29 research outputs found
The effects of opioids and NMDA receptor antagonists on the body temperature and acute nociceptive pain in rats
Uvod: Pored antinocicepcije, opioidi ispoljavaju znaÄajne efekte i na telesnu temperaturu.
Brojni dokazi podržavaju postojanje endogenog glutamatergiÄkog sistema koji moduliÅ”e
telesnu temperaturu preko N-metil-D-aspartat (NMDA) receptora. Ketamin i
magnezijum, NMDA antagonisti, su poznati po svojim anestetiÄkim, anagletiÄkim
svojstvima, kao i dejstvu protiv drhtavice. TakoÄe, oni mogu poveÄati antinociceptivne
efekte opioidnih analgetika u razliÄitim modelima bola kod životinja, kao i kod ljudi.
Cilj ispitivanja: Cilj ovog ispitivanja bilo je poreÄenje antinociceptivnih i hipertermnih
odgovora izmeÄu dve grupe agonista Ī¼-opioidnih receptora: derivata fentanila
(4-anilinopiperidinski tip) i morfina (fenantrenski tip) kod pacova. TakoÄe, 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 izmeÄu ova dva leka i da
ispita da li magnezijum sulfat dodat ketaminu ili kombinaciji morfin-ketamin, poveÄava
analgetiÄki efekt ovih lekova i njihov efekt na telesnu temperaturu.
Metode: AnalgetiÄka 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 Ā±
0,5Ā°C) i kao odgovor mereno je vreme za koje životinja povuÄe rep iz tople vode. Telesna
temperatura je merena stavljanjem termometarske sonde u dužini od 5 cm u debelo
crevo.
Rezultati: Fentanil, (Ā±)-cis-3-metil fentanil (CM), (Ā±)-cis-3-karbometoksi fentanil, (Ā±)-
trans-3-karbometoksi fentanil i (Ā±)-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 poveÄanje 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 viŔe 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 Ī¼-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 0.5Ā°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..
TRPV1: A Promising drug target for the treatment of various conditions
Nobelova nagrada za fiziologiju i medicinu za 2021. dodeljena je nauÄnicima koji su identifikovali receptore
za temperaturu i dodir. Da bi sproveli ovo ispitivanje, istraživaÄi su koristili kapsaicin, jedinjenje koje
Äili paprici daje toplotu, kako bi otkrili receptore koji omogucĢavaju ljudima da osete āgoruÄiā ukus Äilija.
Pokazano je da se transient receptor potential vanilloid 1 (TRPV1), koji predstavlja jonski kanal prisutan na
senzornim neuronima, otvara u prisustvu kapsaicina ili toplote, propuÅ”tajucĢi naelektrisane jone kalcijuma
u cĢeliju. Takav priliv kalcijuma pokrecĢe elektriÄne signale koji se Å”alju u mozak da upozore na toplotu. TRPV1
se nalazi u somatosenzornom sistemu i služi kao multimodalni senzor razliÄitih Å”tetnih stimulusa.
Brojne farmakoloÅ”ke i genetiÄke studije su potvrdile TRPV1 kao terapeutsku metu u nekoliko pretkliniÄkih
modela hroniÄnog bola, ukljuÄujucĢi maligni, neuropatski, postoperativni i miÅ”icĢno-skeletni bol.
Pored toga, ekspresija TRPV1 se takoÄe primecĢuje na ne-neuronskim lokalizacijama, kao Å”to su epitel beÅ”ike
i plucĢa, cĢelije kohlee u uhu. Stoga, lekovi koji mogu da moduliÅ”u aktivnost kanala TRPV1 mogu biti korisni
za leÄenje razliÄitih stanja u rasponu od hroniÄnog bola do gubitka sluha. Iako je utvrÄeno da
antagonisti TRPV1 mogu predstavljati važan dodatak terapiji bola, njihova kliniÄka upotreba je i dalje ograniÄena
znaÄajnim neželjenim efektima, kao Å”to je hipertermija.
U ovom radu cĢemo opisati najvažnije uloge TRPV1 u fizioloÅ”kim i patofizioloÅ”kim 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 chiliās
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
Oboljeli od rijetkih bolesti kao vulnerabilni ispitanici u kliniÄkim studijama
Farmakoterapija rijetkih bolesti suoÄena je s brojnim etiÄkim dilemama. NajveÄi broj oboljelih su djeca, oboljenja su progresivnog tijeka, a lijeÄenje vrlo skupo. Cilj rada bio je ispitati u kojoj mjeri se poÅ”tuju 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. KljuÄne rijeÄi bile su: Gaucherova bolest, etika/etiÄka pitanja i kliniÄka ispitivanja, a posebno su analizirani uÄinkovitost, sigurnost i cijena lijekova za ovu bolest. Provedena je i pilot anketa o stavovima lijeÄnika i kliniÄkih farmaceuta o farmakoterapiji rijetkih bolesti u Srbiji na odabranom uzorku ispitanika (N = 11, Klinika za internu medicinu i Centralna apoteka, KBC āBežanijska Kosaā u Beogradu). Na postavljena pitanja odgovoreno je u 97,2 % sluÄajeva.
UoÄeni su brojni problemi vezani uz lijeÄenje Gaucherove bolesti: npr. visoka cijena lijekova, nedostatak adekvatne procjene odnosa cijene i uÄinkovitosti terapije, nedovoljan broj ispitanika u kliniÄkim studijama i dr. Pilot anketa o rijetkim bolestima ukazuje na nedovoljnu informiranost struÄne javnosti (21 %) i komplicirane procedure oko nabave lijekova (21 %). VeÄina ispitanika (64 %) ocijenila je da je nedovoljno upoznata s postojeÄom zakonskom regulativom o rijetkim bolestima.
Oboljeli od rijetkih bolesti mogu se smatrati vulnerabilnim ispitanicima. Potrebno je formirati registar oboljelih, poboljÅ”ati informiranost struÄne i Å”ire 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 (1.25ā10 mg/kg) before or after induction of inflammation reduced mechanical hyperalgesia and edema with a maximal antihyperalgesic/antiedematous effect of about 40ā100%. Locally applied tramadol (0.125 mg/paw) better reduced edema (50ā100%) than pain (20ā50%) 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 kliniÄkim studijama
Farmakoterapija rijetkih bolesti suoÄena je s brojnim etiÄkim dilemama. NajveÄi broj oboljelih su djeca, oboljenja su progresivnog tijeka, a lijeÄenje vrlo skupo. Cilj rada bio je ispitati u kojoj mjeri se poÅ”tuju 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. KljuÄne rijeÄi bile su: Gaucherova bolest, etika/etiÄka pitanja i kliniÄka ispitivanja, a posebno su analizirani uÄinkovitost, sigurnost i cijena lijekova za ovu bolest. Provedena je i pilot anketa o stavovima lijeÄnika i kliniÄkih farmaceuta o farmakoterapiji rijetkih bolesti u Srbiji na odabranom uzorku ispitanika (N = 11, Klinika za internu medicinu i Centralna apoteka, KBC āBežanijska Kosaā u Beogradu). Na postavljena pitanja odgovoreno je u 97,2 % sluÄajeva.
UoÄeni su brojni problemi vezani uz lijeÄenje Gaucherove bolesti: npr. visoka cijena lijekova, nedostatak adekvatne procjene odnosa cijene i uÄinkovitosti terapije, nedovoljan broj ispitanika u kliniÄkim studijama i dr. Pilot anketa o rijetkim bolestima ukazuje na nedovoljnu informiranost struÄne javnosti (21 %) i komplicirane procedure oko nabave lijekova (21 %). VeÄina ispitanika (64 %) ocijenila je da je nedovoljno upoznata s postojeÄom zakonskom regulativom o rijetkim bolestima.
Oboljeli od rijetkih bolesti mogu se smatrati vulnerabilnim ispitanicima. Potrebno je formirati registar oboljelih, poboljÅ”ati informiranost struÄne i Å”ire javnosti i prilagoditi zakonsku regulativu kada su u pitanju rijetke bolesti
Supplementary data for the article: JevtiÄ, I. I.; SaviÄ VujoviÄ, K.; Srebro, D.; VuÄkoviÄ, S.; IvanoviÄ, M. D.; KostiÄ-RajaÄiÄ, S. V. Synthesis and Pharmacological Evaluation of Novel Cis and Trans 3-Substituted Anilidopiperidines. Pharmacol. Rep 2020, 72 (4), 1069ā1075. 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
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 ā¤ 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 0.625ā0.156 mg/mL to 10ā2.5 mg/mL of NAC combined with 0.062ā0.016 mg/mL to 1ā0.25 mg/mL of propolis inhibited biofilm formation in all bacterial strains. Suprainhibitory concentrations ranging from 2.5ā10 mg/mL to 40ā160 mg/mL of NAC in combination with 0.25ā1 mg/mL to 4ā16 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
Ī¼-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 Ī¼-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 28ā42 % 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 opioidādopamine receptor heterobivalent ligands
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 āmedical cannabisā 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
Pharmacotherapy of Rare Diseases in Serbia: The Current State of Art
Rare diseases affect less than 1Ā in 2000 or 5Ā 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