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Pharmacokinetic characterization of aloin and aloe emodin by biomimetic chromatography and in silico methods
No full textU složenom i skupom procesu kakav je razvoj novog lijeka, svako unaprjeđenje, pojednostavljenje ili ubrzanje postupka mnogo vrijedi. Većina molekula kandidata odbacuje se već u ranim fazama razvoja zbog nepovoljnih farmakokinetičkih karakteristika koje su usko vezane uz fizikalno-kemijska svojstva spoja – lipofilnost, topljivost u vodi, afinitet vezanja za proteine, afinitet za biomembrane i sl. Stoga su metode kojima se takva svojstva određuju od posebnog značaja. Među njima su QSAR i QSPR računalne metode kojima se pomoću računalnih algoritama predviđaju različita svojstva molekule, kao i metode biomimetičke kromatografije kojima se in vitro ispituju takva svojstva. Ovaj rad obuhvaća farmakokinetičku karakterizaciju dviju biološki aktivnih tvari koje se koriste u terapiji upalnih bolesti crijeva – aloin i aloe emodin. Karakterizirani su prvo nizom QSPR metoda koje izračunavaju njihovu lipofilnost, topljivost, humanu crijevnu apsorpciju, oralnu bioraspoloživost te postotak vezanja za proteine plazme, a potom obrnuto-faznom tankoslojnom kromatografijom i obrnuto-faznom tekućinskom kromatografijom visoke djelotvornosti koje pokazuju hidrofobnost analita, tekućinskom kromatografijom visoke djelotvornosti sa stacionarnom fazom koja sadrži imobilizirane umjetne membrane koja pokazuje lipofilnost, zatim sa stacionarnom fazom koja sadrži imobilizirani humani serumski albumin i konačno onom koja sadrži imobilizirani α1-kiseli glikoprotein kojima se dobiva afinitet vezanja analita za HSA i AGP. U konačnici pokazano je kako je aloe emodin hidrofobniji od aloina, manje je topljiv u vodi, ima veću apsorpciju u crijevu kao i oralnu bioraspoloživost te se s većim afinitetom veže za proteine plazme u odnosu na aloin. Pritom su odstupanja među različitim QSPR izračunima vrlo velika i ostaje najpouzdanije farmakokinetička svojstva ispitivati in vitro metodama.In a complex and expensive process such as the development of a new drug, any improvement, simplification or acceleration of the process is worth a lot. Most of the candidate molecules are rejected already in the early stages of development due to unfavorable pharmacokinetic characteristics that are closely related to the physicochemical properties of the compound – lipophilicity, water solubility, binding affinity for proteins, affinity for biomembranes, etc. Therefore, methods used to determine such properties are of special importance. Among them are QSAR and QSPR computer methods that use computer algorithms to predict various properties of a molecule, as well as biomimetic chromatography methods that test such properties in vitro. This paper includes the pharmacokinetic characterization of two biologically active substances used in therapy of inflammatory bowel diseases - aloin and aloe emodin. They are characterized first by a series of QSPR methods that calculate their lipophilicity, solubility, human intestinal absorption, oral bioavailability and the percentage of binding to plasma proteins, and then by reversed-phase thin-layer chromatography and reversed-phase high-performance liquid chromatography that show the hydrophobicity of the analyte, high-performance liquid chromatography with a stationary phase containing immobilized artificial membranes showing lipophilicity, then with a stationary phase containing immobilized human serum albumin and finally one containing immobilized α1-acid glycoprotein to obtain the analyte binding affinity for HSA and AGP. In the end, it was shown that aloe emodin is more hydrophobic than aloin, is less soluble in water, has greater absorption in the intestine as well as oral bioavailability, and binds with greater affinity to plasma proteins compared to aloin. At the same time, deviations between different QSPR calculations are very big, and the most reliable pharmacokinetic properties remain to be investigated by in vitro methods
Validation of an HPLC-MS/MS method for the determination of abemaciclib and letrozole in plasma with phospholipid removal method used in sample preparation
No full textZbog povećanog razvoja rezistencije na ET, ista se često kombinira s inhibitorima CDK4/6 kinaze u liječenju HR-pozitivnog / HER2-negativnog karcinoma dojke. Jedna od takvih kombinacija je kombinacija ABE i LET. Iako je ABE lijek ciljanog djelovanja, postoje velike inter- i intraindividualne razlike u njegovom učinku i toksičnosti zbog čega ga je potrebno terapijski pratiti.
Cilj ovog rada jest validirati bioanalitičku metodu za određivanje ABE i LET u plazmi pacijenata. Ispitani validacijski parametri jesu: selektivnost, linearnost, točnost, preciznost, ekstrakcijski prinos i utjecaj matrice.
Uzorak za analizu sačinjen je od plazme obogaćene standardima ABE i LET, a kao unutarnji standardi korišteni su d4-PAL i d12-ANA. Proteini iz uzorka istaloženi su acetonitrilom te je provedena filtracija na Agilent Captiva EMR-Lipid kolonici za uklanjanje fosfolipida. Nakon filtracije sorbens je ispran otopinom amonijaka u metanolu kako ne bi došlo do gubitka lipofilnijih analita. Filtrat je uparen i suhi ostatak otopljen u 65%-tnom metanolu. Kromatografska analiza provedena je na Agilent 1260 sustavu, na Kinetex biphenyl koloni (150×4,6 mm, 2,6 μm). Mobilna faza sastojala se od faze A (voda i 0,1 %-tna mravlja kiselina) i faze B (acetonitril i 0,1 %-tna mravlja kiselina) uz brzinu protoka 0,5 mL/min. Za detekciju je korišten Ultivo Triple Quadrupole spektrometar masa.
Selektivnost metode potvrđena je usporedbom kromatograma slijepe probe i standarda analita pri LLOQ. Na kromatogramu slijepe probe uočen je neznatan signal (0,56% odgovora analita na LLOQ) na tr LET do kojeg dolazi zbog carry-over-a analita iz prethodećeg uzorka.Metoda je linearna u rasponu od 50 – 500 ng/mL za ABE i 30 – 300 ng/mL za LET. RSD vrijednosti za LET iznosile su 1,66 – 2,7 %, a za ABE 2,79 – 4,81 %. Odstupanje od teorijske koncentracije jest -3,91 - 3,49 % za LET te 1,64 – 3,92% za ABE. ER LET iznosio je 96,58 – 102,52 %, a ABE 71,11 – 73,01 %. Svi su opisani rezultati unutar propisanih vrijednosti što je dokaz uspješne validacije. Relativni utjecaj matrice vrlo je sličan pri različitim koncentracijama LET (razlika < 2%) čime je potvrđeno da je d12-ANA dobar izbor unutarnjeg standarda. D4-PAL nije korigirao utjecaj matrice na ABE jer se značajno razlikuje pri dvije različite koncentracije ABE (94,04% pri 125 ng/mL, 24,11% pri 375 ng/mL). Primjenjivost metode dokazana je određivanjem koncentracije analita u plazmi pacijentica.Due to the increased resistance to ET, it is often combined with CDK4/6 kinase inhibitors in treating HR+/HER2- breast cancer. One such combination is ABE and LET. Despite ABE being a targeted therapy, there are significant inter- and intra-individual differences in its effectiveness and toxicity, necessitating therapeutic monitoring.
The aim of this study is to validate a bioanalytical method for determining ABE and LET in patient plasma. Validation parameters examined include selectivity, linearity, accuracy, precision, extraction yield, and matrix effect.
Samples were prepared from plasma enriched with ABE and LET standards, using d4-PAL and d12-ANA as internal standards. Proteins were precipitated with acetonitrile and filtered using an Agilent Captiva EMR-Lipid column. After filtration, the sorbent was washed with an ammonia solution in methanol to prevent loss of more lipophilic analytes. The filtrate was evaporated, and the residue dissolved in 65% methanol. Chromatographic analysis was performed on an Agilent 1260 system with a Kinetex biphenyl column (150×4,6 mm, 2.6 μm), using a mobile phase consisted of phase A (water and 0,1% formic acid) and phase B (acetonitrile and 0,1% formic acid) at a flow rate of 0,5 mL/min. Detection was done using an Ultivo Triple Quadrupole mass spectrometer.
Selectivity was confirmed by comparing blank sample chromatograms with analyte standards at LLOQ. On the chromatogram of the blank sample, an insignificant signal (0.56% of the analyte response at LLOQ) was observed at the tr due to the carry-over of the analyte from the previous sample.The method is linear between 50-500 ng/mL for ABE and 30-300 ng/mL for LET. RSD values for LET were 1,66-2,7% and for ABE 2,79-4,81%. Deviation from theoretical concentration was -3,91 to 3,49% for LET and 1,64 to 3,92% for ABE. Extraction recovery was 96,58-102,52% for LET and 71,11-73,01% for ABE. All validation results were within reference values, confirming successful validation. The relative matrix effect for LET was consistent (difference <2%), confirming d12-ANA as a suitable internal standard. However, d4-PAL did not adequately compensate for the matrix effect on ABE, as it varied greatly at two different concentrations of ABE (94,04% at 125 ng/mL, 24,11% at 375 ng/mL). Introducing a new internal standard for ABE is recommended. The method's applicability was demonstrated by determining analyte concentrations in patient plasma
Optimization of a micellar electrokinetic chromatography method coupled to a triple quadrupole mass spectrometer for the separation of six breast cancer drugs
No full textRak dojke najčešća je zloćudna bolest kod žena. Da bi ishodi liječenja bili dobri važno je terapijsko
praćenje lijeka u plazmi. Time se sprječavaju nepotrebne nuspojave nastale previsokim dozama, ali
i poddoziranost zbog koje bolest nije liječena na adekvatan način te može napredovati. Metoda
MEKC-MS koja se u ovom radu koristila moćna je tehnika koja do sada nije opisana za analizu ovih
analita.
Cilj ovog rada je optimizirati parametre kapilarne elektroforeze i postići zadovoljavajuću separaciju
analita. Lijekovi koji su se analizirali su letrozol i anastrozol (inhibitori aromataza), fulvestrant
(antagonist estrogenskih receptora) te ribociklib, palbociklib i abemaciklib (inhibitori CDK 4 i 6).
Parametri koji su promatrani su temperatura, napon, koncentracija APFO-a, pH pufera, udio
metanola u puferu i mogućnost upotrebe drugih organskih otapala koja bi zamijenila metanol.
Zaključeno je da je separacija analita najbolja pri temperaturi od 30 °C, naponu od 25 kV,
koncentraciji APFO-a od 125 mM i pH pufera 10,5. Niti jedno organsko otapalo nije pokazalo bolje
rezultate od metanola, a analiza je najbolja pri udjelu metanola od 32% u puferu. Daljnjim
istraživanjima optimizirat će se parametri masene spektrometrije kako bi se razvila kompletna
MEKC-MS metoda za analizu.Breast cancer is the most common cancer in women. In order for treatment outcomes to be good,
therapeutic monitoring of the drugs in plasma is important. This prevents unnecessary side effects
caused by excessive doses of drugs as well as underdosing which can lead to the progression of the
disease. MEKC-MS method used for this final thesis is a powerful technique that so far hasn’t been
described for this kind of analysis.
The aim of this thesis is to optimize the parameters of capillary electrophoresis for the separation of
analytes. The drugs that were analyzed were letrozole and anastrozole (inhibitors of aromatase),
fulvestrant (antagonist of estrogen receptors) and ribociclib, palbociclib and abemaciclib (inhibitors
of CDK 4 and 6). Parameters that were observed are temperature, voltage, concentration of APFO,
buffer pH, percentage of methanol in the buffer and the possibility of using other organic solvents
to replace methanol.
Best analyte separation was performed at a temperature of 30 °C, voltage of 25 kV, APFO
concentration of 125 mM and a buffer pH 10, 5. No organic solvent showed better results than
methanol. The analysis was best with a methanol percentage of 32 % in the buffer. Further research
will be aimed to optimize the parameters of mass spectrometry in order to develop a complete
MEKC-MS method for analysis
Application of total reflection X-ray fluorescence spectrometry for investigating the detoxification potential of zeolites
No full textDetoksifikacijska svojstva zeolita klinoptilolita potaknula su zanimanje za njegovu primjenu u
humanoj medicini. Popularnost zeolita, kao i broj proizvoda sa zeolitom na tržištu svakodnevno
raste. U ovoj studiji analizirani su uzorci urina kod zdravih dobrovoljaca prije i nakon konzumacije
zeolita u vremenskim intervalima od 0, 4, 8, 12 i 24 sata kako bi se ispitala njegova moć vezivanja
metalnih kationa te njegova sposobnost da se ti elementi i eliminiraju iz organizma. U tu svrhu,
korištena je analitička tehnika rendgenska fluorescencijska spektrometrija s totalnom refleksijom
(TXRF) koja se pokazala kao brza i pouzdana tehnika pomoću koje se mogu analizirati ne samo
metali, već i halogeni elementi kao što je brom. Dodatno, tehnika slijedi principe „zelene kemije“
pošto ne zahtjeva potrošnju pogonskih plinova te su potrebne male količine uzoraka i reagensa.
Elementi koji su detektirani i određivani su brom, rubidij, stroncij, mangan i cink. Svi su elementi
pokazali povećane koncentracije u ispitivanim uzorcima u odnosu na kontrolne uzorke što ukazuje
na sposobnost zeolita da adsorbira metale, ali i ostale elemente te povećava njihovu eliminaciju iz
organizma.The detoxification properties of zeolite clinoptilolite have sparked interest in its application in
human medicine. The popularity of zeolite, as well as the number of products containing zeolite in
the market, grows on a daily basis. In this study, urine samples from healthy volunteers were
analyzed before and after zeolite consumption at time intervals of 0, 4, 8, 12 and 24 hours in order
to investigate its metal cation binding capacity and its ability to eliminate these elements from the
organism. For this purpose, an analytical technique of X-ray fluorescence spectrometry with total
reflection (TXRF) was used, which proved to be a fast and reliable technique capable of analysing
not only metals but also halogen elements such as bromine. In addition, the technique follows the
principles of ‘green chemistry’ as it does not require the consumption of drive gases and only small
quantities of samples and reagents are needed. The elements detected and determined were bromine,
rubidium, strontium, manganese, and zinc. All elements showed increased concentrations in the test
samples compared to control samples, indicating the ability of zeolites to adsorb metals as well as
other elements and enhance their elimination from the organism
Analysis of Cu and Zn determination results in follicular fluid samples from women diagnosed with idiopathic infertility undergoing assisted reproductive treatment
No full textNeplodnost je stanje koje karakterizira nemogućnost trudnoće nakon barem 12 mjeseci nezaštićenih spolnih odnosa, a pogađa
otprilike 15 % parova u svijetu. Unatoč brojnim poznatim uzrocima, u nekim slučajevima oni ipak nisu poznati, odnosno radi se o
idiopatskoj neplodnosti. U liječenju se najčešće koristi farmakoterapija u kombinaciji s postupcima potpomognute oplodnje.
Folikularna tekućina prirodno je okruženje oocite, a analiza elemenata te tekućine omogućava procjenu kvalitete jajne stanice i
sposobnosti oplodnje. U sastavu folikularne tekućine nalaze se i bakar i cink koji su, nakon željeza, najzastupljeniji elementi u tragu
u organizmu te imaju brojne funkcije. Njihova koncentracija u folikularnoj tekućini pozitivno korelira sa stopom oplodnje. Hipoteza
ovog istraživanja je da ovarijska stimulacija mijenja koncentraciju bakra i cinka u folikularnoj tekućini žena s dijagnozom
idiopatske neplodnosti u odnosu na modifikaciju prirodnog ciklusa. U istraživanje su bile uključene 52 pacijentice koje su se u
Kliničkom bolničkom centru Sestre milosrdnice liječile postupkom potpomognute oplodnje. 27 pacijentica podvrgnuto je postupku
u modificiranom prirodnom ciklusu, a kod preostalih 25 pacijentica provodila se ovarijska stimulacija. Atomskom apsorpcijskom
spektrometrijom u uzorcima folikularne tekućine određena je koncentracija bakra i cinka te su podatci obrađeni statističkim
programom MedCalc. Uočena je statistički značajna razlika u koncentraciji bakra i cinka u dvije skupine ispitanica te je zaključeno
da ovarijskom stimulacijom ciklusa dolazi do porasta koncentracije bakra i cinka u folikularnoj tekućini u odnosu na modificirani
prirodni ciklus. Povećane koncentracije bakra i cinka povezane su s boljom kvalitetom jajne stanice i većom stopom oplodnje, a
također i s većom aktivnošću superoksid-dismutaze budući da je uslijed stimulacije ciklusa povećan oksidacijski stres kod
pacijentica. Kako nisu poznati referentni intervali za bakar i cink u folikularnoj tekućini, potrebna su daljnja istraživanja u kojima bi
se ispitala optimalna razina tih mikroelemenata u folikularnoj tekućini te njihov utjecaj na jajnu stanicu i oplodnju.Infertility is a condition characterized by the inability to conceive after at least 12 months of unprotected intercourse, affecting
approximately 15% of couples worldwide. Despite numerous known causes, in some cases, the causes remain unknown, resulting in
idiopathic infertility. The most commonly used treatments include pharmacotherapy in combination with assisted reproductive
techniques. Follicular fluid is the natural environment of the oocyte and analyzing the elements within this fluid enables the
assessment of oocyte quality and fertilization potential. Copper and zinc, the most abundant trace elements in the body after iron, are
present in the composition of follicular fluid and have numerous functions in the body. Their concentration in the follicular fluid
positively correlates with fertilization rates. The hypothesis of this study is that ovarian stimulation alters the concentration of copper
and zinc in the follicular fluid of women diagnosed with idiopathic infertility compared to the modification of the natural cycle. The
study included 52 patients undergoing assisted reproductive treatment in the Sestre milosrdnice University Hospital Center. 27
patients underwent the procedure in a modified natural cycle, while the remaining 25 patients underwent ovarian stimulation. The
concentrations of copper and zinc in the follicular fluid samples were determined using atomic absorption spectrometry and the data
were analyzed using the statistical program MedCalc. A statistically significant difference in the concentration of copper and zinc
was observed between the two groups of participants, leading to the conclusion that ovarian stimulation increases the concentration
of copper and zinc in follicular fluid compared to the modified natural cycle. Increased concentrations of copper and zinc are
associated with better oocyte quality and higher fertilization rates, as well as greater activity of superoxide dismutase due to increased
oxidative stress in patients undergoing cycle stimulation. Since reference intervals for copper and zinc in follicular fluid are not
known, further research is needed to determine the optimal levels of these trace elements in follicular fluid and their impact on oocyte
quality and fertilization
Comparison of two methods for determining SMN2 gene copy number in newborn screening for spinal muscular atrophy
No full textSpinalna mišićna atrofija (SMA) naziv je za skupinu neurodegenerativnih mišićnih bolesti koje su
uzrokovane propadanjem alfa-motoričkog neurona kralježničke moždine. U 95% slučajeva uzrok
bolesti je homozigotna delecija egzona 7 gena SMN1 koji kodira za protein SMN. Bolest se
nasljeđuje autosomno recesivnim putem te obuhvaća širok spektar fenotipova. Donedavno je bila
najčešći genetički uzrok smrti u najranijoj dobi. Međutim, suvremenim liječenjem moguće je
značajno promijeniti tijek bolesti. Najbolji rezultati se postižu kada liječenje započne prije pojave
kliničkih simptoma. Novorođenački probir iz uzorka suhe kapi krvi na filtarskom papiru
omogućuje takav dijagnostički pristup i u Republici Hrvatskoj se provodi od ožujka 2023. godine.
U cilju smanjenja lažno pozitivnih rezultata probira, nakon pozitivnog rezultata kvantitativne
reakcije lančane polimeraze, provodi se i drugostupanjski test metodom MLPA. Potonja metoda
koristi se i kao potvrdni test iz uzorka EDTA-krvi. U ovom radu napravljena je usporedba metode
MLPA s novijom metodom AmplideX. Rezultati dviju metoda bili su usporedivi u uzorcima SMA
bolesnika kod kojih je DNA izolirana iz EDTA-krvi i koji su imali do četiri kopije gena SMN2.
Metoda AmplideX pokazala se kao jednostavnija za rutinski rad i analiza se može provesti u bitno
kraćem vremenu od MLPA metode. Međutim, AmplideX metodom nije moguće utvrditi točan broj
kopija gena SMN2 ako je on veći od četiri, te stoga nije prihvatljiva kao jedini potvrdni test u
dijagnostici SMA. Čistoća DNA izolirane iz suhe kapi krvi na filtarskom papiru nije bila
zadovoljavajuća za provođenje drugostupanjskog testa u novorođenačkom probiru na SMA
AmplideX metodom.Spinal muscular atrophy (SMA) is a term for a group of neurodegenerative muscular disorders
caused by the degeneration of alpha motor neurons in the spinal cord. In 95% of cases, the disease
is caused by a homozygous deletion of exon 7 in the SMN1 gene, which encodes the SMN protein.
The disease is inherited in an autosomal recessive manner and encompasses a wide range of
phenotypes. Until recently, it was the most common genetic cause of death in early infancy.
However, modern treatments can significantly alter the course of the disease. The best outcomes
are achieved when treatment begins before the onset of clinical symptoms. Newborn screening
using dried blood spot samples on filter paper enables such a diagnostic approach and has been
implemented in the Republic of Croatia since March 2023. To reduce false-positive screening
results, a second-tier test using the MLPA method is performed following a positive result from
quantitative polymerase chain reaction. The MLPA method is also used as a confirmatory test
from EDTA blood samples. This thesis compares the MLPA method with the newer AmplideX
method. The results of the two methods were comparable in SMA patient samples where DNA
was isolated from EDTA blood and up to four copies of the SMN2 gene were present. The
AmplideX method proved to be simpler for routine use, and the analysis can be completed in
significantly less time compared to the MLPA method. However, the AmplideX method cannot
determine the exact number of SMN2 gene copies if the count exceeds four, and therefore it is not
suitable as the sole confirmatory test in SMA diagnostics. The purity of DNA isolated from dried
blood spots on filter paper was not sufficient for second-tier testing in newborn SMA screening
using the AmplideX method
Potentially inappropriate medications in the prescribed pharmacotherapy in outpatient settings
No full textStarenje stanovništva predstavlja rastući globalni trend koji je prisutan i u Republici Hrvatskoj. Predviđa se da će globalna populacija starijih osoba do 2050. godine doseći 2,1 milijarde, dok 22,5 % stanovnika u Republici Hrvatskoj prema posljednjem popisu stanovništva ima 65 i više godina. Starenjem dolazi do brojnih fizioloških promjena te shodno tome promjena u farmakokinetici i farmakodinamici lijekova. Kod starijih osoba česta je politerapija, polipragmazija i krhkost zbog čega je povećana osjetljivost na nuspojave lijekova i neželjene reakcije istih. Zbog multimorbiditeta, starije osobe često konzultiraju više specijalista koji im propisuju terapije, a primarni liječnik usklađuje njihovu primjenu, dok na kraju ljekarnik provodi konačnu provjeru. Cilj ovog rada bio je analizirati farmakoterapiju izvanbolničkih pacijenata starijih od 65 godina te korištenjem EU(7)-PIM kriterija utvrditi PNL-ove. Utvrđen je značajan udio PNL-ova u sveukupno utvrđenim propisanim lijekovima. Od ukupno 1290 propisanih lijekova PNL-ovi čine gotovo jednu trećinu. Najčešće propisivani lijekovi prema anatomsko terapijskoj klasifikaciji pripadaju skupini A (lijekovi s djelovanjem na probavni sustav i mijenu tvari), dok je najčešća utvrđena dijagnoza prema Međunarodnoj klasifikaciji bolesti esencijalna primarna hipertenzija (I10.). Najveći broj PNL-ova prema ATK klasifikaciji pripada N skupini, odnosno skupini lijekova s djelovanjem na živčani sustav dok su najčešće utvrđeni PNL-ovi pantoprazol, diazepam, tramadol, ibuprofen i alprazolam. Utvrđene su manje razlike u određenim PNL-ovima kod različitih dobnih skupina i također manje razlike u utvrđenim PNL-ovima među različitim ljekarnama. Rezultati ovog rada podudaraju se sa drugim istraživanjima koja su utvrđivala PNL-ove u propisanoj farmakoterapiji bolničkih pacijenata. Provođenje dodatnih ispitivanja o PNL-ovima u terapiji izvanbolničkih pacijenata te sustavna analiza farmakoterapije kod osoba starije životne dobi doprinijeli bi razvoju novih strategija i inicijativa za unaprjeđenje ljekarničke skrbi i kliničke farmacije. Ljekarnička skrb uključuje osiguravanje učinkovite i sigurne terapije za ispravnu indikaciju te u skladu s pacijentovim potrebama. Korištenje alata za identifikaciju PNL-ova prilikom pružanja ljekarničke skrbi kod osoba starije životne dobi ključno je za postizanje terapijskog cilja, sigurnosti pacijenta i bržih ishoda liječenja.Aging of the population represents a growing global trend, which is also present in the Republic of Croatia. It is projected that by 2050, the global population of older adults will reach 2.1 billion, while according to the latest population census, 22.5% of the population in the Republic of Croatia is aged 65 or older. Aging is associated with numerous physiological changes, leading to alterations in the pharmacokinetics and pharmacodynamics of drugs. Among older adults, polypharmacy, excessive prescribing, and frailty are common, increasing their susceptibility to adverse drug reactions and side effects. Due to multimorbidity, older patients frequently consult multiple specialists who prescribe different therapies, while the primary care physician coordinates their administration, and pharmacists conduct the final review. The aim of this study was to analyze the pharmacotherapy of outpatient patients aged 65 and older and to identify potentially inappropriate medications using the EU(7)-PIM criteria. A significant proportion of PIMs (Potentially Inappropriate Medications) was found among the total prescribed medications. Out of a total of 1290 prescribed drugs, PIMs accounted for almost one-third. The most commonly prescribed medications, according to the Anatomical Therapeutic Chemical classification, belonged to group A (drugs affecting the digestive system and metabolism), while the most frequently diagnosed condition according to the International Classification of Diseases was essential primary hypertension (I10). The highest number of PIMs, according to the ATC (Anatomical Therapeutic Chemical classification) system, belonged to group N, which includes drugs acting on the nervous system. The most frequently identified PIMs were pantoprazole, diazepam, tramadol, ibuprofen,
and alprazolam. Minor differences in specific PIMs were observed across different age groups, as well as slight variations in the identified PIMs among different pharmacies. The results of this study align with other research that has identified PIMs in the prescribed pharmacotherapy of hospitalized patients. Conducting further research on PIMs in outpatient therapy and systematically analyzing pharmacotherapy in the elderly could contribute to the development of new strategies and initiatives aimed at improving pharmaceutical care. Pharmaceutical care involves ensuring effective and safe therapy for the appropriate indication while aligning with the patient's needs. The use of tools for identifying potentially inappropriate medications in pharmaceutical care for older adults is essential for achieving therapeutic goals, ensuring patient safety, and improving treatment outcomes
Physicochemical characterization of dietary supplements from the vitamin and mineral group
No full textUpalne bolesti crijeva (IBD) dovode do teških nutritivnih deficita zbog smanjene apsorpcije nutrijenata. Sve veća incidencija ovih bolesti i dugotrajna terapija potiču pacijente na korištenje dodataka prehrani, što nameće potrebu za strožom kontrolom njihove kvalitete. Cilj ovog rada bio je fizikalno-kemijski okarakterizirati vitamine i minerale u dodacima prehrani korištenim u terapiji IBD-a, prema USP standardima.
Ispitana su tri uzorka tableta (P1, P2, P3) različitog sastava i dozirnih oblika. Provedena ispitivanja uključivala su: varijabilnost mase (USP ), tvrdoću (USP ), rastrošljivost (USP ), raspadljivost (USP ) i gubitak sušenjem. Rezultati su pokazali da uzorci P1 i P3 zadovoljavaju sve kriterije: masa tableta bila je ujednačena (RSD 300 N), što ukazuje na neadekvatnu formulaciju. Osim toga, P3 je premašio prag rastrošljivosti (2,6 % gubitka mase), što upozorava na lošu mehaničku otpornost.
Najznačajniji problem otkriven je u gubitku sušenjem, gdje su svi uzorci pokazali visoku varijabilnost (RSD do 42 %), što ukazuje na nedostatke u skladištenju ili stabilnosti sirovina. Ove nedosljednosti mogle bi ugroziti bioraspoloživost osjetljivih nutrijenata, poput vitamina D ili selena, ključnih za pacijente s IBD-om.
Zaključno, iako većina ispitanih dodataka prehrani zadovoljava USP standarde, kritični propusti kod P2 i P3 ističu važnost kontrole svake faze proizvodnje — od formulacije do pakiranja. Za pacijente s IBD-om, čija je apsorpcija već narušena, čak i manja odstupanja mogu imati klinički značajne posljedice. Budući radovi trebali bi se usmjeriti na optimizaciju proizvodnih procesa i prilagodbu standarda specifičnim potrebama osjetljivih populacija.Inflammatory bowel diseases (IBD), chronic conditions with autoimmune components, lead to severe nutritional deficits due to reduced nutrient absorption. The increasing incidence of these diseases and long-term therapy encourage patients to use dietary supplements, which necessitates stricter quality control. The aim of this study was to physically and chemically characterize vitamins and minerals in dietary supplements used in IBD therapy, according to USP standards.
Three tablet samples (P1, P2, P3) of different compositions and dosage forms were examined. The conducted tests included: weight variability (USP ), hardness (USP ), friability (USP ), disintegration (USP ), and loss on drying. The results showed that samples P1 and P3 met all criteria: tablet weight was uniform (RSD 300 N), indicating an inadequate formulation. Additionally, P3 exceeded the friability threshold (2.6% mass loss), suggesting poor mechanical resistance.
The most significant issue was identified in the loss on drying, where all samples showed high variability (RSD up to 42%), indicating deficiencies in storage or raw material stability. These inconsistencies could compromise the bioavailability of sensitive nutrients, such as vitamin D or selenium, which are crucial for IBD patients.
In conclusion, although most of the tested dietary supplements met USP standards, critical shortcomings in P2 and P3 highlight the importance of controlling every stage of production—from formulation to packaging. For IBD patients, whose absorption is already impaired, even minor deviations can have clinically significant consequences. Future work should focus on optimizing production processes and adapting standards to the specific needs of sensitive populations
Clinical utilization of colistin: a review of current clinical guidelines and research aiming to increase its clinical lifespan
No full textKolistin (polimiksin E) je ciklički kationski lipodekapeptidni antibiotik čiji mehanizam djelovanja
uključuje narušavanje integriteta stanične membrane gram-negativnih bakterija. Kolistin je u
kliničku praksu ušao sredinom 20. stoljeća, no njegova je primjena zbog nefrotoksičnosti i
neurotoksičnosti napuštena već desetak godina nakon uvođenja u kliniku. U današnje vrijeme AMR
postaje rastući zdravstveni problem zbog kojeg ponestaje terapijskih opcija za liječenje životno
ugrožavajućih infekcija. Zato je kolistin pronašao svoje mjesto u klinici kao rezervni antibiotik s
obzirom na to da je trenutno stopa rezistencije na kolistin relativno niska. S obzirom na to da je
kolistin u humanoj medicini dugo bio opsolentan tek su 2019. godine donesene kliničke smjernice
za uporabu kolistina koje su konsenzus relevantnih svjetskih kliničkih društava. Iz literature je uočen
je trend porasta potrošnje kolistina u bolničkim sredinama u RH u periodu od 2011.-2021. Stoga
zabrinjava i mogućnost porasta stope rezistencije na kolistin u bliskoj budućnosti. Kako bi se očuvala
klinička efikasnost kolistina trenutno se razvijaju brze dijagnostičke metode za rano otkrivanje
rezistencije na kolistin te se istražuju potencijalni adjuvantni terapeutici za kolistin.Colistin (polymyxin E) is a cyclic cationic lipodecapeptide antibiotic. Its mechanism of action
involves the disruption of the cellular membrane of Gram-negative bacteria. Colistin has been
discovered in 1947. Due to its high nephrotoxicity and neurotoxicity, its clinical use has been
abandoned already a decade after its discovery. AMR is a growing public health issue, as there are
currently few therapeutic options for treating life-threatening infections. Colistin has recently been
re-introduced for clinical use due to its low resistance rates at the moment. In 2019., the first
consensus clinical guidelines among relevant global clinical societies have been published.
Literature has shown an increase in the clinical use of colistin in Croatian hospitals over the period
2011.-2021. Therefore, it is concerning that colistin resistance rates might increase over the
following years. To increase colistin’s clinical lifespan, researchers are developing diagnostic
methods for early resistance diagnostics and searching for potential adjuvant therapeutics for
colistin
Development, validation and assessment of environmental acceptability of an analytical method for the determination of etrasimod content
No full textOsobine upalnih crijevnih bolesti (engl. Inflammatory bowel disease, IBD) jesu da su to kronične
bolesti nepredvidivog tijeka čija incidencija sve više raste. Glavni oblici bolesti su ulcerozni kolitis
i Crohnova bolest koje se razlikuju po lokaciji i prirodi bolesti. Etrasimod je oralni, sfingozin-1-
fosfat receptor modulator koji se trenutno ispituje kao novo terapijsko rješenje u liječenju upalnih
bolesti crijeva, prvenstveno ulceroznog kolitisa. Modulacija sfingozin-1-fosfat receptora (S1P)
ispituje kao potencijalni terapijski put u liječenju različitih imunosnih bolesti. U ovom radu
predložena je analitička metoda za određivanje etrasimoda primjenom tekućinske kromatografije
visoke djelotvornosti. Metoda je validirana sukladno ICH smjernicama te je utvrđeno da je metoda
selektivna, linearna, osjetljiva, precizna i točna. Primjenom računale platforme AGREE procijenjena
je ekološka prihvatljivost predložene metode te je utvrđeno kako je metoda zadovoljava načela
zelene analitičke kemije.Inflammatory bowel disease (IBD) is term for the group of diseases discribed as chronic and
unpredictable with increasing incidence. Main forms of the disease are Ulcerative colitis and
Crohne's disease, which differ by the location and nature of the disease. Etrasimod is oral,
sphigosine-1-phosphate receptor modulator that is currently being reserched as new therapeutic
option in treating inflammatory bowel diseases, primarily for treating ulcerative colitis. Modulation
of sphigosine-1-phosphate (S1P) receptors is researched as potencial therapeutic target in treating
various immune diseases. In this thesis chosen method for the determination of etrasimod is High
performance liquid chromatography. Method has been validated following the ICH guidelines and
it is confirmed that the method is selective, linear, sensitive, precise and accurate Analitical
GREEnness calculator has been used for evaluation of greenness of chosen analitical method and
final result has shown that method meets the 12 priciples of green analitical chemistry