1 5172 155 PREDICTING PAIN AFTER STANDARD PAIN THERAPY FOR KNEE OSTEOARTHRITIS - THE FIRST STEPS TOWARDS PERSONALIZED MECHANISTIC-BASED PAIN MEDICINE IN OSTEOARTHRITIS. OBJECTIVES: THE PREVALENCE OF OSTEOARTHRITIS (OA) IS RISING, AND PAIN IS THE HALLMARK SYMPTOM OF OA. PAIN IN OA IS COMPLICATED AND CAN BE INFLUENCED BY MULTIPLE JOINT-RELATED FACTORS AND FACTORS RELATED TO, E.G., PHYSIOLOGICAL, EPIGENETIC, AND PAIN SENSORY PROFILES. INCREASING EVIDENCE SUGGESTS THAT A SUBSET OF PATIENTS WITH OA ARE PAIN SENSITIVE. THIS CAN BE ASSESSED USING QUANTITATIVE SENSORY TESTING (QST). COMMON TREATMENTS OF OA ARE TOTAL KNEE ARTHROPLASTY (TKA) AND ADMINISTRATION OF 3-WEEKS OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS), WHICH PROVIDE PAIN RELIEF TO MANY PATIENTS WITH OA. HOWEVER, APPROX. 20% OF PATIENTS EXPERIENCE CHRONIC POSTOPERATIVE PAIN AFTER TKA, WHEREAS NSAIDS PROVIDE AN AVERAGE PAIN RELIEF OF APPROX. 25%. THE CURRENT TOPICAL REVIEW FOCUSES ON THE EMERGING EVIDENCE LINKING PRETREATMENT QST TO THE TREATMENT RESPONSE OF TKA AND NSAID TREATMENTS. CONTENT: MEDLINE WAS SYSTEMATICALLY SEARCHED FOR ALL STUDIES FROM 2000 TO 2022 ON PRETREATMENT QST, TKA, AND NSAIDS. PRE-CLINICAL STUDIES, REVIEWS, AND META-ANALYSES WERE EXCLUDED. SUMMARY: CURRENTLY, 14 STUDIES ON TKA AND FOUR STUDIES ON NSAIDS HAVE BEEN PUBLISHED WITH THE AIM TO ATTEMPT PREDICTION OF THE TREATMENT RESPONSE. THE QST METHODOLOGIES IN THE STUDIES ARE INCONSISTENT, BUT 11/14 (79%) STUDIES ON TKA AND 4/4 (100%) STUDIES ON NSAIDS REPORT STATISTICALLY SIGNIFICANT ASSOCIATIONS BETWEEN PRETREATMENT QST AND CHRONIC POSTOPERATIVE PAIN AFTER TKA OR ANALGESIC EFFECT AFTER NSAID TREATMENT. THE STRENGTH OF THE ASSOCIATIONS REMAINS LOW-TO-MODERATE. THE MOST CONSISTENT PRETREATMENT QST PREDICTORS ARE PRESSURE PAIN THRESHOLDS, TEMPORAL SUMMATION OF PAIN, AND CONDITIONED PAIN MODULATION. OUTLOOK: THE USE OF QST AS PREDICTORS OF STANDARD OA TREATMENT IS INTERESTING, BUT THE PREDICTIVE STRENGTH REMAINS LOW-TO-MODERATE. A TRANSITION OF QST FROM A RESEARCH-BASED SETTING AND INTO THE CLINIC IS NOT ADVISED UNTIL THE PREDICTIVE STRENGTH HAS BEEN IMPROVED AND THE METHODOLOGY HAS BEEN STANDARDIZED. 2023 2 5286 34 PRORESOLVING LIPID MEDIATORS: POTENTIAL FOR PREVENTION AND TREATMENT OF PERIODONTITIS. AIM: PERIODONTITIS IS AN INFLAMMATORY DISEASE INITIATED BY MICROBIAL BIOFILM. THE HOST RESPONSE TO THE BIOFILM DESTROYS THE PERIODONTIUM MEDIATED BY AN OVERLY ROBUST INFLAMMATORY RESPONSE IN SUSCEPTIBLE INDIVIDUALS. WHETHER THE EXCESSIVE HOST RESPONSE IS GENETIC, EPIGENETIC OR MEDIATED BY ENVIRONMENT IS UNKNOWN. NEW PATHWAYS OF RESOLUTION OF INFLAMMATION HAVE BEEN DISCOVERED. RESOLUTION OF INFLAMMATION IS AN ACTIVE, AGONIST-MEDIATED, PROGRAMMED RETURN TO TISSUE HOMEOSTASIS. MATERIALS AND METHODS: VARIOUS COMPUTER-BASED SEARCH ENGINES WERE EMPLOYED TO IDENTIFY PAPERS RELEVANT TO RESOLUTION OF INFLAMMATION. RESULTS: RECENT DATA SUGGEST THAT CHRONIC INFLAMMATORY PERIODONTAL DISEASE MAY BE A FAILURE OF RESOLUTION PATHWAYS AS WELL AS OVEREXPRESSION OF PROINFLAMMATORY PATHWAYS. IN THIS REVIEW, THE BIOLOGY OF RESOLUTION OF INFLAMMATION WILL BE EXAMINED IN NORMAL TISSUES AND PERIODONTAL DISEASE. ANTI-INFLAMMATORY PHARMACOLOGIC AGENTS [NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS)] HAVE BEEN SHOWN TO PREVENT AND SLOW THE PROGRESSION OF PERIODONTITIS IN ANIMALS AND HUMANS. HOWEVER, THE SIDE EFFECT PROFILE OF NSAIDS OR OTHER INHIBITORS OR RECEPTOR ANTAGONISTS PRECLUDE THEIR USE IN PERIODONTAL THERAPY. CONCLUSION: THE ISOLATION AND CHARACTERIZATION OF PRORESOLVING LIPID MEDIATORS THAT ARE RECEPTOR AGONISTS HAS OPENED A NEW AREA OF RESEARCH FOR POTENTIAL THERAPEUTIC AGENTS FOR THE MANAGEMENT OF INFLAMMATORY PERIODONTITIS. 2011 3 6331 32 THE ROLE OF COX-2 IN INTESTINAL INFLAMMATION AND COLORECTAL CANCER. COLORECTAL CANCER (CRC) IS A HETEROGENEOUS DISEASE, INCLUDING AT LEAST THREE MAJOR FORMS: HEREDITARY, SPORADIC AND COLITIS-ASSOCIATED CRC. A LARGE BODY OF EVIDENCE INDICATES THAT GENETIC MUTATIONS, EPIGENETIC CHANGES, CHRONIC INFLAMMATION, DIET AND LIFESTYLE ARE THE RISK FACTORS FOR CRC. AS ELEVATED CYCLOOXYGENASE-2 (COX-2) EXPRESSION WAS FOUND IN MOST CRC TISSUE AND IS ASSOCIATED WITH WORSE SURVIVAL AMONG CRC PATIENTS, INVESTIGATORS HAVE SOUGHT TO EVALUATE THE EFFECTS OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) AND SELECTIVE COX-2 INHIBITORS (COXIBS) ON CRC. THE EPIDEMIOLOGICAL STUDIES, CLINICAL TRIALS AND ANIMAL EXPERIMENTS INDICATE THAT NSAIDS ARE AMONG THE MOST PROMISING CHEMOPREVENTIVE AGENTS FOR THIS DISEASE. NSAIDS EXERT THEIR ANTI-INFLAMMATORY AND ANTITUMOR EFFECTS PRIMARILY BY REDUCING PROSTAGLANDIN PRODUCTION BY INHIBITION OF COX-2 ACTIVITY. IN THIS REVIEW, WE HIGHLIGHT BREAKTHROUGHS IN OUR UNDERSTANDING OF THE ROLES OF COX-2 IN CRC AND INFLAMMATORY BOWEL DISEASE. THESE RECENT DATA PROVIDE A RATIONALE FOR RE-EVALUATING COX-2 AS BOTH THE PROGNOSTIC AND THE PREDICTIVE MARKER IN A WIDE VARIETY OF MALIGNANCIES AND FOR RENEWING THE INTEREST IN EVALUATING RELATIVE BENEFITS AND RISK OF COXIBS IN APPROPRIATELY SELECTED PATIENTS FOR CANCER PREVENTION AND TREATMENT. 2010 4 5037 40 PHARMACOGENETICS IN PAIN TREATMENT. PAIN IS AN UNPLEASANT FEELING USUALLY RESULTING FROM TISSUE DAMAGE THAT CAN PERSIST ALONG WEEKS, MONTHS, OR EVEN YEARS AFTER THE INJURY, TURNING INTO PATHOLOGICAL CHRONIC PAIN, THE LEADING CAUSE OF DISABILITY. CURRENTLY, PHARMACOLOGY INTERVENTIONS ARE USUALLY THE FIRST-LINE THERAPY BUT THERE IS A HIGHLY VARIABLE ANALGESIC DRUG RESPONSE. PHARMACOGENETICS (PGX) OFFERS A MEANS TO IDENTIFY GENETIC BIOMARKERS THAT CAN PREDICT INDIVIDUAL ANALGESIC RESPONSE OPENING DOORS TO PRECISION MEDICINE. PGX ANALYZE THE WAY IN WHICH THE PRESENCE OF VARIATIONS IN THE DNA SEQUENCE (SINGLE-NUCLEOTIDE POLYMORPHISMS, SNPS) COULD BE RESPONSIBLE FOR PORTIONS OF THE POPULATION REACHING DIFFERENT LEVELS OF PAIN RELIEF (PHENOTYPE) DUE TO GENE INTERFERENCE IN THE DRUG MECHANISM OF ACTION (PHARMACODYNAMICS) AND/OR ITS CONCENTRATION AT THE PLACE OF ACTION (PHARMACOKINETICS). SNPS IN THE CYTOCHROME P450 ENZYMES GENES (CYP2D6) INFLUENCE METABOLISM OF CODEINE, TRAMADOL, HYDROCODONE, OXYCODONE, AND TRICYCLIC ANTIDEPRESSANTS. BLOOD CONCENTRATIONS OF SOME NSAIDS DEPEND ON CYP2C9 AND/OR CYP2C8 ACTIVITY. ADDITIONAL CANDIDATE GENES ENCODE FOR OPIOID RECEPTORS, TRANSPORTERS, AND OTHER MOLECULES IMPORTANT FOR PHARMACOTHERAPY IN PAIN MANAGEMENT. HOWEVER, PGX STUDIES ARE OFTEN CONTRADICTORY, SLOWING THE UPTAKE OF THIS INFORMATION. THIS IS LIKELY DUE, IN LARGE PART, TO A LACK OF ROBUST EVIDENCE DEMONSTRATING CLINICAL UTILITY AND TO ITS POLYGENIC RESPONSE MODULATED BY OTHER EXOGENOUS OR EPIGENETICS FACTORS. NOVEL THERAPIES, INCLUDING TARGETING OF EPIGENETIC CHANGES AND GENE THERAPY-BASED APPROACHES, BROADEN FUTURE OPTIONS TO IMPROVE UNDERSTANDING OF PAIN AND THE TREATMENT OF PEOPLE WHO SUFFER IT. 2018 5 5519 31 RISK FACTORS FOR ALZHEIMER'S DISEASE: ROLE OF MULTIPLE ANTIOXIDANTS, NON-STEROIDAL ANTI-INFLAMMATORY AND CHOLINERGIC AGENTS ALONE OR IN COMBINATION IN PREVENTION AND TREATMENT. THE ETIOLOGY OF ALZHEIMER'S DISEASE (AD) IS NOT WELL UNDERSTOOD. ETIOLOGIC FACTORS, CHRONIC INFLAMMATORY REACTIONS, OXIDATIVE AND NITROSYLATIVE STRESSES AND HIGH CHOLESTEROL LEVELS ARE THOUGHT TO BE IMPORTANT FOR INITIATING AND PROMOTING NEURODEGENERATIVE CHANGES COMMONLY FOUND IN AD BRAINS. EVEN IN FAMILIAL AD, OXIDATIVE STRESS PLAYS AN IMPORTANT ROLE IN THE EARLY ONSET OF THE DISEASE. MITOCHONDRIAL DAMAGE AND PROTEASOME INHIBITION REPRESENT EARLY EVENTS IN THE PATHOGENESIS OF AD, WHEREAS INCREASED PROCESSING OF AMYLOID PRECURSOR PROTEIN (APP) TO BETA-AMYLOID (ABETA) FRAGMENTS (ABETA(40) AND ABETA(42)) AND FORMATION OF SENILE PLAQUES AND NEUROFIBRILLARY TANGLES (NFTS) REPRESENT LATE EVENTS. WE PROPOSE A HYPOTHESIS THAT IN IDIOPATHIC AD, EPIGENETIC COMPONENTS OF NEURONS SUCH AS MITOCHONDRIA, PROTEASOMES AND POST-TRANSLATION PROTEIN MODIFICATIONS (PROCESSING OF AMYLOID PRECURSOR PROTEIN TO BETA-AMYLOID AND HYPERPHOSPHORYLATION OF TAU), RATHER THAN NUCLEAR GENES, ARE THE PRIMARY TARGETS FOR THE ACTION OF DIVERSE GROUPS OF NEUROTOXINS. BASED ON EPIDEMIOLOGIC, LABORATORY AND LIMITED CLINICAL STUDIES, WE PROPOSE THAT A COMBINATION OF NON STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) AND APPROPRIATE LEVELS AND TYPES OF MULTIPLE MICRONUTRIENTS, INCLUDING ANTIOXIDANTS, MAY BE MORE EFFECTIVE THAN THE INDIVIDUAL AGENTS IN THE PREVENTION, AND THEY, IN COMBINATION WITH A CHOLINERGIC AGENT, MAY BE MORE EFFECTIVE IN THE TREATMENT OF AD THAN THE INDIVIDUAL AGENTS ALONE. IN ADDITION, AGENTS, WHICH CAN PREVENT FORMATION OF PLAQUES OR DISSOLVE THESE PLAQUES MAY FURTHER ENHANCE THE EFFICACY OF OUR PROPOSED TREATMENT STRATEGY. 2002 6 2238 33 EPIGENETIC MODULATION AS A THERAPEUTIC PROSPECT FOR TREATMENT OF AUTOIMMUNE RHEUMATIC DISEASES. SYSTEMIC INFLAMMATORY RHEUMATIC DISEASES ARE CONSIDERED AS AUTOIMMUNE DISEASES, MEANING THAT THE BALANCE BETWEEN RECOGNITION OF PATHOGENS AND AVOIDANCE OF SELF-ATTACK IS IMPAIRED AND THE IMMUNE SYSTEM ATTACKS AND DESTROYS ITS OWN HEALTHY TISSUE. TREATMENT WITH CONVENTIONAL DISEASE MODIFYING ANTIRHEUMATIC DRUGS (DMARDS) AND/OR NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS) IS OFTEN ASSOCIATED WITH VARIOUS ADVERSE REACTIONS DUE TO UNSPECIFIC AND TOXIC PROPERTIES OF THOSE DRUGS. ALTHOUGH BIOLOGIC DRUGS HAVE LARGELY IMPROVED THE OUTCOME IN MANY PATIENTS, SUCH DRUGS STILL POSE SIGNIFICANT PROBLEMS AND FAIL TO PROVIDE A SOLUTION TO ALL PATIENTS. THEREFORE, DEVELOPMENT OF MORE EFFECTIVE TREATMENTS AND IMPROVEMENTS IN EARLY DIAGNOSIS OF RHEUMATIC DISEASES ARE BADLY NEEDED IN ORDER TO INCREASE PATIENT'S FUNCTIONING AND QUALITY OF LIFE. THE REVERSIBLE NATURE OF EPIGENETIC MECHANISMS OFFERS A NEW CLASS OF DRUGS THAT MODULATE THE IMMUNE SYSTEM AND INFLAMMATION. IN FACT, EPIGENETIC DRUGS ARE ALREADY IN USE IN SOME TYPES OF CANCER OR CARDIOVASCULAR DISEASES. THEREFORE, EPIGENETIC-BASED THERAPEUTICS THAT CONTROL AUTOIMMUNITY AND CHRONIC INFLAMMATORY PROCESS HAVE BROAD IMPLICATIONS FOR THE PATHOGENESIS, DIAGNOSIS, AND MANAGEMENT OF RHEUMATIC DISEASES. THIS REVIEW SUMMARISES THE LATEST INFORMATION ABOUT POTENTIAL THERAPEUTIC APPLICATION OF EPIGENETIC MODIFICATION IN TARGETING IMMUNE ABNORMALITIES AND INFLAMMATION OF RHEUMATIC DISEASES. 2016 7 4611 30 NEONATAL IMMUNE CHALLENGE FOLLOWED BY ADULT IMMUNE CHALLENGE INDUCES EPIGENETIC-SUSCEPTIBILITY TO AGGRAVATED VISCERAL HYPERSENSITIVITY. BACKGROUND: ABDOMINAL PAIN IS ONE OF THE MAJOR SYMPTOMS OF INFLAMMATORY BOWEL DISEASE (IBD). THE INFLAMMATORY MEDIATORS RELEASED BY COLON INFLAMMATION ARE KNOWN TO SENSITIZE THE AFFERENT NEURONS, WHICH IS ONE OF THE CONTRIBUTORS TO ABDOMINAL PAIN. HOWEVER, NOT ALL IBD PATIENTS HAVE ABDOMINAL PAIN, AND SOME PATIENTS REPORT ABDOMINAL PAIN DURING REMISSION, SUGGESTING CONTRIBUTIONS OF OTHER PATHOLOGICAL FACTORS TO ABDOMINAL PAIN IN IBD. EPIDEMIOLOGICAL STUDIES FOUND EARLY-LIFE GASTROINTESTINAL INFECTIONS A RISK FACTOR FOR IBD SYMPTOMS AND ADULT-LIFE GASTROINTESTINAL INFECTIONS MAY TRIGGER THE ONSET OF IBD. WE INVESTIGATED THE HYPOTHESIS THAT NEONATAL COLON IMMUNE CHALLENGE FOLLOWED BY AN ADULT COLON IMMUNE CHALLENGE UPREGULATES SPINAL CORD BDNF THAT AGGRAVATES VISCERAL SENSITIVITY OVER AND ABOVE THAT INDUCED BY ADULT COLON IMMUNE CHALLENGE ALONE. METHODS: WE INDUCED NEONATAL AND ADULT COLON IMMUNE CHALLENGES BY INTRALUMINAL ADMINISTRATION OF TRINITROBENZENE SULFONIC ACID TO THE RAT COLON. KEY RESULTS: WE FOUND THAT NEONATAL IMMUNE CHALLENGE TRIGGERS EPIGENETIC PROGRAMMING THAT UPREGULATES TYROSINE HYDROXYLASE IN THE LOCUS CERULEUS WHEN THESE RATS ARE SUBJECTED TO AN ADULT COLON IMMUNE CHALLENGE. THE UPREGULATION OF LOCUS CERULEUS TYROSINE HYDROXYLASE, UPREGULATES NOREPINEPHRINE IN THE CEREBROSPINAL FLUID THAT ACTS ON ADRENERGIC RECEPTORS TO ENHANCE PCREB BINDING TO THE CAMP RESPONSE ELEMENT, WHICH RECRUITS HISTONE ACETYLENE TRANSFERASE (HAT) TO THE BDNF GENE TO ENHANCE ITS TRANSCRIPTION RESULTING IN AGGRAVATED VISCEROMOTOR RESPONSE TO COLORECTAL DISTENSION. HAT AND ADRENERGIC RECEPTOR ANTAGONISTS BLOCK THE AGGRAVATION OF VISCERAL SENSITIVITY. CONCLUSION & INFERENCES: HAT AND ADRENERGIC RECEPTOR INHIBITORS MAY SERVE AS ALTERNATES TO OPIOIDS AND NSAIDS IN SUPPRESSING ABDOMINAL PAIN IN IBD. 2017 8 1160 26 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 9 5265 28 PROMISING THERAPEUTIC TARGETS FOR TREATMENT OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A SYSTEMIC POLY-ARTICULAR CHRONIC AUTOIMMUNE JOINT DISEASE THAT MAINLY DAMAGES THE HANDS AND FEET, WHICH AFFECTS 0.5% TO 1.0% OF THE POPULATION WORLDWIDE. WITH THE SUSTAINED DEVELOPMENT OF DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARDS), SIGNIFICANT SUCCESS HAS BEEN ACHIEVED FOR PREVENTING AND RELIEVING DISEASE ACTIVITY IN RA PATIENTS. UNFORTUNATELY, SOME PATIENTS STILL SHOW LIMITED RESPONSE TO DMARDS, WHICH PUTS FORWARD NEW REQUIREMENTS FOR SPECIAL TARGETS AND NOVEL THERAPIES. UNDERSTANDING THE PATHOGENETIC ROLES OF THE VARIOUS MOLECULES IN RA COULD FACILITATE DISCOVERY OF POTENTIAL THERAPEUTIC TARGETS AND APPROACHES. IN THIS REVIEW, BOTH EXISTING AND EMERGING TARGETS, INCLUDING THE PROTEINS, SMALL MOLECULAR METABOLITES, AND EPIGENETIC REGULATORS RELATED TO RA, ARE DISCUSSED, WITH A FOCUS ON THE MECHANISMS THAT RESULT IN INFLAMMATION AND THE DEVELOPMENT OF NEW DRUGS FOR BLOCKING THE VARIOUS MODULATORS IN RA. 2021 10 5042 31 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 11 429 31 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 12 4685 29 NEW TARGETS AND STRATEGIES FOR RHEUMATOID ARTHRITIS: FROM SIGNAL TRANSDUCTION TO EPIGENETIC ASPECT. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC AUTOIMMUNE DISEASE THAT CAN LEAD TO JOINT DAMAGE AND EVEN PERMANENT DISABILITY, SERIOUSLY AFFECTING PATIENTS' QUALITY OF LIFE. AT PRESENT, THE COMPLETE CURE FOR RA IS NOT ACHIEVABLE, ONLY TO RELIEVE THE SYMPTOMS TO REDUCE THE PAIN OF PATIENTS. FACTORS SUCH AS ENVIRONMENT, GENES, AND SEX CAN INDUCE RA. PRESENTLY, NON-STEROIDAL ANTI-INFLAMMATORY DRUGS, DRMADS, AND GLUCOCORTICOIDS ARE COMMONLY USED IN TREATING RA. IN RECENT YEARS, SOME BIOLOGICAL AGENTS HAVE ALSO BEEN APPLIED IN CLINICAL PRACTICE, BUT MOST HAVE SIDE EFFECTS. THEREFORE, FINDING NEW MECHANISMS AND TARGETS FOR TREATING RA IS NECESSARY. THIS REVIEW SUMMARIZES SOME POTENTIAL TARGETS DISCOVERED FROM THE PERSPECTIVE OF EPIGENETICS AND RA MECHANISMS. 2023 13 4532 30 MULTIMODAL ANALGESIA FOR PERIOPERATIVE MANAGEMENT OF PATIENTS PRESENTING FOR SPINAL SURGERY. MULTIMODAL, NON-OPIOID BASED ANALGESIA HAS BECOME THE CORNERSTONE OF ERAS PROTOCOLS FOR EFFECTIVE ANALGESIA AFTER SPINAL SURGERY. OPIOID SIDE EFFECTS, DEPENDENCE AND LEGISLATION RESTRICTING LONG TERM OPIOID USE HAS LED TO A RESURGENCE IN INTEREST IN OPIOID SPARING TECHNIQUES. THE INCREASING ARRAY OF MULTIMODAL OPIOID SPARING ANALGESICS AVAILABLE FOR SPINAL SURGERY TARGETING NOVEL RECEPTORS, TRANSMITTERS, AND ALTERING EPIGENETICS CAN HELP PROVIDE AN OPTIMAL PERIOPERATIVE EXPERIENCE WITH LESS OPIOID SIDE EFFECTS AND LONG-TERM DEPENDENCE. EPIGENETIC MECHANISMS OF PAIN MAY ENHANCE OR SUPPRESS GENE EXPRESSION, WITHOUT ALTERING THE GENOME ITSELF. SUCH MECHANISMS ARE COMPLEX, DYNAMIC AND RESPONSIVE TO ENVIRONMENT. ALTERATIONS THAT OCCUR CAN AFFECT THE PATHOPHYSIOLOGY OF PAIN MANAGEMENT AT A DNA LEVEL, MODIFYING PERCEIVED PAIN RELIEF. IN THIS REVIEW, WE PROVIDE A BRIEF OVERVIEW OF EPIGENETICS OF PAIN, SYSTEMIC LOCAL ANESTHETICS AND NEURAXIAL TECHNIQUES THAT CONTINUE TO REMAIN USEFUL FOR SPINAL SURGERY, NEUROPATHIC AGENTS, AS WELL AS OTHER COMMON AND LESS COMMON TARGET RECEPTORS FOR A TRULY MULTIMODAL APPROACH TO PERIOPERATIVE PAIN MANAGEMENT. 2019 14 6325 24 THE ROLE OF ANTI-INFLAMMATORY DRUGS IN COLORECTAL CANCER. A LARGE BODY OF EVIDENCE INDICATES THAT GENETIC MUTATIONS, EPIGENETIC CHANGES, CHRONIC INFLAMMATION, DIET, AND LIFESTYLE ARE KEY RISK FACTORS FOR COLORECTAL CANCER (CRC). PREVENTION OF CRC HAS LONG BEEN CONSIDERED A PLAUSIBLE APPROACH FOR THE POPULATION AND INDIVIDUALS AT HIGH RISK FOR DEVELOPING THIS DISEASE. A SIGNIFICANT EFFORT HAS BEEN MADE IN THE DEVELOPMENT OF NOVEL DRUGS FOR BOTH PREVENTION AND TREATMENT OVER THE PAST TWO DECADES. THIS REVIEW HIGHLIGHTS RECENT ADVANCES IN OUR UNDERSTANDING OF THE ROLE OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS IN CRC PREVENTION AND ADJUVANT TREATMENT. MOREOVER, WE FOCUS ON THE MOLECULAR MECHANISMS UNDERLYING THE ANTITUMOR EFFECTS OF THESE DRUGS IN CRC. THE KNOWLEDGE OF HOW ANTI-INFLAMMATORY AGENTS INHIBIT CANCER FORMATION AND PROGRESSION MAY PROVIDE A RATIONALE FOR THE DEVELOPMENT OF MORE EFFECTIVE CHEMOPREVENTIVE AND CHEMOTHERAPEUTIC AGENTS WITH LESS TOXICITY. 2013 15 6776 28 [APPROACHING NEW PHARMACOTHERAPY OPTIONS IN PAIN TREATMENT]. THE EVOLUTION OF MEDICINE IS NOTICEABLE IN MOST THERAPEUTIC AREAS, THE WORSE THE CURRENT THERAPEUTIC RESULT, THE MORE QUICK THE IMPROVEMENT. THIS IS ESPECIALLY TRUE IN SUCH AREAS THAT REQUIRE SUBSTANTIAL SOCIAL RESOURCES, NAMELY ONCOLOGY, DIABETOLOGY AND CNS DISEASES. PAIN IS NOT A DISEASE, IT IS A SYMPTOM. PAIN IS ONE OF THE MOST IMPORTANT COMPONENTS OF HUMAN SUFFERING THUS IT DESERVES SPECIAL ATTENTION. IN RECENT YEARS NEW FORMULATIONS OF OLD MEDICINES WERE INTRODUCED RATHER THAN NEW MEDICINES. MAYBE ZICONITIDE IS THE LAST PAIN KILLER WITH NEW MECHANISM OF ACTION WHICH WAS APPROVED BY FDA IN 2004. HOWEVER, THE NEW INFORMATION AND TECHNIQUES ARE ALSO APPEARING IN THE FIELD OF ANALGESIA. NOWADAYS ONE CAN TALK ABOUT GENETIC/EPIGENETIC TARGETS, RNA THERAPIES, VOLTAGE-GATED CALCIUM CHANNELS, NEW PAIN RECEPTORS (TRPV1, TRPV4, NMDA, NAV RECEPTORS) REGARDING PAIN TREATMENT, INDICATING THAT THE PRACTICE OF THE PHARMACOTHERAPY OF PAIN WILL CHANGE FUNDAMENTALLY IN THE IMMEDIATE FUTURE. THIS PAPER IS INTENDED TO GIVE A SHORT SUMMARY OF THESE NEW OPTIONS. 2017 16 367 34 AMPLIFIED PAIN SYNDROMES IN CHILDREN: TREATMENT AND NEW INSIGHTS INTO DISEASE PATHOGENESIS. PURPOSE OF REVIEW: ALTHOUGH MANY DIAGNOSTIC TERMS ARE USED FOR PEDIATRIC CHRONIC PAIN, EVIDENCE SUGGESTS A COMMON THREAD OF SIGNAL AMPLIFICATION, LEADING TO THE UNIFYING TERM 'AMPLIFIED PAIN SYNDROMES'. ONGOING RESEARCH PROVIDES NEW INSIGHTS INTO BIOPSYCHOSOCIAL CONTRIBUTORS AND TREATMENTS FOR PEDIATRIC AMPLIFIED PAIN SYNDROMES. RECENT FINDINGS: BASIC SCIENCE INDICATES A COMPLEX INTERPLAY OF GENETIC, EPIGENETIC, NEUROCHEMICAL, ENDOCRINE, AND INFLAMMATORY CONTRIBUTORS, ALONG WITH ENVIRONMENTAL AND PSYCHOLOGICAL FACTORS. ALTHOUGH MEDICATIONS AND INTERVENTIONS REMAIN COMMON APPROACHES TO CHILDREN WITH CHRONIC PAIN, THEIR EVIDENCE IS LIMITED. PRELIMINARY EVIDENCE EXISTS FOR MINDFULNESS-BASED THERAPIES, YOGA, AND OTHER COMPLEMENTARY/ALTERNATIVE MEDICINE APPROACHES. THE STRONGEST EVIDENCE IS FOR EXERCISE-BASED AND COGNITIVE-BEHAVIORAL TREATMENTS, IN PARTICULAR, WHEN COMBINED IN A MULTIDISCIPLINARY FORMAT. INTENSIVE APPROACHES (PAIN REHABILITATION) HAVE THE POTENTIAL TO EFFECTIVELY AND EFFICIENTLY TREAT THOSE MOST DISABLED BY AMPLIFIED PAIN SYNDROMES, AND LEAD TO SUSTAINED IMPROVEMENT IN PAIN, FUNCTIONING, AND MEDICAL UTILIZATION. SUMMARY: ALTHOUGH UNDERSTANDING OF THE MECHANISMS UNDERLYING PEDIATRIC AMPLIFIED PAIN SYNDROMES EVOLVES, STANDARD OF CARE IS MULTIDISCIPLINARY EMPHASIZING EXERCISE THERAPY, COGNITIVE-BEHAVIORAL TREATMENT, AND SELF-REGULATION. TREATMENT SHOULD TARGET FULL RETURN TO PHYSICAL FUNCTION, WHICH LEADS TO SUBSEQUENT IMPROVEMENT OR RESOLUTION OF PAIN. MULTIDISCIPLINARY CARE CAN BE COORDINATED BY A RHEUMATOLOGIST OR OTHER PHYSICIAN WITH APPROPRIATE REFERRALS, OR THROUGH A MULTIDISCIPLINARY TEAM. 2014 17 3689 30 INFLAMMATORY AUTO-IMMUNE DISEASES OF THE INTESTINE AND THEIR MANAGEMENT BY NATURAL BIOACTIVE COMPOUNDS. AUTOIMMUNE DISEASES ARE CAUSED BY THE OVERACTIVITY OF THE IMMUNE SYSTEM TOWARDS SELF-CONSTITUENTS. RISK FACTORS OF AUTOIMMUNE DISEASES ARE MULTIPLE AND INCLUDE GENETIC, EPIGENETIC, ENVIRONMENTAL, AND PSYCHOLOGICAL. AUTOIMMUNE CHRONIC INFLAMMATORY BOWEL DISEASES, INCLUDING CELIAC AND INFLAMMATORY DISEASES (CROHN'S DISEASE AND ULCERATIVE COLITIS), CONSTITUTE A SIGNIFICANT HEALTH PROBLEM WORLDWIDE. BESIDES THE COMPLEXITY OF THE SYMPTOMS OF THESE DISEASES, THEIR TREATMENTS HAVE ONLY BEEN PALLIATIVE. NUMEROUS INVESTIGATIONS SHOWED THAT NATURAL PHYTOCHEMICALS COULD BE PROMISING STRATEGIES TO FIGHT AGAINST THESE AUTOIMMUNE DISEASES. IN THIS RESPECT, PLANT-DERIVED NATURAL COMPOUNDS SUCH AS FLAVONOIDS, PHENOLIC ACIDS, AND TERPENOIDS EXHIBITED SIGNIFICANT EFFECTS AGAINST THREE AUTOIMMUNE DISEASES AFFECTING THE INTESTINE, PARTICULARLY BOWEL DISEASES. THIS REVIEW FOCUSES ON THE ROLE OF NATURAL COMPOUNDS OBTAINED FROM MEDICINAL PLANTS IN MODULATING INFLAMMATORY AUTO-IMMUNE DISEASES OF THE INTESTINE. IT COVERS THE MOST RECENT LITERATURE RELATED TO THE EFFECT OF THESE NATURAL COMPOUNDS IN THE TREATMENT AND PREVENTION OF AUTO-IMMUNE DISEASES OF THE INTESTINE. 2022 18 2952 17 GENETIC AND EPIGENETIC ETIOLOGY OF INFLAMMATORY BOWEL DISEASE: AN UPDATE. INFLAMMATORY BOWEL DISEASE (IBD) IS A CHRONIC DISEASE WITH PERIODS OF EXACERBATION AND REMISSION OF THE DISEASE. THE ETIOLOGY OF IBD IS NOT FULLY UNDERSTOOD. MANY STUDIES POINT TO THE PRESENCE OF GENETIC, IMMUNOLOGICAL, ENVIRONMENTAL, AND MICROBIOLOGICAL FACTORS AND THE INTERACTIONS BETWEEN THEM IN THE OCCURRENCE OF IBD. THE REVIEW LOOKS AT GENETIC FACTORS IN THE CONTEXT OF BOTH IBD PREDISPOSITION AND PHARMACOGENETICS. 2022 19 6480 38 TOWARDS PRECISION MEDICINE IN GENERALIZED ANXIETY DISORDER: REVIEW OF GENETICS AND PHARMACO(EPI)GENETICS. GENERALIZED ANXIETY DISORDER (GAD) IS A PREVALENT AND CHRONIC MENTAL DISORDER THAT ELICITS WIDESPREAD FUNCTIONAL IMPAIRMENT. GIVEN THE HIGH DEGREE OF NON-RESPONSE/PARTIAL RESPONSE AMONG PATIENTS WITH GAD TO AVAILABLE PHARMACOLOGICAL TREATMENTS, THERE IS A STRONG NEED FOR NOVEL APPROACHES THAT CAN OPTIMIZE OUTCOMES, AND LEAD TO MEDICATIONS THAT ARE SAFER AND MORE EFFECTIVE. ALTHOUGH INVESTIGATIONS HAVE IDENTIFIED INTERESTING TARGETS PREDICTING TREATMENT RESPONSE THROUGH PHARMACOGENETICS (PGX), PHARMACO-EPIGENETICS, AND NEUROIMAGING METHODS, THESE STUDIES ARE OFTEN SOLITARY, NOT REPLICATED, AND CARRY SEVERAL LIMITATIONS. THIS REVIEW PROVIDES AN OVERVIEW OF THE CURRENT STATUS OF GAD GENETICS AND PGX AND PRESENTS POTENTIAL STRATEGIES TO IMPROVE TREATMENT RESPONSE BY COMBINING BETTER PHENOTYPING WITH PGX AND IMPROVED ANALYTICAL METHODS. THESE STRATEGIES CARRY THE DUAL BENEFIT OF DELIVERING DATA ON BIOMARKERS OF TREATMENT RESPONSE AS WELL AS POINTING TO DISEASE MECHANISMS THROUGH THE BIOLOGY OF THE MARKERS ASSOCIATED WITH RESPONSE. OVERALL, THESE EFFORTS CAN SERVE TO IDENTIFY CLINICAL, GENETIC, AND EPIGENETIC FACTORS THAT CAN BE INCORPORATED INTO A PHARMACO(EPI)GENETIC TEST THAT MAY ULTIMATELY IMPROVE TREATMENT RESPONSE AND REDUCE THE SOCIOECONOMIC BURDEN OF GAD. 2019 20 4850 31 OPIOIDS AND OPIOID RECEPTORS; UNDERSTANDING PHARMACOLOGICAL MECHANISMS AS A KEY TO THERAPEUTIC ADVANCES AND MITIGATION OF THE MISUSE CRISIS. OPIOIDS ARE A MAINSTAY IN ACUTE PAIN MANAGEMENT AND PRODUCE THEIR EFFECTS AND SIDE EFFECTS (E.G., TOLERANCE, OPIOID-USE DISORDER AND IMMUNE SUPPRESSION) BY INTERACTION WITH OPIOID RECEPTORS. I WILL DISCUSS OPIOID PHARMACOLOGY IN SOME CONTROVERSIAL AREAS OF ENQUIRY OF ANAESTHETIC RELEVANCE. THE MAIN OPIOID TARGET IS THE MICRO (MU,MOP) RECEPTOR BUT OTHER MEMBERS OF THE OPIOID RECEPTOR FAMILY, DELTA (DELTA; DOP) AND KAPPA (KAPPA; KOP) OPIOID RECEPTORS ALSO PRODUCE ANALGESIC ACTIONS. THESE ARE NALOXONE-SENSITIVE. THERE IS IMPORTANT CLINICAL DEVELOPMENT RELATING TO THE NOCICEPTIN/ORPHANIN FQ (NOP) RECEPTOR, AN OPIOID RECEPTOR THAT IS NOT NALOXONE-SENSITIVE. BETTER UNDERSTANDING OF THE DRIVERS FOR OPIOID EFFECTS AND SIDE EFFECTS MAY FACILITATE SEPARATION OF SIDE EFFECTS AND PRODUCTION OF SAFER DRUGS. OPIOIDS BIND TO THE RECEPTOR ORTHOSTERIC SITE TO PRODUCE THEIR EFFECTS AND CAN ENGAGE MONOMER OR HOMO-, HETERODIMER RECEPTORS. SOME LIGANDS CAN DRIVE ONE INTRACELLULAR PATHWAY OVER ANOTHER. THIS IS THE BASIS OF BIASED AGONISM (OR FUNCTIONAL SELECTIVITY). OPIOID ACTIONS AT THE ORTHOSTERIC SITE CAN BE MODULATED ALLOSTERICALLY AND POSITIVE ALLOSTERIC MODULATORS THAT ENHANCE OPIOID ACTION ARE IN DEVELOPMENT. AS WELL AS TARGETING LIGAND-RECEPTOR INTERACTION AND TRANSDUCTION, MODULATING RECEPTOR EXPRESSION AND HENCE FUNCTION IS ALSO TRACTABLE. THERE IS EVIDENCE FOR EPIGENETIC ASSOCIATIONS WITH DIFFERENT TYPES OF PAIN AND ALSO SUBSTANCE MISUSE. AS LONG AS THE OPIOID NARRATIVE IS DEFINED BY THE 'OPIOID CRISIS' THE DRIVE TO REMOVE THEM COULD GATHER PACE. THIS WILL DENY USE WHERE THEY ARE EFFECTIVE, AND ACCESS TO MORPHINE FOR PAIN RELIEF IN LOW INCOME COUNTRIES. 2023