TRPV1: A Promising drug target for the treatment of various conditions

Nobelova nagrada za fiziologiju i medicinu za 2021. dodeljena je naučnicima koji su identifikovali receptore za temperaturu i dodir. Da bi sproveli ovo ispitivanje, istraživači su koristili kapsaicin, jedinjenje koje čili paprici daje toplotu, kako bi otkrili receptore koji omogućavaju ljudima da osete “gorući” ukus čilija. Pokazano je da se transient receptor potential vanilloid 1 (TRPV1), koji predstavlja jonski kanal prisutan na senzornim neuronima, otvara u prisustvu kapsaicina ili toplote, propuštajući naelektrisane jone kalcijuma u ćeliju. Takav priliv kalcijuma pokreće električne signale koji se šalju u mozak da upozore na toplotu. TRPV1 se nalazi u somatosenzornom sistemu i služi kao multimodalni senzor različitih štetnih stimulusa. Brojne farmakološke i genetičke studije su potvrdile TRPV1 kao terapeutsku metu u nekoliko pretkliničkih modela hroničnog bola, uključujući maligni, neuropatski, postoperativni i mišićno-skeletni bol. Pored toga, ekspresija TRPV1 se takođe primećuje na ne-neuronskim lokalizacijama, kao što su epitel bešike i pluća, ćelije kohlee u uhu. Stoga, lekovi koji mogu da modulišu aktivnost kanala TRPV1 mogu biti korisni za lečenje različitih stanja u rasponu od hroničnog bola do gubitka sluha. Iako je utvrđeno da antagonisti TRPV1 mogu predstavljati važan dodatak terapiji bola, njihova klinička upotreba je i dalje ograničena značajnim neželjenim efektima, kao što je hipertermija. U ovom radu ćemo opisati najvažnije uloge TRPV1 u fiziološkim i patofiziološkim procesima i predstaviti najperspektivnije lekove koji deluju preko TRPV1.The 2021. Nobel Prize in Physiology or Medicine was awarded to scientists who have identified receptors for temperature and touch. In order to conduct this examination, researchers used capsaicin, the compound that gives chili peppers their heat, to discover receptor proteins that allow people to feel chili’s burn. It is shown that transient receptor potential vanilloid 1 (TRPV1), which represents an ion channel present on sensory neurons, opens when it encounters capsaicin or heat, allowing charged calcium ions into the cell. That flood of calcium triggers electrical signals that are sent to the brain to warn of heat. TRPV1 is found in the somatosensory system and serves as a multimodal sensor of different noxious stimuli. Numerous pharmacological and genetic studies have validated TRPV1 as a therapeutic target in several preclinical models of chronic pain, including cancer, neuropathic, postoperative and musculoskeletal pain. Additionally, expression of TRPV1 is also observed in non-neuronal sites such as the epithelium of bladder and lungs, cells of the cochlea. Therefore, drugs which could modulate TRPV1 channel activity could be useful for the treatment of conditions ranging from chronic pain to hearing loss. While antagonists of TRPV1 were found to be a valuable addition to therapy of pain, their clinical use has still been limited by significant side effects, such as hyperthermia. In this review, we will describe the most important roles of TRPV1 in physiological and pathophysiological processes and present the most promising TRPV1-targeted drugs

Is miR-133a marker of progressive chronic kidney disease?

Chronic kidney disease (CKD) is associated with a high incidence of cardiovascular (CV) disease and numerous risk factor have been implicated to play a role.  Recent studies have shown that the levels of various microRNAs in the serum of patients with CKD have been altered and there are reports that miR-133a serum levels correlated with left ventricular hypertrophy in hemodialysis patients.The aim of this study was to investigate association between circulating miR-133a levels and development of de novo CV events in patients with CKD stage 3-5HD.METHODS: This study included 51 patients with diagnosed CKD and 7 healthy individuals as controls. According to the estimated glomerular filtration ratio (eGFR) patients were divided into three equal subgroups (n=17): patients with CKD stage 3b, 4, and 5HD.  The level of miR-133a was measured in serum by quantitative real-time PCR. Echo parameters were measured by cardiac ultrasound at the beginning and after 12 months of follow-up. The following CV events were reported during 18 months of follow-up: cardiac death, myocardial infarction, cerebrovascular insult, exacerbation of existing and newly discovered angina pectoris and peripheral arterial disease

Oboljeli od rijetkih bolesti kao vulnerabilni ispitanici u kliničkim studijama

Farmakoterapija rijetkih bolesti suočena je s brojnim etičkim dilemama. Najveći broj oboljelih su djeca, oboljenja su progresivnog tijeka, a liječenje vrlo skupo. Cilj rada bio je ispitati u kojoj mjeri se poštuju principi suvremene bioetike, kada je u pitanju farmakoterapija rijetkih bolesti. Za primjer je uzeta Gaucherova bolest. Pretraživali smo dostupne baze podataka (Cochrane database, MEDLINE i Google) za period od 1996. do 2011. Ključne riječi bile su: Gaucherova bolest, etika/etička pitanja i klinička ispitivanja, a posebno su analizirani učinkovitost, sigurnost i cijena lijekova za ovu bolest. Provedena je i pilot anketa o stavovima liječnika i kliničkih farmaceuta o farmakoterapiji rijetkih bolesti u Srbiji na odabranom uzorku ispitanika (N = 11, Klinika za internu medicinu i Centralna apoteka, KBC „Bežanijska Kosa“ u Beogradu). Na postavljena pitanja odgovoreno je u 97,2 % slučajeva. Uočeni su brojni problemi vezani uz liječenje Gaucherove bolesti: npr. visoka cijena lijekova, nedostatak adekvatne procjene odnosa cijene i učinkovitosti terapije, nedovoljan broj ispitanika u kliničkim studijama i dr. Pilot anketa o rijetkim bolestima ukazuje na nedovoljnu informiranost stručne javnosti (21 %) i komplicirane procedure oko nabave lijekova (21 %). Većina ispitanika (64 %) ocijenila je da je nedovoljno upoznata s postojećom zakonskom regulativom o rijetkim bolestima. Oboljeli od rijetkih bolesti mogu se smatrati vulnerabilnim ispitanicima. Potrebno je formirati registar oboljelih, poboljšati informiranost stručne i šire javnosti i prilagoditi zakonsku regulativu kada su u pitanju rijetke bolesti

Oboljeli od rijetkih bolesti kao vulnerabilni ispitanici u kliničkim studijama

Farmakoterapija rijetkih bolesti suočena je s brojnim etičkim dilemama. Najveći broj oboljelih su djeca, oboljenja su progresivnog tijeka, a liječenje vrlo skupo. Cilj rada bio je ispitati u kojoj mjeri se poštuju principi suvremene bioetike, kada je u pitanju farmakoterapija rijetkih bolesti. Za primjer je uzeta Gaucherova bolest. Pretraživali smo dostupne baze podataka (Cochrane database, MEDLINE i Google) za period od 1996. do 2011. Ključne riječi bile su: Gaucherova bolest, etika/etička pitanja i klinička ispitivanja, a posebno su analizirani učinkovitost, sigurnost i cijena lijekova za ovu bolest. Provedena je i pilot anketa o stavovima liječnika i kliničkih farmaceuta o farmakoterapiji rijetkih bolesti u Srbiji na odabranom uzorku ispitanika (N = 11, Klinika za internu medicinu i Centralna apoteka, KBC „Bežanijska Kosa“ u Beogradu). Na postavljena pitanja odgovoreno je u 97,2 % slučajeva. Uočeni su brojni problemi vezani uz liječenje Gaucherove bolesti: npr. visoka cijena lijekova, nedostatak adekvatne procjene odnosa cijene i učinkovitosti terapije, nedovoljan broj ispitanika u kliničkim studijama i dr. Pilot anketa o rijetkim bolestima ukazuje na nedovoljnu informiranost stručne javnosti (21 %) i komplicirane procedure oko nabave lijekova (21 %). Većina ispitanika (64 %) ocijenila je da je nedovoljno upoznata s postojećom zakonskom regulativom o rijetkim bolestima. Oboljeli od rijetkih bolesti mogu se smatrati vulnerabilnim ispitanicima. Potrebno je formirati registar oboljelih, poboljšati informiranost stručne i šire javnosti i prilagoditi zakonsku regulativu kada su u pitanju rijetke bolesti

Pharmacotherapy of Rare Diseases in Serbia: The Current State of Art

Rare diseases affect less than 1 in 2000 or 5 in 10,000 people by definition. Most of those diseases have genetic basis (80% of cases) and first symptoms appear in early childhood (50% of cases). Most of these diseases are chronic and degenerative and pharmacotherapy is not available for many of them. Until today, there are more than 7000 rare diseases. In Serbia, the problem of diagnosis and pharmacotherapy of rare diseases is currently under public scrutiny. Patients who suffer from rare diseases in Serbia face many challenges in terms of awareness, timely diagnosis, and adequate treatment. These people are often misdiagnosed or the diagnosis is delayed due to several problems: lack of awareness among medical professionals, lack of expertise, unavailability and/or high costs of diagnostic tests, etc. According to the National Organization of Patients with Rare Diseases in Serbia (NORBS), many diagnostic procedures have to be conducted abroad and the process comprises many difficulties: high costs, travel expenses, or transportation of biological material. Although national legislation ensures the availability of drugs for those diseases, pharmacotherapy is faced with many problems. In this work, we aim to show that improvement of the knowledge regarding rare diseases among both professionals and patients represents a crucial step for enhancement of perspectives for those patients in our community

Protective Effects of Fruit Wines against Hydrogen Peroxide—Induced Oxidative Stress in Rat Synaptosomes

This study aimed to evaluate, in vitro, the antioxidative potential of fruit wines produced from berry fruits (i.e., black chokeberry, blueberry, blackberry, and raspberry), cherry, and apple by different technological processes. For this purpose, the activities of antioxidant enzymes (catalase, glutathione peroxidase (GPx), and superoxide dismutase (SOD)) and malondialdehyde (MDA) content as a marker of membrane damage were determined in wine-treated synaptosomes with hydrogen peroxide-induced oxidative stress. All studied wines induced increased antioxidant enzyme activities and decreased MDA levels compared to hydrogen peroxide-treated synaptosomes (i.e., control). The highest SOD activity was observed in synaptosomes treated with blackberry wine (6.81 U/mg), whereas blueberry wine induced the highest catalase and glutathione peroxidase activities (0.058 U/mg and 0.017 U/mg, respectively). Black chokeberry proved to be the best in lipid peroxidation protection with the lowest MDA value (1.42 nmol/mg). Finally, principal component analysis and hierarchical cluster analysis additionally highlighted a higher antioxidant capacity of wines produced from dark-skinned fruits (i.e., blackberry, black chokeberry, and blueberry). The results suggest protective effects of the fruit wines against oxidative damage, and, accordingly, their promising application as functional food

Kidney Injury Molecule-1 and Cardiovascular Diseases: From Basic Science to Clinical Practice

Despite the recent findings concerning pathogenesis and novel therapeutic strategies, cardiovascular disease (CVD) still stays the leading cause of morbidity and mortality in patients with renal dysfunction, especially acute kidney injury (AKI). Early detection of patients with impaired renal function with cardiovascular risk may help ensure more aggressive treatment and improve clinical outcome. Kidney injury molecule-1 (KIM-1) is a new, promising marker of kidney damage which is currently the focus of countless studies worldwide. Some recent animal and human studies established KIM-1 as an important marker of acute tubular necrosis (ATN) and reliable predictor of development and prognosis of AKI. Food and Drug Administration (FDA) in USA acclaimed KIM-1 as an AKI biomarker for preclinical drug development. Recent data suggest the importance of monitoring of KIM-1 for early diagnosis and clinical course not only in patients with various forms of AKI and other renal diseases but also in patients with cardiorenal syndrome, heart failure, cardiopulmonary bypass, cardiothoracic surgical interventions in the pediatric emergency setting, and so forth. The aim of this review article is to summarize the literature data concerning KIM-1 as a potential novel marker in the early diagnosis and prediction of clinical outcome of certain cardiovascular diseases

The Efficacy and Safety of Antipsychotic Medications in the Treatment of Psychosis in Patients with Parkinson’s Disease

Psychotic symptoms are present in up to 50% of patients with Parkinson’s disease. These symptoms have detrimental effects on patients’ and caregivers’ quality of life and may predict mortality. The pathogenesis of psychotic symptoms in Parkinson’s disease is complex, but the use of dopaminergic medications is one of the risk factors. The treatment of psychotic symptoms in Parkinson’s disease is complicated due to the ability of antipsychotic medications to worsen motor symptoms. The efficacy of clozapine in the treatment of psychosis in patients with Parkinson’s disease has been confirmed in several clinical trials; however, the adverse effects and the necessity of blood count monitoring are the reasons why the use of this drug is challenging. The studies on safety and efficacy of other antipsychotics conflicting results. The use of antipsychotics in these patients is also associated with increased mortality. Psychotic symptoms in Parkinson’s disease per se are also proven predictors of mortality. Thus it is necessary to treat psychotic symptoms but the choice of an antipsychotic should be based on careful risk/benefit assessment. Pimavanserin as a novel therapeutic option with more favorable adverse effects profile is now available for this indication, but careful postmarketing monitoring is necessary to establish the true picture of this drug’s long-term safety and efficacy

Uticaj klimatskih promena na patogene ratarsko povrtarskih biljaka - mere adaptacije i suzbijanje

The risk of disease and pest damages to agricultural crops has increased significantly as a result of climatic changes. Climate change could have positive, negative or no impact on field and vegetable crops diseases. However, it can be foreseen that in some regions, under very strong temperature-precipitation change 'signal', losses induced by increased infection potential of present and/or new diseases could be significant. The paper includes analysis of the severity of diseases caused by parasitic fungi in small grains, sunflower, sugar beet, potato and tomato. Climatic changes have resulted in the dominance of pathogens that require higher temperatures for their development or are better able to adapt to drought conditions. This is the reason why small grains fungal diseases of the genus Fusarium and Septoria spp. have dominant role, causing significant damage. Because the causal agents of sunflower spots develop very well and rapidly at high temperatures, global warming has caused these diseases to become more severe in Serbia and the damages they cause have increased. Furthermore, today, due to increased temperatures, the successful control of the Cercospora leaf spot requires twice as many chemical treatments as in the previous period. Until recently, one to two treatments (1.5 on average) during the growing season were needed in order to control C. beticola, whereas today two to four treatments are required. The early blight of tomato and potato has in recent years become a major disease and has been causing significant damages in these two crops. The increasing severity is attributed to the increase in temperature and the greater frequency of years having warm and dry summers.U radu su razmotreni odnosi biljke i patogena pod uticajem klimatskih promena. Analizirana je zastupljenost patogena na strnim žitima, suncokretu, šećernoj repi, krompiru i paradajzu i dati su temperaturni okviri za njihovu pojavu u jačem intenzitetu. Na osnovu toga predložene su mere adaptacije i suzbijanja. Sistem predviđanja i izveštavanja o pojavi patogena na određenom području imaće veoma važnu ulogu u savremenim sistemima proizvodnje i racionalne primene mera suzbijanja

Biomarkers of Uremic Cardiotoxicity

Cardiovascular (CV) morbidity and mortality increase along with the progression of chronic kidney disease (CKD). The potential novel biomarkers of cardiotoxicity have been tested with the aim of the early detection of patients at high CV risk, and among them are markers of inflammation, oxidative stress, acute renal injury, and microRNAs. The study analyzed biomarkers in non-dialysis-dependent (NDD; stage 3a-4 CKD) and dialysis-dependent (DD) CKD patients. The prospective cohort study included 87 patients who were followed for 18 months, during which period newly occurred CV events were recorded. Cox regression analysis confirmed serum albumin, urea, interventricular septum thickness diameter (IVST), the use of calcium antagonist, and erythropoiesis-stimulating agent to be significant predictors of CV outcome. No significant difference was observed in biomarkers of inflammation, oxidative stress, acute kidney injury (IL-18, CRP, ferritin, IMA, SOD, NGAL, and KIM-1), and miR-133a, in regards to the presence/absence of CV event, CV death, and left ventricular hypertrophy. Serum albumin, urea, IVST, and the use of calcium antagonist and erythropoiesis-stimulating agents were confirmed to be factors associated with CV events in CKD patients. Apart from traditional risk factors, new research is needed to define novel and reliable biomarkers of cardiotoxicity in CKD patients