1 1160 84 CONTINUING WAR ON PAIN: A PERSONALIZED APPROACH TO THE THERAPY WITH NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND OPIOIDS. SUCCESSFUL PAIN MANAGEMENT REQUIRES THE DELIVERY OF ANALGESIA WITH MINIMAL RISK OF ADVERSE DRUG REACTIONS. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND OPIOIDS REMAIN THE MAINSTAY OF TREATMENT FOR THE MAJORITY OF PATIENTS. UNFORTUNATELY, ALMOST 50% OF ALL PATIENTS EXPERIENCE INADEQUATE PAIN RELIEF AND SERIOUS SIDE EFFECTS. ALLELIC VARIANTS IN GENES CODING FOR TARGET PROTEINS, TRANSPORTERS AND ENZYMES, WHICH GOVERN ANALGESIC DRUGS ACTION AND THEIR FATE IN THE ORGANISM, MIGHT EXPLAIN INTER-INDIVIDUAL VARIABILITY IN PAIN SEVERITY AND IN DRUG-INDUCED PAIN RELIEF AND TOXICITIES. ADDITIONALLY, IT SEEMS THAT EPIGENETIC CHANGES CONTRIBUTE TO THE HIGHLY VARIABLE RESPONSE TO PAIN TREATMENT. THEREFORE, PHARMACOGENOMIC TESTING MIGHT BE A VALUABLE TOOL FOR PERSONALIZATION OF PAIN TREATMENT, WITH A MULTIDISCIPLINARY TEAM APPROACH INVOLVED. 2019 2 3996 16 LOOKING FORWARD: NOVEL THERAPEUTIC APPROACHES IN CHRONIC AND ADVANCED PHASES OF MYELOFIBROSIS. MYELOFIBROSIS (MF) IS COMPLEX AT THE PATHOBIOLOGIC LEVEL AND HETEROGENEOUS AT THE CLINICAL LEVEL. THE ADVANCES IN MOLECULAR CHARACTERIZATION OF MF PROVIDE IMPORTANT INSIGHT INTO THE MECHANISMS DRIVING THIS CHRONIC MYELOID MALIGNANCY, REFINE RISK STRATIFICATION, OFFER NOVEL THERAPEUTIC TARGETS, AND SERVE TO MEASURE THERAPEUTIC RESPONSE. ALTHOUGH JAK2 INHIBITION HAS BEEN THE FOCUS OF LABORATORY AND CLINICAL EFFORTS OVER THE LAST DECADE, CURRENT EXPERIMENTAL THERAPEUTIC APPROACHES HAVE BROADENED TO INCLUDE INHIBITORS OF KEY ALTERNATIVE SIGNALING PATHWAYS, EPIGENETIC MODULATORS, ANTI-FIBROTICS, AND IMMUNOTHERAPIES. BASED ON COMPELLING PRECLINICAL RATIONALE, A NUMBER OF JAK2 INHIBITOR BASED COMBINATION THERAPIES ARE NOW ACTIVELY BEING EVALUATED IN THE CLINIC WITH THE GOAL OF DISEASE COURSE MODIFICATION. THE ROLE AND TIMING OF HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT) FOR MF HAS BEEN CHALLENGED WITH THE AVAILABILITY OF COMMERCIAL RUXOLITINIB AND THE PLETHORA OF EXPERIMENTAL TREATMENT OPTIONS THAT EXIST. INTEGRATION OF PRECONDITIONING JAK2 INHIBITION, REDUCED INTENSITY CONDITIONING REGIMENS, AND ALTERNATIVE DONOR SOURCES ARE ALL BEING EXPLORED IN AN ATTEMPT TO OPTIMIZE THIS POTENTIALLY CURATIVE MODALITY. THIS REVIEW WILL SUMMARIZE MODERN MF RISK STRATIFICATION, CURRENT CLINICAL RESEARCH APPROACHES TO CHRONIC AND ADVANCE PHASE MF FOCUSING ON NOVEL AGENTS ALONE AND IN COMBINATION, AND UPDATE THE READER ON NEW DIRECTIONS IN HSCT. 2015 3 5042 25 PHARMACOGENOMICS IN PAIN TREATMENT. THE EXPERIENCE OF CHRONIC PAIN IS ONE OF THE COMMONEST REASONS FOR SEEKING MEDICAL ATTENTION, BEING A MAJOR ISSUE IN CLINICAL PRACTICE. WHILE PAIN IS A UNIVERSAL EXPERIENCE, ONLY A SMALL PROPORTION OF PEOPLE WHO FELT PAIN DEVELOP PAIN SYNDROMES. IN ADDITION, PAINKILLERS ARE ASSOCIATED WITH WIDE INTER-INDIVIDUAL VARIABILITY IN THE ANALGESIC RESPONSE. THIS MAY BE PARTLY EXPLAINED BY THE PRESENCE OF SINGLE NUCLEOTIDE POLYMORPHISMS IN GENES ENCODING MOLECULAR ENTITIES INVOLVED IN PHARMACODYNAMICS AND PHARMACOKINETICS. HOWEVER, UPTAKE OF THIS INFORMATION HAS BEEN SLOW DUE IN LARGE PART TO THE LACK OF ROBUST EVIDENCES DEMONSTRATING CLINICAL UTILITY. FURTHERMORE, NOVEL THERAPIES, INCLUDING TARGETING OF EPIGENETIC CHANGES AND GENE THERAPY-BASED APPROACHES ARE FURTHER BROADENING FUTURE OPTIONS FOR THE TREATMENT OF CHRONIC PAIN. THE AIM OF THIS ARTICLE IS TO REVIEW THE EVIDENCES BEHIND PHARMACOGENETICS (PGX) TO INDIVIDUALIZE THERAPY (BOOSTING THE EFFICACY AND MINIMIZING POTENTIAL TOXICITY) AND GENES IMPLICATED IN PAIN MEDICINE, IN TWO PARTS: (I) GENETIC VARIABILITY WITH PAIN SENSITIVITY AND ANALGESIC RESPONSE; AND (II) PHARMACOLOGICAL CONCEPTS APPLIED ON PGX. 2016 4 6061 17 THE DEVELOPMENT PROSPECTION OF HDAC INHIBITORS AS A POTENTIAL THERAPEUTIC DIRECTION IN ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS A CHRONIC NEURODEGENERATIVE DISEASE, WHICH IS ASSOCIATED WITH LEARNING AND MEMORY IMPAIRMENT IN THE ELDERLY. RECENT STUDIES HAVE FOUND THAT TREATING AD IN THE WAY OF CHROMATIN REMODELING VIA HISTONE ACETYLATION IS A PROMISING THERAPEUTIC REGIMEN. IN A NUMBER OF RECENT STUDIES, INHIBITORS OF HISTONE DEACETYLASE (HDACS) HAVE BEEN FOUND TO BE A NOVEL PROMISING THERAPEUTIC AGENTS FOR NEUROLOGICAL DISORDERS, PARTICULARLY FOR AD AND OTHER NEURODEGENERATIVE DISEASES. ALTHOUGH HDAC INHIBITORS HAVE THE ABILITY TO AMELIORATE COGNITIVE IMPAIRMENT, SUCCESSFUL TREATMENTS IN THE CLASSIC AD ANIMAL MODEL ARE RARELY TRANSLATED INTO CLINICAL TRIALS. AS FOR THE REDUCTION OF UNWANTED SIDE EFFECTS, THE DEVELOPMENT OF HDAC INHIBITORS WITH INCREASED ISOFORM SELECTIVITY OR SEEKING OTHER DIRECTIONS IS A KEY ISSUE THAT NEEDS TO BE ADDRESSED. THE REVIEW FOCUSED ON LITERATURES ON EPIGENETIC MECHANISMS IN RECENT YEARS, ESPECIALLY ON HISTONE ACETYLATION IN TERMS OF THE ENHANCEMENT OF SPECIFICITY, EFFICACY AND AVOIDING SIDE EFFECTS FOR TREATING AD. 2017 5 1688 18 DUAL BET/HDAC INHIBITION TO RELIEVE NEUROPATHIC PAIN: RECENT ADVANCES, PERSPECTIVES, AND FUTURE OPPORTUNITIES. DESPITE THE INTENSE RESEARCH ON DEVELOPING NEW THERAPIES FOR NEUROPATHIC PAIN STATES, AVAILABLE TREATMENTS HAVE LIMITED EFFICACY AND UNFAVORABLE SAFETY PROFILES. EPIGENETIC ALTERATIONS HAVE A GREAT INFLUENCE ON THE DEVELOPMENT OF CANCER AND NEUROLOGICAL DISEASES, AS WELL AS NEUROPATHIC PAIN. HISTONE ACETYLATION HAS PREVAILED AS ONE OF THE WELL INVESTIGATED EPIGENETIC MODIFICATIONS IN THESE DISEASES. ALTERED SPINAL ACTIVITY OF HISTONE DEACETYLASE (HDAC) AND BROMO AND EXTRA TERMINAL DOMAIN (BET) HAVE BEEN DESCRIBED IN NEUROPATHIC PAIN MODELS AND RESTORATION OF THESE ABERRANT EPIGENETIC MODIFICATIONS SHOWED PAIN-RELIEVING ACTIVITY. OVER THE LAST DECADES HDACS AND BETS HAVE BEEN THE FOCUS OF DRUG DISCOVERY STUDIES, LEADING TO THE DEVELOPMENT OF NUMEROUS SMALL-MOLECULE INHIBITORS. CLINICAL TRIALS TO EVALUATE THEIR ANTICANCER ACTIVITY SHOWED GOOD EFFICACY BUT RAISED TOXICITY CONCERNS THAT LIMITED TRANSLATION TO THE CLINIC. TO MAXIMIZE ACTIVITY AND MINIMIZE TOXICITY, THESE COMPOUNDS CAN BE APPLIED IN COMBINATION OF SUB-MAXIMAL DOSES TO PRODUCE ADDITIVE OR SYNERGISTIC INTERACTIONS (COMBINATION THERAPY). RECENTLY, OF PARTICULAR INTEREST, DUAL BET/HDAC INHIBITORS (MULTI-TARGET DRUGS) HAVE BEEN DEVELOPED TO ASSURE SIMULTANEOUS MODULATION OF BET AND HDAC ACTIVITY BY A SINGLE MOLECULE. THIS REVIEW WILL SUMMARIZE THE MOST RECENT ADVANCES WITH THESE STRATEGIES, DESCRIBING ADVANTAGES AND LIMITATIONS OF SINGLE DRUG TREATMENT VS COMBINATION REGIMENS. THIS REVIEW WILL ALSO PROVIDE A FOCUS ON DUAL BET/HDAC DRUG DISCOVERY INVESTIGATIONS AS FUTURE THERAPEUTIC OPPORTUNITY FOR HUMAN THERAPY OF NEUROPATHIC PAIN. 2021 6 1882 20 EMERGING TREATMENTS IN ACUTE MYELOID LEUKAEMIA. ACUTE MYELOID LEUKAEMIA (AML) IS THE MOST COMMON FORM OF LEUKAEMIA IN YOUNG ADULTS. ALTHOUGH 75-85% OF PATIENTS WILL ACHIEVE COMPLETE REMISSION AFTER INDUCTION CHEMOTHERAPY, THE LONG-TERM SURVIVAL IS STILL < 50% AT 5 YEARS. CHEMOTHERAPY HAS INCREASED IN INTENSITY IN RECENT YEARS AND IS PERCEIVED TO HAVE REACHED THE LIMIT OF TOXICITY. ALLOGENEIC BONE MARROW TRANSPLANTATION, WHICH IS UNDOUBTEDLY THE MOST EFFECTIVE WAY TO PREVENT RELAPSE, MAY NOT ADD SUBSTANTIAL SURVIVAL BENEFITS. SEVERAL NEW PHARMACOLOGICAL APPROACHES TO THE TREATMENT OF AML ARE NOW BECOMING AVAILABLE, WITH VARIOUS MOLECULAR TARGETS IDENTIFIED, INCLUDING THE FARNESYLATION OF RAS FAMILY PROTEINS AND TYROSINE KINASES INVOLVED IN SIGNAL TRANSDUCTION AND EPIGENETIC METHYLATION. MORE SELECTIVE DELIVERY OF CHEMOTHERAPEUTIC AGENTS IS ALSO FEASIBLE USING HUMANISED MONOCLONAL ANTIBODIES, WITH THE INTRIGUING POSSIBILITY OF INCREASING TREATMENT DELIVERY WITHOUT INCREASING THE TOXICITY. HOWEVER, DESPITE THE PROGRESS IN THE RATIONAL DESIGN OF DRUGS IN DISORDERS SUCH AS CHRONIC MYELOID LEUKAEMIA, AML LACKS A SINGLE SPECIFIC PATHOGNOMIC GENETIC EVENT TO ACT AS A DRUG TARGET. THIS REVIEW DISCUSSES THE DRUGS PRESENTLY UNDER INVESTIGATION IN PHASE II OR PHASE III TRIALS IN AML. 2004 7 3275 14 HEPATOCELLULAR CARCINOMA: THERAPEUTIC ADVANCES IN SIGNALING, EPIGENETIC AND IMMUNE TARGETS. HEPATOCELLULAR CARCINOMA (HCC) REMAINS A GLOBAL MEDICAL BURDEN WITH RISING INCIDENCE DUE TO CHRONIC VIRAL HEPATITIS AND NON-ALCOHOLIC FATTY LIVER DISEASES. TREATMENT OF ADVANCED DISEASE STAGES IS STILL UNSATISFYING. BESIDES FIRST AND SECOND GENERATION TYROSINE KINASE INHIBITORS, IMMUNE CHECKPOINT INHIBITORS HAVE BECOME CENTRAL FOR THE TREATMENT OF HCC. NEW MODALITIES LIKE EPIGENETIC THERAPY USING HISTONE DEACETYLASE INHIBITORS (HDACI) AND CELL THERAPY APPROACHES WITH CHIMERIC ANTIGEN RECEPTOR T CELLS (CAR-T CELLS) ARE CURRENTLY UNDER INVESTIGATION IN CLINICAL TRIALS. DEVELOPMENT OF SUCH NOVEL DRUGS IS CLOSELY LINKED TO THE AVAILABILITY AND IMPROVEMENT OF NOVEL PRECLINICAL AND ANIMAL MODELS AND THE IDENTIFICATION OF PREDICTIVE BIOMARKERS. THE CURRENT STATUS OF TREATMENT OPTIONS FOR ADVANCED HCC, EMERGING NOVEL THERAPEUTIC APPROACHES AND DIFFERENT PRECLINICAL MODELS FOR HCC DRUG DISCOVERY AND DEVELOPMENT ARE REVIEWED HERE. 2019 8 2189 16 EPIGENETIC MECHANISMS UNDERLYING THE THERAPEUTIC EFFECTS OF HDAC INHIBITORS IN CHRONIC MYELOID LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A HEMATOLOGICAL DISORDER CAUSED BY THE ONCOGENIC BCR-ABL FUSION PROTEIN IN MORE THAN 90% OF PATIENTS. DESPITE THE STRIKING IMPROVEMENTS IN THE MANAGEMENT OF CML PATIENTS SINCE THE INTRODUCTION OF TYROSINE KINASE INHIBITORS (TKIS), THE APPEARANCE OF TKI RESISTANCE AND SIDE EFFECTS LEAD TO TREATMENT FAILURE, JUSTIFYING THE NEED OF NOVEL THERAPEUTIC APPROACHES. HISTONE DEACETYLASE INHIBITORS (HDACIS), ABLE TO MODULATE GENE EXPRESSION PATTERNS AND IMPORTANT CELLULAR SIGNALING PATHWAYS THROUGH THE REGULATION OF THE ACETYLATION STATUS OF BOTH HISTONE AND NON-HISTONE PROTEIN TARGETS, HAVE BEEN REPORTED TO DISPLAY PROMISING ANTI-LEUKEMIC PROPERTIES ALONE OR IN COMBINATION WITH TKIS. THIS REVIEW SUMMARIZES PRE-CLINICAL AND CLINICAL STUDIES THAT INVESTIGATED THE MECHANISMS UNDERLYING THE ANTICANCER POTENTIAL OF HDACIS AND DISCUSSES THE RATIONALE FOR A COMBINATION OF HDACIS WITH TKIS AS A THERAPEUTIC OPTION IN CML. 2020 9 3333 17 HISTONE DEACETYLASE INHIBITORS AND DIABETIC KIDNEY DISEASE. DESPITE RECENT CLINICAL TRIAL ADVANCES AND IMPROVEMENTS IN CLINICAL CARE, KIDNEY DISEASE DUE TO DIABETES REMAINS THE MOST COMMON CAUSE OF CHRONIC KIDNEY FAILURE WORLDWIDE. IN THE SEARCH FOR NEW TREATMENTS, RECENT ATTENTIONS HAVE TURNED TO DRUG REPURPOSING OPPORTUNITIES, INCLUDING STUDY OF THE HISTONE DEACETYLASE (HDAC) INHIBITOR CLASS OF AGENTS. HDACS ARE A GROUP OF ENZYMES THAT REMOVE FUNCTIONAL ACETYL GROUPS FROM HISTONE AND NON-HISTONE PROTEINS AND THEY CAN AFFECT CELLULAR FUNCTION THROUGH BOTH EPIGENETIC AND NON-EPIGENETIC MEANS. OVER THE PAST DECADE, SEVERAL HDAC INHIBITORS HAVE BEEN ADOPTED INTO CLINICAL PRACTICE, PRIMARILY FOR THE TREATMENT OF HEMATOLOGICAL MALIGNANCY, WHEREAS OTHER EXISTING THERAPIES (FOR INSTANCE VALPROATE) HAVE BEEN FOUND TO HAVE HDAC INHIBITORY EFFECTS. HERE WE REVIEW THE CURRENT HDAC INHIBITORS IN THE CLINIC AND UNDER DEVELOPMENT; THE LITERATURE EVIDENCE SUPPORTING THE RENOPROTECTIVE EFFECTS OF HDAC INHIBITORS IN EXPERIMENTAL DIABETIC KIDNEY DISEASE; AND THE ADVERSE EFFECT PROFILES THAT MAY PREVENT EXISTING THERAPIES FROM ENTERING THE CLINIC FOR THIS INDICATION. WHEREAS RECENT RESEARCH EFFORTS HAVE SHED LIGHT ON THE FUNDAMENTAL ACTIONS OF HDACS IN THE DIABETIC KIDNEY, WHETHER THESE EFFORTS WILL TRANSLATE INTO NOVEL THERAPIES FOR PATIENTS WILL REQUIRE MORE SPECIFIC AND BETTER-TOLERATED THERAPIES. 2018 10 5039 31 PHARMACOGENETICS OF CHRONIC PAIN MANAGEMENT. OBJECTIVE: THE EXPERIENCE OF CHRONIC PAIN IS ONE OF THE COMMONEST REASONS INDIVIDUALS SEEK MEDICAL ATTENTION, MAKING THE MANAGEMENT OF CHRONIC PAIN A MAJOR ISSUE IN CLINICAL PRACTICE. DRUG METABOLISM AND RESPONSES ARE AFFECTED BY MANY FACTORS, WITH GENETIC VARIATIONS OFFERING ONLY A PARTIAL EXPLANATION OF AN INDIVIDUAL'S RESPONSE. THERE IS A PAUCITY OF EVIDENCE FOR THE BENEFITS OF PHARMACOGENETIC TESTING IN THE CONTEXT OF PAIN MANAGEMENT. DESIGN AND METHODS: WE REVIEWED THE LITERATURE BETWEEN 2000 AND 2013, AND REFERENCES CITED THEREIN, USING VARIOUS KEYWORDS RELATED TO PAIN MANAGEMENT, PHARMACOLOGY AND PHARMACOGENETICS. RESULTS: OPIOIDS CONTINUE TO BE THE MAINSTAY OF CHRONIC PAIN MANAGEMENT. SEVERAL NON-OPIOID BASED THERAPIES, SUCH AS TREATMENT WITH CANNABINOIDS, GENE THERAPY AND EPIGENETIC-BASED APPROACHES ARE NOW AVAILABLE FOR THESE PATIENTS. ADJUVANT THERAPIES WITH ANTIDEPRESSANTS, BENZODIAZEPINES OR ANTICONVULSANTS CAN ALSO BE USEFUL IN MANAGING PAIN. CURRENTLY, LABORATORY MONITORING OF PAIN MANAGEMENT PATIENTS, IF PERFORMED, IS LARGELY THROUGH URINE DRUG MEASUREMENTS. CONCLUSIONS: DRUG HALF-LIFE CALCULATIONS CAN BE USED AS FUNCTIONAL MARKERS OF THE CUMULATIVE EFFECT OF PHARMACOGENETICS AND DRUG-DRUG INTERACTIONS. ASSESSMENT OF HALF-LIFE AND THERAPEUTIC EFFECTS MAY BE MORE USEFUL THAN GENETIC TESTING IN PREVENTING ADVERSE DRUG REACTIONS TO PAIN MEDICATIONS, WHILE ENSURING EFFECTIVE ANALGESIA. DEFINITIVE, MASS SPECTROMETRY-BASED METHODS, CAPABLE OF MEASURING PARENT DRUG AND METABOLITE LEVELS, ARE THE MOST USEFUL ASSAYS FOR THIS PURPOSE. URINE DRUG MEASUREMENTS DO NOT NECESSARILY CORRELATE WITH SERUM DRUG CONCENTRATIONS OR THERAPEUTIC EFFECTS. THEREFORE, THEY ARE LIMITED IN THEIR USE IN MONITORING EFFICACY AND TOXICITY. 2014 11 958 18 CHRONIC MYELOMONOCYTIC LEUKEMIA - A REVIEW. INTRODUCTION: CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL MYELOID NEOPLASM, DENOTED BY OVERLAPPING MYELODYSPLASTIC AND MYELOPROLIFERATIVE FEATURES, WITH POOR OVERALL SURVIVAL AND HIGH TRANSFORMATION RATE TO ACUTE MYELOID LEUKEMIA. AREAS COVERED: THIS REVIEW, FOLLOWING A THOROUGH MEDLINE SEARCH OF PERTINENT PUBLISHED LITERATURE, DISCUSSES THE DIAGNOSTIC CRITERIA, THE PATHOGENESIS, AND THE COMPLEX GENETIC LANDSCAPE OF THE DISEASE. PROGNOSTICATION, RESPONSE CRITERIA, THERAPEUTIC MANAGEMENT OF PATIENTS, EFFICACY OF ESTABLISHED AND NOVEL TREATMENT MODALITIES ARE THOROUGHLY REVIEWED. EXPERT OPINION: CYTOGENETIC ABNORMALITIES AND MUTATIONS IN GENES INVOLVED IN EPIGENETIC AND TRANSCRIPTIONAL REGULATION, AND CELL-SIGNALING ARE ABUNDANT IN CMML AND IMPLICATED IN ITS COMPLEX PATHOGENESIS. AS PRESENCE OF THESE MUTATIONS CARRY A PROGNOSTIC IMPACT, THEY ARE INCREASINGLY INCORPORATED IN RISK-STRATIFICATION SCHEMES. NOVEL RESPONSE CRITERIA HAVE BEEN PROPOSED, CONSIDERING THE UNIQUE FEATURES OF THE DISEASE. ALTHOUGH ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION REMAINS THE ONLY TREATMENT WITH CURATIVE INTENT, IT IS RESERVED FOR A MINORITY OF PATIENTS; THEREFORE, THERE IS AN UNMET NEED FOR OPTIMIZING TREATMENT MODALITIES, SUCH AS HYPOMETHYLATING AGENTS, AND INTRODUCING NOVEL AGENTS, WHICH COULD SUBSTANTIALLY IMPROVE SURVIVAL AND QUALITY OF LIFE OF CMML PATIENTS. CLINICAL TRIALS DEDICATED SPECIFICALLY TO CMML ARE NEEDED TO EXPLORE THE EFFICACY AND SAFETY OF NOVEL TREATMENT MODALITIES. 2021 12 429 19 ANTI-INFLAMMATORY TOPICAL MEDICATION - NEW DEVELOPMENTS IN THE TREATMENT OF ATOPIC DERMATITIS. ATOPIC DERMATITIS IS A CHRONIC INFLAMMATORY DISEASE THAT ARISES FROM POLYGENIC DISPOSITION, A DYSFUNCTION OF THE PHYSICOCHEMICAL EPITHELIAL BARRIER, A CUTANEOUS DYSBIOSIS, AND A FAULTY NEUROSENSORY ACTIVITY AND SHOWS A HIGHLY INDIVIDUAL ACUITY DUE TO EPIGENETIC FACTORS. AN ESSENTIAL COMPONENT OF THERAPEUTIC MANAGEMENT IS THE APPLICATION OF ANTI-INFLAMMATORY TOPICAL MEDICATION. CURRENTLY, TOPICAL GLUCOCORTICOIDS AND TOPICAL CALCINEURIN INHIBITORS ARE ROUTINELY USED IN REACTIVE AND PROACTIVE THERAPY. IN RECENT YEARS, THE DEVELOPMENT OF MOLECULAR MEDICINE HAS IDENTIFIED SEVERAL NEW THERAPEUTIC TARGETS THAT HAVE ENABLED THE DEVELOPMENT OF INNOVATIVE THERAPEUTIC APPROACHES. IN ADDITION TO PHOSPHODIESTERASE-4 INHIBITORS AND ARYL HYDROCARBON RECEPTOR MODULATORS, IT IS MAINLY JANUS KINASE INHIBITORS WITH DIFFERENT SELECTIVITY THAT ARE EMERGING AS NEW EFFECTIVE AND SAFE OPTIONS FOR TOPICAL THERAPY. THE CURRENT DATA SUGGESTS THAT IN THE COMING MONTHS AND YEARS REPRESENTATIVES OF THE ABOVE-MENTIONED SUBSTANCE CLASSES WILL BE APPROVED FOR TOPICAL USE. 2021 13 5912 12 TARGETED THERAPIES IN SYSTEMIC LUPUS ERYTHEMATOSUS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM DISORDER CHARACTERISED BY LOSS OF TOLERANCE TO ENDOGENOUS NUCLEAR ANTIGENS AND AUTOANTIBODY FORMATION. RECENT INSIGHT INTO THE IMMUNOPATHOGENESIS OF LUPUS HAS PROVIDED THE FOUNDATION FOR A NOVEL CLASS OF AGENTS WHICH TARGET SPECIFIC, DYSREGULATED COMPONENTS OF THE IMMUNE SYSTEM. EFFORTS HAVE FOCUSED PREDOMINANTLY ON B-CELL DEPLETING THERAPIES, OF WHICH BELIMUMAB WAS THE FIRST TO DEMONSTRATE SUCCESS IN PHASE III STUDIES AND THUS RECEIVE MARKETING AUTHORISATION. OFF-LABEL PRESCRIBING OF RITUXIMAB IN REFRACTORY CASES IS COMMON AND SUPPORTED BY UNCONTROLLED STUDIES, WHICH SUGGEST A FAVOURABLE RISK:BENEFIT PROFILE. HOWEVER, TWO PLACEBO-CONTROLLED TRIALS FAILED TO SHOW BENEFIT, POSSIBLY BECAUSE OF INAPPROPRIATE PATIENT SELECTION AND OTHER ASPECTS OF TRIAL METHODOLOGY. INHIBITION OF DYSREGULATED CO-STIMULATORY SIGNALS AND CYTOKINES ARE OTHER THERAPEUTIC STRATEGIES CURRENTLY UNDER INVESTIGATION. SOME CANDIDATE DRUGS FAILED TO MEET PRIMARY ENDPOINTS IN EARLY-PHASE CLINICAL TRIALS, YET DEMONSTRATED CLINICAL BENEFIT WHEN ALTERNATIVE ASSESSMENT CRITERIA WERE APPLIED OR SPECIFIC PATIENT SUB-GROUPS ANALYSED. WELL-DESIGNED STUDIES OF GREATER SIZE AND DURATION ARE NEEDED TO CLARIFY THE THERAPEUTIC UTILITY OF THESE AGENTS. FUTURE IMMUNOMODULATORY STRATEGIES TARGETING INTERFERON-ALPHA, T CELLS, OXIDATIVE STRESS AND EPIGENETIC ABNORMALITIES MAY REDUCE MULTISYSTEM DISEASE ACTIVITY AND PROLONG SURVIVAL IN THIS COMPLEX AND HETEROGENEIC DISEASE. 2013 14 6617 21 UNDERPINNING THE NEUROBIOLOGICAL INTRICACIES ASSOCIATED WITH OPIOID TOLERANCE. THE OPIOID CRISIS IS A MAJOR THREAT OF THE 21ST CENTURY, WITH A REMARKABLE JUXTAPOSITION OF USE AND ABUSE. OPIOIDS ARE THE MOST POTENT AND EFFICACIOUS CLASS OF ANALGESICS, BUT DESPITE THEIR PROVEN THERAPEUTIC EFFICACY, THEY HAVE RECENTLY BEEN DEGRADED TO THIRD-LINE THERAPY FOR THE MANAGEMENT OF CHRONIC PAIN IN CLINICS. THE REASON BEHIND THIS IS THE DEVELOPMENT OF POTENTIAL SIDE EFFECTS AND TOLERANCE AFTER REPEATED DOSING. OPIOID TOLERANCE IS THE MAJOR LIMITING FACTOR LEADING TO THE WITHDRAWAL OF TREATMENT, SEVERE SIDE EFFECTS DUE TO DOSE ESCALATION, AND SOMETIMES EVEN DEATH OF THE PATIENTS. EVERY DAY MORE THAN 90 PEOPLE DIE DUE TO OPIOIDS OVERDOSE IN AMERICA, AND A SIMILAR TREND HAS BEEN SEEN ACROSS THE GLOBE. OVER THE PAST TWO DECADES, RESEARCHERS HAVE BEEN TRYING TO DISSECT THE NEUROBIOLOGICAL MECHANISM OF OPIOID TOLERANCE. RESEARCH ON OPIOID TOLERANCE SHIFTED TOWARD CENTRAL NERVOUS SYSTEM-BASED ADAPTATIONS BECAUSE TOLERANCE IS MUCH MORE THAN JUST A CELLULAR PHENOMENON. THUS, NEUROBIOLOGICAL ADAPTATIONS ASSOCIATED WITH OPIOID TOLERANCE ARE IMPORTANT TO UNDERSTAND IN ORDER TO FIND NEWER PAIN THERAPEUTICS. THESE ADAPTATIONS ARE ASSOCIATED WITH ALTERATIONS IN ASCENDING AND DESCENDING PAIN PATHWAYS, REWARD CIRCUITRY MODULATIONS, RECEPTOR DESENSITIZATION AND DOWN-REGULATION, RECEPTOR INTERNALIZATION, HETERODIMERIZATION, AND ALTERED EPIGENETIC REGULATION. THE PRESENT REVIEW IS FOCUSED ON NOVEL CIRCUITRIES ASSOCIATED WITH OPIOID TOLERANCE IN DIFFERENT AREAS OF THE BRAIN, SUCH AS PERIAQUEDUCTAL GRAY, ROSTRAL VENTROMEDIAL MEDULLA, DORSAL RAPHE NUCLEUS, VENTRAL TEGMENTAL AREA, AND NUCLEUS ACCUMBENS. UNDERSTANDING THE NEUROBIOLOGICAL MODULATIONS ASSOCIATED WITH CHRONIC OPIOID EXPOSURE AND TOLERANCE WILL PAVE THE WAY FOR THE DEVELOPMENT OF NOVEL PHARMACOLOGICAL TOOLS FOR SAFER AND BETTER MANAGEMENT OF CHRONIC PAIN IN PATIENTS. 2020 15 5778 19 SPINAL CORD INJURY INDUCED NEUROPATHIC PAIN: MOLECULAR TARGETS AND THERAPEUTIC APPROACHES. NEUROPATHIC PAIN, ESPECIALLY THAT RESULTING FROM SPINAL CORD INJURY, IS A TREMENDOUS CLINICAL CHALLENGE. A MYRIAD OF BIOLOGICAL CHANGES HAVE BEEN IMPLICATED IN PRODUCING THESE PAIN STATES INCLUDING CELLULAR INTERACTIONS, EXTRACELLULAR PROTEINS, ION CHANNEL EXPRESSION, AND EPIGENETIC INFLUENCES. PHYSIOLOGICAL CONSEQUENCES OF THESE CHANGES ARE VARIED AND INCLUDE FUNCTIONAL DEFICITS AND PAIN RESPONSES. DEVELOPING THERAPIES THAT EFFECTIVELY ADDRESS THE CAUSE OF THESE SYMPTOMS REQUIRE A DEEPER KNOWLEDGE OF ALTERATIONS IN THE MOLECULAR PATHWAYS. MATRIX METALLOPROTEINASES AND TISSUE INHIBITORS OF METALLOPROTEINASES ARE TWO PROMISING THERAPEUTIC TARGETS. MATRIX METALLOPROTEINASES INTERACT WITH AND INFLUENCE MANY OF THE STUDIED PAIN PATHWAYS. GENE EXPRESSION OF ION CHANNELS AND INFLAMMATORY MEDIATORS CLEARLY CONTRIBUTES TO NEUROPATHIC PAIN. LOCALIZED AND TIME DEPENDENT TARGETING OF THESE PROTEINS COULD ALLEVIATE AND EVEN PREVENT NEUROPATHIC PAIN FROM DEVELOPING. CURRENT THERAPEUTIC OPTIONS FOR NEUROPATHIC PAIN ARE LIMITED PRIMARILY TO ANALGESICS TARGETING THE OPIOID PATHWAY. THERAPIES DIRECTED AT MOLECULAR TARGETS ARE HIGHLY DESIRABLE AND IN EARLY STAGES OF DEVELOPMENT. THESE INCLUDE TRANSPLANTATION OF EXOGENOUSLY ENGINEERED CELL POPULATIONS AND TARGETED GENE MANIPULATION. THIS REVIEW DESCRIBES SPECIFIC MOLECULAR TARGETS AMENABLE TO THERAPEUTIC INTERVENTION USING CURRENTLY AVAILABLE DELIVERY SYSTEMS. 2015 16 750 20 CARDIAC INVOLVEMENT IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES. AUTHORS HAVE REVIEWED LITERATURE ABOUT THE MANAGEMENT OF PATIENTS WITH CARDIOLOGIC DISEASE OCCURRING SECONDARY TO HEMATOLOGIC PATHOLOGY ITSELF OR ITS THERAPY, WITH A FOCUS ON INFILTRATION OF MYOCARDIUM IN ACUTE AND CHRONIC LEUKEMIA, LYMPHOMA, MULTIPLE MYELOMA, AND HYPEREOSINOPHILIC SYNDROME. MOREOVER, THEY EVALUATED CHEMOTHERAPY-ASSOCIATED TOXICITY, PARTICULARLY FOR NEW DRUGS SUCH AS MONOCLONAL ANTIBODY THERAPY, TYROSINE KINASE INHIBITORS, ARSENIC TRIOXIDE, BORTEZOMIB, AND EPIGENETIC THERAPY. IN FACT, CARDIAC TOXICITY MAY RANGE FROM ASYMPTOMATIC SUBCLINICAL ABNORMALITIES, SUCH AS ELECTROCARDIOGRAPHIC CHANGES AND LEFT VENTRICULAR EJECTION DECLINE, TO LIFE-THREATENING EVENTS AND LEAD TO CHEMOTHERAPY DOSE REDUCTION AND DELAY AND, IN SOME CASES, FOR PATIENTS WITH SEVERE SIDE EFFECTS, DISCONTINUATION OF TREATMENT. FINALLY, THEY DISCUSSED ON THE IDENTIFICATION OF EARLY MARKERS OF CARDIAC INJURY AND ON CARDIAC STEM CELL THERAPY AS A PROMISING APPROACH TO FACILITATE MYOCARDIAL REGENERATION. 2010 17 6857 22 [NOVEL CONVENTIONAL THERAPIES IN ONCO-HEMATHOLOGY]. CYTOGENETIC, MOLECULAR AND PHENOTYPING FEATURES OF MALIGNANT HEMATOLOGIC DISEASES SUCCEEDED IN IMPROVING THEIR MANAGEMENT BY A MORE ACCURATE STRATIFICATION OF PATIENTS ACCORDING TO SEVERAL GROUPS OF RISK AND BY PROVIDING A RATIONAL FOR TARGETED THERAPY. THREE MAJOR TYPES OF TREATMENT (EXCLUDING CELLULAR THERAPY) ARE CURRENTLY AVAILABLE IN ONCO-HEMATOLOGY: CONVENTIONAL CHEMOTHERAPY, SMALL MOLECULES FOR TARGETED THERAPY AND MONOCLONAL ANTIBODIES. CONVENTIONAL CHEMOTHERAPY WITH OPTIMIZATION OF DOSES AND MULTIDRUG-BASED REGIMENS ALLOWED TO SUBSTANTIALLY IMPROVE SURVIVAL OF PATIENTS AND KEEPS A PLACE OF CHOICE IN TREATMENT OF THESE DISEASES. TARGETED TREATMENTS CAME FROM THE CYTOGENETIC AND MOLECULAR CHARACTERIZATION OF HEMOPATHIES. THUS, THE KINASE BCR-ABL, AS A RESULT OF THE TRANSLOCATION T(9;22)(Q34;Q11), HAS BEEN SUCCESSFULLY TARGETED BY TYROSINE KINASE INHIBITORS (TKI) IN CHRONIC MYELOID LEUKEMIA AND PH+ ACUTE LYMPHOBLASTIC LEUKEMIA. MOLECULAR ABNORMALITIES LIKE INTERNAL-TANDEM DUPLICATION/POINT ACTIVATING MUTATIONS IN FLT3 IN SOME ACUTE MYELOBLASTIC LEUKEMIA OR EPIGENETIC DYSREGULATIONS IN SOME BLOOD MALIGNANCIES CAN ALSO BE TARGETED BY SMALL MOLECULES. HEMATOPOIETIC MALIGNANT CELLS ARE PHENOTYPICALLY CHARACTERIZED BY EXPRESSION OF CLUSTER OF DIFFERENTIATION (CD) ON THEIR SURFACE. THESE CD ARE DETECTED BY FLOW CYTOMETRY USING SPECIFIC ANTIBODIES. MONOCLONAL ANTIBODIES TARGETING DIFFERENT CD HAVE BEEN DEVELOPED FOR TREATMENT. RITUXIMAB, AN ANTI-CD20 ANTIBODY, WAS THE FIRST MONOCLONAL ANTIBODY SUCCESSFULLY DEVELOPED FOR TREATMENT OF MALIGNANT HEMATOLOGIC DISEASES. SINCE RITUXIMAB, MANY OTHER MONOCLONAL ANTIBODIES ARE BEING DEVELOPED. TRENDS IN MALIGNANT HEMATOLOGIC DISEASES PRESENTED HERE WILL INCLUDE TREATMENTS, WHICH HAVE AT LEAST ENTERED PHASE I/II CLINICAL TRIALS IN ADULT OR CHILDHOOD LEUKEMIA. THEY INCLUDE SOME NOVEL DRUGS OF CONVENTIONAL CHEMOTHERAPY LIKE SECOND-GENERATION NUCLEOSIDE ANALOGUES. WE WILL GIVE AN OVERVIEW OF THE SMALL MOLECULES TARGETING THE DIFFERENT CELLULAR PATHWAYS AND WE WILL HIGHLIGHT THOSE APPEARING AS THE MOST PROMISING LIKE NOVEL TKIS. THE LARGE FIELD OF MONOCLONAL ANTIBODIES WILL BE ALSO APPROACHED FOCUSING ON ANTIBODIES DEVELOPED IN LEUKEMIAS. 2011 18 2141 21 EPIGENETIC INTERVENTIONS FOR EPILEPTOGENESIS: A NEW FRONTIER FOR CURING EPILEPSY. THIS ARTICLE HIGHLIGHTS THE EMERGING THERAPEUTIC POTENTIAL OF SPECIFIC EPIGENETIC MODULATORS AS PROMISING ANTIEPILEPTOGENIC OR DISEASE-MODIFYING AGENTS FOR CURING EPILEPSY. CURRENTLY, THERE IS AN UNMET NEED FOR ANTIEPILEPTOGENIC AGENTS THAT TRULY PREVENT THE DEVELOPMENT OF EPILEPSY IN PEOPLE AT RISK. THERE IS STRONG EVIDENCE THAT EPIGENETIC SIGNALING, WHICH EXERTS HIGH FIDELITY REGULATION OF GENE EXPRESSION, PLAYS A CRUCIAL ROLE IN THE PATHOPHYSIOLOGY OF EPILEPTOGENESIS AND CHRONIC EPILEPSY. THESE MODIFICATIONS ARE NOT HARD-WIRED INTO THE GENOME AND ARE CONSTANTLY REPROGRAMMED BY ENVIRONMENTAL INFLUENCES. THE POTENTIAL EPIGENETIC MECHANISMS, INCLUDING HISTONE MODIFICATIONS, DNA METHYLATION, MICRORNA-BASED TRANSCRIPTIONAL CONTROL, AND BROMODOMAIN READING ACTIVITY, CAN DRASTICALLY ALTER THE NEURONAL GENE EXPRESSION PROFILE BY EXERTING THEIR SUMMATIVE EFFECTS IN A COORDINATED FASHION. SUCH AN EPIGENETIC INTERVENTION APPEARS MORE RATIONAL STRATEGY FOR PREVENTING EPILEPSY BECAUSE IT TARGETS THE PRIMARY PATHWAY THAT INITIALLY TRIGGERS THE NUMEROUS DOWNSTREAM CELLULAR AND MOLECULAR EVENTS MEDIATING EPILEPTOGENESIS. AMONG CURRENTLY APPROVED EPIGENETIC DRUGS, THE MAJORITY ARE ANTICANCER DRUGS WITH WELL-ESTABLISHED PROFILES IN CLINICAL TRIALS AND PRACTICE. EVIDENCE FROM PRECLINICAL STUDIES SUPPORTS THE PREMISE THAT THESE DRUGS MAY BE APPLIED TO A WIDE RANGE OF BRAIN DISORDERS. TARGETING HISTONE DEACETYLATION BY INHIBITING HISTONE DEACETYLASE ENZYMES APPEARS TO BE ONE PROMISING EPIGENETIC THERAPY SINCE CERTAIN INHIBITORS HAVE BEEN SHOWN TO PREVENT EPILEPTOGENESIS IN ANIMAL MODELS. HOWEVER, DEVELOPING NEURONAL SPECIFIC EPIGENETIC MODULATORS REQUIRES RATIONAL, PATHOPHYSIOLOGY-BASED OPTIMIZATION TO EFFICIENTLY INTERCEPT THE UPSTREAM PATHWAYS IN EPILEPTOGENESIS. OVERALL, EPIGENETIC AGENTS HAVE BEEN WELL POSITIONED AS NEW FRONTIER TOOLS TOWARDS THE NATIONAL GOAL OF CURING EPILEPSY. 2017 19 1046 17 CLINICAL DEVELOPMENT OF DECITABINE AS A PROTOTYPE FOR AN EPIGENETIC DRUG PROGRAM. THIS REVIEW HIGHLIGHTS DECITABINE AS A PROTOTYPE EPIGENETIC MODIFYING DRUG TO SHOW HOW THE CLINICAL DEVELOPMENT OF EPIGENETIC AGENTS DIFFERS FROM THAT OF TRADITIONAL CYTOTOXIC CHEMOTHERAPIES. DECITABINE, A CYTOSINE ANALOGUE, IS CYTOTOXIC AT HIGH DOSES BUT HAS SELECTIVE DNA DEMETHYLATING ACTIVITY AT LOW DOSES. THE FOCUS OF CURRENT DECITABINE INVESTIGATIONS IS TWOFOLD: TO ELUCIDATE ALL OF THE MECHANISMS OF ACTION AND TO DETERMINE THE OPTIMAL DOSE, SCHEDULE, AND CONCOMITANT THERAPIES. NEW PHASE I TRIALS HAVE IDENTIFIED A "BIOLOGICALLY EFFECTIVE DOSE," WHICH IS 1 TO 2 LOGS LOWER THAN THE CYTOTOXIC DOSE. A CLINICAL DEVELOPMENT PROGRAM WITH LOW-DOSE DECITABINE IN MALIGNANT DISEASES IS FOCUSED ON MYELODYSPLASTIC SYNDROME (MDS), ACUTE MYELOGENOUS LEUKEMIA (AML), AND CHRONIC MYELOGENOUS LEUKEMIA (CML). A PHASE III TRIAL IN MDS SHOWED OBJECTIVE RESPONSES (COMPLETE [CR] PLUS PARTIAL [PR] REMISSION) AND LONGER MEDIAN TIME TO PROGRESSION TO AML OR DEATH WITH DECITABINE THAN WITH SUPPORTIVE CARE ALONE. THE OPTIMAL USE OF DECITABINE MAY BE IN COMBINATION WITH OTHER AGENTS THAT PROMOTE GENE EXPRESSION, NAMELY, HISTONE DEACETYLASE (HDAC) INHIBITORS. OPTIMIZED DECITABINE DOSES AND COMBINATIONS WITH OTHER EPIGENETIC THERAPIES THAT CAN BE USED AT MINIMALLY TOXIC DOSES PROVIDE POTENTIALLY SAFER THERAPEUTIC OPTIONS AND INTRODUCE NOVEL COMBINATION THERAPIES. 2005 20 6573 14 TREATMENT OF ACUTE MYELOID LEUKEMIA IN THE ERA OF GENOMICS-ACHIEVEMENTS AND PERSISTING CHALLENGES. ACUTE MYELOID LEUKEMIA (AML) REPRESENTS A MALIGNANT DISORDER OF THE HEMATOPOIETIC SYSTEM THAT IS MAINLY CHARACTERIZED BY RAPID PROLIFERATION, DYSREGULATED APOPTOSIS, AND IMPAIRED DIFFERENTIATION OF LEUKEMIC BLASTS. FOR SEVERAL DECADES, THE DIAGNOSTIC APPROACH IN AML WAS LARGELY BASED ON HISTOLOGIC CHARACTERISTICS WITH LITTLE IMPACT ON THE TREATMENT DECISION-MAKING PROCESS. THIS PERSPECTIVE HAS DRASTICALLY CHANGED WITHIN THE PAST YEARS DUE TO THE ADVENT OF NOVEL MOLECULAR TECHNOLOGIES, SUCH AS WHOLE GENOME NEXT-GENERATION SEQUENCING (NGS), AND THE RESULTING KNOWLEDGE GAIN IN AML BIOLOGY AND PATHOGENESIS. AFTER MORE THAN FOUR DECADES OF INTENSIVE CHEMOTHERAPY AS A "ONE-SIZE-FITS-ALL" CONCEPT, SEVERAL TARGETED AGENTS HAVE RECENTLY BEEN APPROVED FOR THE TREATMENT OF AML, EITHER AS SINGLE AGENTS OR AS PART OF COMBINED TREATMENT REGIMENS. SEVERAL OTHER COMPOUNDS, DIRECTED AGAINST REGULATORS OF APOPTOTIC, EPIGENETIC, OR MICROENVIRONMENTAL PATHWAYS, AS WELL AS MODULATORS OF THE IMMUNE SYSTEM, ARE CURRENTLY IN DEVELOPMENT AND BEING INVESTIGATED IN CLINICAL TRIALS. THE CONSTANT PROGRESS IN AML RESEARCH HAS STARTED TO PRODUCE IMPROVED SURVIVAL RATES AND FUELED HOPES THAT A ONCE RAPIDLY FATAL DISEASE CAN BE TRANSFORMED INTO A CHRONIC CONDITION. IN THIS REVIEW, THE AUTHORS PROVIDE A SUMMARY OF RECENT ADVANCES IN THE DEVELOPMENT OF TARGETED AML THERAPIES AND DISCUSS PERSISTENT CHALLENGES. 2020