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

Drug-related pityriasis rubra pilaris with acantholysis

Introduction. Acantholysis is rarely reported histological feature of Pityriasis rubra pilaris (PRP), recently recognized as having diagnostic specificity for differentiating PRP from psoriasis. Case report. Adult male patient one week after the introduction of simvastatin had experienced pruritic erythemo-squamous eruption on head and upper trunk that in a month progressed to erythrodermia, with islands of sparing. Histological picture combined pemphigus-like acantholysis with alternating hyper- and parakeratosis, follicular plugs and dermal inflammation, and confirmed the clinical diagnosis of classic adult type 1 PRP. Acitretin therapy resulted in a resolution of skin disease. Patch test with simvastatin was negative, scratch test was positive, and it was estimated that potential risk of oral challenge with simvastatin outweighed actual need for it. Drug triggering PRP episode is the most likely explanation for temporal relation between the start of simvastatin treatment and skin eruption. Conclusion. In management of rare inflammatory skin disease, such as PRP, we have to carefully observe and evaluate not only diagnostic features but possible external influences on its course also

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

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

Supplementary data for the article: Novaković, M.; Pešić, M.; Trifunović, S.; Vučković, I.; Todorović, N.; Podolski-Renić, A.; Dinić, J.; Stojković, S.; Tešević, V.; Vajs, V.; et al. Diarylheptanoids from the Bark of Black Alder Inhibit the Growth of Sensitive and Multi-Drug Resistant Non-Small Cell Lung Carcinoma Cells. Phytochemistry 2014, 97, 46–54. https://doi.org/10.1016/j.phytochem.2013.11.001

Supplementary material for: [https://doi.org/10.1016/j.phytochem.2013.11.001]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1492

Supplementary data for the article: Novaković, M.; Pešić, M.; Trifunović, S.; Vučković, I.; Todorović, N.; Podolski-Renić, A.; Dinić, J.; Stojković, S.; Tešević, V.; Vajs, V.; et al. Diarylheptanoids from the Bark of Black Alder Inhibit the Growth of Sensitive and Multi-Drug Resistant Non-Small Cell Lung Carcinoma Cells. Phytochemistry 2014, 97, 46–54. https://doi.org/10.1016/j.phytochem.2013.11.001

Supplementary material for: [https://doi.org/10.1016/j.phytochem.2013.11.001]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1492

Evidence that endothelium-dependent relaxation to histamine in the rat common carotid artery is mediated by EDRF

The mechanism of histamine-induced relaxation in the isolated rat common carotid artery was analysed. Histamine (3 × 10-7 -10-4 mol/1) caused a concentration-dependent relaxation of the artery. In-domethacin, a cyclo-oxygenase inhibitor, and diethylcarbamazine, a lipoxygenase inhibitor, did not affect the relaxant response of the artery to histamine. After removal of the vascular endothelium the histamine-induced relaxation was strongly reduced. Moreover, hemoglobin and methylene blue, inhibitors of endothelium-derived relaxing factor (EDRF), prevented or reversed the relaxant effect of histamine. These findings confirm that the histamine-induced relaxation is to a greater extent endothelium dependent. It is concluded that the endothelium-dependent component in the relaxant response of the rat common carotid artery to histamine results from the release of EDRF.Scientific Fund of Serbia (Grant No. 231)

The involvement of peripheral alpha(2)-adrenoceptors in the antihyperalgesic effect of oxcarbazepine in a rat model of inflammatory pain

We studied whether peripheral alpha(2)-adrenergic receptors are involved in the antihyperalgesic effects of oxcarbazepine by examining the effects of yohimbine (selective alpha(2)-adrenoceptor antagonist), BRL 44408 (selective alpha(2A)- adrenoceptor antagonist), MK-912 (selective alpha(2C)-adrenoceptor antagonist), and clonidine (alpha(2)-adrenoceptor agonist) on the antihyperalgesic effect of oxcarbazepine in the rat model of inflammatory pain. METHODS: Rats were intraplantarly (i.pl.) injected with the proinflammatory compound concanavalin A (Con A). A paw-pressure test was used to determine: 1) the development of hyperalgesia induced by Con A; 2) the effects of oxcarbazepine (i.pl.) on Con A-induced hyperalgesia; and 3) the effects of i.pl. yohimbine, BRL 44408, MK-912 and clonidine on the oxcarbazepine antihyperalgesia. RESULTS: Both oxcarbazepine (1000-3000 nmol/paw; i.pl.) and clonidine (1.9-7.5 nmol/paw; i.pl.) produced a significant dose-dependent reduction of the paw inflammatory hyperalgesia induced by Con A. Yohimbine (260 and 520 nmol/paw; i.. pl.), BRL44408 (100 and 200 nmol/paw,-i.pl.),and MK-912 (10and 20 nmol/paw;i.pl.) significantly depressed the antihyperalgesic effects of oxcarbazepine (2000 nmol/pav\T,I i.pl.) in a close-dependent mariner. The effects of antagonists were due to local effects since they were not observed after admirdstration into the contralateral hindpaw. Oxcarbazepine and clonidine administered jointly in fixed-dose fractions of the ED50 (1/4, 1/2, and 3/4) caused significant and dose-dependent reduction of hyperalgesia induced by Con A. lsobolographic analysis revealed an additive antihyperalgesic effect. CONCLUSIONS: Our results indicate that the peripheral a,A and a,c adrenoceptors could be involved in the antihyperalgesic effects of oxcarbazepine in a rat model of inflammatory hyperalgesia. (Anesth Analg 2007;105:1474-81