Discovery and Optimization of Potent and Orally Available CTP Synthetase Inhibitors for Use in Treatment of Diseases Driven by Aberrant Immune Cell Proliferation.

Herein, we report the discovery of a first-in-class chemotype 2-(alkylsulfonamido)thiazol-4-yl)acetamides that act as pan-selective inhibitors of cytidine 5'-triphosphate synthetase (CTPS1/2), critical enzymes in the de novo pyrimidine synthesis pathway. Weak inhibitors identified from a high-throughput screening of 240K compounds have been optimized to a potent, orally active agent, compound 27, which has shown significant pharmacological responses at 10 mg/kg dose BID in a well-established animal model of inflammation.

Usage of high-flow oxygen therapy outside the intensive care unit: a possibility to delay or prevent the need for mechanical ventilation among COVID-19 patients / Nagy áramlású oxigénnel végzett terápia az intenzív osztály keretein kívül alkalmazva: lehetoség a gépi lélegeztetés késleltetésére vagy elkerülésére COVID­19-ben

Összefoglaló. Bevezetés és célkituzés: Szakirodalmi adatok a súlyos lefolyású COVID-19 terápiájában a noninvazív megoldások elonyét jelezték a prompt invazív megoldásokhoz képest. A COVID-19-pandémia drámai helyzetében felmerült a nagy áramlású oxigénnel (HFO) végzett terápia alkalmazásának létjogosultsága az intenzív terápiás osztály (ITO) keretein kívül. A szerzok a súlyos hypoxiával érkezo páciensek számára a "high-flow" kezelés legjobb orvosi gyakorlatát keresték. Módszer: Áttekintették a COVID-19-pandémia elso három hullámában a Somogy Megyei Kaposi Mór Oktató Kórház Infektológiai Osztályán HFO-val kezelt páciensek dokumentációját (n = 193). Nemparaméteres statisztikai módszerekkel elemezték a HFO-kezelés elott és alatt mért oxigénszaturáció-értékeket, a HFO-kezeléssel töltött napok számát és az egyes páciensek kórlefolyásának kimenetelét: a hazabocsátást, az ITO-ra áthelyezést vagy a halálozást mint három lehetséges végpontot megjelölve. Külön értékelték a harmadik hullám idoszakát (a standard terápia ekkorra kialakult). Eredmények: A járvány elorehaladtával a MET- (Medical Emergency Team) rendszer igénybevétele 811%-ra emelkedett, a HFO-készülékek száma 567%-kal nott. A COVID-19-protokoll szerinti kezelés mellett HFO-terápiára szoruló páciensek 18,7%-a invazív megoldást elkerülve, gyógyultan távozhatott, optimális terhelés és szakmai tapasztalat mellett ez az arány elérte a 36%-ot is. A hazabocsátható páciensek csoportjában a kezdeti szaturációk medián értéke 78%, a teljes HFO-kezelés ideje 8,5 nap volt. A páciensek 1%-ában pneumothoraxot, pneumomediastinumot észleltek. A végül közvetlenül hazabocsátható, illetve ITO-ra került páciensek kezdeti oxigénszaturáció-értékének különbsége nem bizonyult szignifikánsnak. Következtetés: A jelen közlemény is alátámasztja, hogy a kezdeti alacsony szaturációérték önmagában nem jelenti az invazív beavatkozás létjogosultságát ebben a kórképben. "High-flow" kezeléseket az intenzíves kezelés eloszobájaként nem intenzíves szakemberek is végezhetnek COVID-19-betegekben, rendszeres intenzíves konzultáció mellett, hogy a HFO-kezelés melletti rosszabbodás minél inkább felfedezheto legyen. Orv Hetil. 2022; 163(7): 254-266. INTRODUCTION AND OBJECTIVES: Previous studies have shown the advantage of non-invasive over prompt invasive approaches in the treatment of patients with severe COVID-19. The dramatic situation of the pandemic raised the legitimacy of using high-flow oxygen therapy (HFO) outside the intensive care unit (ICU). The authors investigated ways of its best practice. METHOD: They retrospectively analysed documentation of patients receiving HFO in the first three waves of the pandemic on the Infectious Diseases' Ward (n = 193), to record oxygen saturation levels before and during HFO, number of treatment days. Discharge at home, transfer to intensive care unit and death were chosen as the three possible endpoints. The period of the third wave (standard therapy established) was analysed separately. RESULTS: As the pandemic progressed, the usage of MET (Medical Emergency Team) grew to 811%, the number of HFO devices grew by 567%. With concomitant standard COVID-19 therapy, 18.7% of the patients requiring HFO could be discharged home, avoiding invasive solutions. With optimal workload and experience, this ratio reached 36%. Among patients later discharged home, the median oxygen saturation before HFO was 78%, the total time with HFO was 8,5 days. The occurrence of pneumothorax or pneumomediastinum was 1%. The difference in oxygen saturation before HFO between the patients later discharged home and those transferred to ICU was not significant. CONCLUSION: The results support the assumption that low oxygen saturation at admission does not inevitably require invasive intervention in COVID-19 patients, high-flow oxygen therapy can also be performed by non-ICU professionals as ante-room to the ICU, under regular supervision by ICU experts, so that the deterioriation of the patients' condition is discovered appropriately. Orv Hetil. 2022; 163(7): 254-266.

Mannich Ketones as Possible Antimycobacterial Agents.

Twenty-three known unsaturated and fused Mannich ketones and their reduced derivatives (amino alcohols) were selected for an antituberculotic study. They were screened against several mycobacterial strains including Mycobacterium tuberculosis, M. xenopi, and M. gordonae, and minimum inhibitory concentration values were also determined using the standard antituberculotic drug isoniazid (INH) as a reference. Structure-activity relationships were also studied. The mode of action of the test compounds was investigated using transmission electron microscopy, high-performance liquid chromatography, and matrix-assisted desorption/ionization mass spectrometry. Several test substances proved to be as potent as INH, but their antimycobacterial spectra were broader than that of INH. Our findings suggest that their mode of action is probably through the inhibition of mycobacterial cell wall biosynthesis.

Antipsychotic treatment and the prevalence of diabetes among elderly patients in psychiatric rehabilitation.

We aimed to compare the risk of diabetes in a Hungarian schizophrenic population treated with atypical antipsychotics with that of the non-schizophrenic population. We wished to reveal the effects of gender and age. A schizophrenic population (n=135 male and n=110 female patients of different age groups) was examined by studying hospital charts in the Gálfi Béla Hospital specialized on gerontopsychiatric attendance with a main profile of rehabilitation. Data were given by the National Health Insurance Fund registry in the period of 2000-2006, while the Hungarian Central Statistical Office presented data on the prevalence of diabetes in the Hungarian population. Binomial distribution was used for the hypothesis testing. The examination shows higher prevalence of diabetes among schizophrenic patients (12.72%) in comparison with the Hungarian population (6.85%) in the age group of 18-64 among both sexes, while there was no higher risk of diabetes found in the age group of above 65 among both sexes. As a conclusion, we emphasize that continuous weight, glucose and lipid level monitoring should be considered during treatment with antipsychotics in all age groups, even if our study does not show higher risk of diabetes among elderly schizophrenic patients.