Prevencija kardiovaskularnih bolesti – ko želi da živi večno?

Atherosclerotic cardiovascular diseases (ASCVDs) are the leading cause of death globally. Most cardiovascular diseases can be prevented or have better clinical outcomes, by appropriate (non)pharmacological measures. According to Heraclitus’ pattern, how a person’s habits, environment, and national morbidity changed, so did the recommendations for cardiovascular disease prevention. Current guidelines of the European Society of Cardiology propose individual and population-level interventions for cardiovascular prevention in apparently healthy people (primary prevention) and patients with established ASCVD or its equivalents, such as diabetes and chronic kidney disease (secondary prevention) (1). The cornerstone of prevention is an individual’s cardiovascular risk estimation and education on the importance of modifiable risk factor control. General preventive measures include the adoption of healthy lifestyle (smoking cessation, physical activity, Mediterranean diet, and reduced alcohol intake) and risk modifiers control (e.g., psychosocial stress). Individual‐level interventions depend on the estimated cardiovascular risk and age category, with a holistic approach to patient. The higher the cardiovascular risk, the greater the benefit of risk factor treatment. The introduction of pharmacotherapy for optimal control of dyslipidemia, arterial hypertension, and/or diabetes is reserved for patients with (very) high cardiovascular risk. A stepwise treatment-intensification approach is advocated to achieve the treatment targets. The outcome of preventive measures is adversely affected by comorbidities (mental disorders, inflammatory diseases, atrial fibrillation), which should therefore be adequately treated. Policy interventions at the population level are still a weak link in most countries and should include promotion of physical activity and diet, restrictions on tobacco/alcohol consumption, and air pollution reduction.Aterosklerotske kardiovaskularne bolesti (ASKVB) su vodeći uzrok mortaliteta u svetu. Većina kardiovaskularnih bolesti se može sprečiti ili se mogu unaprediti klinički ishodi primenom odgovarajućih (ne)farmakoloških mera. Po Heraklitovom obrascu, kako su se menjale životne navike čoveka, njegovo okruženje i nacionalni morbiditet, tako su se prilagođavale preporuke za prevenciju kardiovaskularnih bolesti. Aktuelne smernice Evropskog udruženja kardiologa predlažu individualne i populacione mere za kardiovaskularnu prevenciju kod naizgled zdravih osoba (primarna prevencija) i pacijenata sa ASKVB ili njenim ekvivalentima poput dijabetesa i hronične bolesti bubrega (sekundarna prevencija) (1). Ključan korak prevencije je procena kardiovaskularnog rizika pojedinca i edukacija o značaju korekcije promenljivih faktora rizika. Opšte preventivne mere uključuju usvajanje zdravih životnih navika (obustava pušenja, fizička aktivnost, mediteranska ishrana i smanjen unos alkohola) i kontrolu tzv. modifikatora rizika (npr. psihosocijalni stres). Intervencije na individualnom nivou zavise od nivoa procenjenog kardiovaskularnog rizika i starosne kategorije, uz holistički pristup pacijentu. Što je kardiovaskularni rizik veći, to je veća korist od regulisanja faktora rizika. Uvođenje farmakoterapije u cilju bolje kontrole dislipidemije, arterijske hipertenzije i/ili dijabetesa namenjeno je za pacijente sa (veoma) visokim kardiovaskularnim rizikom. Preporučuje se postepeno intenziviranje terapije do postizanja ciljnih vrednosti faktora rizika. Na ishod preventivnih mera nepovoljno utiče prisustvo komorbiditeta (mentalni poremećaji, inflamatorne bolesti, atrijalna fibrilacija i dr.), koje stoga treba adekvatno lečiti. Preventivne mere na populacionom nivou još uvek su slaba karika većine zemalja, a trebalo bi da uključuju promovisanje fizičke aktivnosti i zdrave ishrane, ograničavanje konzumacije duvana i alkohola, kao i redukciju aerozagađenja.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Antinociceptive effect, mechanism of action and interactions of levetiracetam in somatic, visceral and neuropathic pain models

Svrha studije: Levetiracetam, antiepileptik novije generacije, ostvaruje antinociceptivno dejstvo u nekim animalnim modelima bola. Cilj našeg rada bio je da se ispita: 1) antinociceptivni efekat levetiracetama u somatskom (inflamatornom), visceralnom i neuropatskom modelu bola, 2) mehanizam antinociceptivnog efekta levetiracetama u inflamatornom modelu bola, 3) efekat kombinovane primene levetiracetama i standardnih/alternativnih analgetika u inflamatornom, visceralnom i neuropatskom modelu bola i 4) uticaj antinociceptivnih doza levetiracetama na motornu spretnost eksperimentalnih životinja. Metode: Kao model inflamatornog bola korišćen je model inflamatorne hiperalgezije izazvane karageninom u pacova. Hiperalgezija i efekti lekova/kombinacija lekova mereni su u modifikovanom testu pritiska na šapu pacova. U ovom modelu bola ispitan je i mehanizam antinociceptivnog dejstva levetiracetama, ispitivanjem uticaja levetiracetama na GABAAergičke, opioidergičke, α2-adrenergičke, serotonergičke i adenozinske receptore, nakon sistemske i lokalne periferne primene levetiracetama i odgovarajućih antagonista. U testu grčeva u miševa izazvanih sirćetnom kiselinom, model visceralnog bola, ispitivani su efekti lekova/kombinacija lekova. Kao model neuropatskog bola korišćen je model dijabetesne neuropatije u miševa. Dijabetes je izazivan streptozotocinom, a hiperalgezija i efekti lekova/kombinacija lekova mereni su u testu izmicanja repa pod uticajem toplote. Rotarod test korišćen je za procenu uticaja antinociceptivnih doza levetiracetama na motornu spretnost miševa i pacova. Rezultati: U inflamatornom modelu bola u pacova: 1) levetiracetam je ostvario dozno-zavisno antihiperalgezijsko dejstvo nakon sistemske i lokalne periferne primene, 2) antagonisti GABAA, opioidergičkih, α2-adrenergičkih, serotonergičkih i adenozinskih receptora inhibirali su antihiperalgezijsko dejstvo levetiracetama, 3) levetiracetama primenjen u kombinaciji sa ibuprofenom/celekoksibom/paracetamolom/ceftriaksonom/kofeinom ostvario je sinergističku interakciju. U visceralnom modelu bola u miševa, levetiracetam je ostvario dozno-zavisno antinociceptivno dejstvo i sinergističku interakciju sa paracetamolom i ceftriaksonom. U modelu dijabetesne neuropatije u miševa levetiracetam je ispoljio antinociceptivno dejstvo na dozno zavisan način i sinergizam sa ibuprofenom, paracetamolom, gabapentinom, duloksetinom i alfalipoinskom kiselinom...Background and aim: Levetiracetam, a novel antiepileptic drug, exerts antinociceptive effects in some animal pain models. The aim of our study was to investigate: 1) the antinociceptive effects of levetiracetam in the somatic (inflammatory), visceral and neuropathic pain models, 2) the mechanism of levetiracetam’s antinociceptive effect in the inflammatory pain model, 3) the effects of two-drug combinations of levetiracetam with standard/alternative analgesics in the inflammatory, visceral and neuropathic pain models, and 4) the influence of levetiracetam’s antinociceptive doses on motor performance in experimental animals. Methods: The inflammatory hyperalgesia induced by carrageenan in rats was used as a model of inflammatory pain. Hyperalgesia and drug/drug combinations effects were examined by a modified paw pressure test. In this pain model, levetiracetam's mechanism of action was evaluated by examining the influence of levetiracetam on GABAA-ergic, opioidergic, α2- adrenergic, serotonergic and adenosine receptors, after systemic and local peripheral administration of levetiracetam and corresponding antagonists. In the acetic acid-induced writhing test in mice, model of visceral pain, drug/drug combinations effects were examined. The model of diabetic neuropathy in mice was used as a model of neuropathic pain. The diabetes was induced by streptozotocine and the hyperalgesia and drug/drug combinations effects were assessed by the radiant heat tail flick test. Rotarod test was used to evaluate the influence of antinociceptive doses of levetiracetam on motor performance in both rats and mice. Results: In the inflammatory pain model in rats: 1) levetiracetam exerted dose-dependent antihyperalgesic effects after sistemic and local peripheral administration, 2) the antagonists of GABAA-ergic, opioidergic, α2-adrenergic, serotonergic and adenosine receptors inhibited the antihyperalgesic effects of levetiracetam, 3) levetiracetam exerted synergistic interactions with ibuprofen/celecoxib/paracetamol/ceftriaxone/caffeine. In the visceral pain model in mice, levetiracetam exerted dose-dependent antinociceptive effects and synergistic interactions with paracetamol and ceftriaxone. In the model of diabetic neuropathy in mice, levetiracetam exerted antinociceptive effects, in a dose-dependent manner, and synergistic interactions with ibuprofen,paracetamol, gabapentin, duloxetine and alfa-lipoic acid..

Novine u terapiji multiple skleroze

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, which usually affects young adults. The most common clinical course of the disease is the relapsing-remitting form of multiple sclerosis (RRMS). Although there is no causative therapy, treatment outcomes in patients with RRMS have been significantly improved with the introduction of disease modifying therapy (DMT), which decreases disease activity and delays progression of disability. Drugs used as DMT are immune modulator and immunosuppressive drugs. The conventional immunomodulatory drugs, interferons (IFN-β 1b and IFN-β 1a) and glatiramer acetate, applied parenterally, have been the first line therapy for many years in patients with RRMS. IFN-β and GA are generally safe and well-tolerated. However, due to the heterogeneity of the pathophysiology and clinical presentation of MS, their efficacy is modest, which requires substitution of IFN-β with GA or the use of certain novel immunomodulatory therapies: monoclonal antibodies, alemtuzumab and natalizumab, (parenteral administration) or teriflunomide, dimethyl-fumarate and fingolimod (peroral administration). The antineoplastic agent, mitoxantrone, is used for the treatment of aggressive forms of MS. The overall benefit/risk ratio for novel approaches in the treatment of MS has yet to be determined.Multipla skleroza (MS) je hronično autoimunsko oboljenje centralnog nervnog sistema koje uglavnom pogađa mlade odrasle osobe. Najčešća klinička forma bolesti je relapsno- remitentna multipla skleroza (RRMS). Iako ne postoji kauzalna terapija, ishod lečenja pacijenata sa RRMS značajno je poboljšan uvođenjem terapije koja modifikuje prirodni tok bolesti (disease modifying therapy, DMT), u smislu smanjenja aktivnosti bolesti i odlaganja razvoja progresivne onesposobljenosti pacijenata. Lekovi koji se koriste u DMT su imunomodulatori i imunosupresivi. Standardni imunomodulatorni lekovi, interferoni (IFN-β 1b i IFN-β 1a) i glatiramer acetat (GA), koji se primenjuju parenteralno, prva su terapijska linija dugi niz godina kod pacijenata sa RRMS. Bezbednosni profil IFN-β i GA je generalno dobar. Međutim, zbog heterogenosti patogeneze i kliničke prezentacije MS, njihova efikasnost je delimična, što nameće potrebu za međusobnom zamenom IFN-β i GA ili za ustupanjem mesta nekoj od novih odobrenih imunomodulatornih terapija: alemtuzumab i natalizumab (parenteralna primena) ili teriflunomid, dimetil-fumarat i fingolimod (peroralna primena). Citostatik, mitoksantron, primenjuje se kod agresivne forme MS. Odnos korist/rizik novih terapijskih opcija u MS tek treba da se proceni/potvrdi

Neopioidni analgetici u savremenom lečenju bola

Pain is a symptom of most diseases that can significantly impair the patient's quality of life. In many diseases it is impossible to eliminate the cause of pain therefore the real goal of treatment is the removal of pain as a symptom, by application of analgesics. Contemporary pharmacotherapy employs conventional (opioid and non-opioid analgesics - NSAIDs and paracetamol) and adjuvant analgesics (antiepileptics, antidepressants and others). Analgesic effect of non-opioid analgesics is mainly the consequence of prostaglandin synthesis inhibition. They are effective for pain of mild/moderate intensity. In acute pain there is no difference in efficiency between NSAIDs and paracetamol, so the choice of the drug is individual. In chronic pain, when inflammation is present, NSAIDs are more effective than paracetamol. Long-term use of high doses of NSAIDs is often accompanied by side effects. In order to reduce their frequency, a careful assessment of risk for each patient should be made, a drug with a low risk of certain side effects should be chosen, the dose and duration of treatment should be limited and the possibility of topical application should be considered. The need for long-term use of NSAIDs should be reviewed periodically.Bol je simptom većine oboljenja koji može značajno narušiti kvalitet života pacijenta. Kod mnogih oboljenja nemoguće je otkloniti uzrok bola, stoga je realni cilj lečenja uklanjanje bola kao simptoma, primenom analgetika. Savremena farmakoterapija raspolaže klasičnim (opioidni i ne-opiodini analgetici: NSAIL i paracetamol) i adjuvantnim analgeticima (antiepileptici, antidepresivi i drugi). Analgetičko dejstvo ne-opioidnih analgetika uglavnom je posledica inhibicije sinteze prostaglandina. Efikasni su kod bola blagog/umerenog intenziteta. Kod akutnog bola nema razlike u efikasnosti između NSAIL i paracetamola pa je izbor leka individualan. NSAIL su efikasniji kod hroničnih bolnih stanja u kojima je prisutna inflamacija, ali njihovu dugotrajnu primenu često prate neželjena dejstva. Kako bi se smanjila učestalost neželjenih efekata NSAIL, treba izvršiti pažljivu procenu rizika za svakog pacijenta, odabrati lek sa niskim rizikom za određeno neželjeno dejstvo, ograničiti dozu i trajanje tretmana i razmotriti mogućnost topikalne primene. Potrebu za dugotrajnom primenom NSAIL treba povremeno preispitivati

Synergism between metformin and analgesics/vitamin B12 in a model of painful diabetic neuropathy

Metformin (a widely used antidiabetic drug) has demonstrated efficacy in models of painful diabetic neuropathy (PDN), as well as certain clinical efficacy in relieving/preventing PDN. This study aimed to determine the type of interaction between metformin and duloxetine/oxycodone/eslicarbazepine acetate [ESL]/vitamin B12 in relieving diabetic pain hypersensitivity. Antihyperalgesic efficacy was determined using a Von Frey apparatus in mice with streptozotocin-induced PDN. We examined metformin’s efficacy following oral (acute and prolonged 7-day treatment) and local (spinal and peripheral) application. The examined analgesics were administered in a single oral dose, whereas vitamin B12 was intraperitoneally administered for 7 days. In combination experiments, metformin (prolonged treatment) and analgesics/vitamin B12 were co-administered in fixed-dose fractions of their ED50 values and the type of interaction was determined using isobolographic analysis. Metformin produced dose-dependent antihyperalgesic effects in diabetic mice after oral (acute and prolonged 7-day treatment) and local spinal/peripheral application. Two-drug metformin combinations with analgesics/vitamin B12 also dose- dependently reduced mechanical hyperalgesia. The isobolographic analysis revealed that metformin synergises with analgesics/vitamin B12, with a 6–7 fold dose reduction of both drugs in the examined combinations. In conclusion, metformin reduces hyperalgesia in diabetic animals, most likely by acting at the spinal and pe- ripheral level. Additionally, it synergizes with duloxetine/oxycodone/ESL/vitamin B12 in reducing hyperalgesia. Metformin co-treatment may increase analgesic efficacy and enable the use of lower (and potentially safer) analgesic doses for treating PDN. Combined metformin-vitamin B12 use may provide more effective pain relief and mitigate metformin-induced vitamin B12 deficiency

Učešće serotonergičkih mehanizama u antinociceptivnom dejstvu metformina

Metformin, a well-known antidiabetic drug, has been shown to possess analgesic properties in inflammatory pain models, but the mechanisms of its antinociceptive effects are not completely understood (1,2). We aimed to examine the involvement of serotonergic mechanisms in metformin-induced antinociception in a model of inflammatory pain, using the formalin test in mice. Firstly, we examined the antinociceptive effects of intraperitoneally administered metformin in the first and second phase of the test. Then, the involvement of serotonergic receptors was evaluated by intraperitoneally pretreating mice with a 5-HT1B/1D (GR127935) or 5-HT1A receptor antagonist (WAY100635). Further, we examined the effect of metformin after depletion of endogenous serotonin with a tryptophan-hydroxylase inhibitor (PCPA; applied intraperitoneally for 4 days). Additionally, to avoid misinterpretation of motor incoordination, we performed the rotarod test with the highest tested metformin dose. Metformin (50-200 mg/kg) produced significant and dose-dependent antinociceptive effects (17-81%) in the second (inflammatory) phase of the test. Pretreatment with antagonists significantly reduced the antinociceptive effect of metformin (150 mg/kg). GR127935 inhibited the effects of metformin by 67% (1 mg/kg) and 100% (3 mg/kg), whereas the inhibitory effects for WAY100635 were 19% (1 mg/kg) and 68% (3 mg/kg). Depletion of serotonin with PCPA (100 mg/kg/day) significantly reduced the antinociceptive effects of higher metformin doses (150 and 200 mg/kg). Metformin (200 mg/kg) had no influence on rotarod performance. This study demonstrates that 5-HT1B/1D and 5-HT1A receptors are involved in metformin’s antinociceptive effects and that metformin’s action on these receptors seems to be indirect (mediated by endogenous serotonin released by metformin).Metformin je dobro poznat antidijabetik, za koji je pokazano da poseduje analgetička svojstva u modelima inflamatornog bola. Međutim, mehanizmi njegovog antinociceptivnog dejstva nisu u potpunosti rasvetljeni (1,2). Cilj ovog rada je bio ispitati učešće serotonergičkih mehanizama u antinociceptivnom dejstvu metformina u inflamatornom modelu bola – korišćenjem formalinskog testa kod miševa. Inicijalno su ispitani antinociceptivni efekti metformina, nakon intraperitonealne primene, u prvoj i drugoj fazi testa. Uključenost serotoninskih receptora je procenjena nakon intraperitonealne primene antagonista 5-HT 1B/1D (GR127935) ili 5-HT1A (WAY100635) receptora. U nastavku eksperimenata, efekat metformina je ispitan nakon deplecije endogenog serotonina, primenom inhibitora triptofan-hidroksilaze (PCPA; primenjen intraperitonealno tokom 4 dana). Dodatno, efekat najveće testirane doze metformina je ispitan u rotarod testu, kako bi se isključila mogućnost pogrešnog tumačenja motorne inkoordinacije. Metformin (50-200 mg/kg) je pokazao značajno i dozno-zavisno antinociceptivno dejstvo (17-81%) u drugoj (inflamatornoj) fazi testa. Primena antagonista je značajno smanjila antinociceptivni efekat metformina (150 mg/kg). GR127935 je inhibirao efekte metformina za 67% (1 mg/kg) i 100% (3 mg/kg), dok su inhibitorni efekti WAY100635 bili 19% (1 mg/kg) i 68% (3 mg/kg). Deplecija serotonina korišćenjem PCPA (100 mg/kg/dan) je značajno smanjila antinociceptivne efekte metformina primenjenog u većim dozama (150 i 200 mg/kg). Metformin (200 mg/kg) nije imao značajan uticaj na performanse miševa u rotarod testu. Ova studija je pokazala uključenost 5-HT1B/1D i 5-HT1A receptora u antinociceptivnom dejstvu metformina, koje je verovatno posledica indirektnog uticaja leka na receptore (posredstvom oslobađanja endogenog serotonina od strane metformina).VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Multimodalna kontrola hroničnog bola i komorbiditeta sa atipičnim analgeticima ‐,,više muva jednim udarcem“

Osteoarthritis (OA) is the most common rheumatic disease, affecting over 300 million people worldwide. It causes chronic pain, disability and is commonly associated with comorbid diseases (CMD) that cause worse health outcomes, more complex management, and increased healthcare costs. Current treatments (typical/atypical analgesics) have limited efficacy and/or tolerability and usually do not affect or can even worse CMD. In era of longer life expectancy, extended professional life and reduced pension funds in Serbia and Europe, there is a compelling need for maintaining functionality and working capability of older population. Our aim is to search for novel treatments that could concomitantly treat chronic pain and its major CMD: depression, cognitive impairment and/or cardiovascular disease (CVD). It was planned to test the effects of vortioxetine, a novel antidepressant with multimodal mechanism of action, on pain, depressive and cognitive-impairment behaviour and CV status in rat model of knee OA. Its effects will be compared to the effects of duloxetine, the only antidepressant used for pain relief in OA. Next, we will test the effects of 2-component combinations of vortioxetine/duloxetine with adjuvant treatments (regular exercise/metformin/nicotinamide), that showed the potential to alleviate pain, depression, reduced cognition and/or CVD in preclinical/clinical research. If proved effective and well tolerated, new treatment(s) could be implemented in clinical practice much faster and with significantly less investment, than those required to develop brand new drug, as they consist of drugs already approved for human use and safe, widely available and inexpensive non- pharmacologic measures.Osteoartritis (OA) je najčešć a reumatska bolest, koja pogađa preko 300 miliona ljudi širom sveta. Prouzrokuje hronični bol, invaliditet i obično je povezan sa komorbiditetima koji dovode do lošijih zdravstvenih ishoda, složenijeg lečenja i povećanja troškova zdravstvene zaštite. Trenutno dostupne terapijske opcije (tipični/atipični analgetici) imaju ograničenu efikasnost i/ili lošu podnošljivost, i obično ne utiču ili čak mogu pogoršati komorbiditete. U vremenu kada su ljudski i radni vek produženi, a penzioni fondovi u Srbiji i Evropi smanjeni, postoji velika potreba za održavanjem funkcionalnosti i radne sposobnosti starije populacije. Naš cilj je da pronađemo nove terapijske opcije koje bi istovremeno mogle da leče hronični bol i njegove glavne komorbiditete: depresiju, kognitivno oštećenje i/ili kardiovaskularne bolesti (KVB). Planirano je ispitivanje efekata vortioksetina, novog antidepresiva sa multimodalnim mehanizmom delovanja, na bol, depresivno ponašanje, kognitivno ošteć enje i kardiovaskularni status pacova u modelu OA kolena. Efekti vortioksetina biće poređeni sa efektima duloksetina, jedinog antidepresiva koji se koristi za ublažavanje bola kod OA. Zatim će biti ispitani efekti dvokomponentnih kombinacija vortioksetina/duloksetina sa adjuvantnim tretmanima (redovna fizička aktivnost/metformin/nikotinamid), koji su pokazali efikasnost u ublažavanju bola, depresije, narušene kognicije i/ili KVB u pretkliničkim/kliničkim istraživanjima. Ukoliko se pokaže da su efikasne i da se dobro tolerišu, nove terapijske opcije bi se mogle implementirati u kliničku praksu mnogo brže i sa znatno manje finansijskih ulaganja u poređenju sa vremenom i ulaganjima koja su potrebna za razvoj novog leka, jer se sastoje od lekova koji su već odobreni za ljudsku upotrebu i bezbednih, široko dostupnih i ekonomski povoljnih nefarmakoloških mera.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Efikasnost vortioksetina u modelu osteoartritisa kod pacova

Osteoarthritis is the most common rheumatic degenerative condition, with chronic joint pain being the major source of disability. Currently, available treatment options for alleviating pain are often ineffective and/or associated with unfavorable safety profiles (1). Vortioxetine is a novel multimodal antidepressant, an inhibitor of serotonin reuptake, but also an agonist, partial agonist, or antagonist of several serotonin (5-HT) receptors subtypes involved in pain modulation (2). The study aimed to examine the efficacy of vortioxetine compared to duloxetine, an antidepressant recommended for the treatment of osteoarthritis, in the rat model of osteoarthritis. Osteoarthritis was induced by intra-articular injection of monosodium iodoacetate (MIA; 2 mg/25 μL) in the right knee of male Wistar rats. Vortioxetine/duloxetine was administered orally for 28 days following MIA injection. The antinociceptive effect of vortioxetine/duloxetine was assessed using von Frey, acetone, and weight-bearing test. The influence of treatments on animals’ well-being and motor performance was examined in the burrowing and rotarod test, respectively. Vortioxetine (2 and 10 mg/kg) and duloxetine (15 and 25 mg/kg) significantly reduced mechanical and cold allodynia, and improved weight borne on the ipsilateral hind paw in von Frey, acetone, and weight-bearing test, respectively. Vortioxetine had no significant effect on burrowing behavior, whereas duloxetine significantly reduced this inherent rodent activity. The rotarod test did not demonstrate a significant effect of treatment on motor performance/sedation. This study suggests comparable antinociceptive efficacy of vortioxetine with duloxetine, a referent drug, as well as a better impact on the animals’ well-being of vortioxetine.Osteoartritis predstavlja najčešće reumatsko degenerativno oboljenje, praćeno hroničnim bolom, glavnim uzrokom onesposobljenosti pacijenata. Postojeće terapijske opcije za otklanjanje bola su neretko nedovoljno efikasne i/ili udružene sa brojnim neželjenim efektima (1). Vortioksetin je noviji antidepresiv multimodalnog mehanizma dejstva; inhibira transporter za preuzimanje serotonina, a deluje i kao agonist, parcijalni agonist ili antagonist različitih podtipova serotoninskih (5-HT) receptora uključenih u modulaciju bola (2). Cilj ovog rada je bio ispitati efikasnost vortioksetina u poređenju sa duloksetinom, antidepresivom preporučenim za lečenje osteoartritisa, u modelu osteoartritisa kod pacova. Osteoartritis je indukovan intraartikularnom injekcijom natrijum-monojodacetata (MIA; 2 mg/25 μL) u desno koleno mužjaka pacova Wistar soja. Vortioksetin/duloksetin je primenjivan oralno svakodnevno tokom 28 dana nakon injekcije MIA. Procena antinociceptivne efikasnosti vortioksetina/duloksetina ispitivana je korišćenjem von Frey, aceton testa i testa raspodele težine (eng. weight‐bearing). Uticaj tretmana na dobrobit životinja (eng. well‐being), kao i motornu spretnost ispitivan je u testu kopanja i rotarod testu, redom. Vortioksetin (2 i 10 mg/kg) i duloksetin (15 i 25 mg/kg) su značajno smanjili mehaničku i hladnu alodiniju, i poboljšali oslanjanje životinja na ipsilateralnu šapu u von Frey, aceton i testu raspodele težine, redom. Vortioksetin nije imao značajan uticaj na aktivnost životinja u testu kopanja, dok je duloksetin značajno smanjio ovu inherentnu aktivnost glodara. U rotarod testu nije pokazan značajan uticaj tretmana na motorne performanse/sedaciju životinja. Ova studija je pokazala da su antinociceptivni efekti vortioksetina i referentnog leka duloksetina uporedivi, kao i povoljniji uticaj vortioksetina na opštu dobrobit životinja.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Aktivacija perifernih serotoninskih 5‐HT1A i 5‐HT 1B/1D receptora doprinosi antinociceptivnom dejstvu metformina

Several lines of (pre)clinical evidence have emerged that the antidiabetic drug metformin can alleviate inflammatory/neuropathic pain (1). Although the mechanism is not completely understood, there are reports that metformin can affect neurotransmitters involved in pain modulation, such as its ability to increase peripheral serotonin release (2). Here, we evaluated metformin’s efficacy following local peripheral administration in an inflammatory pain model and examined the potential involvement of serotonin receptors. We used the formalin test in mice, where we measured duration of nociceptive behavior in the first and second phase of the test. First, we examined the metformin’s antinociceptive effects following intraplantar administration. Additionally, the highest tested metformin dose was applied contralateral to the formalin-injected side, to exclude possible systemic effects. In the second part, we evaluated the effects of a 5-HT1A (WAY100635) and 5-HT1B/1D antagonist (GR127935) on the antinociceptive effects of a fixed, effective dose of metformin (antagonists were co-administered intraplantarly with metformin). Metformin (0.1-2 mg/paw) produced significant and dose-dependent antinociceptive effects (32-72%) in the second (inflammatory) phase. Contralateral application of metformin (2 mg/paw) had no significant antinociceptive effects. Both antagonists significantly reduced the antinociceptive effects of metformin (1 mg/paw). The levels of inhibition of metformin’s antinociceptive effect produced by WAY100635 were 56% (5 μg/paw) and 82% (7.5 μg/paw), whereas GR127935 inhibited metformin’s efficacy by 24% (3.75 μg/paw) and 80% (5 μg/paw). This study demonstrates that peripheral metformin application can produce antinociceptive effects against inflammatory pain and that activation of peripheral 5-HT 1A and 5-HT1B/1D receptors contributes to these effects.Postoje brojni dokazi iz (pre)kliničkih studija da metformin, lek iz grupe antidijabetika, može ublažiti inflamatorni/neuropatski bol (1). Iako mehanizam dejstva nije u potpunosti razjašnjen, podaci ukazuju da metformin može uticati na neurotransmitere uključene u modulaciju bola, poput sposobnosti da poveća oslobađanje serotonina na periferiji (2). U ovom radu je ispitana efikasnost metformina nakon lokalne periferne primene u modelu inflamatornog bola, kao i potencijalna uključenost serotoninskih receptora. Korišćen je formalinski test kod miševa, u kome je mereno vreme provedeno u nociceptivnom ponašanju, u prvoj i drugoj fazi testa. Prvo su ispitani antinociceptivni efekti metformina nakon intraplantarne primene. Dodatno, najveća testirana doza metformina je primenjena kontralateralno u odnosu na mesto injektovanja formalina, kako bi se isključili mogući sistemski efekti. U drugom delu studije, ispitani su efekti antagoniste 5-HT 1A (WAY100635) i 5-HT1B/1D (GR127935) receptora na antinociceptivno dejstvo fiksne, efektivne doze metformina (antagonisti su primenjeni intraplantarno, istovremeno sa metforminom). Metformin (0,1-2 mg/šapi) je ispoljio značajan i dozno-zavisan antinociceptivni efekat (32-72%) u drugoj (inflamatornoj) fazi testa. Kontralateralna primena metformina (2 mg/šapi) nije imala značajan antinociceptivni efekat. Primenjeni antagonisti su značajno smanjili antinociceptivne efekte metformina (1 mg/šapi). Stepeni inhibicije antinociceptivnog dejstva metformina koje je postigao WAY100635 su bili 56% (5 μg/šapi) i 82% (7,5 μg/šapi), dok je GR127935 inhibirao efikasnost metformina za 24% (3,75 μg/šapi) i 80% (5 μg/šapi). Ova studija je pokazala da periferna primena metformina proizvodi antinociceptivni efekat kod inflamatornog bola i da aktivacija perifernih 5-HT1A i 5- HT1B/1D receptora doprinosi ovom efektu.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Lekovi u lečenju demencija - unapred izgubljena bitka?

Alzheimer’s disease (AD), the most common cause of dementia, is growing health, social and economic issue because of the increasing number of sufferers, limited efficacy of available treatment options, and high total healthcare costs. It is clinically characterized by cognitive and behavioral impairments, both of which need to be treated appropriately to improve patients’ quality of life and their caregivers as well. Currently, available anti-dementia medications provide only modest and transient cognitive benefits. Donepezil, rivastigmine and galantamine (cholinesterase inhibitors) are indicated for the symptomatic management of mild to moderately severe AD, while memantine (NMDA glutamate receptors antagonist) is recommended for moderate-to-severe AD. A special focus on behavioral symptoms (e.g. anxiety, depression, aggression) management is required as they cause great suffering in patients/caregivers. The use of medications that can impair cognitive function, such as drugs with anticholinergic activity, should be avoided in patients with dementia. Additionally, interventions that could delay or prevent dementia onset in some subjects are focused on minimizing modifiable risk factors (hypertension, diabetes, depression) and maximizing protective factors (physical activity, healthy diet, leisure, and social activities). The treatment of AD remains a challenge.Alzheimer-ova bolest (AB), najčešći oblik demencije, rastući je zdravstveni, socijalni i ekonomski problem zbog sve većeg broja obolelih, nedovoljne efikasnosti postojećih terapijskih mera, kao i velikih ukupnih troškova nege. Klinički se manifestuje smanjenjem kognitivnih funkcija i poremećajima ponašanja, koje treba adekvatno lečiti kako bi se popravio kvalitet života obolelih i njihovih negovatelja. Raspoloživi lekovi za lečenje demencija ostvaruju umereno i prolazno poboljšanje kognitivnih funkcija. Donepezil, rivastigmin i galantamin (inhibitori holinesteraza) su indikovani kao simptomatska terapija blage do umereno teške forme AB, dok se memantin (antagonist glutamatergičkih NMDA receptora) preporučuje za lečenje umerene do teške AB. Poseban aspekt lečenja predstavlja terapija bihejvioralnih simptoma (anksioznost, depresija, agresivnost), koji su veliki problem za pacijente i negovatelje. Trebalo bi izbegavati primenu lekova koji nepovoljno utiču na kogniciju, kao što su lekovi sa antiholinegičkim dejstvom, kod pacijenata sa demencijom. Dodatno, kontrola promenljivih faktora rizika (hipertenzija, dijabetes, depresija) i usvajanje protektivnih faktora (fizička aktivnost, zdrava ishrana, socijalne aktivnosti i aktivnosti u slobodno vreme) možda može da spreči ili odloži pojavu demencije kod izvesnih ljudi. Lečenje AB i dalje je veliki izazov