The effects of opioids and NMDA receptor antagonists on the body temperature and acute nociceptive pain in rats

Uvod: Pored antinocicepcije, opioidi ispoljavaju značajne efekte i na telesnu temperaturu. Brojni dokazi podržavaju postojanje endogenog glutamatergičkog sistema koji moduliše telesnu temperaturu preko N-metil-D-aspartat (NMDA) receptora. Ketamin i magnezijum, NMDA antagonisti, su poznati po svojim anestetičkim, anagletičkim svojstvima, kao i dejstvu protiv drhtavice. Takođe, oni mogu povećati antinociceptivne efekte opioidnih analgetika u različitim modelima bola kod životinja, kao i kod ljudi. Cilj ispitivanja: Cilj ovog ispitivanja bilo je poređenje antinociceptivnih i hipertermnih odgovora između dve grupe agonista μ-opioidnih receptora: derivata fentanila (4-anilinopiperidinski tip) i morfina (fenantrenski tip) kod pacova. Takođe, ova studija imala je za cilj ispitivanje efekata ketamina i magnezijum sulfata na telesnu temperaturu i akutni nociceptivni bol kod pacova, da utvrdi tip interakcije između ova dva leka i da ispita da li magnezijum sulfat dodat ketaminu ili kombinaciji morfin-ketamin, povećava analgetički efekt ovih lekova i njihov efekt na telesnu temperaturu. Metode: Analgetička aktivnosti procenjivana je testom potapanja repa mužjaka Wistar pacova (200-250 g) u toplu vodu. Distalnih 5 cm repa stavljano je u toplu vodu (55 ± 0,5°C) i kao odgovor mereno je vreme za koje životinja povuče rep iz tople vode. Telesna temperatura je merena stavljanjem termometarske sonde u dužini od 5 cm u debelo crevo. Rezultati: Fentanil, (±)-cis-3-metil fentanil (CM), (±)-cis-3-karbometoksi fentanil, (±)- trans-3-karbometoksi fentanil i (±)-cis-3-butil- fentanil, kao i morfin, oksikodon (O), tebakon i 6,14-etenomorfinan-7-metanol, 4,5-epoksi-6-fluoro-3-hidroksi-,,17-trimetil-, (5,7) izazivali su dozno-zavisno povećanje antinocicepcije i hipertermije. Derivati morfina (fenantrenski tip) i fentanila (4-anilinopiperidinski tip) izazivali su hipertermiju kod pacova u dozama koje su oko 2 puta niže i 6-11 puta više od njihovih srednjih antinociceptivnih doza...Introduction: In addition to producing antinociception, opioids exert profound effects on body temperature. A large body of evidence supports the existence of an endogenous glutamate system that tonically modulates body temperature viaN-methyl-D-aspartate (NMDA) receptors. Ketamine and magnesium, both NMDA receptor antagonists, are known for their anesthetic, analgesic and anti-shivering properties. They also enhance the antinociceptive effects of opioid analgesics in different animal models of pain, as well as in humans. Aim: This study aimed at comparing antinociceptive and hyperthermic responses between two groups of μ-opioid receptor agonists: fentanyl (4-anilinopiperidine-type) and morphine (phenanthrene-type) derivatives in rats. Also, study is aimed at evaluating the effects of ketamine and magnesium sulphate on body temperature and acute nociceptive pain in rats, to determine the type of interaction between them and at evaluating whether magnesium sulfate added to ketamine or morphine-ketamine combination produces higher level of analgesia and higher effect on body temperature. Methods: Analgesic activity was assessed by tail-immersion test in male Wistar rats (200- 250 g). The distal 5 cm of the tail was immersed in a warm water bath (55 0.5°C) and the time for tail-withdrawal was measured as a response latency. The body temperature was measured by insertion of a thermometer probe 5 cm into the colon of unrestrained rats. Results: Fentanyl, ()cis-3-methyl fentanyl, ()cis-3-carbomethoxy fentanyl, ()trans-3- carbomethoxy fentanyl and ()cis-3 butyl fentanyl and morphine, oxycodone, thebacon and 6,14-Ethenomorphinan-7-methanol, 4,5-epoxy-6-fluoro-3-hydroxy-,,17-trimethyl- , (5,7)produced dose-dependent increase in antinociception and hyperthermia. Morphine (phenanthrene-type) and fentanyl (4-anilinopiperidine-type) derivatives produced hyperthermia in rats at doses about 2 times lower, and 6 to 11 times higher, than their median antinociceptive doses..

Supplementary data for the article: Jevtić, I. I.; Savić Vujović, K.; Srebro, D.; Vučković, S.; Ivanović, M. D.; Kostić-Rajačić, S. V. Synthesis and Pharmacological Evaluation of Novel Cis and Trans 3-Substituted Anilidopiperidines. Pharmacol. Rep 2020, 72 (4), 1069–1075. https://doi.org/10.1007/s43440-020-00121-2

Supplementary material for: [ https://doi.org/10.1007/s43440-020-00121-2]Related to published version: [https://cherry.chem.bg.ac.rs/handle/123456789/4211

TRPV1: A Promising drug target for the treatment of various conditions

Nobelova nagrada za fiziologiju i medicinu za 2021. dodeljena je naučnicima koji su identifikovali receptore za temperaturu i dodir. Da bi sproveli ovo ispitivanje, istraživači su koristili kapsaicin, jedinjenje koje čili paprici daje toplotu, kako bi otkrili receptore koji omogućavaju ljudima da osete “gorući” ukus čilija. Pokazano je da se transient receptor potential vanilloid 1 (TRPV1), koji predstavlja jonski kanal prisutan na senzornim neuronima, otvara u prisustvu kapsaicina ili toplote, propuštajući naelektrisane jone kalcijuma u ćeliju. Takav priliv kalcijuma pokreće električne signale koji se šalju u mozak da upozore na toplotu. TRPV1 se nalazi u somatosenzornom sistemu i služi kao multimodalni senzor različitih štetnih stimulusa. Brojne farmakološke i genetičke studije su potvrdile TRPV1 kao terapeutsku metu u nekoliko pretkliničkih modela hroničnog bola, uključujući maligni, neuropatski, postoperativni i mišićno-skeletni bol. Pored toga, ekspresija TRPV1 se takođe primećuje na ne-neuronskim lokalizacijama, kao što su epitel bešike i pluća, ćelije kohlee u uhu. Stoga, lekovi koji mogu da modulišu aktivnost kanala TRPV1 mogu biti korisni za lečenje različitih stanja u rasponu od hroničnog bola do gubitka sluha. Iako je utvrđeno da antagonisti TRPV1 mogu predstavljati važan dodatak terapiji bola, njihova klinička upotreba je i dalje ograničena značajnim neželjenim efektima, kao što je hipertermija. U ovom radu ćemo opisati najvažnije uloge TRPV1 u fiziološkim i patofiziološkim procesima i predstaviti najperspektivnije lekove koji deluju preko TRPV1.The 2021. Nobel Prize in Physiology or Medicine was awarded to scientists who have identified receptors for temperature and touch. In order to conduct this examination, researchers used capsaicin, the compound that gives chili peppers their heat, to discover receptor proteins that allow people to feel chili’s burn. It is shown that transient receptor potential vanilloid 1 (TRPV1), which represents an ion channel present on sensory neurons, opens when it encounters capsaicin or heat, allowing charged calcium ions into the cell. That flood of calcium triggers electrical signals that are sent to the brain to warn of heat. TRPV1 is found in the somatosensory system and serves as a multimodal sensor of different noxious stimuli. Numerous pharmacological and genetic studies have validated TRPV1 as a therapeutic target in several preclinical models of chronic pain, including cancer, neuropathic, postoperative and musculoskeletal pain. Additionally, expression of TRPV1 is also observed in non-neuronal sites such as the epithelium of bladder and lungs, cells of the cochlea. Therefore, drugs which could modulate TRPV1 channel activity could be useful for the treatment of conditions ranging from chronic pain to hearing loss. While antagonists of TRPV1 were found to be a valuable addition to therapy of pain, their clinical use has still been limited by significant side effects, such as hyperthermia. In this review, we will describe the most important roles of TRPV1 in physiological and pathophysiological processes and present the most promising TRPV1-targeted drugs

In Vitro Antibiofilm Effect of N-Acetyl-L-cysteine/Dry Propolis Extract Combination on Bacterial Pathogens Isolated from Upper Respiratory Tract Infections

Bacterial biofilms play an important role in the pathogenesis of chronic upper respiratory tract infections. In addition to conventional antimicrobial therapy, N-acetyl-L-cysteine (NAC) and propolis are dietary supplements that are often recommended as supportive therapy for upper respiratory tract infections. However, no data on the beneficial effect of their combination against bacterial biofilms can be found in the scientific literature. Therefore, the aim of our study was to investigate the in vitro effect of N-acetyl-L-cysteine (NAC) and dry propolis extract in fixed combinations (NAC/dry propolis extract fixed combination) on biofilm formation by bacterial species isolated from patients with chronic rhinosinusitis, chronic otitis media, and chronic adenoiditis. The prospective study included 48 adults with chronic rhinosinusitis, 29 adults with chronic otitis media, and 33 children with chronic adenoiditis. Bacteria were isolated from tissue samples obtained intraoperatively and identified using the MALDI-TOF Vitek MS System. The antimicrobial activity, synergism, and antibiofilm effect of NAC/dry propolis extract fixed combination were studied in vitro. A total of 116 different strains were isolated from the tissue samples, with staphylococci being the most frequently isolated in all patients (57.8%). MICs of the NAC/dry propolis extract fixed combination ranged from 1.25/0.125 to 20/2 mg NAC/mg propolis. A synergistic effect (FICI ≤ 0.5) was observed in 51.7% of strains. The majority of isolates from patients with chronic otitis media were moderate biofilm producers and in chronic adenoiditis they were weak biofilm producers, while the same number of isolates in patients with chronic rhinosinusitis were weak and moderate biofilm producers. Subinhibitory concentrations of the NAC/propolis combination ranging from 0.625–0.156 mg/mL to 10–2.5 mg/mL of NAC combined with 0.062–0.016 mg/mL to 1–0.25 mg/mL of propolis inhibited biofilm formation in all bacterial strains. Suprainhibitory concentrations ranging from 2.5–10 mg/mL to 40–160 mg/mL of NAC in combination with 0.25–1 mg/mL to 4–16 mg/mL of propolis completely eradicated the biofilm. In conclusion, the fixed combination of NAC and dry propolis extract has a synergistic effect on all stages of biofilm formation and eradication of the formed biofilm in bacteria isolated from upper respiratory tract infections

Oboljeli od rijetkih bolesti kao vulnerabilni ispitanici u kliničkim studijama

Farmakoterapija rijetkih bolesti suočena je s brojnim etičkim dilemama. Najveći broj oboljelih su djeca, oboljenja su progresivnog tijeka, a liječenje vrlo skupo. Cilj rada bio je ispitati u kojoj mjeri se poštuju principi suvremene bioetike, kada je u pitanju farmakoterapija rijetkih bolesti. Za primjer je uzeta Gaucherova bolest. Pretraživali smo dostupne baze podataka (Cochrane database, MEDLINE i Google) za period od 1996. do 2011. Ključne riječi bile su: Gaucherova bolest, etika/etička pitanja i klinička ispitivanja, a posebno su analizirani učinkovitost, sigurnost i cijena lijekova za ovu bolest. Provedena je i pilot anketa o stavovima liječnika i kliničkih farmaceuta o farmakoterapiji rijetkih bolesti u Srbiji na odabranom uzorku ispitanika (N = 11, Klinika za internu medicinu i Centralna apoteka, KBC „Bežanijska Kosa“ u Beogradu). Na postavljena pitanja odgovoreno je u 97,2 % slučajeva. Uočeni su brojni problemi vezani uz liječenje Gaucherove bolesti: npr. visoka cijena lijekova, nedostatak adekvatne procjene odnosa cijene i učinkovitosti terapije, nedovoljan broj ispitanika u kliničkim studijama i dr. Pilot anketa o rijetkim bolestima ukazuje na nedovoljnu informiranost stručne javnosti (21 %) i komplicirane procedure oko nabave lijekova (21 %). Većina ispitanika (64 %) ocijenila je da je nedovoljno upoznata s postojećom zakonskom regulativom o rijetkim bolestima. Oboljeli od rijetkih bolesti mogu se smatrati vulnerabilnim ispitanicima. Potrebno je formirati registar oboljelih, poboljšati informiranost stručne i šire javnosti i prilagoditi zakonsku regulativu kada su u pitanju rijetke bolesti

Evaluation of Prophylactic and Therapeutic Effects of Tramadol and Tramadol Plus Magnesium Sulfate in an Acute Inflammatory Model of Pain and Edema in Rats

Background: Inflammatory pain is the most commonly treated clinical pain, since it develops following trauma or surgery, and accompanies rheumatic or arthritic diseases. Tramadol is one of the most frequently used opioid analgesics in acute and chronic pain of different origin. Magnesium is a widely used dietary supplement that was recently shown to be a safe analgesic drug in different models of inflammatory pain.Aim: This study aimed to evaluate the effects of systemically or locally injected tramadol with/without systemically injected magnesium sulfate in prophylactic or therapeutic protocols of application in a rat model of somatic inflammation.Methods: Inflammation of the rat hind paw was induced by an intraplantar injection of carrageenan (0.1 ml, 0.5%). The antihyperalgesic/antiedematous effects of tramadol (intraperitoneally or intraplantarly injected), and tramadol-magnesium sulfate (subcutaneously injected) combinations were assessed by measuring the changes in paw withdrawal thresholds or paw volume induced by carrageenan. The drugs were administered before or after inflammation induction.Results: Systemically administered tramadol (1.25–10 mg/kg) before or after induction of inflammation reduced mechanical hyperalgesia and edema with a maximal antihyperalgesic/antiedematous effect of about 40–100%. Locally applied tramadol (0.125 mg/paw) better reduced edema (50–100%) than pain (20–50%) during 24 h. Administration of a fixed dose of tramadol (1.25 mg/kg) with different doses of magnesium led to a dose-dependent enhancement and prolongation of the analgesic effect of tramadol both in prevention and treatment of inflammatory pain. Magnesium increases the antiedematous effect of tramadol in the prevention of inflammatory edema while reducing it in treatment.Conclusion: According to results obtained in this animal model, systemic administration of low doses of tramadol and magnesium sulfate given in combination is a potent, effective and relatively safe therapeutic option for prevention and especially therapy of somatic inflammatory pain. The best result is achieved when tramadol is combined with magnesium sulfate at a dose that is equivalent to the average human recommended daily dose and when the drugs are administered when inflammation is maximally developed

Oboljeli od rijetkih bolesti kao vulnerabilni ispitanici u kliničkim studijama

Farmakoterapija rijetkih bolesti suočena je s brojnim etičkim dilemama. Najveći broj oboljelih su djeca, oboljenja su progresivnog tijeka, a liječenje vrlo skupo. Cilj rada bio je ispitati u kojoj mjeri se poštuju principi suvremene bioetike, kada je u pitanju farmakoterapija rijetkih bolesti. Za primjer je uzeta Gaucherova bolest. Pretraživali smo dostupne baze podataka (Cochrane database, MEDLINE i Google) za period od 1996. do 2011. Ključne riječi bile su: Gaucherova bolest, etika/etička pitanja i klinička ispitivanja, a posebno su analizirani učinkovitost, sigurnost i cijena lijekova za ovu bolest. Provedena je i pilot anketa o stavovima liječnika i kliničkih farmaceuta o farmakoterapiji rijetkih bolesti u Srbiji na odabranom uzorku ispitanika (N = 11, Klinika za internu medicinu i Centralna apoteka, KBC „Bežanijska Kosa“ u Beogradu). Na postavljena pitanja odgovoreno je u 97,2 % slučajeva. Uočeni su brojni problemi vezani uz liječenje Gaucherove bolesti: npr. visoka cijena lijekova, nedostatak adekvatne procjene odnosa cijene i učinkovitosti terapije, nedovoljan broj ispitanika u kliničkim studijama i dr. Pilot anketa o rijetkim bolestima ukazuje na nedovoljnu informiranost stručne javnosti (21 %) i komplicirane procedure oko nabave lijekova (21 %). Većina ispitanika (64 %) ocijenila je da je nedovoljno upoznata s postojećom zakonskom regulativom o rijetkim bolestima. Oboljeli od rijetkih bolesti mogu se smatrati vulnerabilnim ispitanicima. Potrebno je formirati registar oboljelih, poboljšati informiranost stručne i šire javnosti i prilagoditi zakonsku regulativu kada su u pitanju rijetke bolesti

μ-opioid/D2 dopamine receptor pharmacophore containing ligands: Synthesis and pharmacological evaluation

Herein, the synthesis and pharmacological evaluation of 13 novel compounds, designed as potential heterobivalent ligands for μ-opioid receptor (MOR) and dopamine D2 receptors (D2DAR), are reported. The compounds consisted of anilido piperidine and N-aryl piperazine moieties, joined by a variable-length methylene linker. The two moieties represent MOR and D2DAR pharmacophores, respectively. The synthesis encompassed four steps, securing the final products in 28–42 % overall yields. The approach has a considerable synthetic potential, providing access to various related structures. Pharmacological tests involved in vitro competitive assay for D2DAR using [3H] spiperon, as a standard radioligand, and in vivo antinociceptive tests for MOR. The measured dopamine affinities were modest to low, while antinociceptive activity was completely absent. Therefore, the compounds of the general structure prepared in this research are unlikely to be useful as opioid–dopamine receptor heterobivalent ligands

Pharmacotherapy of Rare Diseases in Serbia: The Current State of Art

Rare diseases affect less than 1 in 2000 or 5 in 10,000 people by definition. Most of those diseases have genetic basis (80% of cases) and first symptoms appear in early childhood (50% of cases). Most of these diseases are chronic and degenerative and pharmacotherapy is not available for many of them. Until today, there are more than 7000 rare diseases. In Serbia, the problem of diagnosis and pharmacotherapy of rare diseases is currently under public scrutiny. Patients who suffer from rare diseases in Serbia face many challenges in terms of awareness, timely diagnosis, and adequate treatment. These people are often misdiagnosed or the diagnosis is delayed due to several problems: lack of awareness among medical professionals, lack of expertise, unavailability and/or high costs of diagnostic tests, etc. According to the National Organization of Patients with Rare Diseases in Serbia (NORBS), many diagnostic procedures have to be conducted abroad and the process comprises many difficulties: high costs, travel expenses, or transportation of biological material. Although national legislation ensures the availability of drugs for those diseases, pharmacotherapy is faced with many problems. In this work, we aim to show that improvement of the knowledge regarding rare diseases among both professionals and patients represents a crucial step for enhancement of perspectives for those patients in our community

Cannabinoids and Pain: New Insights From Old Molecules

Cannabis has been used for medicinal purposes for thousands of years. The prohibition of cannabis in the middle of the 20th century has arrested cannabis research. In recent years there is a growing debate about the use of cannabis for medical purposes. The term ‘medical cannabis’ refers to physician-recommended use of the cannabis plant and its components, called cannabinoids, to treat disease or improve symptoms. Chronic pain is the most commonly cited reason for using medical cannabis. Cannabinoids act via cannabinoid receptors, but they also affect the activities of many other receptors, ion channels and enzymes. Preclinical studies in animals using both pharmacological and genetic approaches have increased our understanding of the mechanisms of cannabinoid-induced analgesia and provided therapeutical strategies for treating pain in humans. The mechanisms of the analgesic effect of cannabinoids include inhibition of the release of neurotransmitters and neuropeptides from presynaptic nerve endings, modulation of postsynaptic neuron excitability, activation of descending inhibitory pain pathways, and reduction of neural inflammation. Recent meta-analyses of clinical trials that have examined the use of medical cannabis in chronic pain present a moderate amount of evidence that cannabis/cannabinoids exhibit analgesic activity, especially in neuropathic pain. The main limitations of these studies are short treatment duration, small numbers of patients, heterogeneous patient populations, examination of different cannabinoids, different doses, the use of different efficacy endpoints, as well as modest observable effects. Adverse effects in the short-term medical use of cannabis are generally mild to moderate, well tolerated and transient. However, there are scant data regarding the long-term safety of medical cannabis use. Larger well-designed studies of longer duration are mandatory to determine the long-term efficacy and long-term safety of cannabis/cannabinoids and to provide definitive answers to physicians and patients regarding the risk and benefits of its use in the treatment of pain. In conclusion, the evidence from current research supports the use of medical cannabis in the treatment of chronic pain in adults. Careful follow-up and monitoring of patients using cannabis/cannabinoids are mandatory