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The Background of Retinoids
Ayse Serap Karadag, Berna Aksoy, and Lawrence Charles Parish
Introduction
Retinoids are among the most valuable drugs in the dermatologic armamentarium. This up-to-date reference on the use of retinoids in dermatology presents how retinoids function in the skin, how they can be used to treat and prevent various skin diseases, and how they can be effectively monitored. Providing an in-depth update on the pharmacology, clinical use, side effects, and follow-up of retinoid therapy in dermatology, this source also addresses topics related to retinoid use in special circumstances, including vulnerable populations, concomitant surgery, and aesthetic procedures. With chapters by internationally recognized authors, this book will stand as an up-to-date source on the topic.
Historical Background
General History of Vitamin A and Retinoids
The importance of vitamin A has been recognized for over 3500 years, especially as a factor in treating deficiency diseases (1). Night blindness was recognized by the ancient Egyptians (Eber’s Papyrus, 1500 bce and Kahun 1 Papyrus, 1825 bce) who treated the affliction with roasted lamb or ox liver that was squeezed to be applied over the eye and then probably eaten (1–3). Night blindness and goat liver treatment were also later described by the ancient Greeks and by Hippocrates (460–327 bce) (1). By the late nineteenth century, the effects of vitamin A deficiency on growth had been recognized, and milk was discovered to be essential for healthy growth in the laboratory (1,4). Minimal qualitative factors in milk, egg, and butter were found that provided healthy growth and maintenance (1,4,5). By 1915, “fat-soluble factor A” was identified (1,2,6).
The unknown factors in milk which support life were termed “accessory food factors,” The term “vitamine” (persisted as “vitamin”) was created to describe these “accessory factors” that are vital to life and probably of an amine (chemically, contains a nitrogen atom with a lone pair of electrons) in 1911 (4,6,7). Fat-soluble factor A was found to be associated with a yellow pigment extracted from plant sources, butter, or eggs (carotene: provitamin), and converted to an active colorless form (vitamin A: retinol) in the animal body in 1920–1930 (1).
The chemical structure of vitamin A (β-carotene) was described in 1931, crystallized in 1937, and synthesized in 1947 (1–3,5–7). Between the 1950s and 1980s, the biochemical pathways, anticarcinogenic activity, and nuclear retinoic acid receptors of vitamin A were established (1,2,8).
An international meeting was convened by the World Health Organization (WHO) in 1974 to determine the status of vitamin A acid. It was at this congress in Jakarta, Indonesia that the compound was recognized as having comedolytic activity more than just an irritating effect (2,9).
The antikeratotic effects of vitamin A have been recognized since 1932 (9). Three to eight million U of oral retinyl palmitate was used in the treatment of psoriasis, but such high dosage led to the development of hypervitaminosis A; hence, this therapy was abandoned (9). Following the report of 100,000 IU of systemic vitamin A in 1949 (10), this regimen was often used in acne therapy. Vitamin A acid (tretinoin) was discovered in 1946 and became commercially available in 1969 (5). This was followed by the synthesis of isotretinoin (13-cis retinoic acid) in 1971 (3,5) and acitretin in 1980 (11).
The historical discovery of vitamin A and retinoids are depicted in Table 1.1.
| Table 1.1 Vitamin A and Retinoids in Dermatology |
| •1900–1910s/Stepp, Hopkins, McCollum, Osborne, Mendel/Fat-soluble growth factor extracted from eggs, milk, butter, liver •1911/Funk/Vitamine •1915/McCollum/Fat-soluble A •1930/Moore/Carotene and vitamin A •1931/Karrer/Chemical structure of vitamin A (retinol) •1946/Arens/Vitamin A acid (tretinoin) •1947/Isler/Synthesis of vitamin A (retinol) •1960s/Stüttgen, Kligman/Topical effects of tretinoin •1971/Bollag/Synthesis of isotretinoin •1972/Synthesis of etretinate •1973–1976/First clinical studies with 13-cis retinoic acid •1980/Palmskog/Synthesis of acitretin •1997/Miller/Bexarotene in CTCL •1999/Bollag/Alitretinoin in chronic hand dermatitis |
Topical Retinoid...
