Ákos Kocsis

Novel Antiarrhythmic Compounds with Combined Class IB and Class III Mode of Action

Cardiac arrhythmias represent a major area of cardiovascular research, and for drug therapy, a large choice of antiarrhythmic agents have been available. However, clinical trials with antiarrhythmic drugs have recently indicated that serious side effects may considerably limit the use of various antiarrhythmic agents, in particular, for preventing arrhythmia-related mortality. Amiodarone with its complex mode of action, while exerting a strong and favorable antiarrhythmic action, posseses extracardiac untoward side effects originating from its chemical structure. In this paper, we report on our attempt to develop conceptually new, therapeutically valuable antiarrhythmic compounds, in which Class I/B and Class III features were combined into single molecules bearing no structural resemblance to amiodarone. Synthesis and pharmacological screening of series of N-(phenylalkyl)-N-(phenoxyalkyl)amines led us to discover some new promising compounds with the required dual mode of action. GYKI-16638, selected for further investigation, was also found to possess a remarkable in vivo antiarrhythmic effect, and it is now considered as a safe new antiarrhythmic drug candidate.

Sarcosine-Based Glycine Transporter Type-1 (GlyT-1) Inhibitors Containing Pyridazine Moiety: A Further Search for Drugs with Potential to Influence Schizophrenia Negative Symptoms.

We have synthesized a novel series of N-substituted sarcosines, analogues of NFPS (N-[3-(biphenyl-4- yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine), as type-1 glycine transporter (GlyT-1) inhibitors. Several compounds incorporated a diazine ring inhibited recombinant hGlyT-1b expressed permanently in CHO cells and GlyT-1 in rat brain synaptosomal preparations. A structure-activity relationship for the newly synthesized compounds was obtained and discussed on the ground of their GlyT-1 inhibitory potencies. Replacement of the biphenyl-4-yloxy moiety in NFPS with a 5-pyridazinylphenoxy moiety (compounds 3, 4, 5, and 6) or a 2-phenyl-5- pyridazinyloxy moiety (compounds 10, 11, and 12) afforded compounds exhibiting potent inhibition on GlyT-1 activity. The GlyT-1 inhibitory properties of NFPS analogues, in which sarcosine was closed into a ring forming (methylamino)pyridazine-3-(2H)-one, were markedly reduced (compounds 13 and 14). The pyridazine-containing GlyT-1 inhibitors with in vitro GlyT-1 inhibitory potency also enhanced extracellular glycine concentrations in conscious rat striatum as was measured by microdialysis technique. In contrast to NFPS, sarcosine-based pyridazine containing GlyT-1 inhibitors failed to evoke compulsive running behavior whereas they inhibited phencyclidine- induced hypermotility in mice. It is believed that increase of extracellular concentrations of glycine by inhibition of its reuptake may probably influence positively glutamate N-methyl-D-aspartate (NMDA)-type ionotropic receptors in the central nervous system. This may have importance in the treatment of neuropsychiatric disorders associated with hypofunctional NMDA receptor-mediated glutamatergic neurochemical transmission. Thus, impaired NMDA receptor functions have been shown to be involved in the development of the negative symptoms and the cognitive deficit of schizophrenia and the treatment of these symptoms is the possible clinical indication of GlyT-1 inhibitors including those containing pyridazine moiety.

Formation of trioxadamantane type aglucones of 3-methoxy secologanin derivatives

Abstract Acidic transformation of some 3,4-dihydro-3-substituted secologanin derivatives produced trioxadamantane type compounds. The formation of the bridged tricyclic products from monocyclic educts is interpreted as multistep hydrolysis and transacetalation accompanied by deglucosylation.

An nmr study of the solution conformation of two asperuloside derivatives

Abstract 3-Methoxy-3,4-dihydro- and the 3-methoxy-3,4,7,8- tetrahydro-asperuloside-tetraacetate were prepared. Total assignment of their 1 H and 13 C NMR spectra was accomplished using 2D shift correlation measurements. The configurations and the conformations of these compounds were determined by the combined analysis of the 3 J coupling constants and NOE factors of the 1 H NMR spectra.

Successful surgical treatment of tracheal rupture caused by endotracheal intubation

Rupture of the trachea is a rare complication of endotracheal intubation. The most common cause of the injury is the overinflation of the cuff. The authors present the case of a 45-year-old male in whom a 6 cm long trachea lesion was perceived during the operation due to a meso-hypopharyngeal tumor. Primary intervention resulted in successful reconstruction and full recovery. The case demonstrates the importance of prompt diagnosis and adequate therapy that helped in preventing an assumingly life-long complication or even death.

Nem tapintható tüdőgócok drót- és izotópjelölés segítségével történő minimálinvazív műtéti eltávolítása

INTRODUCTION Nowadays ever smaller, sub-centimetre lung nodules are screened and diagnosed. For these, minimally invasive resection is strongly recommended both with diagnostic and therapeutic purpose. AIM Despite many advantages of minimally invasive thoracic surgery, thorough palpation of the lung lobes and thus the localization of lung nodules are still limited. There are several options to solve this problem. From the possibilities we have chosen and tried wire- and isotope-guided lung nodule localization. MATERIALS AND METHODS In 2017, at the Thoracic Surgery Department of the National Institute of Oncology we performed wire- and isotope-guided minimally invasive pulmonary nodule resection in five patients. The diameter of the lung nodules was between 0.5 and 1.2 cm. The age of the patients was between 44 and 65 years and none of them had severe comorbidities, which meant low risk for complications. RESULTS We successfully performed the minimally invasive atypical resection in all cases. After the wire and isotope placement we found a 2-3 mm pneumothorax in one patient that did not need urgent drainage. In another patient we found that high amount of intraparenchymal bleeding surrounded the channel of the wire. During the operation, two wires were displaced when the lung collapsed, and in another case the mentioned bleeding got into the thoracic cavity and made it difficult to detect the nodule. In one case we resected the wire-guided lung tissue, but the isotope-guided lung nodule was below the resection line. CONCLUSION Both techniques could help to localize the non-palpable lung nodules. Based on our initial experiences, the isotope-guided method provides more details to estimate the exact depth of the nodule from the visceral surface of the pleura and we can avoid the unpleasantness of wire displacement. On the other hand, the production of the isotope requires a more developed infrastructure and the exact timing of the operation after the isotope injection is more strict. Orv Hetil. 2018; 159(34): 1399-1404.INTRODUCTION Nowadays ever smaller, sub-centimetre lung nodules are screened and diagnosed. For these, minimally invasive resection is strongly recommended both with diagnostic and therapeutic purpose. AIM Despite many advantages of minimally invasive thoracic surgery, thorough palpation of the lung lobes and thus the localization of lung nodules are still limited. There are several options to solve this problem. From the possibilities we have chosen and tried wire- and isotope-guided lung nodule localization. MATERIALS AND METHODS In 2017, at the Thoracic Surgery Department of the National Institute of Oncology we performed wire- and isotope-guided minimally invasive pulmonary nodule resection in five patients. The diameter of the lung nodules was between 0.5 and 1.2 cm. The age of the patients was between 44 and 65 years and none of them had severe comorbidities, which meant low risk for complications. RESULTS We successfully performed the minimally invasive atypical resection in all cases. After the wire and isotope placement we found a 2-3 mm pneumothorax in one patient that did not need urgent drainage. In another patient we found that high amount of intraparenchymal bleeding surrounded the channel of the wire. During the operation, two wires were displaced when the lung collapsed, and in another case the mentioned bleeding got into the thoracic cavity and made it difficult to detect the nodule. In one case we resected the wire-guided lung tissue, but the isotope-guided lung nodule was below the resection line. CONCLUSION Both techniques could help to localize the non-palpable lung nodules. Based on our initial experiences, the isotope-guided method provides more details to estimate the exact depth of the nodule from the visceral surface of the pleura and we can avoid the unpleasantness of wire displacement. On the other hand, the production of the isotope requires a more developed infrastructure and the exact timing of the operation after the isotope injection is more strict. Orv Hetil. 2018; 159(34): 1399-1404.

A nagyméretű retrosternalis strumák műtéti megoldása – fej-nyak sebész és mellkassebész sikeres együttműködése

Absztrakt Bevezetes: A megnagyobbodott, akar a tracheat is komprimalo pajzsmirigy műteti kezelese legtobb esetben a totalis thyreoidectomia, amely mind a fej-nyak sebeszek, mind az altalanos sebeszek koreben ismert eljaras. A megnagyobbodott pajzsmirigy az esetek korulbelul 1–10%-aban a szegycsont moge er, ezaltal elterő műteti technikat igenyel az eltavolitasa. Betegek es modszerek: Munkacsoportunk 2000–2014-ig 182 substernalis struma miatt vegzett műtetet. Substernalisnak azon pajzsmirigylebenyeket tekintettuk, amelyek legalabb a jugulum szintje ala ertek. Retrospektive vizsgaltuk a 182 esetet, amelyek substernalisan elhelyezkedő pajzsmirigylebenyek miatt kerultek műtetre az elmult 14evben. Eredmenyek: Minden beteg panaszokkal erkezett, amelyek kozul a fulladas es nehezlegzes volt a leggyakoribb. A műtetet minden esetben megelőzte kepalkoto vizsgalat. 31 esetben praeoperativ nyaki ultrahang keszult, 13 esetben MR- es 138 esetben CT-vizsgalat jelentette a kepalkoto eljarast. 15 beteg eseteben tortent kor...

Aspergillus empyema kezelése nyitott thoracostomiával és izomplasztikával, a tüdő funkciójának megőrzésével – esetismertetés

CASE REPORT Invasive aspergillosis is a life threatening complication in immune-compromised patients causing lung tissue destruction. Aspergillus empyema requires aggressive multimodality treatment. MATERIAL AND METHOD We present a case of Aspergillus empyema treated by thoracic and plastic surgery preserving the lung function in an 18 year-old male patient suffering dermatomyositis and treated with steroids for a long time. After open window thoracostomy (OWT) we used pedicled musculus latissimus dorsi (MLD) flap and mobilised the anterior serratus muscle to close the pleural cavity. CONCLUSION The intrathoracic use of muscle flaps after OWT in case of chronic Aspergillus empyema can preserve the underlying lung tissue. Cooperation of thoracic and plastic surgeons - as in the cases presented - provides an excellent opportunity to treat successfully of otherwise hopeless patients.

Synthetic Modification of Iridoids to Non-natural Indole Alkaloids

As a continuation of our studies on iridoids1–4, we now report on some novel reactions of various aglycones of this class of compounds.