Permeacija losartana kroz humani respiratorni epitel: In vitro ispitivanja na Calu-3 stanicama

The potential for nasal delivery of losartan, a drug with poor oral bioavailability, was investigated using Calu-3 cells. Epithelial permeation of the drug with or without dimethyl-β-cyclodextrin (DM--CD) and glycocholate was investigated. Possible transport mechanism of the compound and epithelial mucosal tolerance were screened. Reversibility of epithelial membrane perturbation was also investigated by measuring transepithelial electrical resistance (TEER) recovery over a 24-h period following drug formulation exposure. The permeability coefficient of losartan was 1.3 ± 0.5 × 10-6 cm s-1. This flux was not significantly different from that of formulations containing DM--CD (0.5 and 1.0 %) or glycocholate (0.5 %). However, the formulation with 1.0 % glycocholate significantly increased losartan permeation 7-fold. Losartan flux across the cells was concentration-dependent. Serosal to mucosal permeation was significantly higher than mucosal to serosal permeation. Concentration-dependency, as well as polarity in transport indicated that the flux of the compound across Calu-3 cells was not limited to passive diffusion. Cells exposed to DM--CD (0.5 and 1.0 %) and glycocholate (0.5 %) caused no significant change in TEER and mitochondrial dehydrogenase activity (MDH). The results of the study showed that losartan may be a suitable drug candidate for nasal delivery.U radu je ispitivana mogućnost nazalne primjene losartana, lijeka sa slabom bioraspoloživošću nakon peroralne uporabe, koristeći Calu-3 stanice. Ispitivana je permeacija lijeka kroz epitel u prisutnosti dimetil-β-ciklodekstrina (DM--CD) i glikokolata te bez njihove prisutnosti. Predložen je mogući mehanizam transporta kroz epitel i određena je tolerancija epitelne mukoze. Reverzibilnost promjena u epitelu praćena je mjerenjem povrata transepitelnog električnog otpora (TEER) kroz razdoblje od 24 h nakon izlaganju pripravku lijeka. Koeficijent permeabilnosti losartana bio je 1.3 ± 0.46 × 106 cm s1. Taj se dotok značajno ne razlikuje od pripravaka koji sadrže DM--CD (0,5 i 1,0 %), odnosno glikokolat (0,5 %) (faktor povećanja 1,0). Međutim, iz pripravka s 1,0 % glikokolata povećala se permeacija losartana 7 puta. Protok losartana kroz stanice ovisio je o koncentraciji. Permeacija iz seruma u mukozu bila je značajno veća nego u obrnutom smjeru. Ovisnost o koncentraciji te polarnost u transportu ukazuju na to da protok losartana kroz Calu-3 stanice nije ograničen samo na pasivnu difuziju. Stanice izložene dimetil-β-ciklodekstrinu (0,5 i 1,0 %) i glikokolatu (0,5 %) nisu uzrokovale značajne promjene TEER-a i aktivnosti mitohondrijske dehidrogenaze (MDH). Rezultati pokazuju da je losartan pogodan za nazalnu isporuku

Metabolomics and Biomarkers for Drug Discovery

Metabolomics and biomarkers are increasingly used in drug discovery and development, and are applied to personalized medicine. Progress in these research areas has increased our understanding of disease pathology and improved therapeutic strategies for many diseases with unmet challenges. Further advances will ultimately result in the development of better drugs and breakthrough therapies, which will benefit millions of patients suffering from chronic and life-threatening diseases worldwide

Adenosine 5′-Triphosphate Metabolism in Red Blood Cells as a Potential Biomarker for Post-Exercise Hypotension and a Drug Target for Cardiovascular Protection

The importance of adenosine and ATP in regulating many biological functions has long been recognized, especially for their effects on the cardiovascular system, which may be used for management of hypertension and cardiometabolic diseases. In response to ischemia and cardiovascular injury, ATP is broken down to release adenosine. The effect of adenosine is very short lived because it is rapidly taken up by erythrocytes (RBCs), myocardial and endothelial cells, and also rapidly catabolized to oxypurine metabolites. Intracellular adenosine is phosphorylated back to adenine nucleotides via a salvage pathway. Extracellular and intracellular ATP is broken down rapidly to ADP and AMP, and finally to adenosine by 5′-nucleotidase. These metabolic events are known to occur in the myocardium, endothelium as well as in RBCs. Exercise has been shown to increase metabolism of ATP in RBCs, which may be an important mechanism for post-exercise hypotension and cardiovascular protection. The post-exercise effect was greater in hypertensive than in normotensive rats. The review summarizes current evidence in support of ATP metabolism in the RBC as a potential surrogate biomarker for cardiovascular protection and toxicities. It also discusses the opportunities, challenges, and obstacles of exploiting ATP metabolism in RBCs as a target for drug development and precision medicine

Metabolomic biomarkers in mental disorders : bipolar disorder and schizophrenia

Psychiatric disorders are some of the most impairing human diseases. Among them, bipolar disorder and schizophrenia are the most common. Both have complicated diagnostics due to their phenotypic, biological, and genetic heterogeneity, unknown etiology, and the underlying biological pathways, and molecular mechanisms are still not completely understood. Given the multifactorial complexity of these disorders, identification and implementation of metabolic biomarkers would assist in their early detection and diagnosis and facilitate disease monitoring and treatment responses. To date, numerous studies have utilized metabolomics to better understand psychiatric disorders, and findings from these studies have begun to converge. In this chapter, we briefly describe some of the metabolomic biomarkers found in these two disorders111827129