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13-cis-Retinoic acid, a drug used at high doses in the treatment of recalcitrant acne, increased the permeability of rat-liver microsomal membranes to mannose 6-phosphate in vitro, as indicated by an increase in mannose-6-phosphatase activity. At the same concentrations, four other amphiphiles, including all-trans-retinoic acid, were much less effective. 13-cis-Retinoic acid also inhibited retinol esterification and benzo[a]pyrene hydroxylation in microsome preparations in vitro. Although the molecular mechanism and the reversibility of these effects have not yet been studied, the interaction of 13-cis-retinoic acid with cell membranes may well be involved in both its therapeutic and toxic manifestations.
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Whole rat embryos cultured during the early stages of organogenesis were subjected to a panel of selected chemicals. Of seventeen known in vivo teratogens, seventeen also induced specific malformations in embryos grown in culture. Of ten chemicals which were reported to be negative in in vivo rat teratogenicity studies, eight also did not provoke dysmorphogenic effects in vitro. Of five additionally tested retinoids, all induced multiple malformations. However, concentrations used to induce these effects varied considerably, isotretinoin inducing malformations at 10(-5) M and arotinoid at 10(-11) M. The results indicate qualitatively as well as quantitatively a high predictability of this in vitro system and suggest that the postimplantation embryo culture system may also be useful in the prospective testing of new drugs and environmental chemicals.
Isotretinoin is effective in treating severe acne, but it is also teratogenic. To minimize pregnancies among exposed women, the manufacturer, together with the U.S. Food and Drug Administration, implemented a multicomponent Pregnancy Prevention Program in 1988. We report the results of an ongoing survey designed to assess compliance with this program.
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The prognosis of patients with metastasised follicular thyroid carcinoma (FTC) is limited, necessitating the search for new treatment options. Beneficial effects of retinoids have been suggested in thyroid cancer and the present study was performed to investigate the effects of retinoic acid (RA) on important determinants of metastatic behaviour in FTC: the disengagement of tumour cells from the primary tumour and the degradation of extracellular matrix, focusing on the role of the plasmin activation system and the integrin and E-cadherin families of attachment molecules. Three FTC cell lines were studied: FTC-133, derived from the primary tumour; and FTC-236 and FTC-238, derived from metastases. FTC cell lines were cultured with 0.1, 1 and 10 microM 13-cis-RA or with the solvent DMSO for 1 and 5 days. Extracellular matrix degradation by these cell lines was studied by assessing the 48-h release of radioactivity from (35)S-methionine labelled extracellular matrix proteins synthesised by the MC3T3 cell line coated onto plastic. The involvement of constituents of the plasmin activation system was investigated by semi-quantitative RT-PCR and zymography. Attachment to extracellular matrix was studied by determining the number of adhering FTC cells to extracellular matrix coated onto plastic, 3 h after seeding. The involvement of attachment molecules was studied by RT-PCR with primers for integrin subclasses and E-cadherin and immunofluorescence for E-cadherin. Five days culturing with 10 microM RA reduced the degradation of extracellular matrix significantly in all cell lines: FTC-133 by 35%, FTC-236 by 74% and FTC-238 by 31%. Zymography revealed diminished activity of urokinase type plasminogen activator (uPA) in FTC-236 and FTC-238, but not in FTC-133 cultured with RA. mRNA expression of the uPA receptor was diminished in FTC-236. In the attachment assay, 10 microM RA for 5 days increased the number of adherent cells to extracellular matrix significantly by 91% in FTC-133, 64% in FTC-236 and 87% in FTC-238. No effects of RA on integrin or E-cadherin mRNA expression were observed. Immunofluorescence, however, revealed enhanced organisation of E-cadherin along the cell membrane by RA treatment. In conclusion, the present study demonstrates beneficial effects of RA on important determinants of metastatic behaviour in FTC cell lines, e.g. decreased degradation of extracellular matrix which may in part be explained by effects on the plasmin activation system and enhanced attachment to extracellular matrix. These findings may add to the explanations for beneficial effects of retinoids in thyroid cancer.
This review summarizes important clinical developments in acne treatment identified in five systematic reviews and two significant primary research studies, published between March 2010 and February 2011. Although evidence showing a direct link between development of bacterial resistance and oral antibiotic therapy for acne is not convincing, prescribers can still tailor their practice to minimize future risks by stopping treatment when appropriate, using benzoyl peroxide, and avoiding combining topical and systemic antimicrobials. A systematic review evaluating combination products containing benzoyl peroxide did not show convincing evidence that such products are superior to monotherapies. A systematic review of combined oral contraceptives confirmed their efficacy for acne in women. However, another systematic review of botanical products for acne failed to provide any good-quality evidence of benefit. A large, well-reported retrospective cohort study attempted to clarify the potential link between isotretinoin and depression/suicide. Although suicide risk peaked 6 months after isotretinoin treatment, an increased risk was present before initiation of isotretinoin, making it difficult to attribute the increased risk to isotretinoin alone. However, those with a history of suicide attempts before treatment made fewer new attempts than those whose behaviour started during treatment. This suggests that patients with severe acne with a history of attempted suicide should not automatically be refused isotretinoin. Another randomized controlled trial of 60 patients from Korea suggested that low-dose isotretinoin dose than might provide a better long-term outcome with minimal side-effects for people with moderate acne.
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The EVI-1 gene encodes a Zn finger, DNA binding protein previously detected in some acute myelogenous leukemias (AML) and myelodysplasias (MDS), but not in normal marrow or cord blood cells. Experimental studies suggest EVI-1 blocks cellular differentiation by binding to GATA-1 or other specific DNA sequences controlling gene expression, and may be involved in the pathogenesis of some AMLs. To further define potential roles for EVI-1 in leukemia pathogenesis, we studied its regulation in acute promyelocytic leukemias (APL). Seven of 11 APL cases expressed EVI-1 RNA detected by RNA PCR at diagnosis, and expression was detected in two additional cases after treatment with all-trans retinoic acid (ATRA). Two of four cases studied at relapse also expressed EVI-1 RNA. To investigate regulation of EVI-1 expression in APL, we examined its expression in the NB4 APL cell line. NB4 cells did not express EVI-1 under basal conditions, but expressed EVI-1 after ATRA-induced differentiation. When NB4 cells were exposed to ATRA and transferred to cultures with N,N'-hexamethylene-bis-acetamide (HMBA), differentiation occurred but EVI-1 RNA was not detected, indicating that EVI-1 expression was not required for terminal, NB4 differentiation. ATRA-resistant NB4 cells were obtained by continuous culture in gradually increasing concentrations of ATRA. These cells did not express markers of differentiation but continued to express EVI-1 for several weeks even after ATRA withdrawal. To assess whether expression of the APL PML-RAR alpha fusion gene alone was sufficient for ATRA induction of EVI-1, the PML-RAR alpha gene cDNA was expressed in U937 histiocytic lymphoma cells. ATRA treatment of PML-RAR alpha-transfected or control U937 cells did not induce EVI-1 expression. In conclusion, this study demonstrates the EVI-1 gene is consistently expressed in APL cells either constitutively or after ATRA treatment. ATRA represents the first biologically active agent shown to specifically regulate EVI-1 expression in blood cells. In contrast to previous studies in AML and MDS, the pattern of EVI-1 expression suggests it may facilitate rather than inhibit myeloid differentiation during ATRA treatment. However, effects of EVI-1 expression are likely to be complex, and expression in ATRA-resistant APL cells may indicate multiple roles for this gene.
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The trials were generally small and of poor quality and in many cases the published reports were inadequate for our purpose. Pooling of the studies was not attempted due to the lack of common outcome measures and endpoints and the unavailability of some primary data. Although minocycline was shown to be an effective treatment for acne vulgaris, in only two studies was it found to be superior to other tetracyclines. Both of these were conducted under open conditions and had serious methodological problems. A third study showed it to be more effective than 2% fusidic acid, applied topically, against inflammatory lesions in mild to moderate acne. Differences in the way adverse drug reactions were identified could have accounted for the wide variation between studies in numbers of events reported. This meant that no overall evaluation could be made of incidence rates of adverse events associated with minocycline therapy. No RCT evidence was found to support the benefits of minocycline in acne resistant to other therapies and the dose response has only been evaluated up to eight weeks of therapy. (ABSTRACT TRUNCATED)
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A cross-sectional retrospective analysis was made of patients with RCS. Demographic data, clinical features, histology, blood parameters, radiology and management and response to therapy were recorded.
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To test this hypothesis, we measured insulin resistance in 48 patients with acne vulgaris (AV) before and after 3 months of isotretinoin treatment.
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Ganglioglioma is an uncommon brain tumor with glial and neuronal cellular components and a somewhat benign course. We are presenting an unusual case of ganglioglioma with malignant transformation in both cellular components associated with an aggressive clinical course. An almost complete resolution of the recurrent progressing tumor was achieved after treatment with cis-retinoic acid (cRA) as a single agent. A possible differential effect of cRA on the neuronal component of the tumor is suggested.
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Previous national and international studies of quality of life (QoL) in patients with skin diseases have revealed different levels of QoL impairment. The aims of this study were to assess QoL in patients with skin diseases in central Saudi Arabia using the newly validated Skindex-16 instrument and to determine the association between QoL in patients with skin disease, sociodemographic data, and disease characteristics.
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The growing number of reported cases of depression and suicide associated with isotretinoin (a retinoid receptor agonist) use in patients with acne has prompted concern among dermatologists, patients, and their relatives and has triggered new warnings from regulators including depression-related, patient-informed consent forms. In establishing a cause-effect relationship, it is useful to judiciously consider whether there is an association, what is the nature of that association, if there is a plausible biological mechanism of action, the validity and reliability of measures used and the strength of study designs. Hoffmann-La Roche estimates that by April 2001 approximately 12 million patients worldwide have used isotretinoin, with 5 million patients in the US.A MEDLINE search between January 1966 and May 14 2003 of the published medical literature found 24 documented cases of isotretinoin-associated depression, with 3 suicides. One additional patient committed suicide during the fourth month of isotretinoin treatment and 3 further patients attempted suicide by taking an overdose of isotretinoin. The US FDA's Adverse Event Reporting System (AERS) contains almost 23,000 reports for isotretinoin from its approval in 1982 to December 2002. As of November 30, 2002, AERS contained 3,104 reports (US and foreign) with at least one reported psychiatric event. The FDA is aware of 173 reports of suicide (both US and foreign) in association with isotretinoin. Reports of positive dechallenge and rechallenge present a strong signal pointing to an association between isotretinoin and depression. A Hoffmann-La Roche sponsored epidemiological study failed to find any evidence of an association between isotretinoin and depression or suicide. However, the design of the study was flawed and the evidence was deemed inconclusive. Further studies using strong study designs, reliable and valid measures, and adequate sample sizes may bring us closer to the answer. The evidence suggesting a relationship between isotretinoin and depression needs to be weighed against the increasing prevalence of depression among adolescents and young adults and the psychological impact of acne. The literature contains credible evidence that isotretinoin treatment may reduce the psychosocial impact of acne in some patients. At the present time, there is no known pharmacological mechanism that would account for psychiatric symptomatology as a result of isotretinoin treatment; however, retinoid receptors are widely distributed in the brain and more research is needed to ascertain whether they have a role in depression. In the meantime, for the practitioner, the obvious benefit of isotretinoin in treating acne should encourage continued use. However, patients and their relatives must be informed and depressive symptoms should be actively assessed at each visit and, if necessary, referral to a psychiatrist, antidepressant therapy or discontinuation of isotretinoin should be considered.
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Combining chemotherapy and immunotherapeutic agents such as interleukin-2 and interferon alpha-2b might improve treatment results in metastatic melanoma (MM) patients compared with chemotherapy alone. This prospective study evaluated the potential efficacy of a biochemotherapy regimen followed by maintenance biotherapy for the treatment of MM. Twenty-two patients with stage IV melanoma were treated for 5 consecutive days with cisplatin at 20 mg/m, vinblastine at 1.6 mg/m, and dacarbazine at 160 mg/m. Pegylated interferon alpha-2b at a dose of 50 microg every week, subcutaneous interleukin-2, 1.8 MIU, and oral 13-cis-retinoic acid (13-cis-RA) at 0.5 mg/kg were given 5 days/week for 3 weeks each month during the period of chemotherapy administration. Maintenance biotherapy was continued in patients who had a complete or partial response or disease stability (clinical benefit) after six courses of biochemotherapy. The primary endpoint was response; secondary endpoints were the evaluation of the immunologic parameters, toxicity, progression-free survival, and overall survival. Twelve patients (54.5%) achieved a response, and seven (31.8%) maintained stable disease for at least 6 months with maintenance biotherapy. The median progression-free survival and overall survival were 23.3 and 45.7 months, respectively. The most important toxicities from chemotherapy were grades 3 and 4 neutropenia and thrombocytopenia in 41 and 18% of patients, respectively, whereas grade 2 autoimmune reactions were observed in 21% of patients after maintenance biotherapy. A prolonged enhancement of immunologic function was observed in the 19 patients treated with maintenance therapy. A regimen of six cycles of biochemotherapy followed by maintenance immunotherapy is well tolerated, and shows significant activity in patients with MM.
Of the 8609 women included, 90 became pregnant, an annual incident pregnancy rate during isotretinoin treatment of 32.7 per 1000 person-years of treatment (95% confidence interval 26.6, 40.1). Of the 90 women who became pregnant while on the drug, 76 terminated the pregnancy (84%), three had a spontaneous abortion (3%), two had trauma during delivery resulting in neonatal deaths (2%) and nine had a live birth (10%). Among the live births, only one had a congenital anomaly of the face and neck (11%). Adjusting for potential confounders, predictors of becoming pregnant while on isotretinoin were lower socio-economic level, one or more visits to the doctor or to the emergency department, or one or more hospitalization while on isotretinoin; concomitant isotretinoin and oral contraceptive use had a preventive effect.
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Of 51 HIV-positive patients with itchy folliculitis, the predominant lesion was EF in 23 (45.1%) followed by bacterial folliculitis in 21 (41.2%), Pityrosporum folliculitis in five (9.8%) and Demodex folliculitis in two (3.9%) patients. The diagnosis was based on characteristic histopathological features and was also associated with microbiology confirmation wherever required. EF was associated with a lower mean CD4 count (180.58 +/- 48.07 cells/mm3, P-value < 0.05), higher mean CD8 count (1675.42 +/- 407.62 cells/mm3) and CD8/CD4 ratio of 9.27:1. There was significant reduction in lesions following specific treatment for the specific lesion identified.
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Isotretinoin is a remarkably effective drug for severe, recalcitrant acne vulgaris. Soon after the drug's release in the early 1980s, a number of important adverse effects were reported subsequently leading to a variety of medical and medicolegal controversies. Three of these controversies will be highlighted concerning the putative role of isotretinoin in (1) depression and suicide, (2) inflammatory bowel disease, and (3) iPledge and pregnancy prevention programs. It appears that a very small subset of patients receiving isotretinoin for acne are at risk for depression, which is very manageable provided there is adequate patient awareness of the possibility, maximum communication between the patient and physician, and cessation of therapy if clinically important depression occurs (after which the depression rapidly resolves in a week or less). Multiple controlled studies actually suggest a very favorable effect of isotretinoin on depression and anxiety common in the population requiring isotretinoin. With regard to inflammatory bowel disease, in just one study, only ulcerative colitis association with isotretinoin reached statistical significance. The actual incidence of this association is strikingly low. Finally, it is clear that even the most recent pregnancy prevention program (iPledge) is no more successful than prior programs; there will likely always be a small number of female patients becoming pregnant while receiving isotretinoin for acne vulgaris.
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The diagnosis of pityriasis rubra pilaris is based essentially on characteristic clinical features. Although the histologic features are not pathognomonic, a lesional skin biopsy for evaluation is important to rule out other papulosquamous and erythematous disorders. The presence of prominent seborrheic keratoses occurring in two cases of pityriasis rubra pilaris is presented. Our understanding of the relationship between vitamin A metabolism and pityriasis rubra pilaris is discussed. Currently available systemic therapeutic modalities for pityriasis rubra pilaris are reviewed. Although pityriasis rubra pilaris does not represent a vitamin A deficiency state, it is responsive to isotretinoin, etretinate, and vitamin A. Antimetabolites remain an alternative therapy.
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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.
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Cholecalciferol levels in plasma and pleural fluid of patients with TB and healthy controls were 67.45 (10.71) nmol/L and 21.40 (8.58) nmol/L compared with 117.43 (18.40) nmol/L (P < 0.001) and 94.73 (33.34) nmol/L (P = 0.0049), respectively. 13-cis-RA level in the plasma of patients with TB and healthy controls were 1.51 (0.72) nmol/L and 6.67 (0.81) nmol/L (P < 0.001), respectively. 13-cis-RA was not detectable in pleural fluid. The levels of both the agents were lower in patients with TB than in controls.
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Isotretinoin, a teratogen, is widely used to treat cystic acne. Although the risks of pregnancy during isotretinoin therapy are well recognized, there are doubts about the level of adherence with the pregnancy prevention program in Canada. Our objective was to evaluate the effectiveness of the Canadian pregnancy prevention program in 4 provinces: British Columbia, Saskatchewan, Manitoba and Ontario.
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Retinoic acids exert a wide physiological role in development and differentiation. Retinoic acids have also been used in the treatment of human cancers, particularly in acute promyelocytic leukemia (APL). A structure-function relationship of the RA isomers in terms of clinical effect has been observed since all-trans retinoic acid (ATRA) induces a high complete remission rate while 13-cis retinoic acid (13-cis RA) shows much poorer effect. In this study, we examined the effect of RA isomers, including ATRA, 13-cis RA and 9-cis RA, on the proliferation and differentiation of NB4 cells. A number of parameters such as cell growth curve, dynamics of cell cycle, expression of clusters of differentiation and reduction of nitro blue tetrazolium (NBT) as well as immunofluorescence staining of PML were used to evaluate the effects of three isomers at two concentrations (10(-8) M and 10(-7) M). It has been shown that during the first 48 h of RA treatment, the APL cell differentiation was coupled with the cell proliferation. Although similar effects of proliferation inhibition and differentiation induction were observed among the three isomers at 10(-7) M, significant differences appeared at a concentration of 10(-8) M, 9-cis RA showed a higher activity than that of ATRA, while ATRA showed better results than 13-cis RA. Our results provide further evidence that 9-cis RA could be a promising molecule in differentiation induction of malignant cells.
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One-fifth (18.5%) of patients reported no adverse effects during the study period. Cheilitis was the most commonly reported adverse effect, affecting 78% of users, followed by eczema and tiredness, seen in 12% each. However, these were clearly dose-dependent, as the group treated with doses of isotretinoin under 0.25 mg/kg/day only reported cheilitis in 47%, eczema in 7% and tiredness in 5%, compared with 96%, 16% and 18%, respectively, in those treated with more than 0.75 mg/gm/day. Twenty-four patients (1.4%) stopped isotretinoin because of adverse effects; a further three patients complained of severe adverse effects on at least one occasion, but continued taking the medication. The adverse effect(s) that led to patients stopping isotretinoin were cheilitis (22 patients), mood change (13), tiredness (12), eczema (6) and pregnancy (2). There were no reported instances of suicidal ideation or attempted suicide.
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This study assessed the effect of topical and systemic 13-cis-retinoic acid on rat palatal epithelial proliferation with bromodeoxyuridine labelling and silver stained nucleolar organizer regions. Sixty male Wistar rats were assigned randomly to a control group or treatment groups of topical orabase, RA in orabase, 5 times/week or twice weekly systemic doses of 12 mg RA in coconut oil. The rats were treated for 1, 2, 4 or 8 weeks and killed 1 h post-injection of 40 mg/kg BrdUrd. The palatal mucosae were processed, using immunoperoxidase staining or silver stain to visualize BrdUrd utilization or AgNORs, respectively. The number of BrdUrd positive nuclei/mm overlying epithelium and number and area of AgNORs in the basal cells were assessed using image analysis. ANOVA indicated there was no significant effect of treatment on LN/mm or the numbers or areas of AgNORs. The LN/mm for the 8 w group (29.5) was significantly lower than the other groups. RA did not influence rat palatal epithelial proliferation, but across all groups increased age was associated with decreased proliferation. It would appear that the proliferation of normal oral mucosa may not be subject to altered proliferation when treated with therapeutic doses of topical or systemic RA.