Pain is one of many medical problems of modern society. Together with a number of other diseases such as heart attacks, strokes, tumors, etc. it ranks among the first in manifestation. There are a huge number of medical drugs more or less effective against pain in a practice. Globally, the searching of new molecules with analgesic activity and better selectivity or greater effect at lower doses continues. In addition, some groups trying to improve the properties of known molecules in medical practice as various heterocyclic compounds by modifying one or another of their part. Other groups work on the creation of new mimetics of natural molecules with well established physiological activity. In this global context, here we report the synthesis of two new compounds which are hybrid molecules between the specifically substituted pyrrole (Pyr) and analogues of Tyr-MIF-1 peptide. All investigations on the analgesic activity show better activity at the same dose than natural Tyr-MIF-1 peptide for the analogue Pyr-Tyr-Phe-Leu-Ala-OH. Compound Pyr-AlaLeu-Phe-Tyr-OH has no better effect comparable to that of the parent peptide. The obtained results clearly show that it is essential that Tyr residue occupies N-terminal position of MIF-1 analogue. The lack of better activity of the analogue Pyr-Ala-Leu-Phe-Tyr-OH reveals that Pyr residue does not influence on the analgesic activity. In addition we found that C-terminal amide function generally presented in natural MIF-1 is not absolutely necessary for activity.

Aiming to develop more potent analgesic substances a new series of hexapeptides containing β(2)-tryptophan analogues was synthesized. The Trp in position 4 and 5, respectively in Ac-Arg-Phe-Met-Trp-Met-Lys-NH2 (opioid receptor antagonist) and Ac-Arg-Tyr-Tyr-Arg-Trp-Lys-NH2 (highly potent and selective NOP-receptor agonist) was substituted by the (S)-2-(1-methyl-1H-indol-3-yl)propionic residue or the (S)-2-(5-methoxy-1H-indol-3-yl)propionic residue. The analgesic effect of the four newly synthesized compounds has been evaluated in male Wistar rats by PP- and HP tests and compared to the native templates. Further estimation of the mechanisms of action of each compound was achieved using specific antagonists-naloxone for opioid and JTC801 for the NOP receptor. Replacement of Trp with β(2)-tryptophan analogues in 4th position (Ac-Arg-Phe-Met-Trp-Met-Lys-NH2) led to increased and longer lasting analgesic effect. The results obtained permit us to assume that both opioid and NOP receptors take part in the newly synthesized compounds analgesic effects.

Biochemical, physiological and behavioural changes take place during stress. Various stress models have been reported to induce analgesia. This is a phenomenon referred to as stress-induced analgesia (SIA). Two forms of SIA are commonly distinguished: an opioid-mediated and a non-opioid one.In the last decade special attention has been attributed to the endocannabinoid system (ECS) as a component of non-opioid SIA.The Tyr-MIF-1 peptides proved to have opioid-like as well as anti-opioid effects.It has been shown that the endogenous opioid and the endocannabinoid systems have been involved in stress-induced analgesia.We found no literature data about the effects of Tyr-MIF-1 neuropeptides on the endocannabinoid system after stress.The aim of the study was to investigate the effects on nociception of Tyr-MIF-1 peptides (MIF-1, Tyr-MIF-1, Tyr-W-MIF-1 and Tyr-K-MIF-1) on the endocannabinoid system after immobilization stress.Anandamide (CB1 agonist) and AM251 (CB1 antagonist) were used. Nociception was measured in male Wistar rats by paw-pressure and hot-plate tests. All drugs were injected intraperitoneally.The results showed that anandamide and AM251 were involved in the analgesic effects of Tyr-MIF-1 peptides after immobilization SIA. The effects are probably due to different interaction between Tyr-MIF-1 receptors and endocannabinoid ones and the different involvement of the opioid and the antiopioid component in immobilization stress.

Zusammenfassung Hintergrund Die proliferative diabetische Retinopathie (PDR) ist eine der häufigsten Erblindungsursachen weltweit, in deren Verlauf sich sehr oft eine Glaskörperblutung als Komplikation entwickelt. Ziel unserer Untersuchung ist es, die ultrastrukturellen und klinischen Unterschiede bei entweder mit Ranibizumab oder mit Aflibercept behandelten PDR-Patienten zu vergleichen. Methoden In diese prospektive Untersuchung wurden 27 PDR-Patienten eingeschlossen. Bei 14 Patienten wurde Ranibizumab verwendet und mit Aflibercept wurden 13 Patienten behandelt. Bei 12 PDR-Patienten (6 von jeder Gruppe) wurde eine Vitrektomie durchgeführt und die entnommenen Membranen wurden ultrastrukturell im Transmissions- und Rasterelektronenmikroskop weiter analysiert. Ergebnisse In beiden Gruppen war die Größe von neu gebildeten Blutgefäßen nach Applikation von Anti-VEGF-Medikamenten deutlich vermindert. Bei mit Eylea behandelten Patienten war das deutlicher bis zu 7 mm2 Größe. Die Sehschärfe war 2 Zeilen verbessert und diese Ergebnisse wurden für 12 Wochen gehalten. Im Unterschied zu Lucentis hat Eylea sehr starken Einfluss bei schweren Formen von PDR. Das proliferative Gewebe bei PDR-Patienten bestand meistens aus verschiedenen Typen von neu gebildeten Blutgefäßen, die sich durch eine Schicht fenestrierter Endothelzellen auszeichneten. Diese Fenestrierung ist nach der Anwendung von Lucentis oder Eylea deutlich reduziert. Die Fenestrierung der Endothelzellen in den mit Eylea behandelten Patienten war signifikant vermindert. Elektronenmikroskopisch wurden durch thrombotisches Material verschlossene Gefäße gefunden. Schlussfolgerung Unsere Ergebnisse weisen darauf hin, dass beide Medikamente Lucentis und Eylea eine gute Wirkung auf PDR-Patienten haben. Sie verursachen eine Verminderung der endothelialen Fenestrierung und eine starke thrombotische Mikroangiopathie, die eine positive Auswirkung auf die Makulaödeme und Neovaskularisationen sowie die ganze Pathophysiologie von diabetischer Retinopathie haben.

Purpose: To screen a series of newly synthesized N-pyrrolyl hydrazide hydrazones for analgesic activity via Paw-pressure (PP) test and hot plate test (HPT). Methods: The compounds newly synthesized through the classical Paal-Knor cyclization, N-pyrrolyl hydrazide-hydrazones were administered intraperitoneally at a dose of 20 mg/kg. Paw pressure and hot plate tests were applied to assess the analgesic properties. In addition, stress-induced analgesia with naloxone as a non-selective opioid receptor antagonist was performed. Results: The compound (DI-5g), containing an izatine carbonyl fragment, was the most promising. It presented the highest paw pressure threshold (25 AU at 30th min) by exceeding the analgesic activity of the referent metamizole (23 AU at 30th min). The relative effect from the hot plate test was consistent with the paw pressure results. Opioid receptors were involved in the analgesic activities of N-pyrrolyl hydrazide-hydrazones. Conclusion: The N-pyrrolyl carboxylic acids are synthesized and identified as new compounds and their hydrazide-hydrazone derivatives as promising leads for future design and synthesis of drugs with possibly prolonged analgesic activity.