Isotretinoin Vitamin

Retinoic acid (RA) describes a group of vitamin A acid (synonym Vitamin A1 acid) derivatives such as all-irans-retinoic acid (tretinoin), 9-cis-retinoic acid and 13-cis retinoic acid (isotretinoin). Retinoic acids act through binding to retinoic acid and retinoid X response elements. 

The answer is d. (Hardman, p 1575.) Isotretinoin is actually a form of high-dose vitamin A therapy Vitamin A itself or retinol (vitamin A could be used, but they have less advantageous pharmacokinetic properties. Antibiotics such as tetracyclines are used in acne, but they have little effect on the nodulocystic form... 

Spontaneous reports of osteoporosis, osteopenia, bone fractures, and delayed healing of bone fractures have been seen in the isotretinoin population. While causality to isotretinoin has not been established, an effect cannot be ruled out. Physicians should use caution when prescribing isotretinoin to patients with a genetic predisposition for age-related osteoporosis, a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic corticosteroids and any anticonvulsants. 

There are many retinol containing preparations to treat vitamin deficiency states. Retinoids are also used to treat dermatological diseases like acne, psoriasis, Darier s disease, and ichthyosis. Tretinoin, all-trans-retinoic acid, is a topical preparation while isotretinoin or 13-cis-retinoic acid, and etretinate are available for oral administration. 

The past twenty years have witnessed considerable progress in the synthesis and use of other retinoid-like molecules related to vitamin A. The aromatic retinoid etretin (8.54) and its ester etretinate (8.55) had some effectiveness in the treatment of psoriasis, a disorder of skin. 13-cA-Retinoic acid (isotretinoin) produces sebaceous gland atrophy and could prove useful in the treatment of severe acne vulgaris. Although these compounds have toxic side effects and are not in regular use, they have opened up new therapeutic possibilities. Retinoic acid (tretinoin, 8.56) has been employed in the treatment of acne. 

As shown in Scheme 1, isotretinoin (1) was first synthesized by Garbers et al. in 1968 utilizing a key Wittig condensation. Phosphonium salt 8 was prepared from direct treatment of vinyl p-ionol 7 with triphenylphosphonium bromide (PhsPaHBr) in ethanol. Subsequent addition of an excess of sodium ethoxide to 8 was followed by an ethanol solution of cij-3-formyl crotonic acid (9) to produce isotretinoin (1,2-cjs-vitamin A acid. 

In a 1985 patent by Hoffmann-La Roche, the Wittig condensation was also the crucial step in assembling isotretinoin (1, Scheme 2). Under the optimized conditions, 1.03 equivalents of phosphonium salt 8 was condensed with 1 equivalent of hydroxybutenolide 9 in the presence of 1.25 equivalents of 2 N KOH in isopropanol at -30°C for 1 to 1.5 h. The product (91.5% total yield) consisted of 75.9% of 2-cis-4-cis-vitamin A acid (10) and 16.7% of isotretinoin (1). Without separation, the mixture of 10 and 1 was subjected to palladium-catalyzed isomerization conditions the mixture was heated at 50°C for 1 h in acetonitrile in the presence of 0.10 mol% of palladium(n) nitrate, four equivalents (based on palladium nitrate) of triphenylphosphine and 2... 

Retinoic acid (vitamin A acid), in which the alcohol group has been oxidized, shares some but not all of the actions of retinol. Retinoic acid is ineffective in restoring visual or reproductive function in certain species in which retinol is effective. Flowever, retinoic acid is very potent in promoting growth and controlling differentiation and maintenance of epithelial tissue in vitamin A-deficient animals. Indeed, all-trans-retinoic acid (tretinoin) appears to be the active form of vitamin A in all tissues except the retina, and is 10- to 100-fold more potent than retinol in various systems in vitro. Isomerization of this compound in the body yields 13-n.v-rctinoic acid (isotretinoin), which is nearly as potent as tretinoin in many of its actions on epithelial tissues but may be as much as fivefold less potent in producing the toxic symptoms of hypervitaminosis A. 

There are many types of preparations that contain retinol. Absorption is greatest for aqueous preparations, intermediate for emulsions, and slowest for oil solutions. Whereas oil-soluble preparations may lead to greater hepatic storage of the vitamin, water-miscible preparations usually provide higher concentrations in plasma. Vitamin A is available as capsules. Tretinoin (all-trans-retinoic acid Retin A) is available for topical use. Isotretinoin (13-ri.s-retinoic acid Accutane) is available for oral use, as is etretinate (Tegison). 

Isotretinoin is a variant of tretinoin, which is better known as vitamin A acid, and has the chemical name 3,7-dimethyl-9-(2,6,6-trimethyl-i-cyclohexen-i-yl)-2,4,6,8-nonatetraenoic acid. Its structure contains a chain of 9 carbons with double bonds between alternative carbon pairs along the chain. Tretinoin has trans double bonds which means they... 

Figure 29-3. Chemical structures of important vitamin A species and the provitamin A carotenoid i-carotene. All-fra/w-fi-carolene (T) is the most important provitamin A carotenoid, which can be converted to all-fraws-retinal and then all-tram-retinol (If), which by definition is vitamin A. All-tram-retinol can be esterified with long-chain fatty acids to form retinyl ester (III), the storage form of vitaminA in the body.The active form of vitamin A in vision is 11-cts-retinal (TV).The transcriptionally active forms of vitaminA are all-tram-retinoic acid (V) and 9-cts-retinoic acid (VI). 13-cA-Retinoic acid (VII) has poor transcriptional regulatory activity but is used clinically as isotretinoin to treat skin diseases.

An analogue of vitamin A, isotretinoin (Accutane), or 13-cfs-retinoic acid, is used for control of severe recalcitrant cystic acne and other keratinizing dermatoses. Oral administration of 1 to 2 mg/kg body weight daily temporarily suppresses sebaceous gland activity, changes surfece lipid composition of the skin, and inhibits kera-tinization. The therapeutic effect is resolution of lesions and, in most patients, prolonged remission of the disease. 

Corticosteroids TetracycUnes (including minocycline, doxycycUne) Nitrofurantoin NaUdixic acid Vitamin A (retinoids, including isotretinoin) Oral contraceptives... 

Excessive use of vitamin A can result in ocular dryness, loss of lashes, night blindness, and even intracranial hypertension, the latter of which is similar to that occurring with the other forms of vitamin A such as isotretinoin, approved for the treatment of cystic acne. With large doses, increased intracranial pressure is considered certain. ... 

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