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词条 Griseofulvin
释义

  1. Medical uses

  2. Side effects

  3. Mechanism

  4. Biosynthetic process

  5. References

  6. External links

{{Drugbox
| Watchedfields = changed
| verifiedrevid = 459852842
| IUPAC_name = (2S,6'R)- 7-chloro- 2',4,6-trimethoxy- 6'-methyl- 3H,4'H-spiro [1-benzofuran- 2,1'-cyclohex[2]ene]- 3,4'-dione
| image = Griseofulvin.svg
| image2 = Griseofulvin 3D.png
| tradename = Gris-peg, Grifulvin V, others
| Drugs.com = {{drugs.com|monograph|griseofulvin}}
| MedlinePlus = a682295
| pregnancy_AU = B3
| pregnancy_US = C
| legal_UK = POM
| legal_US = Rx-only
| routes_of_administration = by mouth
| bioavailability = Highly variable (25 to 70%)
| metabolism = liver (demethylation and glucuronidation)
| elimination_half-life = 9–21 hours
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 126-07-8
| ATC_prefix = D01
| ATC_suffix = AA08
| ATC_supplemental = {{ATC|D01|BA01}}
| PubChem = 441140
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00400
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 389934
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 32HRV3E3D5
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00209
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 27779
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 562
| C=17 | H=17 | Cl=1 | O=6
| molecular_weight = 352.766 g/mol
| SMILES = O=C2c3c(O[C@@]21C(/OC)=C\\C(=O)C[C@H]1C)c(Cl)c(OC)cc3OC
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C17H17ClO6/c1-8-5-9(19)6-12(23-4)17(8)16(20)13-10(21-2)7-11(22-3)14(18)15(13)24-17/h6-8H,5H2,1-4H3/t8-,17+/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = DDUHZTYCFQRHIY-RBHXEPJQSA-N
}}Griseofulvin is an antifungal medication used to treat a number of types of dermatophytoses (ringworm).[1] This includes fungal infections of the nails and scalp, as well as the skin when antifungal creams have not worked.[2] It is taken by mouth.[1]

Common side effects include allergic reactions, nausea, diarrhea, headache, trouble sleeping, and feeling tired.[1] It is not recommended in people with liver failure or porphyria.[1] Use during or in the months before pregnancy may result in harm to the baby.[1][2] Griseofulvin works by interfering with fungal mitosis.[1]

Griseofulvin was discovered in 1939 from a type of Penicillium mold.[3][4] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[5] The wholesale cost in the developing world is about US$0.05–0.18 per day.[6] In the United States a course of treatment costs $100–200.[7]

Medical uses

Griseofulvin is used orally only for dermatophytosis. It is ineffective topically. It is reserved for cases with nail, hair, or large body surface involvement.[8]

Terbinafine given for 2 to 4 weeks is at least as effective as griseofulvin given for 6 to 8 weeks for treatment of Trichophyton scalp infections. However, griseofulvin is more effective than terbinafine for treatment of Microsporum scalp infections.[9][10]

Side effects

Known side effects of griseofulvin include:

  • Can reduce the effectiveness of oral contraceptives as it is a cytochrome P450 enzyme inducer
  • Confusion
  • Considered unsafe for those with porphyria
  • Diarrhea
  • Dizziness
  • Fatigue
  • Headache
  • Urticaria
  • Impairment of performance of routine activities{{clarify|date=August 2015}}
  • Impairment of liver enzymatic activity
  • Insomnia
  • Itching
  • Loss of taste sensation{{clarify|date=August 2015}}
  • Nausea
  • Oral thrush (yeast infection of the mouth)
  • Mutagen
  • Sensitivity to alcohol, with a disulfiram-like reaction
  • Phototoxicity
  • Skin rashes
  • Stevens–Johnson syndrome
  • Swelling
  • Paresthesia
  • Upper abdominal pain

Mechanism

The drug binds to tubulin, interfering with microtubule function, thus inhibiting mitosis.

It binds to keratin in keratin precursor cells and makes them resistant to fungal infections. The drug reaches its site of action only when hair or skin is replaced by the keratin-griseofulvin complex. Griseofulvin then enters the dermatophyte through energy-dependent transport processes and bind to fungal microtubules. This alters the processing for mitosis and also underlying information for deposition of fungal cell walls.

Biosynthetic process

It is produced industrially by fermenting the fungus Penicillium griseofulvum.[11][12][13]

The first step in the biosynthesis of griseofulvin by P. griseofulvin is the synthesis of the 14-carbon poly-β-keto chain by a type I iterative polyketide synthase (PKS) via iterative addition of 6 malonyl-CoA to an acyl-CoA starter unit. The 14-carbon poly-β-keto chain undergoes cyclization/aromatization, using cyclase/aromatase, respectively, through a Claisen and aldol condensation to form the benzophenone intermediate. The benzophenone intermediate is then methylated via S-adenosyl methionine (SAM) twice to yield griseophenone C. The griseophenone C is then halogenated at the activated site ortho to the phenol group on the left aromatic ring to form griseophenone B. The halogenated species then undergoes a single phenolic oxidation in both rings forming the two oxygen diradical species. The right oxygen radical shifts alpha to the carbonyl via resonance allowing for a stereospecific radical coupling by the oxygen radical on the left ring forming a tetrahydrofuranone species.[14] The newly formed grisan skeleton with a spiro center is then O-methylated by SAM to generate dehydrogriseofulvin. Ultimately, a stereoselective reduction of the olefin on dehydrogriseofulvin by NADPH affords griseofulvin.[15][16]

References

1. ^1 2 3 4 5 {{cite web|title=Griseofulvin|url=https://www.drugs.com/monograph/griseofulvin.html|publisher=The American Society of Health-System Pharmacists|accessdate=8 December 2016|deadurl=no|archiveurl=https://web.archive.org/web/20161220231300/https://www.drugs.com/monograph/griseofulvin.html|archivedate=20 December 2016|df=}}
2. ^1 {{cite book|title=WHO Model Formulary 2008|date=2009|publisher=World Health Organization|isbn=9789241547659|page=149|url=http://apps.who.int/medicinedocs/documents/s16879e/s16879e.pdf|accessdate=8 December 2016|deadurl=no|archiveurl=https://web.archive.org/web/20161213060118/http://apps.who.int/medicinedocs/documents/s16879e/s16879e.pdf|archivedate=13 December 2016|df=}}
3. ^{{cite book|last1=Block|first1=Seymour Stanton|title=Disinfection, Sterilization, and Preservation|date=2001|publisher=Lippincott Williams & Wilkins|isbn=9780683307405|page=631|url=https://books.google.ca/books?id=3f-kPJ17_TYC&pg=PA631|language=en|deadurl=no|archiveurl=https://web.archive.org/web/20161220092415/https://books.google.ca/books?id=3f-kPJ17_TYC&pg=PA631|archivedate=2016-12-20|df=}}
4. ^{{cite book|author1=Michael Ash|author2=Irene Ash|title=Handbook of Preservatives|url=https://books.google.com/books?id=XZ2QB7bu5LwC&pg=PA406|year=2004|publisher=Synapse Info Resources|isbn=978-1-890595-66-1|pages=406|deadurl=no|archiveurl=https://web.archive.org/web/20131231115328/http://books.google.com/books?id=XZ2QB7bu5LwC&pg=PA406|archivedate=2013-12-31|df=}}
5. ^{{cite web|title=WHO Model List of Essential Medicines (19th List)|url=http://www.who.int/medicines/publications/essentialmedicines/EML_2015_FINAL_amended_NOV2015.pdf?ua=1|work=World Health Organization|accessdate=8 December 2016|date=April 2015|deadurl=no|archiveurl=https://web.archive.org/web/20161213052708/http://www.who.int/medicines/publications/essentialmedicines/EML_2015_FINAL_amended_NOV2015.pdf?ua=1|archivedate=13 December 2016|df=}}
6. ^{{cite web|title=Griseofulvin|url=http://mshpriceguide.org/en/single-drug-information/?DMFId=381&searchYear=2014|website=International Drug Price Indicator Guide|accessdate=8 December 2016}}
7. ^{{cite book|last1=Hamilton|first1=Richart|title=Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition|date=2015|publisher=Jones & Bartlett Learning|isbn=9781284057560|page=44}}
8. ^{{cite book|last=Tripathi|title=Textbook of Pharmacology|publisher=Jaypee Brothers|isbn=81-8448-085-7|pages=761–762|url=http://jaypeebrothers.com|deadurl=no|archiveurl=https://web.archive.org/web/20170603211336/https://www.jaypeebrothers.com/|archivedate=2017-06-03|df=}}
9. ^{{cite journal |vauthors=Fleece D, Gaughan JP, Aronoff SC |title=Griseofulvin versus terbinafine in the treatment of tinea capitis: a meta-analysis of randomized, clinical trials |journal=Pediatrics |volume=114 |issue=5 |pages=1312–5 |date=November 2004 |pmid=15520113 |doi=10.1542/peds.2004-0428 |url=}}
10. ^{{cite journal |vauthors=Chen X, Jiang X, Yang M, González U, Lin X, Hua X, Xue S, Zhang M, Bennett C |title=Systemic antifungal therapy for tinea capitis in children |journal=Cochrane Database Syst Rev |volume= |issue=5 |pages=CD004685 |date=May 2016 |pmid=27169520 |doi=10.1002/14651858.CD004685.pub3 |url=}}
11. ^{{cite journal|url=http://www.biochemj.org/content/33/2/240|title=Studies in the biochemistry of micro-organisms: Griseofulvin, C17H17O6Cl, a metabolic product of Penicillium griseo-fulvum Dierckx|first1=Albert Edward|last1=Oxford|first2=Harold|last2=Raistrick|first3=Paul|last3=Simonart|date=1 February 1939|publisher=|journal=Biochemical Journal|volume=33|issue=2|pages=240–248|via=www.biochemj.org|doi=10.1042/bj0330240|pmid=16746904}}
12. ^J.F. Grove, D. Ismay, J. Macmillan, T.P.C. Mulholland, M.A.T. Rogers, Chem. Ind. (London), 219 (1951).
13. ^{{Cite journal | doi = 10.1039/JR9520003977| title = 762. Griseofulvin. Part IV. Structure| journal = Journal of the Chemical Society (Resumed)| pages = 3977| year = 1952| last1 = Grove | first1 = J. F. | last2 = MacMillan | first2 = J.| last3 = Mulholland | first3 = T. P. C.| last4 = Rogers | first4 = M. A. T. }}
14. ^{{cite journal|last=Birch|first=Arthur|title=Studies in relation to biosynthesis I. Some possible routes to derivatives of orcinol and phloroglucinol|journal=Australian Journal of Chemistry|date= 1953|volume=6|issue=4|pages=360|doi=10.1071/ch9530360}}
15. ^{{cite book|last=Dewick|first=Paul M.|title=Medicinal Natural Products: A Biosynthetic Approach (3rd ed.)|year=2009|publisher=John Wiley & Sons Ltd|location=UK|isbn=0-471-97478-1}}
16. ^{{cite journal|last=Harris|first=Constance|title=Biosynthesis of Griseofulvin|journal=Journal of the American Chemical Society|date= 1976|volume=98|issue=17|pages=5380–5386|doi=10.1021/ja00433a053 }}

External links

  • [https://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a682295.html Griseofulvin (Medline Plus)]
  • dermnetnz Mentions alcohol, contraceptive interactions
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