It is given either by mouth or by injection into a vein.

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

Miconazole, sold under the brand name Monistat among others, is an antifungal medication used to treat ring worm, pityriasis versicolor, and yeast infections of the skin or vagina. It is used for ring worm of the body, groin, and feet. It is applied to the skin or vagina as a cream or ointment.

Azoles are a class of five-membered heterocyclic compounds containing a nitrogen atom and at least one other non-carbon atom as part of the ring. Their names originate from the Hantzsch–Widman nomenclature. The parent compounds are aromatic and have two double bonds; there are successively reduced analogs with fewer. One, and only one, lone pair of electrons from each heteroatom in the ring is part of the aromatic bonding in an azole. Names of azoles maintain the prefix upon reduction. The numbering of ring atoms in azoles starts with the heteroatom that is not part of a double bond, and then proceeds towards the other heteroatom.

<i>Nakaseomyces glabratus</i> Species of fungus

Nakaseomyces glabratus is a species of haploid yeast of the genus Nakaseomyces, previously known as Candida glabrata. Despite the fact that no sexual life cycle has been documented for this species, N. glabratus strains of both mating types are commonly found. C. glabrata is generally a commensal of human mucosal tissues, but in today's era of wider human immunodeficiency from various causes, N. glabratus is often the second or third most common cause of candidiasis as an opportunistic pathogen. Infections caused by N. glabratus can affect the urogenital tract or even cause systemic infections by entrance of the fungal cells in the bloodstream (Candidemia), especially prevalent in immunocompromised patients.

<span class="mw-page-title-main">Econazole</span> Antifungal medication

Econazole is an antifungal medication of the imidazole class.

<span class="mw-page-title-main">Posaconazole</span> Pharmaceutical drug

Posaconazole, sold under the brand name Noxafil among others, is a triazole antifungal medication.

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

Fenticonazole is an imidazole antifungal drug, used locally as the nitrate in the treatment of vulvovaginal candidiasis. It is active against a range of organisms including dermatophyte pathogens, Malassezia furfur, and Candida albicans. Fenticonazole has also been shown to exhibit antibacterial action, with a spectrum of activity that includes bacteria commonly associated with superinfected fungal skin and vaginal infections, and antiparasitic action against the protozoan Trichomonas vaginalis.

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

Butoconazole is an imidazole antifungal used in gynecology. It is administered as a vaginal cream.

<span class="mw-page-title-main">Sterol 14-demethylase</span> Class of enzymes

In enzymology, a sterol 14-demethylase (EC 1.14.13.70) is an enzyme of the cytochrome P450 (CYP) superfamily. It is any member of the CYP51 family. It catalyzes a chemical reaction such as:

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

Clotrimazole, sold under the brand name Lotrimin, among others, is an antifungal medication. It is used to treat vaginal yeast infections, oral thrush, diaper rash, tinea versicolor, and types of ringworm including athlete's foot and jock itch. It can be taken by mouth or applied as a cream to the skin or in the vagina.

<span class="mw-page-title-main">Vaginal yeast infection</span> Medical condition

Vaginal yeast infection, also known as candidal vulvovaginitis and vaginal thrush, is excessive growth of yeast in the vagina that results in irritation. The most common symptom is vaginal itching, which may be severe. Other symptoms include burning with urination, a thick, white vaginal discharge that typically does not smell bad, pain during sex, and redness around the vagina. Symptoms often worsen just before a woman's period.

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

Prochloraz, brand name Sportak, is an imidazole fungicide that was introduced in 1978 and is widely used in Europe, Australia, Asia, and South America within gardening and agriculture to control the growth of fungi. It is not registered for use in the United States. Similarly to other azole fungicides, prochloraz is an inhibitor of the enzyme lanosterol 14α-demethylase (CYP51A1), which is necessary for the production of ergosterol – an essential component of the fungal cell membrane – from lanosterol. The agent is a broad-spectrum, protective and curative fungicide, effective against Alternaria spp., Botrytis spp., Erysiphe spp., Helminthosporium spp., Fusarium spp., Pseudocerosporella spp., Pyrenophora spp., Rhynchosporium spp., and Septoria spp.

<i>Candida tropicalis</i> Species of fungus

Candida tropicalis is a species of yeast in the genus Candida. It is a common pathogen in neutropenic hosts, in whom it may spread through the bloodstream to peripheral organs. For invasive disease, treatments include amphotericin B, echinocandins, or extended-spectrum triazole antifungals.

<span class="mw-page-title-main">Ibrexafungerp</span> Medication

Ibrexafungerp, sold under the brand name Brexafemme, is an antifungal medication used to treat vulvovaginal candidiasis (VVC). It is taken orally. It is also currently undergoing clinical trials for other indications via an intravenous (IV) formulation. An estimated 75% of women will have at least one episode of VVC and 40 to 45% will have two or more episodes in their lifetime.

Topical antifungaldrugs are used to treat fungal infections on the skin, scalp, nails, vagina or inside the mouth. These medications come as creams, gels, lotions, ointments, powders, shampoos, tinctures and sprays. Most antifungal drugs induce fungal cell death by destroying the cell wall of the fungus. These drugs inhibit the production of ergosterol, which is a fundamental component of the fungal cell membrane and wall.

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

Oteseconazole, a novel orally bioavailable and selective inhibitor of fungal cytochrome P450 enzyme 51 (CYP51), has shown promising efficacy in the treatment of recurrent vulvovaginal candidiasis (RVVC) in patients.

References

  1. ↑ Tolman EL, Isaacson DM, Rosenthale ME, McGuire JL, Van Cutsem J, Borgers M, et al. (June 1986). "Anticandidal activities of terconazole, a broad-spectrum antimycotic". Antimicrobial Agents and Chemotherapy. 29 (6): 986–991. doi:10.1128/aac.29.6.986. PMC   180489 . PMID   3729366.
  2. ↑ Sood G, Nyirjesy P, Weitz MV, Chatwani A (2000). "Terconazole cream for non-Candida albicans fungal vaginitis: results of a retrospective analysis". Infectious Diseases in Obstetrics and Gynecology. 8 (5–6): 240–243. doi: 10.1155/S1064744900000351 . PMC   1784691 . PMID   11220485.
  3. ↑ Denison HJ, Worswick J, Bond CM, Grimshaw JM, Mayhew A, Gnani Ramadoss S, et al. (August 2020). "Oral versus intra-vaginal imidazole and triazole anti-fungal treatment of uncomplicated vulvovaginal candidiasis (thrush)". The Cochrane Database of Systematic Reviews. 2020 (8): CD002845. doi:10.1002/14651858.CD002845.pub3. PMC   8095055 . PMID   32845024.
  4. ↑ Slavin MB, Benrubi GI, Parker R, Griffin CR, Magee MJ (October 1992). "Single dose oral fluconazole vs intravaginal terconazole in treatment of Candida vaginitis. Comparison and pilot study". The Journal of the Florida Medical Association. 79 (10): 693–696. PMID   1460451.
  5. 1 2 Schmitt C, Sobel J, Meriwether C (September 1990). "Comparison of 0.8% and 1.6% terconazole cream in severe vulvovaginal candidiasis". Obstetrics and Gynecology. 76 (3 Pt 1): 414–416. PMID   2381618.
  6. ↑ Maibach HI, Farage MA, eds. (2006). "Vulvar Therapies: Evidence vs. Testimony. Fungal: Candidiasis.". The Vulva: Anatomy, Physiology and Pathology (1st ed.). New York: Informa Healthcare USA, Inc. pp. 128–129. ISBN   978-0-8493-3608-9.
  7. ↑ Workowski KA, Berman S (December 17, 2010). "Sexually Transmitted Diseases Treatment Guidelines, 2010. Vol. 59. No. RR-12" (PDF). USA Centers for Disease Control and Prevention. 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. Retrieved 10 July 2015.
  8. ↑ Faro S, Apuzzio J, Bohannon N, Elliott K, Martens MG, Mou SM, et al. (March 1997). "Treatment Considerations in Vulvovaginal Candidiasis". The Female Patient. 22 (1): 1–17.
  9. ↑ Mancano MA, Gallagher JC (2013). Frequently Prescribed Medications: Drugs You Need to Know (2nd ed.). Burlington, MA: Jones & Bartlett Learning. p. 312. ISBN   978-1-4496-9884-3.
  10. ↑ Melbourne Sexual Health Centre. "Vaginal thrush". Better Health Channer. State Government of Victoria. Archived from the original on 5 October 2015. Retrieved 10 July 2015.
  11. ↑ Grayson ML, Crowe SM, McCarthy JS, Mills J, Mouton JW, Norrby SR, Paterson DL, Pfaller MA, eds. (2010). Kucers' the Use of Antibiotics Sixth Edition: a Clinical Review of Antibacterial, Antifungal, Antiparasitic, and Antiviral Drugs (6th ed.). Boca Raton, FL: CRC Press. Taylor & Francis Group. pp. 1933–5. ISBN   978-0340927670.
  12. ↑ Heeres J, Hendrickx R, Van Cutsem J (April 1983). "Antimycotic azoles. 6. Synthesis and antifungal properties of terconazole, a novel triazole ketal". Journal of Medicinal Chemistry. 26 (4): 611–613. doi:10.1021/jm00358a032. PMID   6834396.
  13. 1 2 Cauwenbergh G, Vanden Bossche H (August 1989). "Terconazole. Pharmacology of a new antimycotic agent". The Journal of Reproductive Medicine. 34 (8 Suppl): 588–592. PMID   2677363.
  14. ↑ Fromtling RA (April 1988). "Overview of medically important antifungal azole derivatives". Clinical Microbiology Reviews. 1 (2): 187–217. doi:10.1128/CMR.1.2.187. PMC   358042 . PMID   3069196.
  15. ↑ Yoshida Y (1988). "Cytochrome P450 of Fungi: Primary Target for Azole Antifungal Agents". Current Topics in Medical Mycology. Vol. 2. pp. 388–418. doi:10.1007/978-1-4612-3730-3_11. ISBN   978-1-4612-8323-2. PMID   3288361.
  16. ↑ Isaacson DM, Tolman EL, Tobia AJ, Rosenthale ME, McGuire JL, Vanden Bossche H, et al. (March 1988). "Selective inhibition of 14 alpha-desmethyl sterol synthesis in Candida albicans by terconazole, a new triazole antimycotic". The Journal of Antimicrobial Chemotherapy. 21 (3): 333–343. doi:10.1093/jac/21.3.333. PMID   3129389.
  17. ↑ "C-4 Methylsterol Oxidase Activity". Saccharomyces Genome Database. Stanford University, Stanford, CA 94305. Retrieved 10 July 2015.
  18. ↑ Sobel JD (1994). "Mini Review. Candida Vaginitis". Infectious Diseases in Clinical Practice. 3 (5): 334–339. doi: 10.1097/00019048-199409000-00002 . S2CID   220575082.
  19. ↑ Sheehan DJ, Hitchcock CA, Sibley CM (January 1999). "Current and emerging azole antifungal agents". Clinical Microbiology Reviews. 12 (1): 40–79. doi:10.1128/cmr.12.1.40. PMC   88906 . PMID   9880474.
  20. ↑ Maertens JA (March 2004). "History of the development of azole derivatives". Clinical Microbiology and Infection. 10 (Suppl 1): 1–10. doi: 10.1111/j.1470-9465.2004.00841.x . PMID   14748798.
  21. ↑ Heeres J, Hendrickx R, Van Cutsem J (April 1983). "Antimycotic azoles. 6. Synthesis and antifungal properties of terconazole, a novel triazole ketal". Journal of Medicinal Chemistry. 26 (4): 611–613. doi:10.1021/jm00358a032. PMID   6834396.
  22. ↑ Mosby (2012). "Terconazole". In White K, Watrous J (eds.). Mosby's Drug Reference for Health Professions (3rd ed.). St. Louis, Missouri: Elsevier. pp. 1558–1559. ISBN   978-0-323-09574-7.
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