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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. Beograd

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. Beograd

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. Beograd

Migraine is one of the most common neurological diseases and about 20% of patients suffer from frequent episodic or chronic forms of the disease, which represent a significant global cause of chronic disability. Despite its high prevalence, the pathophysiology of migraine is still not completely understood. However, it has been known for several decades that the development of migraine attacks is dependent on the calcitonin gene-related peptide (CGRP), a neuropeptide that modulates nociceptive signaling within neuronal pathways important for migraine pain. Drugs that reduce the effects of CGRP (CGRP antagonists) have recently become available and include small-molecule CGRP-receptor antagonists (so-called gepants) that are approved for acute treatment and/or prevention of migraine attacks (ubrogepant, atogepant, rimegepant), as well as monoclonal antibodies, which are approved for prevention of migraine attacks (anti-CGRP antibodies: fremanezumab, galcanezumab, eptinezumab; anti-CGRP receptor antibody: erenumab). The effectiveness of gepants in alleviating migraine attacks is somewhat lower compared to triptans (standard drugs for treating migraine attacks), but gepants are considered safer than triptans with regard to cardiovascular side effects and the risk of medication-overuse headache. Monoclonal anti- CGRP antibodies have been shown to be useful drugs for patients who have not responded to standard prophylactic therapy (e.g., β-blockers or antiepileptics), but their high cost limits widespread use. Although the effectiveness of CGRP antagonists has been unequivocally proven, it will take time to precisely define the role of these drugs in modern migraine pharmacotherapy, and it is especially important to examine the safety of their long-term use. Migrena spada u najčešća neurološka oboljenja i oko 20% pacijenata ima čestu epizodičnu ili hroničnu formu bolesti, koje predstavljaju značajan uzrok hronične onesposobljenosti na globalnom nivou. Uprkos visokoj prevalenciji, patofiziologija migrene je još uvek nedovoljno razjašnjena. Međutim, već nekoliko decenija je poznato da u nastanku napada migrene veliku ulogu igra peptid srodan kalcitoninu (engl. calcitonine gene related peptide – CGRP), neuropeptid koji moduliše nociceptivnu signalizaciju u okviru neuronskih puteva značajnih za nastanak migrenoznog bola. Lekovi koji smanjuju efekte CGRP-a (CGRP antagonisti) su nedavno postali dostupni i obuhvataju antagoniste CGRP-receptora male molekulske mase (tzv. gepanti) koji su odobreni za akutni tretman i/ili prevenciju napada migrene (ubrogepant, atogepant, rimegepant), kao i monoklonska antitela koja su odobrena za prevenciju napada (anti-CGRP antitela: fremanezumab, galkanezumab, eptinezumab; anti- CGRP receptorsko antitelo: erenumab). Efikasnost gepanta u ublažavanju napada migrene je nešto niža u poređenju sa triptanima (standardnim lekovima za tretman napada), međutim smatra se da su gepanti bezbedniji od triptana u pogledu kardiovaskularnih neželjenih efekata i rizika od izazivanja glavobolje prekomerne upotrebe analgetika. Monoklonska anti- CGRP antitela su se pokazala kao korisni lekovi za pacijente koji nisu odgovorili na standardnu profilaktičku terapiju (npr. β-blokatorima ili antiepilepticima), međutim visoka cena ograničava njihovu širu upotrebu. Iako je efikasnost CGRP antagonista nesumnjivo dokazana, za precizno definisanje uloge ovih lekova u savremenoj farmakoterapiji migrene će biti potrebno vreme, a posebno značajno je ispitati bezbednost njihove dugoročne primene. VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beograd

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. Beograd

Bol je kompleksno senzorno iskustvo koje ima jasnu zaštitnu ulogu, ali pod određenim uslovima može da postane hronično stanje koje značajno narušava kvalitet života. Postojeći analgetici, iako nesumnjivo korisni u terapiji različitih bolnih stanja, neretko su nedovoljno efikasni ili bezbedni. Zato postoji potreba za razvojem novih ili otkrivanjem efikasnih kombinacija postojećih analgetika kako bi se poboljšala terapija bola. Ciljevi ovog rada su bili ispitivanje efekata, mehanizama dejstva i interakcija dva potencijalna alternativna analgetika, antiepileptika eslikarbazepin acetata (ESL) i antidijabetika metformina u modelima inflamatornog i neuropatskog bola. Efekti ESL i metformina su ispitani u modelima inflamatornog trigeminalnog, visceralnog i somatskog bola, kao i modelu bolne dijabetesne neuropatije. Mehanizmi dejstva ESL u modelu trigeminalnog bola su ispitani farmakološkim pristupom, korišćenjem antagonista receptora značajnih za modulaciju bola. Vrsta interakcije između ESL/metformina i analgetika u modelima inflamatornog i neuropatskog bola je utvrđena izobolografskom analizom. ESL i metformin su pokazali efikasnost u svim korišćenim modelima inflamatornog bola i u modelu bolne dijabetesne neuropatije. Utvrđeno je da ESL ublažava trigeminalni bol posredstvom serotoninskih 5-HT1B/1D, α2/β1-adrenergičkih, muskarinskih, CB1/CB2 kanabinoidnih i opioidnih receptora. ESL i metformin stupaju u aditivne ili sinergističke interakcije sa različitim analgeticima u modelima inflamatornog i neuropatskog bola. Efikasnost ESL i metformina u modelima bola bi mogla da ukaže na njihovu potencijalnu kliničku primenu kao analgetika. Dodatno, poznavanje mehanizama dejstva ESL može doprineti uspešnoj primeni ovog leka u terapiji bola. Na kraju, oba leka stupaju u povoljne interakcije sa postojećim analgeticima. Ovaj nalaz ukazuje na potencijalno bolju efikasnost i/ili bezbednost kombinovane u odnosu na monoterapiju, kao i koji analgetici bi mogli biti povoljan izbor za lečenje bola kod ljudi koji već primenjuju ESL/metformin zbog komorbiditeta. Pain is a complex sensory experience, which has a clear protective role, but under certain circumstances pain can become a chronic condition that significantly impairs the quality of life. Existing analgesics, although undoubtedly useful in the treatment of various painful conditions, are often insufficiently effective or safe. Therefore, there is a need to develop new drugs or to discover effective combinations of existing drugs in order to improve pain therapy. The objectives of this study were to investigate the effects, mechanisms of action, and interactions of two potential alternative analgesics, the antiepileptic eslicarbazepine acetate (ESL) and the antidiabetic metformin in models of inflammatory and neuropathic pain. The effects of ESL and metformin were examined in models of inflammatory trigeminal, visceral and somatic pain, as well as in a model of painful diabetic neuropathy. The mechanisms of action of ESL in the model of trigeminal pain were examined by a pharmacological approach, using antagonists of different receptors important for pain modulation. The type of interaction between ESL/metformin and analgesics in models of inflammatory and neuropathic pain was determined using isobolographic analysis. ESL and metformin were effective in all models of inflammatory pain that were used, as well as in the model of painful diabetic neuropathy. ESL was found to relieve trigeminal pain by activating serotonin 5-HT1B/1D, α2/β1-adrenergic, muscarinic, CB1/CB2 cannabinoid and opioid receptors. ESL and metformin interacted in an additive or synergistic manner with different analgesics in models of inflammatory and neuropathic pain. The efficacy of ESL and metformin in pain models may indicate their potential clinical application as analgesics. In addition, knowledge of the mechanisms of action of ESL may contribute to the successful use of this drug in the treatment of pain. Finally, both drugs interact favorably with existing analgesics. This finding indicates potentially better efficacy and/or safety of combination therapy compared to monotherapy, as well as which analgesics could be a favorable choice for the treatment of pain in people already using ESL/metformin due to comorbidities.

Метформин је широко употребљивани антидијабетик. Показано је да системски примењен метформин испољава антиноцицептивни ефекат у који су укључени одређени серотонински рецептори. Metformin is a widely used antidiabetic. Systemically administered metformin has been shown to have an antinociceptive effect involving certain serotonin receptors.

Кандесартан, лек из групе антагониста ангиотензинских AT1 рецептора, користи се у терапији кардиоваскуларних болести. Међутим, извесни претклинички и клинички подаци подржавају потенцијалну примену кандесартана као аналгетика. Candesartan, an angiotensin AT1 receptor antagonist, is used for the treatment of cardiovascular disorders. However, certain preclinical and clinical data support the potential use of candesartan as an analgesic.