Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0851184 (thinning)
 11,252 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arotinoids, which are analogs of retinoic acid (RA) and retinol (RO) with the carbon skeleton in a rigid conformation, have more favorable therapeutic indices relative to all-trans-RA and all-trans-RO. The purpose of this investigation was to obtain preliminary in vivo toxicity data on SMR-2(analog of RO) and SMR-6 (analog of RA), arotinoids with promising activity (ED50's of 20 X 10(-11) and 5 X 10(-11) M, respectively; ED50 of RA = 1 X 10(-11) M) for reversal of keratinization in tracheal organ culture. A preliminary toxicity study was conducted in male B6D2F1 mice with gavage of retinoids in corn oil (0.01, 0.05, and 0.1 mg/kg/day of SMR-2 or SMR-6; 1, 5, and 10 mg/kg/day of RA as reference control). Due to lack of toxicity, each dose level for SMR-2 and SMR-6 was increased by 4-fold on Day 29 of dosing. The study was terminated on Day 57. Hypervitaminosis A (weight loss, alopecia, skin scaling, and bone thinning) was induced in the mid- and high-dose SMR groups; weight-gain depression was predominant in the high-dose RA group. The SMR compounds were approximately 100-fold more toxic, based on weight loss, than RA. In the SMR dose groups with hypervitaminosis A, white blood cell counts were elevated 2- to 4-fold; and there were microscopic lesions in skin, testes, epididymis, bone, thymus, bone marrow, peripheral lymph nodes, spleen, stomach, adrenal, and pituitary. The leukocytosis was attributed to leukopoiesis in spleen and bone marrow, which may be due to either a direct effect and/or a secondary response to a subacute inflammatory reaction in skin. Only peripheral lymph node hyperplasia was observed in SMR-2 and RA low-dose groups. Enlarged thymus, lymph node hyperplasia, leukopoiesis in spleen and bone marrow, elevated alkaline phosphatase with bone hypertrophy, and testicular degeneration were observed in the mid-dose RA group. The results indicate that immune stimulation may be a primary early response to retinoids and that skin, leukopoietic tissues, reproductive organs, stomach, and bone are primary targets for retinoid toxicity.
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PMID:Preliminary toxicity profile of arotinoids SMR-2 and SMR-6 in male B6D2F1 mice. 360 38

Hypervitaminosis A and D is a potential cause of "hyena disease" in cattle, which results from premature growth-plate closure in long bones of calves. This study showed that vitamin A induced growth-plate closure if calves were given an intramuscular injection of vitamins A and D (2,000,000 IU and 300,000 IU, respectively) on the first day after birth and, in addition, vitamin A (30,000 IU/kg body weight) in a water dispersible form was added to the milk substitute daily. Gross lesions were observed in the proximal tibial growth plates of each of seven calves after 3 weeks of vitamin-A treatment. Microscopical examination showed commencing premature growth-plate closure in the proximal tibia at 2 weeks. After one week, the growth plate showed focal thinning, and there was premature endochondral ossification of columnar cartilage. Longitudinal bone growth was dramatically reduced before growth plate closure at one week (25 microns/day in a treated animal versus 136 microns/day in a control). Liver concentrations of retinol and retinyl palmitate became strikingly elevated at on week, and thereafter increased slowly until the third week. Elevation of plasma retinol and retinyl palmitate was rapid, reaching a maximum on day 10. Plasma all-trans-retinoic acid was undetectable in many samples from treated animals, but plasma concentrations of derivatives of retinoic acid (9-cis-retinoic acid, 13-cis-retinoic acid, 13-cis-4-oxoretinoic acid, and 9, 13 dicis-retinoic acid) were elevated. The vitamin-A intake required to induce growth-plate closure in calves was found to be exceedingly high. Vitamin-A toxicity must be considered as a potential cause of hyena disease, but it would seem likely that other factors also play a role.
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PMID:Vitamin (A and D)-induced premature physeal closure (hyena disease) in calves. 917 48