IN SILICO EVALUATION OF ANGIOTENSIN II RECEPTOR ANTAGONIST’S PLASMA PROTEIN BINDING USING COMPUTED MOLECULAR DESCRIPTORS

The discovery of new pharmacologically active substances and drugs modeling led to necessity of predicting drugs properties and its ADME data. Angiotensin II receptor antagonists are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system and today represent the most commonly prescribed anti-hypertensive drugs. The aim of this study was to compare different molecular properties of seven angiotensin II receptor antagonists / blockers (ARBs), (eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan) and their plasma protein binding (PPB) data. Several ARBs molecular descriptors were calculated using software package Molinspiration Depiction Software as well as Virtual Computational Chemistry Laboratory (electronic descriptor – PSA, constitutional parameter – Mw, geometric descriptor – Vol, lipophilicity descriptors - logP values, aqueous solubility data – logS). The correlations between all collected descriptors and plasma protein binding data obtained from relevant literature were established. In the simple linear regression poor correlations were obtained in relationships between PPB data and all calculated molecular descriptors. In the next stage of the study multiple linear regression (MLR) was used for correlation of PPB data with two different descriptors as independent variables. The best correlation (R2=0.70 with P<0.05) was established between PPB data and molecular weight with addition of volume values as independent variables. The possible application of computed molecular descriptors in drugs protein binding evaluation can be of great importance in drug research

CORRELATION BETWEEN ANGIOTENSIN-CONVERTING ENZYME INHIBITORS LIPOPHILICITY AND PROTEIN BINDING DATA

Angiotensin-converting enzyme (ACE) inhibitors represent a significant group of drugs primarily used in the treatment of hypertension and congestive heart failure. In this research, seven ACE inhibitors (enalapril, quinapril, fosinopril, lisinopril, cilazapril, ramipril, benazepril) were studied to evaluate the relationship between their protein binding and calculated (logP values) or ultra-high performance liquid chromatographytandem mass spectrometry (UHPLC-MS) and reversed-phase thin-layer chromatography (RP-TLC) lipophilicity data (ϕ0, CHI or C0 parameters, respectively). Their protein binding data varied from negligible (lisinopril) to 99% (fosinopril), while calculated logPKOWWINvalues ranged from -0.94 (lisinopril) to 6.61 (fosinopril). The good correlations were established between protein binding values and logPKOWWIN data (R2=0.7520) as well as between protein binding and chromatographic hydrophobicity data, ϕ0, CHI or C0parameters (R2 were 0.6160, 0.6242 and 0.6547, respectively). The possible application of hydrophobicity data in drugs protein binding evaluation can be of great importance in drug bioavailability

Hromatografske metode u proučavanju lipofilnosti biološki aktivnih supstanci

This paper presents the review of the methods used in research of the biological active substances hydrophobicity, a very important property. The biological activity of some substances depends on their pharmacokinetics and pharmacodynamics. These processes depend on the molecule's capability to interact with two different media: aqueous (cells interior) and non-aqueous (cells membrane), or on the molecule lipophilicity. Today, great attention is given to investigation and systematic determination of drugs lipophilicity. In these researches chromatography methods have an important role.U ovom radu dat je pregled metoda koje nalaze primenu u proučavanju hidrofobnosti biološki aktivnih supstanci, što je njihova veoma značajna osobina. Biološka aktivnost neke supstance uslovljena je procesima njene farmakokinetike i farmakodinamike, koji zavise od sposobnosti molekula da interaguje sa dve različite sredine: nevodenom (ćelijska membrana) i vodenom (unutrašnjost ćelije), odnosno od njegove lipofilnosti. Danas se velika pažnja pridaje proučavanju i sistematskom određivanju lipofilnosti lekovitih supstanci. U ovim ispitivanjima hromatografske metode zauzimaju značajno mesto

Zavisnost lipofilnosti i vezivanja za proteine plazme inhibitora angiotenzin konvertujućeg enzima

Angiotensin-converting enzyme (ACE) inhibitors represent a significant group of drugs primarily used in the treatment of hypertension and congestive heart failure. In this research, seven ACE inhibitors (enalapril, quinapril, fosinopril, lisinopril, cilazapril, ramipril, benazepril) were studied to evaluate the relationship between their protein binding and calculated (logP values) or ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS) and reversed-phase thin-layer chromatography (RP-TLC) lipophilicity data (φ0, CHI or C0 parameters, respectively). Their protein binding data varied from negligible (lisinopril) to 99% (fosinopril), while calculated logPKOWWIN values ranged from -0.94 (lisinopril) to 6.61 (fosinopril). The good correlations were established between protein binding values and logPKOWWIN data (R2=0.7520) as well as between protein binding and chromatographic hydrophobicity data, φ0, CHI or C0 parameters (R2 were 0.6160, 0.6242 and 0.6547, respectively). The possible application of hydrophobicity data in drugs protein binding evaluation can be of great importance in drug bioavailability.Inhibitori angiotenzin konvertujućeg enzima (ACE inhibitori) predstavljaju veliku grupu lekova koji nalaze primenu u lečenju hipertenzije. U ovom radu analizirano je sedam ACE inhibitora (enalapril, kvinapril, fosinopril, lizinopril, cilazapril, ramipril i benazepril) kako bi se ispitala zavisnost između njihovog vezivanja za proteine plazme i lipofilnosti. Korelisane su vrednosti izračunatih (logPKOWWIN) ili hromatografski (UHPLC-MS i RP-TLC) dobijenih (φ0, CHI ili C0) hidrofobnih parametara. Procenat vezivanja za proteine plazme ispitivanih ACE inhibitora kretao se u opsegu od 0% do 99%, dok su vrednosti izračunatih logPKOWWIN vrednosti iznosile od -0.94 do 6.61. Dobijene su zadovoljavajuće korelacije između vrednosti vezivanja ACE inhibitora za proteine plazme i izračunatih logPKOWWIN vrednosti (R2=0,7520) kao i hromatografski dobijenih parametara hidrofobnosti, φ0, CHI, C0 (R2: 0,6160; 0,6242; 0,6547). PR Projekat Ministarstva nauke Republike Srbije, br. TR 34031

Eliminacija inhibitora angiotenzin konvertujućeg enzima putem peritoneumskog dijalizata

Angiotensin-converting enzyme (ACE) inhibitors are a significant group of drugs that are primarily used in the treatment of hypertension and congestive heart failure. Even though they belong to the same group of drugs and have similar efficacy, ACE inhibitors exhibit different pharmacological characteristics. The lipophilicity is one of the most important properties of biologically active substances. It influences their absorption, distribution, tissue penetration, action, elimination. In this paper, the elimination of ACE inhibitors by peritoneal dialisate in patients on peritoneal dialysis was investigated. The influence of ACE inhibitors' hydrophibicity in this way of elimination was discussed.Inhibitori angiotenzin-konvertujućeg enzima (ACE inhibitori) najčešće su propisivani antihipertenzivni lekovi. Iako pripadaju istoj grupi lekova i pokazuju sličnu kliničku efikasnost, pojedini ACE inhibitori imaju različite farmakološke osobine, što može biti posledica njihovih različitih hemijskih karakteristika. Jedna od najznačajnijih osobina biološki aktivnih supstanci je njihova lipofilnost. Ona utiče na njihovu apsorpciju, raspodelu u tkiva, aktivnost, eliminaciju. U ovom radu proučavana je eliminacija ACE inhibitora fosinoprila i cilazaprila dijalizatom kod bolesnika na peritoneumskoj dijalizi i uticaj lipofilnosti na ovaj put njihove eliminacije.

Normal-phase thin-layer chromatography of some angiotensin converting enzyme (ACE) inhibitors and their metabolites

The separation and chromatographic behaviour of five ACE (angiotensin converting enzyme) inhibitors and their four active metabolites were investigated by normal-phase thin-layer chromatography on silica using several mono- and binary non-aqueous solvent systems. The linear relationship between the RM values and the composition of employed mobile phase was obtained. The hydrophobicity parameters RM0 and C0 were determined from the regression data of the plots, analogous to reversed-phase chromatography. The chromatographically obtained hydrophobicity parameters were correlated with the calculated log P values. The current results were correlated with the lipophilicity of the studied ACE inhibitors and their metabolites, previously estimated by reversed-phase chromatography

Hromatografske metode - visoko-efikasna tečna i tankoslojna hromatografija

Chromatographic methods represent the most frequently used methods in both qualitative and quantitative studies of various samples. High performance and thin layer chromatography have important place among these methods. They are widely applied in many scientific and technological researches. The choice of specific chromatographic method depends on the type of research, and sometimes two or more methods are combined. The main features, advantages and disadvantages of the two most widely used chromatographic methods has been discussed in this short presentation.Hromatografske metode se danas često primenjuju kako u kvalitativnim tako i u kvantitativnim ispitivanjima različitih uzoraka. Među njima značajno mesto zauzimaju visoko-efikasna tečna i tankoslojna hromatografija koje se često takmiče u mogućnostima svoje primene. Izbor hromatografske metode u raznim oblastima nauke i tehnologije (medicina, farmaceutska industrija, industrija hrane, kozmetologija, ekologija) najviše zavisi od problema koji treba rešiti, pri čemu često jedna metoda nije dovoljna već je potrebno kombinovati različite hromatografske tehnike

Inhibitori angiotenzin - konvertujućeg enzima - osnovne farmakološke osobine i metode određivanja

Angiotensin-converting enzyme inhibitors (ACE inhibitors) lower blood pressure, reduce morbidity and mortality in patients with heart failure, decrease mortality and the incidence of heart failure in patients with myocardial infarction and preserve kidney function in diabetic and non-diabetic patients. Even though they belong to the same group of drugs and have similar efficacy, ACE inhibitors exhibit different pharmacological characteristics. Furthermore, different methods for their determination are used in practice.Inhibitori angiotenzin - konvertujućeg enzima (ACE inhibitori) su lekovi izbora u lečenju hipertenzije, što ih svrstava među najčešće propisivane lekove u praksi. Primenjuju se i u lečenju srčane insuficijencije, infarkta miokarda i bubrežne slabosti dijabetesne i nedijabetesne etiologije. Iako pripadaju istoj grupi lekova i pokazuju sličnu kliničku efikasnost, pojedini ACE inhibitori imaju različite farmakološke osobine, a u praksi se koriste različite metode za njihovo određivanje

Procena stepena vezivanja inhibitora angiotenzin-konvertujućeg enzima za proteine plazme primenom hromatografski dobijenih parametara hidrofobnosti

Introduction Angiotensin-converting enzyme (ACE) inhibitors represent a significant group of drugs primarily used in the treatment of hypertension and congestive heart failure. Objective Selected ACE inhibitors (enalapril, quinapril, fosinopril, lisinopril, cilazapril) were studied in order to establish a fast and easy estimation method of their plasma protein binding degree based on their lipophilicity data. Methods Chromatographic hydrophobicity data (parameter C0) were obtained on cellulose layers under conditions of normal-phase thin-layer chromatography (NPTLC), using different binary solvent systems. The ACE inhibitors lipophilicity descriptors (logP) values were calculated using the software package Virtual Computational Chemistry Laboratory. The ACE inhibitors plasma protein binding data were collected from relevant literature. Results ACE inhibitors protein binding data varied from negligible (lisinopril) to 99% (fosinopril). The calculated lipophilicity descriptors, logPKOWWIN values ranged from -0.94 (lisinopril) to 6.61 (fosinopril). Good correlations were established between plasma protein binding values and calculated logPKOWWIN values (R2=0.8026) as well as chromatographic hydrophobicity data, C0 parameters (R2=0.7662). Even though good correlation coefficients (R2) were obtained in both relations, unacceptable probability value with p>0.05 was found in relation between protein binding data and calculated logPKOWWIN values. Subsequently, taking into consideration the request for probability value lower than 0.05, a better relationship was observed between protein binding data and chromatographically obtained hydrophobicity parameters C0 values. Conclusion Cellulose layers are easily available and cost effective sorbent to assess hydrophobicity. Experimentally obtained data on ACE inhibitors hydrophobicity and plasma protein binding estimation are important parameters in evaluating bioavailability of these drugs.Uvod Inhibitori angiotenzin-konvertujućeg enzima (ACE) su velika grupa lekova izuzetno značajna u lečenju hipertenzije. Cilj rada Analizirani su izabrani ASE-inhibitori (enalapril, kvinapril, fozinopril, lizinopril, cilazapril) radi postavljanja novog pristupa pogodnog za brzu i jednostavnu procenu vezivanja za proteine plazme na osnovu njihovih parametara lipofilnosti. Metode rada Hromatografski parametri hidrofobnosti (vrednosti C0) dobijeni su u uslovima normalnofazne hromatografije (NPTLC) na tankom sloju celuloze, uz korišćenje dvokomponentnih mobilnih faza. Vrednosti parametara lipofilnosti ACE-inhibitora (logP) izračunate su pomoću softverskog paketa Virtual Computational Chemistry Laboratory. Podaci o procentu vezivanja ACE-inhibitora za proteine plazme preuzeti su iz odgovarajuće literature. Rezultati Procenat vezivanja za proteine plazme ispitivanih ASE-inhibitora bio je u opsegu od 0% (lizinopril) do 99% (fozinopril), dok su vrednosti izračunatih parametara lipofilnosti (vrednosti logP KOWWIN) bile od -0,94 (lizinopril) do 6,61 (fozinopril). Dobijene su zadovoljavajuće korelacije između vrednosti vezivanja ASE- inhibitora za proteine plazme i izračunatih logP KOWWIN vrednosti (koeficijent korelacije R2 bio je 0,8026), kao i hromatografski dobijenih parametara hidrofobnosti, C0 (R2=0,7662). Iako su zadovoljavajući koeficijenti korelacije dobijeni u obe relacije, neprihvatljive vrednosti verovatnoće (p>0,05) dobijene su za zavisnost između vrednosti vezivanja ASE-inhibitora za proteine plazme i izračunatih logP KOWWIN vrednosti. Stoga se, uzimajući u obzir zahtev da vrednosti verovatnoće budu niže od 0,05, boljom može smatrati zavisnost između vrednosti vezivanja ASE-inhibitora za proteine plazme i hromatografski dobijenih parametara hidrofobnosti. Zaključak Primena hidrofobnih parametara ASE-inhibitora eksperimentalno dobijenih u uslovima normalnofazne hromatografije na tankom sloju celuloze za procenu stepena njihovog vezivanja za proteine plazme značajna je za razvoj i ispitivanje lekova ove grupe i procenu njihove bioraspoloživosti

Kvalitet života starih u urbanoj i ruralnoj sredini u Srbiji

Background/Aim. The number of elderly people in the world is growing, in Serbia as well. Serbia is already among the top ten countries with the oldest population, it is the fact. Aging influences the quality of life in different ways. The aim of this study was to assess the health-related quality of life of the elderly in urban and rural areas in Serbia. Methods. The study included 100 elderly people aged 65 years and above in urban and rural areas in Serbia. The next questionnaires were used: a sociodemographic questionnaire and a Serbian version of standardized European Euro-QoL questionnaire (EQ-5D-3L), as a basic index for the assessment and description of the quality of life. Results. In the structure of the respondents, according to the achieved social contacts (p = 0.012), the life of those with family members (p = 0.009), and health status (p = 0.000), in relation to the place of residence there was a statistically significant difference. There was a significant difference (p = 0.040), predominantly poor score for anxiety/depression within the rural population. The average value of quality of life in urban and rural areas was not statistically significant (p = 0.720). For those living in rural areas there was a statistically significant positive correlation between anxiety/depression and age, wealth status, marital status, living with family members and achieving social contacts, while a negative correlation was observed between anxiety/depression and education. Conclusion. On the basis of the data of our study, we can say that the presence of anxiety/depression among older people is greater in rural than in urban areas. The results of this study show that the perception of anxiety/depression among older in rural areas is bigger with the age and poverty increasing, the loss of a spouse, life without family members, lack of achievement of social contacts and lower education.Uvod/Cilj. Broj starih osoba u svetu i Srbiji raste, a činjenica je i da se Srbija već nalazi među deset zemalja sveta sa najstarijim stanovništvom. Proces starenja na različite načine utiče na kvalitet života. Cilj rada bio je da se proceni kvalitet života u vezi sa zdravljem starih u urbanoj i ruralnoj sredini u Srbiji. Metode. Istraživanje je obuhvatilo 100 starih osoba od 65 godina i više, u urbanoj i ruralnoj sredini. Korišćeni upitnici bili su sociodemografski upitnik i srpska verzija standardizovanog evropskog upitnika Euro- QoL (EQ-5D-3L), kao bazični indeks za procenu i opis kvaliteta života. Rezultati. U strukturi ispitanika prema ostvarivanju socijalnih kontakata (p = 0,012), životu ispitanika sa članovima porodice (p = 0,009) i zdravstvenom stanju (p = 0,000), u odnosu na mesto stanovanja, utvrđena je statistički značajna razlika. Nađena je značajna razlika (p = 0,040), sa dominacijom loših ocena, za usamljenost unutar ruralne populacije. Kod ispitanika koji žive u ruralnoj sredini utvrđena je statistički značajna pozitivna povezanost između usamljenosti i godina života, materijalnog stanja, bračnog statusa, života sa članovima domaćinstva i ostvarivanja socijalnih kontakata, dok je negativna povezanost uočena između usamljenosti i obrazovanja. Zaključak. Na osnovu podataka ove studije možemo reći da su usamljenije stare osobe u ruralnoj sredini. Rezultati ovog istraživanja pokazuju da se percepcija anksioznosti/ depresije kod starih u ruralnoj sredini povećava porastom godina starosti i siromaštva, gubitkom bračnog druga, životom bez članova porodice, neostvarivanjem socijalnih kontakata i nižim stepenom obrazovanja