Griseofulvin production

In 1939, the isolation of griseofulvin from mycelia of Penicillium griseofulvum was reported [1], This compound has the empirical formula C17H17CIO6 and Grove et al. [2] determined its structure 1 in 1952. Fermentation conditions for griseofulvin production have appeared infrequently in the scientific literature, because this substance is of great economic importance. It is one of the few antifungal compounds that are... 

The optimum chloride concentration for optimal griseofulvin production was found to be 0.001-0.05 % KC1 [15]. Fe2+ shows a specific effect on the formation of mycelianamide, a second compound, which is considered as interfering substance. By a proper strain selection and by keeping FeS04 content in the media at 0.1% the formation of mycelianamide was eliminated [16]. 

In 450 liter batch fermentation medium [9] containing (in g/1) com steep liquor (2), lactose (70), CaC03 (8), K2HPO4 (4) and KC1 (1), the maximum production by the P. patulum mutant was about 1500 pg/ml. A significant improvement in the fermentation technology of griseofulvin production was realized with the introduction of the fed batch process described by Hockenhull [19]. A yield of 6000 pg/ml of griseofulvin was obtained after a 220-h cultivation. 

Figure 9.17 compares the mean plasma concentration of griseofulvin at 30 min with the dissolution rate in vitro at 30 min in simulated intestinal fluid for four griseofulvin products. 

Rhodes, A. Griseofulvin Production and biosynthesis. Progr. Ind. Microbiol. 4, 167 (1963). 

The combined pharmaceutical appHcations account for an estimated 25% of DMF consumption. In the pharmaceutical industry, DMF is used in many processes as a reaction and crystallizing solvent because of its remarkable solvent properties. For example, hydrocortisone acetate [50-03-3] dihydrostreptomycin sulfate [5490-27-7] and amphotericin A [1405-32-9] are pharmaceutical products whose crystallization is faciHtated by the use of DMF. Itis also a good solvent for the fungicide griseofulvin/72%(97-< 7 and is used in its production. 

Griseofulvin is listed in the following compendia The United States Pharmacopia (1) The British Pharmacoepia (2) The Europeon Pharmacoepia (3) and the Merck Index (4). A previously published review (5) is a good source for physical and chemical data, production, use, occurrence and biological information. 

Griseofulvin was first isolated in 1938 by Oxford (10) et. al., (1939) its total synthesis was accomplished in 1960 and following years in several laboratories (Brossi et al., 1960 (11) Grove, 1963 (12) Mutant strains of P. patulum are used for the commercial production of the antibiotic by fermentation (9). 

Essentially the same sort of enolate anion aldol and Claisen reactions occur in the production of the more complex structures mycophenolic acid, griseofulvin, and tetracycline. However, the final structure is only obtained after a series of further modifications. 

The antifungal agent griseofulvin in plasma (318) in plasma concentrations of 50 ng/ml could be measured using 10-ftl samples. The bac-teriostat, 3,4,4 -trichk>rocarbanilide, and its metabolic products have been determined subsequent to a single-step sample cleanup 1319). The trichomonacide metronidazole, misonidazole, and their metabolites have been analyzed from serum and urine samples with similar sensitivity (320). 

Absorption from the gastrointestinal tract can be affected by other drugs and by food. Aluminum, calcium, and magnesium ions in antacids or dairy products form insoluble chelates with all tetracyclines and inhibit their absorption. Food inhibits tetracycline absorption but enhances doxycycline absorption food delays but does not diminish metronidazole absorption fatty food enhances griseofulvin absorption. 

Griseofulvin is successfully transformed to 5-fluorogriseofulvin (as the major product) and 3,5-difluorogriseofulvin,62 while in the fluorination of ethyl TV-acetyl-L-tyrosinate at —22 C in chloroform, an addition process to the aromatic ring to give 38 is observed.22... 

Numerous examples of natural products with the benzo[6]furan nucleus have been identified. It occurs under many guises dibenzofurans, /3-coumaranones, a-pyranobenzo[6]furans, y-pyranobenzo[6]furans, and the spiro-2,3-dihydrobenzofurans such as griseofulvin. Many of the natural benzo[6]furans have physiological, pharmacological and toxic properties and as a result an active interest exists in their chemical synthesis. 

In contrast to the well documented conjugate addition of carbon nucleophiles to activated alkenes, similar intermolecular attempts with activated alkynes with non-cuprate reactants are typically non-productive due to competing multiple addition processes.87 6 However, protic intramolecular conjugate additions of ketones as shown for the syntheses of griseofulvin and hirsutic acid,222 are successful. Recently, several aprotic intramolecular conjugate additions to activated alkynes have been reported, as... 

Griseofulvin interferes with porphyrin metabolism. In man, transient increases in erythrocyte protoporphyrin concentrations have been demonstrated, and the production and excretion of porphyrins is increased. Acute intermittent porphyria is an absolute contraindication to griseofulvin. In patients with other forms of porphyria it should also be avoided, in view of the many alternatives (458-463). 

Cytoskeletal elements may also be involved in mediating the effects of prolactin on the mammary gland. Colchicine, which disrupts intracellular microtubules, completely blocks the effect of prolactin on casein mRNA production [86]. However, griseofulvin, another microtubule-disrupting drug, has no such effect. 

Chattopadhyay, P. Gupta, R.B. Production of griseofulvin nanoparticles using supercritical CO2 antisolvent with enhanced mass transfer. Int. J. Pharm. 2001, 228 (1-2), 19-31. 

Oxford AE, Raistrick H, Simonart P. Studies in the biochemistry of microorganisms Griseofulvin, C17H1706C1, a metabohc product of Penicilhum griseofulvum. Biochem J 1939 33 240-8. 

The range of substances over which there is pharmacopoeial control of particle size is shown in Table 1.7 sometimes the aim is to achieve uniformity in a product rather than any direct benefit. The control exercised over the particle size of cortisone acetate and griseofulvin is due to their very low solubility the experience is that if the solubility of a dmg substance is about 0.3% or less then the dissolution rate in vivo may be the rate-controlling step in absorption. 

Griseofulvin is exclusively active against dermatophytes, through inhibition of cellular mitosis. It also binds to host cell keratin and reduces its degradation by fungal keratinases. It may also interfere with dermatophyte DNA production. 

Gallagher PM, Coffey MP, Krukonis VJ, Klasutis N. Gas anti-solvent recrystallization new process to recrystallize compounds insoluble in supercritical fluids. In Johnston KP, Penniger JML, eds. Supercritical Fluid Science and Technology. Washington, DC American Chemical Society, 1989 334-354. Dixon D, Johnston KP, Bodmeier R. Polymeric materials formed by precipitation with a compressed fluid antisolvent. AIChE J 1993 39 127-136. Chattopadhyay P, Gupta RB. Production of griseofulvin nanoparticles using supercritical CO2 antisolvent with enhanced mass transfer. Int J Pharm 2001 228 19-31. 

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