tretinoin and Drug-Overdose

Cleft lip with or without palate (CL/P) is a common congenital anomaly in humans and is thought to be caused by genetic and environmental factors. However, the epigenetic mechanisms underlying orofacial clefts are not fully understood. Here, we investigate how the overdose of retinoic acid (RA), which can induce cleft palate in mice and humans, regulates histone methyltransferase, Wolf-Hirschhorn syndrome candidate 1 (WHSC1) during palatal development in mice. We treated mouse embryonic fibroblasts (MEFs) with 1 μM all-trans RA and discovered that the global level of H3K36me3 was downregulated and that expression of the H3K36 methyltransferase gene, Whsc1, was reduced. The expression level of WHSC1 in embryonic palatal shelves was reduced during palatogenesis, following maternal administration of 100 mg/kg body weight of RA by gastric intubation. Furthermore, the expression of WHSC1 in palatal shelves was observed in epithelial and mesenchymal cells at all stages, suggesting an important role for palatal development. Our results suggest that the pathogenesis of cleft palate observed after excessive RA exposure is likely to be associated with a reduction in the histone methyltransferase, WHSC1.

Topics: Animals; Cell Line; Cleft Palate; Down-Regulation; Drug Overdose; Female; Histone-Lysine N-Methyltransferase; Histones; Methylation; Mice; Mice, Inbred C57BL; Palate; RNA, Messenger; Tretinoin

Precise tissue concentration of retinoic acid (RA) is indispensable for proper interaction of second heart field cells with cardiac neural crest cells and induction of signalling pathways important for normal myocardial growth.. Since RA deficiency during embryogenesis induces noncompaction, we hypothesised that excess RA at the stage of heart tube elongation may cause thinning of the myocardial wall which leads to noncompaction.. RA was administered at 70 mg/kg b.w. on 8.5 days post coitus (dpc) to pregnant mice to elicit cardiac malformations in foetuses. We studied noncompaction development in RA-treated mouse offspring. The cardiac noncompaction was evaluated in different stages of heart development as the quotient of the distance between the epicardial surface and trabecular tips(represented by a) and the distance between the epicardial surface and trabecular recesses (represented by b) in RA-treated hearts compared to control non-treated.. We demonstrated that apart from outflow tract defects such as double outlet right ventricle, transposition of the great arteries and tetralogy of Fallot in foetuses in mouse offspring, noncompaction occurs in about 42% of cases. At the stage of 13 dpc and later in development the ratio a/b was higher in RA-treated hearts exhibiting noncompaction compared to the control hearts. This cardiomyopathy was more evident in the right ventricle than in the left ventricle.. Noncompaction caused by RA overdose can be elicited in part of the mouse offspring by administering RA at the stage of cardiac tube elongation.

Topics: Animals; Disease Models, Animal; Drug Overdose; Female; Heart; Heart Defects, Congenital; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Myocardium; Pregnancy; Prenatal Exposure Delayed Effects; Tomography, X-Ray Computed; Tretinoin

Tretinoin (Vesanoid) is an all-trans-retinoic acid, and is related to retinol (Vitamin A). To date, there have been several case reports on overdose with its isomer isotretinoin, but none involving overdose of tretinoin. We report the first known case of a patient who ingested a massive overdose of tretinoin.. A 31-year-old man ingested 1000 mg of tretinoin (100 pills of Vesanoid 10 mg) in a suicide attempt. He developed nonbloody diarrhea, but otherwise had no complaints. Clinical examination was normal. The patient was treated with activated charcoal and was hydrated. The patient's blood results did not show any deterioration on the third consecutive day. He was discharged well on the third day, but was subsequently lost to follow-up.. Although there has been no reported experience with acute tretinoin overdose in humans, our patient took a dose approximately 3 times the recommended maximum tolerated daily dose in patients with myelodysplastic syndrome or solid tumors (195 mg/m2 per day). Overdose with other retinoids such as isotretinoin have been associated with only minor symptoms that resolved quickly. Our patient had diarrhea, which also resolved quickly with symptomatic treatment and hydration.. We believe this to be the first case report of an acute oral overdose of tretinoin. The patient developed diarrhea, but was otherwise asymptomatic.

Topics: Adult; Antineoplastic Agents; Charcoal; Diarrhea; Drug Overdose; Fluid Therapy; Humans; Male; Suicide, Attempted; Treatment Outcome; Tretinoin