Primjena lijekova kod odabranih vulnerabilnih skupina: stare osobe u kliničkim ispitivanjima

“Vulnerabilna osoba je osoba koja ima veći rizik od ispitivača u kliničkoj studiji nego od samog oboljenja. Primjeri vulnerabilnih osoba uključuju bolesnike s vrlo ozbiljnim oboljenjima koji imaju velika pozitivna očekivanja od primjene novog lijeka, osobe koje imaju profesionalni odnos s istraživačima (npr. studenti medicine, medicinske sestre, zaposleni u farmaceutskim kompanijama i sl.).” Klinički istraživači u prošlosti su štitili vulnerabilne osobe isključujući ih iz istraživanja, ali taj pristup nije više moralno prihvatljiv. Istraživače se potiče da dizajniraju kliničke studije koje bi uključile vulnerabilne subjekte. Da bi postigli moralno valjane rezultate, klinički ispitivači moraju biti svjesni i prihvatiti smjernice i zahtjeve lokalnih etičkih odbora. Nije nerazumno zahtijevati od vulnerabilne osobe da prihvati razumni stupanj rizika u cilju dobrobiti budućih bolesnika

Uticaj pentobarbitala i pentilenetetrazola na nivo azot oksida u frontalnom korteksu pacova

Levels of nitric oxide (NO) in the rats frontal cortex were continuously monitored before and after intraperitoneal administration of an antiepileptic drug-pentobarbital (20 and 40 mg/kg) or convulsant drug - pentylenetetrazol (50 mg/kg). Pentobarbital decreased the levels of NO in a dose dependent manner However, NO levels had a tendency to increase following the administration of pentylenetetrazol. It is suggested that central NO participates in the modulation of neuronal excitability, supporting the idea that NO is an important excitatory factor involved in the regulation of seizure susceptibility. Also, our results on anaesthetized rats suggests that endogenous NO may be involved in the mechanism of action of antiepileptic and analeptic drugs and this further suggest that NO levels in the human brain may decrease during antiepileptic therapy and increase during epileptic attacks or administration of excitatory drugs. The aim of the present study was to determine the possible role of NO levels in the brain during neuronal excitability and seizures.Nivo azot oksida (NO) u frontalnom korteksu pacova meren je kontinuirano kako pre, tako i nakon intraperitonealne primene antiepileptika pentobarbitala (u dozi od 20 i 40 mg/kg) ili konvulzivnog agensa pentilenetetrazola (u dozi od 50 mg/kg). Rezultati ovih eksperimenta su ukazali da pentobarbital smanjuje nivo NO u frontalnom korteksu pacova, dok koncentracija NO ima tendeciju rasta nakon primene pentilenetetrazola. Osim toga, dokazano je da endogeni NO ima važnu ekscitatornu ulogu u centralnim mehanizmima nastanka epilepsije. Takođe, naši rezultati su ukazali da kod anestetisanih životinja endogeni nivo NO ima uticaja na dejstvo kako antikonvulzivnih, tako i prokonvulzivnih lekova. Nivo NO u mozgu pacova je bio snižen tokom terapije antiepilepticima, a povišen tokom epileptičkih napada ili primene lekova iz grupe centralnih stimulansa

Ispitivanje neurotoksičnosti analoga fentanila kod pacova

This study aimed at evaluating the neurotoxicity of fentanyl analogs: (+/-)-cis-3-carbomethoxy fentanyl (C) and (+/-)-trans-3-carbomethoxy fentanyl (T) in rats. C and Tare less potent (2.4-3.1 and 8.4-12.3 times, respectively) than fentanyl (F) in producing both antinociception and morphine-like neurotoxic effects: loss of pinna reflex, Straub tail, impairment of motor coordination, catalepsy, loss of corneal reflex and loss of righting reflex. All of the effects tested were dose-dependent and they were abolished by pretreatment with naloxone, nonselective antagonist of opioid receptors, indicating that they are mediated via opioid receptors. Further, F, C and T exhibited similar relative potencies in producing all tested effects, indicating that similar receptors are involved in producing antinociceptive and neurotoxic effects, most probably of mu type. By using equiantinociceptive doses, C and T produced significantly shorter duration of both antinociception and neurotoxicity than F No significant differences between therapeutic indices for F, C and T were found, indicating that these compounds are equally safe and tolerable in respect to the neurotoxic effects tested. Neurotoxicity testing presented in this paper may be useful in studying the structure-activity relationship of opioid congeners.Cilj studije bio je da se ispita neurotoksičnost analoga fentanila: (±)-cis-3-karbometoksi fentanila (C) i (±)-trans-3-karbometoksi fentanil (T) kod pacova. C je oko 2,4-3,1, a T oko 8,4-12,3 puta manje potentan od fentanila u izazivanju antinocicepcije i morfinu-sličnih neurotoksičnih efekata u koje spadaju: refleks ušne školjke, Straub-ov rep, poremećaj motorne koordinacije, katalepsija, gubitak kornealnog refleksa i gubitak refleksa uspravljanja. Svi ispitivani efekti su dozno-zavisni i bivaju poništeni ako se u pretretmanu primeni nalokson, neselektivni antagonist opioidnih receptora, što ukazuje da se efekti odigravaju posredstvom opioidnih receptora. Dalje, F, C i T ispoljavaju sličnu relativnu jačinu u izazivanju ispitivanih efekata, što ukazuje da su slični receptori uključeni u mehanizam antinocicepcije i neurotoksičnih efekata, i to su najverovatnije μ receptori. Kad se primenjuju ekviantinociceptivne doze, C i T izazivaju značajno kraće i antinociceptivno i neurotoksično dejstvo od F. Nisu dokazane značajne razlike u terapijskim indeksima između F, C i T, što ukazuje da su ovi lekovi jednako bezbedni i podnošljivi kad su u pitanju ispitivani neurotoksični efekti. Ispitivanje neurotoksičnosti prikazano u ovom radu može biti korisno u proučavanju odnosa između strukture i aktivnosti hemijski srodnih opioida

Sinteza i farmakološko ispitivanje (±)-2,3-seco-analoga fentanila

An efficient, five-step synthetic approach to various acyclic 1,3-diamines has been developed and applied to the preparation of a novel class of open-chained fentanyl analogues. The acyclic derivatives 5.1-5.5 (all new compounds) were synthesized with the aim of estimating the significance of the piperidine ring for the opioid analgesic activity of anilido-piperidines. The starting beta-keto-amide 1.1, prepared by the aminolysis of methyl acetoacetate with methyl phenethylamine, (93% yield), was successively reacted with NaH and BuLi, to form the highly reactive alpha,gamma-dienolate anion 1.1a. Regio and chemoselective gamma-alkylation of the dienolate with various primary and secondary alkyl halides furnished the beta-keto-amides 1.2-1.5 (76-91%). Reductive amination of the keto-amides 1.1-1.5 with aniline and Zn powder in acetic acid, via the enamine intermediates 2.1-2.5. afforded the beta-anilino amides 3.1-3.5 (74-85%). After reductive deoxygenation of the tertiary amide group, using in situ generated diborane, the corresponding 1,3-diamines 4.1-4.5 were obtained (87-97%). The synthesis of (+/-)-2,3-seco-fentanyls 5.1-5.5 was completed by N-acylation of the diamines 4.1-4.5 with propionyl chloride, followed by precipitation of the monooxalate salts (86-95%). The parent compound, 2,3-seco-fentanyl 5.1, was found to be a 40 times less potent narcotic analgesic than fentanyl but still 5-6 times more active than morphine in rats. while i-Pr derivative 5.3 was inactive. Apart from the pharmacological significance. the general procedure described herein may afford various functionalized, 1,3-diamines as potential complexing agents and building blocks for the synthesis of aza-crown ethers.Razvijen je efikasan postupak za dobijanje različitih acikličnih 1,3-diamina u pet faza, i primenjen u sintezi nove klase analoga fentanila otvorenog niza. Derivati 5.1–5.5 (svi su nova jedinjenja) sintetisani su sa ciljem da se proceni uticaj piperidinskog prstena na opioidnoanalgetičku aktivnost anilido-piperidina. Polazni β-keto-amid 1.1, dobijen aminolizom metilacetoacetata metilfenetilaminom (prinos 93 %), bio je sukcesivno tretiran sa NaH i BuLi, pri čemu je postao veoma reaktivni α,γ-dienolatni anjon 1.1a. Regio- i hemoselektivnim γ-alkilovanjem ovog dienolata različitim primarnim i sekundarnim alkil-halogenidima, dobijeni su β-keto-amidi 1.2–1.5 (prinos 76–91 %). Reduktivnim aminovanjem keto-amida 1.1–1.5 pomoću Zn praha i sirćetne kiseline, preko enaminskih intermedijera 2.1–2.5, postali su -anilino-amidi 3.1–3.5 (prinos 74–85 %). Posle reduktivne deoksigenacije tercijene amidne funkcije, koristeći in situ generisani diboran, odgovarajući 1,3-diamini 4.1–4.5 izolovani su u prinosima 87–97 %. Sinteza (±)-2,3-seco-fentanila 5.1–5.5 završena je N-acilovanjem diamina 4.1–4.5 propionil-hloridom, a zatim taloženjem u obliku monooksalatnih soli (prinos 86–95 %). Nađeno je da je osnovno jedinjenje, 2,3-seco fentanil 5.1, 40 puta slabiji narkotički analgetik od fentanila, ali još uvek 5–6 puta aktivniji od morfina u pacova, dok je i-Pr derivat 5.3 bio neaktivan. Osim farmakološkog značaja, opštim postupkom prikazanim u ovom radu, mogu se sintetisati različiti 1,3-diamini, uključujući i one sa funkcionalnim grupama. Ova jedinjenja mogu biti potencijalno značajna kao kompleksirajući agensi i kao intermedijeri u sintezi aza-kraun-etara

Antiepileptici u terapiji neuropatskog bola

Neuropathic pain, a form of chronic pain, caused by injury or disease of the peripheral or central nervous system, is a therapeutic challenge to clinicians because it does not respond well to traditional pain therapies. Basic research of pathophysiological mechanisms of neuropathic pain has shown many similarities between the morphological and biochemical changes observed in epilepsy and neuropathic pain, which gave the rational for examination and use of antiepileptic drugs (AED) in management of neuropathic pain disorders. Carbamazepine was the first AED studied in clinical trials, achieving positive results predominantly in the treatment of trigeminal neuralgia, and took its place in therapy of this particular neuropathic pain disorder. Gabapentin, a newer AED, has the most clearly demonstrated analgesic effect for the treatment of neuropathic pain, specifically for treatment of painful diabetic neuropathy and postherpetic neuralgia and is considered the first choice of therapy for neuropathic pain. There is increasing evidence that effect in both experimental and clinical studies. Due to less frequency and severity of adverse effects it is considered as an alternative to carbamazepine in a treatment of neuropathic pain. There is insufficient evidence about efficacy of phenitoin, lamotrigine and some others AED in the treatment of neuropathic pain disorders. Future advances in treatment of neuropathic pain are directed on understanding the pathophysiological mechanisms underlying neuropathic pain and further examining the mechanisms of action of AED, and their efficacy and safety in treatment of neuropathic pain.Neuropatski bol je oblik hroničnog bola izazvan povredom ili oboljenjem perifernog ili centralnog nervnog sistema. Predstavlja terapijski izazov za kliničare, jer se primenom konvencionalnih analgetika u terapiji ovog tipa bola ne postižu zadovoljavajući rezultati. Bazična istraživanja patofizioloških mehanizama neuropatskog bola pokazala su mnoge sličnosti između morfoloških i biohemijskih promena koje se javljaju kod neuropatskog bola i onih koje se javljaju kod epilepsije, što čini osnovu za ispitivanje i upotrebu antiepileptika u terapiji ovog tipa bola. Prvi klinički ispitani antiepileptik, karbamazepin, ostvario je pozitivne rezultate prevashodno u terapiji neuralgije trigeminusa, gde je i našao svoje mesto u kliničkoj praksi. Lek novije generacije, gabapentin, je za sada najjasnije pokazao analgetičko dejstvo kod neuropatskog bola, posebno kod dijabetičke neuropatije i postherpetičke neuralgije i danas se smatra lekom prvog izbora u terapiji neuropatskih bolnih stanja. Sve je više dokaza o analgetičkom dejstvu okskarbazepina, koji je keto-derivat karbamazepina. U eksperimentalnim i kliničkim ispitivanjima okskarbazepin se pokazao kao moguća zamena za karbamazepin u terapiji neuropatskog bola, zbog niže učestalosti i manjeg intenziteta neželjenih efekata. Znatno je manje dokaza o efikasnosti fenitoina, lamotrigina i nekih drugih antiepileptika u suzbijanju neuropatskog bola. Dalje usavršavanje terapije neuropatskog bola usmereno je ka rasvetljavanju njegovih složenih patofizioloških mehanizama, kao i daljem ispitivanju mehanizama dejstva, efikasnosti i bezbednosti primene antiepileptika u terapiji neuropatskog bola

Pharmacological evaluation of 3-carbomethoxy fentanyl in mice

In many animal species, as well as in humans, high doses of fentanyl (F) produce marked neurotoxic effects, such as muscular rigidity and respiratory depression. The antinociception (hot-plate test), impairment of motor coordination (rotarod test) and acute toxicity of intraperitoneal newly synthesized analogs, (±)cis-3-carbomethoxy- fentanyl (C) and (±)trans-3-carbomethoxyfentanyl (T) were evaluated in mice. The compounds tested induced antinociception, impairment of performance on the rotarod, and lethality in a dosedependent manner. The relative order of antinociceptive potency was similar to motor impairment potency, as well as lethality: F gt C gt T. Naloxone hydrochloride (1 mg/kg; sc) abolished all the effects observed, suggesting that they are mediated via opioid receptors, most probably of μ type. There were no significant differences between the therapeutic indices of F, C and T. It is concluded, the introduction of 3-carbomethoxy group in the piperidine ring of the fentanyl skeleton reduced the potency, but did not affect tolerability and safety of the compound. © 2011 by the authors

Experience with developing antibiotic stewardship programmes in Serbia : potential model for other Balkan countries?

Introduction: Antimicrobial resistance (AMR) and inappropriate use of antibiotics in children are important issues. Consequently, there is a need to develop comprehensive stewardship programmes even in hospitals with limited resources starting with children’s hospitals. Method: Retrospective observational analysis of antimicrobial utilization and resistance patterns over five years in a tertiary care children’s hospital in Serbia. Results: Cumulative AMR decreased but were still high, with high cumulative resistance rates among the most widely used antibiotics in the hospital. Total antibiotic use decreased from 2010 to 2014 although there was still high prescribing of reserved antibiotics. Conclusion: Concerns with inappropriate use, and high resistance rates, among some antibiotics used in the hospital are being used to develop guidance on future antibiotic use in this hospital, building on the recently introduced antibiotic stewardship programme, as well as encourage other hospitals in Serbia to review their policies