tretinoin and Hypervitaminosis-A

This review of the central nervous system (CNS) and behavioral teratology of the retinoids over the last 50 years is a commemorative retrospective organized by decade to show the prominent research focus within each period and the most salient findings. In the 1960s, research focused on the gross CNS malformations associated with exposure and the delineation of dose-response and stage-specific responses in rodent models. Relevant scientific events before and during the 1960s are also discussed to provide the zeitgeist in which the field of neurobehavioral teratology emerged in the 1970s. During this period, studies demonstrated that adverse effects on postnatal behavior could be produced in animals exposed to doses of vitamin A lower than those that were teratogenic or impacted growth. Work during the 1980s showed an overrepresentation of behavioral studies focused on the reliability of screening methods, while the marked effects of human exposure were illustrated in children born to women treated with isotretinoin during pregnancy. The human catastrophe invigorated research during the 1990s, a period when technological advances allowed more elegant examinations of the developing CNS, of biochemical, cellular, and molecular developmental events and regulatory actions, and of the effects of direct genetic manipulations. Likewise, research in the 1990s reflected a reinvigoration of research in neurobehavioral teratology evinced in studies that used animal models to try to better understand human vulnerability. These foci continued in the 2000-2010 period while examinations of the role of retinoids in brain development and lifelong functioning became increasingly sophisticated and broader in scope. This review of the work on retinoids also provides a lens on the more general ontogeny of the field of neurobehavioral teratology. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

Topics: Abnormalities, Drug-Induced; Animals; Brain; Central Nervous System; Female; History, 20th Century; History, 21st Century; Humans; Hypervitaminosis A; Isotretinoin; Male; Pregnancy; Retinoids; Teratogens; Teratology; Tretinoin

Topics: Diagnosis, Differential; Humans; Hypervitaminosis A; Isotretinoin; Prognosis; Pseudotumor Cerebri; Retinol-Binding Proteins; Tretinoin; Vitamin A

Topics: Acyltransferases; Animals; Carboxylic Ester Hydrolases; Carrier Proteins; Humans; Hypervitaminosis A; Lipid Metabolism; Liver; Liver Cirrhosis; Receptors, Retinoic Acid; Retinol-Binding Proteins; Tretinoin; Vitamin A Deficiency

Primary care physicians should be familiar with the effects and appropriate uses of retinoids. Topical tretinoin (Retin-A) can reverse photoaging of the skin, although some transient, undesirable side effects usually occur. In patients with acne vulgaris, topical tretinoin and systemic isotretinoin (Accutane) are the only agents that act upon the apparent underlying causes. Recurrence is unlikely after successful results are achieved. Chronic hypervitaminosis A presents insidiously, and physicians must maintain a high index of suspicion. Complete history taking should always include questions about the patient's use of vitamin supplements.

Topics: Acne Vulgaris; Administration, Topical; Animals; Drug Eruptions; Drug Therapy, Combination; Humans; Hypervitaminosis A; Isotretinoin; Medical History Taking; Physical Examination; Skin Aging; Skin Neoplasms; Tretinoin

Vitamin A refers collectively to a number of compounds, the most biologically active of which is retinol. Named after its earliest discovered function, visual excitation, retinol is also needed for growth and reproduction, and differentiation of epithelial tissue. A closely related form, retinoic acid, has selective biologic activity for normal growth and epithelial differentiation. The term retinoids has been used in recent years to include both natural and synthetic analogs of vitamin A. Carotene and carotenoids refer to vitamin A precursors (pro-vitamins) of vegetable origin. Following a brief historical account of vitamin A and description of dietary information this article focuses on the chemistry and physiology of retinoids. The biological roles of vitamin A compounds are elaborated, as well as the clinical significance of vitamin A deficiency and excess. Discussion of retinoids in therapy includes their use as anti-cancer agents and as therapeutics for dermatological disorders. Finally, a review of analytical techniques for laboratory assessment of vitamin A is presented.

Topics: Adult; Animals; Antineoplastic Agents; Carcinogens; Carotenoids; Chemical and Drug Induced Liver Injury; Chemical Phenomena; Chemistry; Female; Humans; Hypervitaminosis A; Infant; Male; Pregnancy; Rhodopsin; Tretinoin; Vitamin A; Vitamin A Deficiency

Calcific aortic valve disease (CAVD) is a major public health problem with no effective treatment available other than surgery. We previously showed that mature heart valves calcify in response to retinoic acid (RA) treatment through downregulation of the SRY transcription factor Sox9. In this study, we investigated the effects of excess vitamin A and its metabolite RA on heart valve structure and function in vivo and examined the molecular mechanisms of RA signaling during the calcification process in vitro.. Using a combination of approaches, we defined calcific aortic valve disease pathogenesis in mice fed 200 IU/g and 20 IU/g of retinyl palmitate for 12 months at molecular, cellular, and functional levels. We show that mice fed excess vitamin A develop aortic valve stenosis and leaflet calcification associated with increased expression of osteogenic genes and decreased expression of cartilaginous markers. Using a pharmacological approach, we show that RA-mediated Sox9 repression and calcification is regulated by classical RA signaling and requires both RA and retinoid X receptors.. Our studies demonstrate that excess vitamin A dietary intake promotes heart valve calcification in vivo. Therefore suggesting that hypervitaminosis A could serve as a new risk factor of calcific aortic valve disease in the human population.

Topics: Animals; Aortic Valve; Calcinosis; Cell Line; Chick Embryo; Collagen Type II; Dietary Supplements; Disease Models, Animal; Diterpenes; Gene Expression Profiling; Gene Expression Regulation; Heart Valve Diseases; Hypervitaminosis A; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Osteogenesis; Osteopontin; Receptors, Retinoic Acid; Retinoid X Receptors; Retinyl Esters; RNA Interference; Signal Transduction; SOX9 Transcription Factor; Time Factors; Tissue Culture Techniques; Transfection; Tretinoin; Vitamin A; Vitamins

Vitamin A (VA) has a key role in vertebrate morphogenesis, determining body patterning and growth through the control of cell proliferation and differentiation processes. VA regulates primary molecular pathways of those processes by the binding of its active metabolite (retinoic acid) to two types of specific nuclear receptors: retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which promote transcription of downstream target genes. This process is well known in most of higher vertebrates; however, scarce information is available regarding fishes. Therefore, in order to gain further knowledge of fish larval development and its disruption by nutritional VA imbalance, the relative expression of some RARs and RXRs, as well as several genes involved in morpho- and skeletogenesis such as peroxisome proliferator-activated receptors (PPARA, PPARB and PPARG); retinol-binding protein (RBP); insulin-like growth factors I and II (IGF1 and IGF2, respectively); bone morphogenetic protein 2 (Bmp2); transforming growth factor β-1 (TGFB1); and genes encoding different extracellular matrix (ECM) proteins such as matrix Gla protein (mgp), osteocalcin (bglap), osteopontin (SPP1), secreted protein acidic and rich in cysteine (SPARC) and type I collagen α1 chain (COL1A1) have been studied in gilthead sea bream.. During gilthead sea bream larval development, specific expression profiles for each gene were tightly regulated during fish morphogenesis and correlated with specific morphogenetic events and tissue development. Dietary hypervitaminosis A during early larval development disrupted the normal gene expression profile for genes involved in RA signalling (RARA), VA homeostasis (RBP) and several genes encoding ECM proteins that are linked to skeletogenesis, such as bglap and mgp.. Present data reflects the specific gene expression patterns of several genes involved in larval fish RA signalling and skeletogenesis; and how specific gene disruption induced by a nutritional VA imbalance underlie the skeletal deformities. Our results are of basic interest for fish VA signalling and point out some of the potential molecular players involved in fish skeletogenesis. Increased incidences of skeletal deformities in gilthead sea bream fed with hypervitaminosis A were the likely ultimate consequence of specific gene expression disruption at critical development stages.

Topics: Animals; Bone Development; Bone Morphogenetic Protein 2; Cell Differentiation; Cell Proliferation; Collagen Type I; Collagen Type I, alpha 1 Chain; Extracellular Matrix Proteins; Gene Expression; Gene Expression Profiling; Gene Expression Regulation, Developmental; Hypervitaminosis A; Morphogenesis; Peroxisome Proliferator-Activated Receptors; Receptors, Retinoic Acid; Retinoid X Receptors; Retinol-Binding Proteins; Reverse Transcriptase Polymerase Chain Reaction; Sea Bream; Somatomedins; Transforming Growth Factor beta; Tretinoin; Vitamin A

Evaluation of 13-cis-12-substituted analogues of retinoic acid in a series of dermatologic screens has revealed that structural modifications can lead to selectivity and specificity. An analogue, 11-cis,13-cis-12-hydroxymethylretinoic acid, delta-lactone, has been found to have good activity and to be devoid of topical and systemic toxicity.

Topics: Administration, Topical; Animals; Cricetinae; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Guinea Pigs; Hypervitaminosis A; Male; Mesocricetus; Mice; Mice, Hairless; Rabbits; Skin; Skin Diseases; Structure-Activity Relationship; Tretinoin

Preclinical studies pertaining to the pharmacology and toxicology of BMY 30123 (4-acetamidophenyl retinoate) are reported. BMY 30123 is a novel compound which has topical retinoid activity. This compound exhibits lower toxicity, both local and systemic, than other clinically used topical retinoids such as tretinoin (all-trans retinoic acid) in animal models. BMY 30123 is effective in a number of retinoid sensitive skin models including the rhino mouse utriculi reduction assay, the mouse epidermal hyperplasia model and in the suppression of DNA synthesis in mouse skin stimulated with phorbol ester. BMY 30123 was equipotent with tretinoin in these topical models. In the rhino mouse model the ED30 values for BMY 30123 and tretinoin were 0.037 and 0.015 mM, respectively. In addition, BMY 30123 was active in the UVB-induced photodamaged mouse model, another retinoid sensitive model. One of the problems associated with topically applied tretinoin is local irritation. Therefore, for topical therapy to be optimal, it is important to reduce or minimize local irritation. Repeated applications of BMY 30123 to rabbit skin resulted in low skin irritation. The first perceptible signs of skin irritation produced by BMY 30123 occurred at a dose 10 times higher than that observed for tretinoin. BMY 30123 also exhibits low retinoid activity after oral or i.p. administration in mice and produced no signs of hypervitaminosis A-related toxicity at twenty times the no effect dose of tretinoin. Because retinoids are effective modulators of epidermal growth and differentiation, this compound should be useful for the treatment of cutaneous disorders that exhibit altered epidermal differentiation such as acne, psoriasis, ichthyosis and epithelial tumours.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetaminophen; Administration, Topical; Animals; Collagen; Dose-Response Relationship, Drug; Female; Hyperplasia; Hypervitaminosis A; Irritants; Mice; Mice, Hairless; Phorbol Esters; Rabbits; Retinoids; Saccule and Utricle; Tretinoin; Ultraviolet Rays

In the treatment of various dermatological disorders, topically applied retinoids have potential therapeutic use with the advantage of improved localized activity and lower toxicity over systemically administered retinoids. However, most retinoids cause a significant degree of local irritation. In the present study, the ability to produce local activity with low local irritation potential was evaluated with a novel retinoic acid derivative. BMY 30047 (11-cis, 13-cis-12-hydroxymethylretinoic acid delta-lactone) is one of a series of retinoic acid derivatives in which the carboxyl function of the polar end was modified with the aim of achieving reduced local irritation and systemic toxicity while retaining the local therapeutic effect. BMY 30047 was evaluated and compared with all-trans retinoic acid for topical retinoid activity in several preclinical assay systems, including the utricle reduction assay in rhino mice, 12-o-tetradecanoylphorbol 13-acetate ester-stimulated ornithine decarboxylase induction in hairless mice and the UV light-induced photodamaged skin model in hairless mice. BMY 30047 was assessed for retinoid-type side effects by evaluating the skin irritation potential in rabbits after repeated topical application, and hypervitaminosis A-inducing potential in mice after i.p. injection. BMY 30047 demonstrated significant topical retinoid activity in several in vivo models with less skin irritation potential relative to the most used clinical concentrations of all-trans retinoic acid. BMY 30047 also showed very little systemic activity and did not produce any evidence of hypervitaminosis A syndrome at systemic doses 20 times greater than the no-effect dose of all-trans retinoic acid.

Topics: Administration, Topical; Animals; Drug Evaluation, Preclinical; Female; Hypervitaminosis A; Injections, Intraperitoneal; Lactones; Male; Mice; Mice, Inbred Strains; Ornithine Decarboxylase; Phorbol Esters; Rabbits; Retinoids; Saccule and Utricle; Skin; Tretinoin; Ultraviolet Rays

The present study was designed to investigate the embryo-fetotoxicity of vitamin A in protein-energy malnourished animals. Retinyl palmitate (66, 99 and 132 mg/kg) suspended in corn oil was given by gavage to well-nourished and malnourished rats from gestational days 8 to 10 and cesarean sections were performed on day 20. All fetuses were weighed and examined for malformations before being prepared for skeletal evaluation. The proportion of malformed fetuses was higher in the malnourished group at each one of the three dose levels. The data indicate that malnourished animals are more susceptible to the toxic effects of retinyl esters.

Topics: Animals; Body Weight; Congenital Abnormalities; Diterpenes; Female; Hypervitaminosis A; Pregnancy; Protein-Energy Malnutrition; Rats; Rats, Inbred Strains; Retinyl Esters; Tretinoin; Vitamin A

Topics: Animals; Cartilage; Cycloheximide; Hypervitaminosis A; Proteoglycans; Rats; Tretinoin

Vitamin A is essential for growth and development, reproduction and vision in humans. Chemical modification of vitamin A has yielded compounds showing therapeutic promise in skin and neoplastic diseases. The medicinal use of retinoids (vitamin A and its derivatives) is limited by the toxicity associated with this group of compounds. One retinoid, 13-cis-retinoic acid, has proved to be quite effective in the treatment of severe recalcitrant cystic acne under conditions in which toxicity is manageable.

Topics: Acne Vulgaris; Adolescent; Humans; Hypervitaminosis A; Isotretinoin; Male; Retinoids; Tretinoin; Vitamin A Deficiency

The authors have studied--in the plasma--the changes of zinc, retinol binding protein (RBP), retinol and retinoic acid with reference to the dermatological status of fifty chronically haemodialysed renal insufficiency patients divided into four subgroups (normal skin, dry skin, dry skin with keratosis, and only keratosis). The results of these groups were compared to those of thirty healthy subjects. The values of these variables do not show any significant difference in function of the dermatological subgroups; but, despite the considerable rise in the retinol binding protein and retinol levels in comparison with the controls (haemodialysis patients: RBP = 11.77 +/- 2.83 mumol X l(-1), retinol = 7 +/- 2.57 mumol X l(-1); controls; RBP = 2.76 +/- 0.62 mumol X l(-1), retinol = 2.16 +/- 0.53 mumol X l(-1] the electromicroscopic examination of skin biopsy samples from some of the patients did not reveal any sign of hypervitaminosis A in the lesions.

Topics: Humans; Hypervitaminosis A; Keratosis; Renal Dialysis; Retinol-Binding Proteins; Retinol-Binding Proteins, Plasma; Skin; Skin Diseases; Tretinoin; Vitamin A; Zinc

Ethyl (E,Z,E,E)-3,7-dimethyl-4-fluoro-9-(4-methoxy-2,3,6-trimethylphenyl)nonatetraenoate (10a) has been found to cause a marked regression of chemically induced skin papillomas in mice. A new synthesis of this compound was achieved by condensation of 4-fluoro aldehyde 7 or 8 with the aromatic phosphonium salt 9a. Several analogues (101-e) having different substituted aromatic moieties were also prepared and tested for their antipapilloma effect. The monochloro analogue 10b was shown to have comparable activity to the parent compound 10a.

Topics: Animals; Antineoplastic Agents; Chemical Phenomena; Chemistry; Hypervitaminosis A; Mice; Neoplasms, Experimental; Papilloma; Tretinoin

Topics: Hypervitaminosis A; Tretinoin; Vitamin A