Isotretinoin

It was developed to be used as a chemotherapy medication for the treatment of brain cancer, pancreatic cancer and more.

Pityriasis rosea-like eruption induced by isotretinoin.[Pubmed:28359163]

Cutan Ocul Toxicol. 2018 Mar;37(1):100-102.

Pityriasis rosea is a common, self-limited and inflammatory skin disease. The etiology is not clearly known. Viral agents, autoimmunity, psychogenic factors and drugs have all been suggested as risk factors. Isotretinoin is usually used in the treatment of resistant, nodulocytic acne. We present a case of pityriasis rosea-like eruption induced by Isotretinoin. To our knowledge, this is the second clinical case of pityriasis rosea-like eruption induced by Isotretinoin.

A Systematic Review on Oral Isotretinoin Therapy and Clinically Observable Wound Healing in Acne Patients.[Pubmed:28362520]

J Cutan Med Surg. 2017 Jul/Aug;21(4):325-333.

The association between Isotretinoin and atypical wound healing remains controversial. It is common practice to delay elective procedures for 6 to 24 months after oral Isotretinoin therapy. The studies supporting common practices (SCP) recommend extending this period to include the 6 to 24 months preceding treatment. The opposing studies (challenging common practices; CCP) state that the rate of scarring in Isotretinoin patients is low and that delaying elective procedures is unnecessary. These practices impact a large number of dermatology patients undergoing acne treatment. This systematic review compiled articles obtained from online databases and examined data from both SCP and CCP studies. The inconsistencies in the reported data and the methodological flaws in the literature preclude any firm conclusions that can resolve the controversy. As such, this review demonstrates that there is insufficient evidence to either corroborate or refute delaying elective procedures in Isotretinoin acne patients. Although the recent literature trends toward removing the procedural delay, we advocate for clinicians to consider the research presented in this review in the context of their own clinical experience and each individual patient's situation. The possible negative procedural outcomes must be weighed against the severity of the patient's acne scarring and the psychosocial impact of this scarring on the patient.

Dose dependent treatment with isotretinoin induces more changes in the ileum than in the duodenum and jejunum in Wistar rats.[Pubmed:28341060]

Tissue Cell. 2017 Apr;49(2 Pt B):203-208.

Acne is the most common skin disorder and can directly affect the patients' self-esteem. Systemic treatment has been indicated for nodular, cystic or persistent acne rather than another type of treatment, such as a topic one. Isotretinoin is an analogue of vitamin A and by suppressing the sebaceous glands the disease can be controlled. This study was designed to mimic the treatment performed in young patients using the dosage of 1mg/kg, and a higher one of 10mg/kg, for 60days in young male Wistar rats. 24 Wistar rats were divided into four groups: control(water), D0(soybean oil, control group), D1(1mg/kg of Isotretinoin solution), D10(10mg/kg of Isotretinoin solution). Using the morphometry tool and histochemical techniques we evaluated the villus, intestinal crypts, and goblet cells to find signs of possible alterations of the duodenum, jejunum and ileum segments of the small intestine. We found no signs of changes in the jejunum mucosa after 60 days of treatment with 1mg/kg and 10mg/kg. The duodenum is also less affected, whereas significant modifications were found in the ileum. The goblet cell frequency was altered, indicating a proliferative potential for the substance. Although some patients have described intestinal symptoms, no important alterations were found with this protocol, reaffirming the security involved in the treatment with this substance.

Metabolic characteristics of 13-cis-retinoic acid (isotretinoin) and anti-tumour activity of the 13-cis-retinoic acid metabolite 4-oxo-13-cis-retinoic acid in neuroblastoma.[Pubmed:25039756]

Br J Pharmacol. 2014 Dec;171(23):5330-44.

BACKGROUND AND PURPOSE: Isotretinoin (13-cis-retinoic acid; 13-cRA) is a differentiation inducer used to treat minimal residual disease after myeloablative therapy for high-risk neuroblastoma. However, more than 40% of children develop recurrent disease during or after 13-cRA treatment. The plasma concentrations of 13-cRA in earlier studies were considered subtherapeutic while 4-oxo-13-cis-RA (4-oxo-13-cRA), a metabolite of 13-cRA considered by some investigators as inactive, were greater than threefold higher than 13-cRA. We sought to define the metabolic pathways of 13-cRA and investigated the anti-tumour activity of its major metabolite, 4-oxo-13-cRA. EXPERIMENTAL APPROACH: Effects of 13-cRA and 4-oxo-13-cRA on human neuroblastoma cell lines were assessed by DIMSCAN and flow cytometry for cell proliferation, MYCN down-regulation by reverse transcription PCR and immunoblotting, and neurite outgrowth by confocal microscopy. 13-cRA metabolism was determined using tandem MS in human liver microsomes and in patient samples. KEY RESULTS: Six major metabolites of 13-cRA were identified in patient samples. Of these, 4-oxo-13-cRA was the most abundant, and 4-oxo-13-cRA glucuronide was also detected at a higher level in patients. CYP3A4 was shown to play a major role in catalysing 13-cRA to 4-oxo-13-cRA. In human neuroblastoma cell lines, 4-oxo-13-cRA and 13-cRA were equi-effective at inducing neurite outgrowth, inhibiting proliferation, decreasing MYCN mRNA and protein, and increasing the expression of retinoic acid receptor-beta mRNA and protein levels. CONCLUSIONS AND IMPLICATIONS: We showed that 4-oxo-13-cRA is as active as 13-cRA against neuroblastoma cell lines. Plasma levels of both 13-cRA and 4-oxo-13-cRA should be evaluated in pharmacokinetic studies of Isotretinoin in neuroblastoma.

Chemical genetics reveals a complex functional ground state of neural stem cells.[Pubmed:17417631]

Nat Chem Biol. 2007 May;3(5):268-73.

The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.

Cellular metabolism and actions of 13-cis-retinoic acid.[Pubmed:11606944]

J Am Acad Dermatol. 2001 Nov;45(5):S129-35.

Retinoids (vitamin A and its derivatives) are potent substances for regulating the expression of many different genes within the body. The gene regulatory activities of retinoids are mediated primarily by the all-trans and 9-cis isomers of retinoic acid. Although 13-cis-retinoic acid (Isotretinoin) does not have the potent gene regulatory activity of the other two isomers, it is an effective pharmacologic agent for treating a variety of dermatologic conditions. Because 13-cis-retinoic acid is also a naturally occurring retinoid that is present in the circulation, question is raised as to the biochemical mechanism(s) responsible for its pharmacologic efficacy. Some of this efficacy likely arises from the ability of 13-cis-retinoic acid to undergo isomerization to the significantly more active all-trans and 9-cis isomers; however, this does not account for all of the pharmacologic effects observed upon use of this retinoid. Some recent studies suggest that 13-cis-retinoic acid may act by inhibiting the actions of enzymes that are needed to metabolize steroids, while other recent studies indicate that 13-cis-retinoic acid acts through membrane receptors present on the surface of cells. At the present, it is not possible to rule out still other possible biochemical actions of 13-cis-retinoic acid in the body. It is clear, however, that if we are to fully understand the basis for the clinical efficacy of 13-cis-retinoic acid, a better understanding of such biochemical actions is needed.