Tretinoin
Retinoids are intracrine and paracrine mediators of cell differentiation and proliferation, apoptosis (programmed cell death), and reproduction. Cells regulate the formation of specific retinoid isomers depending upon the cellular action required. The numerous effects of retinoids reflect the complex biology of the nuclear receptors that mediate retinoid activity. Retinoid receptors are divided into retinoid X receptors (RXRs) and retinoic acid receptors (RARs); both types can be further divided into 3 subtypes: Alpha, beta, and gamma. These receptor subtypes are further divided into many isoforms. Retinoid receptors are structurally similar but have different affinities for different types of retinoids and distribution varies throughout the body resulting in a wide range of actions. Tretinoin binds to all three RARs, but does not bind to RXRs except at very high concentrations. RAR-alpha and RAR-beta have been associated with the development of acute promyelocytic leukemia and squamous cell cancers, respectively. RAR-gamma is associated with retinoid effects on mucocutaneous tissues and bone.
•Skin Disorders: By binding to RARs, tretinoin modifies gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation. It has not been established whether the clinical effects of tretinoin are mediated through activation of RARs, other mechanisms such as irritation, or both. Tretinoin appears to prevent horny cell cohesion and to increase epidermal cell turnover and mitotic activity. Subsequently, in patients with acne, expulsion of existing comedones occurs, and formation of new comedones is prevented through sloughing and expulsion of horny cells from the follicle. Tretinoin reduces the cell layers of the stratum corneum. The bacterium involved in acne, Propionibacterium acnes, and sebum production are unaffected. An additional action of tretinoin may involve keratinization inhibition, which would explain its effectiveness in treating keratinization disorders.
•Photodamage: Topical tretinoin is effective in reducing fine wrinkling, mottled hyperpigmentation, roughness, and laxity associated with photodamaged skin. Ultraviolet irradiation induces three metalloproteinases in human skin: collagenase, 92-kd gelatinase, and stromelysin-1. The combined actions of these enzymes can fully degrade skin collagen. Pretreatment of skin with tretinoin inhibits the induction of these skin matrix metalloproteinase proteins and activity by 70—80% in both connective tissue and outer layers of irradiated skin.(22)
•Acute Promyelocytic Leukemia: Similar to other retinoids, tretinoin induces cellular differentiation in malignant cells. Acute promyelocytic leukemia (APL) is caused by a genetic lesion that disrupts the alpha retinoic acid receptor (RAR-alpha) gene found on the long arm of chromosome 17 and the PML gene found on chromosome 15. The fusion protein that is formed, PML-RAR-alpha, inhibits apoptotic pathways and blocks myeloid differentiation when present in levels greater than those of the normal RAR-alpha protein. The presence of this gene translocation [t(15;17)] is used for diagnosis of APL and as a marker of response following treatment with either cytotoxic agents or tretinoin. During tretinoin treatment, cells expressing PML/RAR-alpha undergo cellular differentiation at a rate higher than normal cells. At therapeutic doses of tretinoin, the activity of the fusion protein on differentiation converts from inhibitory to stimulatory. Terminal differentiation of APL cells as the mechanism of tretinoin therapy is supported by 1) the absence of bone marrow aplasia during treatment; 2) the appearance of cells during treatment with the morphologic characteristics of maturation stages intermediate between promyelocytes and neutrophils; 3) the presence, during treatment, of PML and RAR-alpha rearrangements in peripheral blood neutrophils that disappear after treatment.(23) Treatment with tretinoin reverses the bleeding diathesis seen in APL, before any morphologic response is noted. A retinoic acid syndrome, similar to capillary leak syndrome, may be seen in some patients (see Adverse Reactions). The etiology of this syndrome is unknown, but may be due to decreases in leukocyte adhesion protein activity. Resistance to tretinoin may develop due to pharmacokinetic reasons (decreased bioavailability) and/or changes in proteins involved in the cellular activity of tretinoin.
Niacinamide
Dietary requirements for niacin can be met by the ingestion of either nicotinic acid or nicotinamide; as vitamins, both have identical biochemical functions. As pharmacologic agents, however, they differ markedly. Nicotinic acid is not directly converted into nicotinamide by the body; nicotinamide is only formed as a result of coenzyme metabolism. Nicotinic acid is incorporated into a coenzyme known as nicotinamide adenine dinucleotide (NAD) in erythrocytes and other tissues. A second coenzyme, nicotinamide adenine dinucleotide phosphate (NADP), is synthesized from NAD. These two coenzymes function in at least 200 different redox reactions in cellular metabolic pathways. Nicotinamide is released from NAD by hydrolysis in the liver and intestines and is transported to other tissues; these tissues use nicotinamide to produce more NAD as needed. Together with riboflavin and other micronutrients, the NAD and NADP coenzymes work to convert fats and proteins to glucose and assist in the oxidation of glucose.
In addition to its role as a vitamin, niacin (nicotinic acid) has other dose-related pharmacologic properties. Nicotinic acid, when used for therapeutic purposes, acts on the peripheral circulation, producing dilation of cutaneous blood vessels and increasing blood flow, mainly in the face, neck, and chest. This action produces the characteristic “niacin-flush”. Nicotinic acid-induced vasodilation may be related to release of histamine and/or prostacyclin. Histamine secretion can increase gastric motility and acid secretion. Flushing may result in concurrent pruritus, headaches, or pain. The flushing effects of nicotinic acid appear to be related to the 3-carboxyl radical on its pyridine ring. Nicotinamide (niacinamide), in contrast to nicotinic acid, does not contain a carboxyl radical in the 3 position on the pyridine ring and does not appear to produce flushing.
Nicotinic acid may be used as an antilipemic agent, but nicotinamide does not exhibit hypolipidemic activity. Niacin reduces total serum cholesterol, LDL, VLDL, and triglycerides, and increases HDL cholesterol. The mechanism of nicotinic acid’s antilipemic effect is unknown but is unrelated to its biochemical role as a vitamin. One of nicotinic acid’s primary actions is decreased hepatic synthesis of VLDL. Several mechanisms have been proposed, including inhibition of free fatty acid release from adipose tissue, increased lipoprotein lipase activity, decreased triglyceride synthesis, decreased VLDL-triglyceride transport, and an inhibition of lipolysis. This last mechanism may be due to niacin’s inhibitory action on lipolytic hormones. Nicotinic acid possibly reduces LDL secondary to decreased VLDL production or enhanced hepatic clearance of LDL precursors. Nicotinic acid elevates total HDL by an unknown mechanism, but is associated with an increase in serum levels of Apo A-I and lipoprotein A-I, and a decrease in serum levels of Apo-B. Nicotinic acid is effective at elevating HDL even in patients whose only lipid abnormality is a low-HDL value. Niacin does not appear to affect the fecal excretion of fats, sterols, or bile acids. Clinical trial data suggest that women have a greater hypolipidemic response to niacin therapy than men at equivalent doses.
Vitamin E Acetate
Vitamin E (alpha-tocopherol) is a lipid soluble vitamin with actions related to its antioxidant properties. Vitamin E can be found naturally in cellular membranes where it plays an important role in the suppression of free radical-induced lipid peroxidation. A free radical is an oxygen molecule which roams the body in search of an electron, sometimes damaging healthy tissue in a process called oxidation. Free radicals are known to initiate peroxidative chain reactions of unsaturated cell membrane lipids. This reaction between the membrane-bound lipid and free radicals disrupts cell membrane integrity. As a free radical scavenger, vitamin E protects membrane-bound polyunsaturated fatty acids and other oxygen-sensitive substances from oxidation. Vitamin E is hypothesized to reduce atherosclerosis and subsequent cardiovascular disease (CVD) by preventing oxidative changes to low-density lipoproteins (LDL). Oxidized LDL particles are taken up more readily by macrophages than by native LDLs, which leads to the formation of cholesterol-laden foam cells found in fatty streak or early atherosclerosis. Alpha tocopherol is the predominant lipophilic antioxidant for LDL. Antioxidants protect LDL from oxidative modification and therefore may contribute to the reduction of CVD. Although the clinical benefits of vitamin E supplementation were demonstrated in patients with documented CVD in early studies, more recent trials including the Heart Outcomes Prevention Evaluation and the Women’s Health Study failed to confirm the efficacy of vitamin E in reducing CVD.(24)(25)(26)(27)
Oxidative injury has also been implicated in cancer; many carcinogens create free radicals that damage DNA and other cellular structures, initiating and promoting tumor development.(28) Therefore, it is attractive to consider vitamin E as an agent to inhibit the development of neoplasms. Alpha tocopherol may prevent cancer by inhibiting proliferation and angiogeneses, inducing apoptosis, and enhancing immune function. Unfortunately, human trials that have evaluated the association between vitamin E intake and the incidence of cancer have been generally inconclusive. Contrary to earlier findings, recent trials have shown a lack of benefit after prolonged periods of treatment and observation.(29)(30)
Although vitamin E is most commonly noted for its antioxidant activity, vitamin E may also act through several other mechanisms including immunomodulation and antiplatelet effects. Vitamin E appears to enhance lymphocyte proliferation, decrease production of immunosuppressive prostaglandins E2, and decrease levels of immunosuppressive serum lipid peroxides. The antiplatelet effects of Vitamin E have been confirmed repeatedly during in vitro studies; however, the antiplatelet effects have not been consistently demonstrated during in vivo studies. One study reports that alpha-tocopherol markedly reduces the sensitivity of platelets to activation in normal subjects when administered at daily doses of 267 to 800 mg (400 to 1,200 International Units) for 2 weeks. This effect is related to inhibition of protein kinase C stimulation as opposed to the vitamin’s antioxidant properties.(31) Finally, vitamin E may decrease the incidence of red blood cell hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
The purported mechanisms of topically applied vitamin E involve antioxidant effects and purported effects against photoaging; the FDA has not evaluated these claims, and the ability of topical vitamin E products to aid in the healing of minor burns and sunburns has not been substantiated. Vitamin E is found in the skin and increases from childhood to maturity and then decreases significantly in old age. Vitamin E and coenzyme Q10 have been found to synergistically inhibit the ultraviolet (UV) deletion of squalene, cholesterol, and unsaturated fatty acids in skin surface lipids.(32) Topically applied vitamin E may result in antioxidant effects in the skin. Vitamin E absorbs UV light in the region of the solar spectrum, which is responsible for sun-induced effects on the skin. In animal models, vitamin E has been shown to prevent oxidative stress and cutaneous and systemic immunosuppression caused by UV light.(33) In addition, in animal models, topical vitamin E application has been shown to decrease the incidence of UV-induced skin cancer.
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