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Lymphatic Research and Biology Feb 2019The fibroblast growth factor receptor (FGFR) family includes transmembrane receptors involved in a wide range of developmental and postdevelopmental biologic processes...
BACKGROUND
The fibroblast growth factor receptor (FGFR) family includes transmembrane receptors involved in a wide range of developmental and postdevelopmental biologic processes as well as a wide range of human diseases. In particular, FGFR3 has been implicated in the mechanism by which 9-cis retinoic acid (9-cisRA) induces lymphangiogenesis and improves lymphedema. The purpose of this study was to validate the efficacy of a novel small peptide FGFR3 inhibitor, peptide P3 (VSPPLTLGQLLS), and to elucidate the role of FGFR3 in 9-cisRA-induced lymphangiogenesis using this peptide.
METHODS AND RESULTS
Peptide P3 effectively inhibited FGFR3 phosphorylation. In vitro, peptide P3-mediated FGFR3 inhibition did not decrease lymphatic endothelial cell (LEC) proliferation, migration, or tubule formation. However, peptide P3-mediated FGFR3 inhibition did block 9-cisRA-stimulated LEC proliferation, migration, and tubule formation. In vivo, peptide P3-mediated FGFR3 inhibition was sufficient to inhibit 9-cisRA-induced tracheal lymphangiogenesis.
CONCLUSION
FGFR3 does not appear to be essential to nonpromoted LEC proliferation, migration, and tubule formation. However, FGFR3 may play a key role in LEC proliferation, migration, tubule formation, and postnatal in vivo lymphangiogenesis when pharmacologically induced by 9-cisRA. P3 may have the potential to be used as a precise regulatory control element for 9-cisRA-mediated lymphangiogenesis.
Topics: Alitretinoin; Amino Acid Sequence; Animals; Biological Assay; Cell Movement; Cell Proliferation; Endothelial Cells; Gene Expression Regulation; Humans; Lymphangiogenesis; Lymphedema; Mice; Mice, Transgenic; Oligopeptides; Phosphorylation; Receptor, Fibroblast Growth Factor, Type 3; Signal Transduction; Trachea
PubMed: 30648916
DOI: 10.1089/lrb.2018.0035 -
JAAD Case Reports Jan 2019
PubMed: 30581938
DOI: 10.1016/j.jdcr.2018.09.024 -
Drug Safety - Case Reports Oct 2018Two female patients aged 45 and 51 years experienced curling of hair during treatment with alitretinoin (Toctino). For one patient, the indication for use was severe...
Two female patients aged 45 and 51 years experienced curling of hair during treatment with alitretinoin (Toctino). For one patient, the indication for use was severe chronic hand eczema, but for the second patient the indication was not reported. After 5 and 9 months, respectively, the patients developed hair texture changes and their straight hair began to curl. The dose of alitretinoin was reduced in both cases, but the patients' hair had not straightened at the time of reporting (9 months and 2 years after onset of the event). Based on the described reports received by the Netherlands Pharmacovigilance Centre Lareb, the case reports in the literature, and the possible mechanisms, we suggest a causal relationship between curling of the hair and the use of alitretinoin. Using the World Health Organization Uppsala Monitoring Centre (WHO-UMC) system for standardized case causality assessment, the association in our cases can be assessed as likely.
PubMed: 30327960
DOI: 10.1007/s40800-018-0092-1 -
Orphanet Journal of Rare Diseases Sep 2018IgA pemphigus is an exceedingly rare autoimmune blistering disorder, caused by IgA autoantibodies against desmosomal proteins. No treatment option has been found to be...
IgA pemphigus is an exceedingly rare autoimmune blistering disorder, caused by IgA autoantibodies against desmosomal proteins. No treatment option has been found to be universally effective. The disease is often recalcitrant to oral steroids and immunosuppressants. Here, we describe the use of systemic retinoids for the treatment of recalcitrant IgA pemphigus in 3 cases. Although the use of acitretin has been reported before, we present for the first time the positive effects of alitretinoin in treatment of 2 patients with IgA pemphigus. Besides hyperlipoproteinaemia requiring use of hypolipidemic agents in one case, alitretinoin was well-tolerated and has generally a more favorable side effect spectrum than immunosuppressants.
Topics: Alitretinoin; Female; Fluorescent Antibody Technique, Direct; Humans; Immunoglobulin A; Pemphigus; Retinoids
PubMed: 30227880
DOI: 10.1186/s13023-018-0899-y -
Scientific Reports Aug 2018The detection of left main coronary artery disease (LMCAD) is crucial before ST-segment elevated myocardial infarction (STEMI) or sudden cardiac death. The aim of this... (Clinical Trial)
Clinical Trial
The detection of left main coronary artery disease (LMCAD) is crucial before ST-segment elevated myocardial infarction (STEMI) or sudden cardiac death. The aim of this study was to identify characteristic metabolite modifications in the LMCAD phenotype, using the metabolomics technique. Metabolic profiles were generated based on ultra-performance liquid chromatography and mass spectrometry, combined with multivariate statistical analysis. Plasma samples were collected prospectively from a propensity-score matched cohort including 44 STEMI patients (22 consecutive LMCAD and 22 non-LMCAD), and 22 healthy controls. A comprehensive metabolomics data analysis was performed with Metaboanalyst 3.0 version. The retinol metabolism pathway was shown to have the strongest discriminative power for the LMCAD phenotype. According to biomarker analysis through receiver-operating characteristic curves, 9-cis-retinoic acid (9cRA) dominated the first page of biomarkers, with area under the curve (AUC) value 0.888. Next highest were a biomarker panel consisting of 9cRA, dehydrophytosphingosine, 1H-Indole-3-carboxaldehyde, and another seven variants of lysophosphatidylcholines, exhibiting the highest AUC (0.933). These novel data propose that the retinol metabolism pathway was the strongest differential pathway for the LMCAD phenotype. 9cRA was the most critical biomarker of LMCAD, and a ten-metabolite plasma biomarker panel, in which 9cRA remained the weightiest, may help develop a potent predictive model for LMCAD in clinic.
Topics: Aged; Alitretinoin; Biomarkers; Coronary Artery Disease; Female; Humans; Male; Metabolomics; Middle Aged; ST Elevation Myocardial Infarction
PubMed: 30154509
DOI: 10.1038/s41598-018-30219-w -
Skin Therapy Letter Jul 2018Chronic hand dermatitis is a debilitating inflammatory dermatosis that has a significant impact on the quality of life of those affected. Alitretinoin is an oral... (Review)
Review
Chronic hand dermatitis is a debilitating inflammatory dermatosis that has a significant impact on the quality of life of those affected. Alitretinoin is an oral retinoid which has proven efficacy and safety in the treatment of chronic hand dermatitis through randomized controlled trials. Real-world evidence, information gathered in the clinic or community setting, as opposed to a research environment, can complement knowledge gained from clinical trials. Herein, real-world evidence supporting the safety and effectiveness of alitretinoin in the management of chronic hand dermatitis will be reviewed.
Topics: Administration, Oral; Alitretinoin; Chronic Disease; Eczema; Hand Dermatoses; Humans; Randomized Controlled Trials as Topic; Retinoids
PubMed: 30086182
DOI: No ID Found -
BMJ Open Jul 2018Systemic treatment with alitretinoin is registered for all clinical types of severe chronic hand eczema. However, it is especially effective in the hyperkeratotic...
Study protocol: efficacy of oral alitretinoin versus oral cyclosporine A in patients with severe recurrent vesicular hand eczema (ALICsA): a randomised prospective open-label trial with blinded outcome assessment.
INTRODUCTION
Systemic treatment with alitretinoin is registered for all clinical types of severe chronic hand eczema. However, it is especially effective in the hyperkeratotic subtype and less effective in non-hyperkeratotic forms. Cyclosporine A (cyclosporine) is prescribed for hand eczema in daily practice as well. It has shown to be particularly effective in patients with vesicular hand eczema. The primary objective of this study is to compare efficacy of alitretinoin and cyclosporine in the treatment of severe recurrent vesicular hand eczema.
METHODS AND ANALYSIS
This is an investigator-initiated randomised prospective open-label trial with blinded outcome assessment. Severity assessments and laboratory measurements will be conducted corresponding to daily practice. The study population will consist of 72 adult patients (age 18-75 years) with severe recurrent vesicular hand eczema. Patients are treated with either (group I) alitretinoin 30 mg once daily or (group II) cyclosporine with a starting dose of 5 mg/kg/day and a decrease in dosage after 8 weeks to 3-3.5 mg/kg/day. The treatment period is 24 weeks for both drugs. Primary endpoint for efficacy is response to treatment, defined as an improvement of ≥2 steps on a Physician Global Assessment, using a validated Photoguide, after 24 weeks of treatment. Secondary endpoints are improvement of Hand Eczema Severity Index, Quality of Life in Hand Eczema Questionnaire and a Patient Global Assessment. Adverse events and time to response will be registered. Furthermore, cost-utility, quality-adjusted life years and cost-effectiveness will be assessed with the EQ-5D-5L questionnaire while monitoring costs.
ETHICS AND DISSEMINATION
This protocol was reviewed and approved by the Medical Ethical Review Board of the University Medical Centre Groningen (reference METc 2015/375). The study will be conducted according to the principles of the Declaration of Helsinki, in accordance with the Dutch Medical Research Involving Human Subjects Act.
TRIAL REGISTRATION NUMBER
NCT03026946; Pre-results.
Topics: Adolescent; Adult; Aged; Alitretinoin; Chronic Disease; Cyclosporine; Dermatologic Agents; Eczema; Female; Hand Dermatoses; Humans; Immunosuppressive Agents; Male; Middle Aged; Patient Reported Outcome Measures; Pregnancy; Prospective Studies; Psychometrics; Quality of Life; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Severity of Illness Index; Young Adult
PubMed: 29997136
DOI: 10.1136/bmjopen-2017-020192 -
Nucleic Acids Research Jul 2018Allostery tweaks innumerable biological processes and plays a fundamental role in human disease and drug discovery. Exploration of allostery has thus been regarded as a...
Allostery tweaks innumerable biological processes and plays a fundamental role in human disease and drug discovery. Exploration of allostery has thus been regarded as a crucial requirement for research on biological mechanisms and the development of novel therapeutics. Here, based on our previously developed allosteric data and methods, we present an interactive platform called AlloFinder that identifies potential endogenous or exogenous allosteric modulators and their involvement in human allosterome. AlloFinder automatically amalgamates allosteric site identification, allosteric screening and allosteric scoring evaluation of modulator-protein complexes to identify allosteric modulators, followed by allosterome mapping analyses of predicted allosteric sites and modulators in human proteome. This web server exhibits prominent performance in the reemergence of allosteric metabolites and exogenous allosteric modulators in known allosteric proteins. Specifically, AlloFinder enables identification of allosteric metabolites for metabolic enzymes and screening of potential allosteric compounds for disease-related targets. Significantly, the feasibility of AlloFinder to discover allosteric modulators was tested in a real case of signal transduction and activation of transcription 3 (STAT3) and validated by mutagenesis and functional experiments. Collectively, AlloFinder is expected to contribute to exploration of the mechanisms of allosteric regulation between metabolites and metabolic enzymes, and to accelerate allosteric drug discovery. The AlloFinder web server is freely available to all users at http://mdl.shsmu.edu.cn/ALF/.
Topics: Alitretinoin; Allosteric Regulation; Allosteric Site; Datasets as Topic; Drug Discovery; Gene Expression Regulation; Humans; Internet; Ligands; Molecular Docking Simulation; Mutagenesis, Site-Directed; Receptors, Retinoic Acid; Receptors, Thyroid Hormone; STAT3 Transcription Factor; Small Molecule Libraries; Software; Transcription, Genetic; Triiodothyronine
PubMed: 29757429
DOI: 10.1093/nar/gky374 -
Cancer Science Jul 2018Deciphering the molecular networks that discriminate organ-confined breast cancer from metastatic breast cancer may lead to the identification of critical biomarkers for...
Deciphering the molecular networks that discriminate organ-confined breast cancer from metastatic breast cancer may lead to the identification of critical biomarkers for breast cancer invasion and aggressiveness. Here metabolomics, a global study of metabolites, has been applied to explore the metabolic alterations that characterize breast cancer progression. We profiled a total of 693 metabolites across 87 serum samples related to breast cancer (46 clinically localized and 41 metastatic breast cancer) and 49 normal samples. These unbiased metabolomic profiles were able to distinguish normal individuals, clinically localized and metastatic breast cancer patients. 9-cis-Retinoic acid, an isomer of all-trans retinoic acid, was identified as a differential metabolite that significantly decreased during breast cancer progression to metastasis, and its levels were also reduced in urine samples from biopsy-positive breast cancer patients relative to biopsy-negative individuals and in invasive breast cancer cells relative to benign MCF-10A cells. The addition of exogenous 9-cis-retinoic acid to MDA-MB-231 cells and knockdown of aldehyde dehydrogenase 1 family member A1, a regulatory enzyme for 9-cis-retinoic acid, remarkably impaired cell invasion and migration, presumably through preventing the key regulator cofilin from activation and inhibiting MMP2 and MMP9 expression. Taken together, our study showed the potential inhibitory role for 9-cis-retinoic acid in breast cancer progression by attenuating cell invasion and migration.
Topics: Adult; Aged; Alitretinoin; Breast Neoplasms; Disease Progression; Female; Humans; Metabolomics; Middle Aged; Tretinoin
PubMed: 29737597
DOI: 10.1111/cas.13629 -
Orphanet Journal of Rare Diseases Apr 2018Acitretin is the main retinoid used to treat severe inherited ichthyosis. Alternatives may be considered if it results ineffective or there are side-effects, or for...
BACKGROUND
Acitretin is the main retinoid used to treat severe inherited ichthyosis. Alternatives may be considered if it results ineffective or there are side-effects, or for women of childbearing age. Our objective is evaluation of the effects and tolerance of alitretinoin. An observational retrospective multicentric study was designed to analyse patients with inherited ichthyosis treated by alitretinoin.
RESULTS
A total of 13 patients were included, 11 of whom were receiving acitretin at inclusion. The main reason for switching to alitretinoin was a desire for pregnancy, but also because of side-effects or unsatisfactory efficacy. Starting dose was 10 mg/day, increased to 20 or 30 mg/day. Alitretinoin seemed to be more effective than acitretin at reducing erythema, but was less effective at reducing scaling or hyperkeratosis. Global efficacy was considered low for two patients, moderate for nine, and high for two. Treatment was well-tolerated, except for one patient who presented with benign intracranial hypertension leading to discontinuation of treatment.
CONCLUSIONS
Alitretinoin may be suitable for hereditary ichthyosis with prominent erythema, especially for women of childbearing age.
Topics: Adult; Alitretinoin; Child; Dermatologic Agents; Erythema; Female; Genetic Predisposition to Disease; Humans; Ichthyosis; Male; Retrospective Studies; Young Adult
PubMed: 29618363
DOI: 10.1186/s13023-018-0783-9