(+)-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: 2024-11-21 17:11:28
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) |
Exclamation Mark Irritant GHS07 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 |
Abamectin manufacturer
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