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HomeProduct name list(+)-Griseofulvin

(+)-Griseofulvin

Synonym(s):(2S)-trans-7-Chloro-2′,4,6-trimethoxy-6′-methylspiro(benzofuran-2[3H],1′-[2]cyclohexene)-3,4′-dione;Griseofulvin

  • CAS NO.:126-07-8
  • Empirical Formula: C17H17ClO6
  • Molecular Weight: 352.77
  • MDL number: MFCD00082343
  • EINECS: 204-767-4
  • SAFETY DATA SHEET (SDS)
  • Update Date: 2024-11-04 20:04:50
(+)-Griseofulvin Structural

What is (+)-Griseofulvin?

Absorption

Poorly absorbed from GI ranging from 25 to 70% of an oral dose. Absorption is significantly enhanced by administration with or after a fatty meal.

Toxicity

Side effects are minor: headaches, gastrointestinal reactions and cutaneous eruptions.

Description

Griseofulvin (126-07-8) is an antifungal antimitotic agent. Induces apoptosis of human germ cell tumor cells via disruption of connexin 43/tubulin association concomitant with enhanced translocation of connexin 43 from the cytoplasm to the nucleus.1?Inhibits the growth of adrenocortical cancer cells?in vitro.2 Griseofulvin inhibits centrosome clustering, induces spindle multipolarity, mitotic arrest and cell death in multiple tumor cell lines but not in diploid fibroblasts and keratinocytes with normal centrosome content.3

Chemical properties

Crystalline Solid

Originator

Grifulvin,McNeil,US,1959

The Uses of (+)-Griseofulvin

It is an antifungal drug. It is used both in animal and in humans, to treat rigworm infections of the skin and nails. It is derived from the mold Penicillium griseofulvum.Environmental contaminants; Food contaminants.

The Uses of (+)-Griseofulvin

adrenegic blocker, Ca channel blocker, coronary vasodilator, antiarrhythmic

The Uses of (+)-Griseofulvin

antifungal, inhibits mitosis in metaphase

The Uses of (+)-Griseofulvin

Griseofulvin is a spirobenzofuran produced by a number of Penicillium species, first isolated in the 1930s by Raistrick's group. Griseofulvin is a selective antifungal agent used to treat skin infections in animals and humans. Griseofulvin acts by binding to fungal tubulin and inhibiting the mitotic spindle. Griseofulvin's ability to bind to keratin is considered an important aspect of the metabolite's access to dermatophytic fungi. More recently, griseofulvin has become an important phenotypic marker in Penicillium taxonomy.

The Uses of (+)-Griseofulvin

An antifungal and antiproliferative agent that affects microtubules.

Indications

For the treatment of ringworm infections of the skin, hair, and nails, namely: tinea corporis, tinea pedis, tinea cruris, tinea barbae, cradle cap or other conditions caused by Trichophyton or Microsporum fungi.

Background

An antifungal antibiotic. Griseofulvin may be given by mouth in the treatment of tinea infections.

What are the applications of Application

Griseofulvin is an antifungal and antiproliferative agent that affects microtubules

Definition

ChEBI: An oxaspiro compound produced by Penicillium griseofulvum. It is used by mouth as an antifungal drug for infections involving the scalp, hair, nails and skin that do not respond to topical treatment.

Indications

Griseofulvin (Fulvicin, Grifulvin V) has been used safely and effectively for decades for dermatophyte infections of scalp and nails and for more widespread skin eruptions. However, infections in certain sites (e.g.. toenails) respond poorly. The drug is generally well tolerated, even in the long-term courses necessary for nail disease.

Indications

Griseofulvin (Gris-PEG, Grifulvin, Grisactin, Fulvicin) is an oral fungistatic agent used in the long-term treatment of dermatophyte infections caused by Epidermophyton, Microsporum, and Trichophyton spp. Produced by the mold Penicillium griseofulvin, this agent inhibits fungal growth by binding to the microtubules responsible for mitotic spindle formation, leading to defective cell wall development.
Ineffective topically, griseofulvin is administered orally but has poor gastrointestinal absorption; absorption can be improved by microcrystalline processing of the drug and by taking the drug with fatty meals. Peak serum levels occur 4 hours after dosing. Griseofulvin is metabolized in the liver and has a half-life of 24 to 36 hours. The drug binds to keratin precursor cells and newly synthesized keratin in the stratum corneum of the skin, hair, and nails, stopping the progression of dermatophyte infection.

Manufacturing Process

The experiment was carried out on the 1,000 gallon scale. Three impellers 1'8" diameter at 220 rpm were employed. The air rates were 0 to 5 hours, 40 cfm, 5 to 10 hours, 80 cfm and after 10 hours, 125 cfm. The inoculum rate was 10% v/v. It was prepared by the standard inoculum development technique on the following medium:
This was inoculated with a spore suspension of P. patulurn (1 liter containing 3-5 x 107 spores/ml) and grown at 25°C in 100 gallon tank. The inoculum is transferred at 40 hours or when the mycelial volume (after spinning 10 minutes at 3,000 rpm) exceeds 25%. The fermentation is conducted as near to the ideal pH curve as possible by addition of crude glucose, according to US Patent 3,069,328.

brand name

Fulvicin Bolus [Veterinary] (Schering-Plough Animal Health); Fulvicin-P/G (Schering); Fulvicin-U/F (Schering); Fulvicin-U/F Powder and Tablets [Veterinary] (Schering-Plough Animal Health); Grifulvin V (Ortho Pharmaceutical); Grisactin (Wyeth- Ayerst); Gris-PEG (Allergan Herbert);B-gf;Delmofluvina;Flugolin;Fulcine-125;Fulcine-s;Fulvicin p/g;Fulvicin u/f;Fulvicina;Gefulvine;Grfulvin v;Grisaltin;Grisefalin;Grisefulvin;Griseomed;Griseostatin;Grisovina fp;Grisovine;Grisovin-fp;Grisowen;Lamoryl-novum;Lamoyl;Likuden m;Microcidal;Neo fulcin;Neo-filcin;Norofluvin;Ocufen;Sulvina.

Therapeutic Function

Antifungal

World Health Organization (WHO)

Griseofulvin, isolated from a penicillin producing mould, has been widely used as a systemically administered antifungal agent in man for over 20 years. It is effective in dermatophyte infections (including tinea barbae and tinea capitis) but it is inactive against yeasts and bacteria. Evidence that very high doses of griseofulvin are carcinogenic, teratogenic and fetotoxic in laboratory animals has led to an acceptance that it should not be used to treat trivial infections that respond to topical therapy. Oral formulations of griseofulvin are included in the WHO Model List of Essential Drugs. (Reference: (WHTAC1) The Use of Essential Drugs, 2nd Report of the WHO Expert Committee, 722, , 1985)

Antimicrobial activity

The spectrum of useful activity is restricted to dermatophytes causing skin, nail and hair infections (Epidermophyton, Microsporum and Trichophyton spp.). Resistance has seldom been reported.

General Description

White to pale cream-colored crystalline powder. Odorless or almost odorless. Tasteless. Sublimes without decomposition at 410°F.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

(+)-Griseofulvin is incompatible with strong oxidizing agents. .

Hazard

Possible carcinogen.

Fire Hazard

Flash point data for (+)-Griseofulvin are not available. (+)-Griseofulvin is probably combustible.

Pharmaceutical Applications

A fermentation product of various species of Penicillium, including Pen. griseofulvum. Available as fine-particle or ultrafine- particle formulations for oral use.

Mechanism of action

The mechanism of action of griseofulvin is through binding to the protein tubulin, which interferes with the function of the mitotic spindle and, thereby, inhibits cell division. Griseofulvin also may interfere directly with DNA replication. Griseofulvin is gradually being replaced by newer agents .

Pharmacokinetics

Griseofulvin is a mycotoxic metabolic product of Penicillium spp. It was the first available oral agent for the treatment of dermatophytoses and has now been used for more than forty years. Griseofulvin is fungistatic with in vitro activity against various species of Microsporum Epidermophyton, and Trichophyton. It has no effect on bacteria or on other genera of fungi. Following oral administration, griseofulvin is deposited in the keratin precursor cells and has a greater affinity for diseased tissue. The drug is tightly bound to the new keratin which becomes highly resistant to fungal invasions. Once the keratin-Griseofulvin complex reaches the skin site of action, it binds to fungal microtubules (tubulin) thus altering fungal mitosis.

Pharmacokinetics

Absorption from the gastrointestinal tract is dependent on drug formulation. Administration with a high-fat meal will increase the rate and extent of absorption, but individuals tend to achieve consistently high or low blood concentrations. It appears in the stratum corneum within 4–8 h as a result of secretion in perspiration. However, levels begin to fall soon after the drug is discontinued, and within 48–72 h it can no longer be detected. It is metabolized in the liver, the metabolites being excreted in the urine. The elimination half-life is 9–21 h.

Clinical Use

Dermatophyte infections of hair, skin and nail

Clinical Use

In the treatment of ringworm of the beard, scalp, and other skin surfaces, 4 to 6 weeks of therapy is often required. Therapy failure may be to the result of an incorrect diagnosis; superficial candidiasis, which may resemble a dermatophyte infection, does not respond to griseofulvin treatment. Onychomycosis responds very slowly to griseofulvin (1 year or more of treatment is commonly required) and cure rates are poor; itraconazole and terbinafine hydrochloride are more effective than griseofulvin for onychomycosis.

Side Effects

Adverse reactions occur in about 15% of patients and include headache, nausea, vomiting, rashes and photosensitivity.

Side Effects

Griseofulvin is usually well tolerated. Headache is common with initiation of therapy. Hepatotoxicity (especially in patients with acute intermittent porphyria), dermatitis, and gastrointestinal distress also occur. Griseofulvin increases warfarin metabolism, and griseofulvin metabolism is increased by phenobarbital.

Synthesis

Griseofulvin, 7-chloro-2,4,6-trimethoxy-6-methylspiro[benzofuran- 2(3H),1-[2]-cyclohexen]-3,4-dione (35.4.1), is an antibiotic produced by the mycelial fungus Penicillium patulum.

Veterinary Drugs and Treatments

In veterinary species, griseofulvin is approved for use in dogs and cats to treat dermatophytic fungal (see below) infections of the skin, hair and claws, and to treat ringworm (caused by T. equinum and M. gypseum) in horses. It has also been used in laboratory animals and ruminants for the same indications. The oral tablets approved for dogs and cats are no longer marketed in the USA, but human dosage forms are available.

Drug interactions

Potentially hazardous interactions with other drugs
Anticoagulants: metabolism of coumarins accelerated (reduced anticoagulant effect).
Ciclosporin: griseofulvin possibly reduces ciclosporin concentration (two reports of such an interaction in literature).
Oestrogens and progestogens: metabolism of oral contraceptives accelerated (reduced contraceptive effect).
Ulipristal: possibly reduced contraceptive effect - avoid.

Metabolism

Primarily hepatic with major metabolites being 6-methyl-griseofulvin and its glucuronide conjugate.

Metabolism

Griseofulvin is metabolized by the liver, and its metabolites are excreted in the urine. It is highly protein bound and, therefore, may have high tissue levels. However, tissue levels decrease and fall as soon as griseofulvin is discontinued such that its presence is no longer detectable 2 to 3 days after cessation of therapy.

Purification Methods

Crystallise it from *benzene or EtOH. Purify 2g of griseofulvin by chromatography on Alumina (40 x 1.5cm) and elute with *C6H6/MeOH (199:1) and follow the UV blue fluorescent band. [MacMillan J Chem Soc 1823 1959, Beilstein 18 III/IV 3160, 18/5 V 150.]

Dosage forms

The average treatment time for tinea capitis is 4 to 6 weeks; for tinea corporis, 2 to 4 weeks; and for tinea pedis, 4 to 8 weeks. Because of the low cure rate and length of therapy, griseofulvin is not commonly used for onychomycosis of the fingernails or toenails. Complete blood count (CBC) is monitored every 3 months during long-term therapy.

References

1) Mauro?et al. (2013),?The anti-mitotic drug griseofulvin induces apoptosis of human germ cell tumor cells through a connexin 43-dependent molecular mechanism; Apoptosis,?18?480 2) Bramann?et al. (2013),?Griseofulvin inhibits the growth of adrenocortical cancer cells in vitro; Horm. Metab. Res.,?45?297 3) Rebacz?et al. (2007),?Identification of griseofulvin as an inhibitor of centrosomal clustering in a phenotype-based screen; Cancer Res., 67?6342

Properties of (+)-Griseofulvin

Melting point: 218-220 °C(lit.)
Boiling point: 469.04°C (rough estimate)
alpha  354 º (c=1, dimethylform)
Density  1.2579 (rough estimate)
refractive index  1.4429 (estimate)
storage temp.  2-8°C
solubility  Practically insoluble in water, freely soluble in dimethylformamide and in tetrachloroethane, slightly soluble in anhydrous ethanol and in methanol
form  Powder
color  White to yellow-white
Water Solubility  practically insoluble
λmax 321nm(CHCl3)(lit.)
Merck  14,4549
BRN  95226
Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO, ethanol, or DMF may be stored at -20° for up to 3 months.
CAS DataBase Reference 126-07-8(CAS DataBase Reference)
IARC 2B (Vol. Sup 7, 79) 2001
NIST Chemistry Reference Griseofulvin(126-07-8)
EPA Substance Registry System Griseofulvin (126-07-8)

Safety information for (+)-Griseofulvin

Signal word Danger
Pictogram(s)
ghs
Exclamation Mark
Irritant
GHS07
ghs
Health Hazard
GHS08
GHS Hazard Statements H317:Sensitisation, Skin
H351:Carcinogenicity
Precautionary Statement Codes P202:Do not handle until all safety precautions have been read and understood.
P261:Avoid breathing dust/fume/gas/mist/vapours/spray.
P272:Contaminated work clothing should not be allowed out of the workplace.
P280:Wear protective gloves/protective clothing/eye protection/face protection.
P302+P352:IF ON SKIN: wash with plenty of soap and water.
P308+P313:IF exposed or concerned: Get medical advice/attention.

Computed Descriptors for (+)-Griseofulvin

InChIKey DDUHZTYCFQRHIY-RBHXEPJQSA-N

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