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COVID 19 – današnje mogućnosti liječenja
No full textCilj istraživanja: Cilj ovog rada je pregledno prikazati današnje terapijske mogućnosti u prevenciji i liječenju bolesti COVID-19 i značajne znanstvene spoznaje vezano za njihovu djelotvornost i sigurnost.
Materijali i metode: U tu svrhu korištena je trenutno dostupna stručna i znanstvena literatura te publikacije baza lijekova Europske agencije za lijekove i Agencije za lijekove i medicinske proizvode u Hrvatskoj te drugi raspoloživi izvori u razdoblju od pojave pandemije 2019. do rujna 2023.
Rezultati: Pregledno su prikazani cjepiva (mRNA, proteinska, vektorska ili inaktivirana cjepiva) i lijekovi (antivirusna monoklonska protutijela, oralni antivirusni lijekovi, imunomodulatori, antivirotici za sistemsku primjenu) koji su trenutno odobreni za prevenciju i liječenje COVID-19 bolesti.
Zaključak: Zahvaljujući iznimnim naporima stručne i znanstvene javnosti od proglašenja pandemije COVID-19 u ožujku 2020., danas postoje učinkovita cjepiva i lijekovi protiv bolesti COVID-19 s prihvatljivim sigurnosnim profilom.
Cjepiva protiv bolesti COVID-19 su prošla kroz opsežna klinička ispitivanja koja su uključivala desetke tisuća ispitanika kako bi se osigurala njihova sigurnost i učinkovitost. Na temelju tih podataka dobili su regulatorno odobrenje za stavljanje u promet.
Kontinuiranim istraživanjem i razvojem cjepiva, danas postoje i prilagođena cjepiva koja pružaju bolju zaštitu protiv prevladavajućih varijanti virusa SARS-CoV-2.
Dok su COVID-19 cjepiva primarno dizajnirana za prevenciju bolesti COVID-19, danas su dostupni lijekovi koji se mogu koristiti za liječenje već zaraženih pojedinaca virusom SARS-CoV-2 i tako doprinositi u kontroli i smanjenju napredovanja bolesti odmah nakon njihove primjene.
Budući da je situacija s bolesti COVID-19 dinamična, ključno je pratiti najnovije smjernice i preporuke zdravstvenih regulatornih tijela i stručnjaka o najnovijim informacijama o liječenju i prevenciji bolesti COVID-19.Objectives: The goal of this thesis is to present an overview of today's therapeutic possibilities in the prevention and treatment of COVID-19 and significant scientific knowledge related to their efficacy and safety.
Materials and methods: For this purpose, currently available professional and scientific literature, including publications of the European Medicines Agency and the Agency for Medicinal Products and Medical Devices of Croatia drug database and other available sources were examined in the period from the pandemic onset in 2019 until September 2023.
Results: Vaccines (mRNA, protein, vector or inactivated vaccines) and medicinal products (antiviral monoclonal antibodies, oral antiviral medicinal products, immunomodulators, antivirals for systemic use) that are currently approved for the prevention and treatment of COVID-19 disease are presented in one place.
Conclusion: Due to the exceptional efforts of the professional and scientific public from the declaration of the COVID-19 pandemic in March 2020, today there are effective vaccines and medicinal products against COVID-19 disease with an acceptable safety profile.
COVID-19 vaccines have gone through extensive clinical trials involving tens of thousands of participants to ensure their safety and efficacy. Based on these data, they received regulatory approval for their placement on the market.
Due to continuous vaccine research and development, there are now adapted vaccines that provide better protection against the prevailing variants of the SARS-CoV-2 virus.
While the COVID-19 vaccines are primarily designed for the prevention of COVID-19 disease, today's available medicinal products can be used to treat individuals already infected with the SARS-CoV-2 virus and thus contribute to controlling and reducing the progression of the disease immediately after their administration.
Since the situation with the COVID-19 disease is dynamic, it is crucial to follow the latest guidelines and recommendations from health authorities and experts regarding the latest information on COVID-19 treatment and prevention
Effects of incretin mimetics on the cardiovascular system
No full textInkretinomimetici, razvijeni po uzoru na endogene inkretine - glukagonu sličan peptid-1 (GLP-1) i o glukozi-ovisan inzulinotropni peptid (GIP), su lijekovi peptidne strukture koji se primarno koriste u liječenju dijabetesa tipa 2 i pretilosti. Oba stanja predstavljaju veliki i rastući javnozdravstveni problem, te su povezana s povećanim rizikom od kardiovaskularnih smrti. Svi lijekovi djeluju kao potentni agonisti receptora za GLP-1, dok je jedino tirzepatid dualni agonist GLP-1 i GIP receptora. Trenutno su za pretilost indicirani samo liraglutid i semaglutid. Lijekovi značajno smanjuju glukozu u krvi i tjelesnu težinu, no zbog široko rasprostranjenih receptora, pokazuje direktne i indirektne pozitivne učinke na različite organske sustave, uključujući i kardiovaskularni sustav. Relevantnost djelovanja inkretinomimetika na pojedini sustav predmet je mnogih istraživanja te, između ostalog, ovisi o farmakodinamici i farmakokinetici lijekova. Do sada su provedene brojne velike randomizirane placebom kontrolirane kliničke studije, kao i meta-analize koje su istraživale djelotvornost i podnošljivost inkretinomimetika u bolesnika s kardiovaskularnim rizicima. Mnoga od njih pokazala su koristi ovih lijekova za određenu populaciju bolesnika, te su podloga za potencijalno širenje indikacija u kliničkoj praksi.Incretin mimetics, developed based on endogenous incretins - glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), are peptide-based drugs primarily used in the treatment of type 2 diabetes and obesity. Both conditions represent major and growing public health concerns and are associated with an increased risk of cardiovascular mortality. All these drugs act as potent GLP-1 receptor agonists, with tirzepatide being the only dual agonist of GLP-1 and GIP receptors. Currently, liraglutide and semaglutide are indicated for obesity. These drugs significantly reduce blood glucose and body weight. Additionally, due to their widespread receptor distribution, they show direct and indirect positive effects on various organ systems, including the cardiovascular system. The relevance of actions on each system is the subject of extensive research, influenced among other factors by the pharmacodynamics and pharmacokinetics of the drugs. To date, numerous large randomized placebo-controlled clinical trials and meta-analyses have been conducted to investigate the efficacy and tolerability of incretin mimetics in patients at cardiovascular risk. Many of these studies have demonstrated the benefits of these drugs for specific patient populations, and are the basis for the potential expansion of indications in clinical practice
NMR study of the H/D exchange reaction in 1,1-dimethylpropargyl alcohol. The effect of the organic solvent
No full textPotaknut potrebom za jednostavnom i ekonomičnom pripravom, sintetski korisnih, deuteriranih terminalnih alkina, u ovom se radu nastavlja istraživanje o izotopnoj H/D izmjeni na terminalnom alkinu 1,1-dimetil-propargilnog alkohola (ROH). Ranije je prikazano uspješno deuteriranje upotrebom teške vode (D2O) kao jedinog reaktanta uz ROH, a ovaj rad proširuje istraživanje tog procesa dodatkom organskih otapala u reakcijsku smjesu. U ovome su slučaju to deuterirani aceton i deuterirani acetonitril. Razlog njihovom dodatka je taj što Budući da nisu svi spojevi s terminalnom alkinskom skupinom topljivi u vodi, dodatak organskog otapala može povećati njihovu topljivost u smjesi vode i organskog otapala. Stoga je važno ispitati kako se mijenja brzina H/D izmjene dodatkom organskog otapala, te dolazi li do inhibicije reakcije.
Za istraživanje je korištena 1H NMR spektroskopija. Snimanjem spektara kroz određeno vrijeme uočava se postepeni pad signala alkinske skupine jer se 1H proton supstituira izotopom 2H čiji signal nije vidljiv u 1H NMR spektru. Obradom rezultata dolazi se do spoznaje da dodatak dvaju organskih otapala smanjuje brzinu reakcije te da je ovisnost poluvremena reakcije o masenom udjelu otapala eksponencijalna. Pri relativnom malim masenim udjelima org.otapala ( do 20%) smanjenje brzine nije značajano, dok se pri višim masenim udjelima lako uočava ovisnost brzine H/D izmjene o dielektričnoj konstanti organskog otapala.. Ovaj diplomski rad može poslužiti za nastavak istraživanja utjecaja niza drugih otapala na ishod reakcije.Driven by the need for simple and economical preparation of synthetically useful deuterated terminal alkynes, this work continues the investigation into the isotopic H/D exchange on the terminal alkyne of 1,1-dimethyl-propargyl alcohol (ROH). Previously, successful deuteration using heavy water (D2O) as the sole reactant with ROH was demonstrated. This study extends that research by adding organic solvents to the reaction mixture. In this case, deuterated acetone and deuterated acetonitrile were used. The reason for their addition is that not all compounds with terminal alkyne groups are soluble in water, and the addition of an organic solvent can increase their solubility in a water-organic solvent mixture. Therefore, it is important to examine how the rate of H/D exchange changes with the addition of organic solvents and whether the reaction is inhibited.
1H NMR spectroscopy was used for the investigation. By recording spectra over time, a gradual decrease in the signal of the alkyne group is observed as the 1H proton is substituted by the 2H isotope, whose signal is not visible in the 1H NMR spectrum. Analysis of the results reveals that the addition of the two organic solvents reduces the reaction rate and that the dependence of the reaction's half-life on the solvent's mass fraction is exponential. At relatively low mass fractions of the organic solvent (up to 20%), the reduction in rate is not significant, while at higher mass fractions, the dependence of the H/D exchange rate on the dielectric constant of the organic solvent is easily noticeable. This thesis can serve as a basis for further research into the influence of various other solvents on the reaction outcome
Antioxidant activity of spinach and arugula extracts biofortified with selenium nanoparticles
No full textSelen je esencijalan mikronutrijent čiji je nedovoljan unos zabilježen u Hrvatskoj, ali i u ostatku svijeta. Biljke apsorbiraju selen iz tla te su odgovorne za njegovu primarnu akumulaciju u hranidbenom lancu. Zbog toga je biofortifikacija biljaka selenom koristan način za osiguravanje optimalnog unosa selena u populaciji. Selen u obliku nanočestica je noviji oblik selena za koji se pretpostavlja da ima poboljšanu bioraspoloživost i manju toksičnost u odnosu na anorganske i organske oblike selena. Biofortifikacija selenom može dovesti do optimalnog sadržaja selena u biljkama za ljudsku prehranu te povećan sadržaj antioksidansa, budući da može utjecati na biosintezu fenolnih spojeva i ostalih sekundarnih metabolita u biljaka.
U ovom radu istražena je antioksidativna aktivnost ekstrakata rukole i špinata biofortificiranih različitim kemijskim oblicima selena. Najveći antiradikalni i redukcijski potencijal je pokazan za ekstrakte rukole i špinata biofortificiranih s nanočesticama selena funkcionaliziranih huminskom kiselinom. Svi ekstrakti su se pokazali biokompatibilnima na HepG2 stanicama. Dokazan je i protektivni antioksidativni učinak ekstrakata protiv prooskidansa. On je ovisio o kemijskom obliku selena primjenjenom za biofortifikaciju. U slučaju rukole najjači učinak je pokazan za ekstrakt biljaka biofortificiranih nanočesticama selena funkcionaliziranih polisorbatom, dok je kod špinata najjači učinak primjećen za ekstrakt biljaka biofortificiranih nanočesticama selena funkcionaliziranih huminskom kiselinom.
Biofortifikacija je imala utjecaj na antioksidativnu aktivnost ekstrakata te je ovisila o primjenjenom kemijskom obliku selena. Nanočestice su se pokazale kao moguća alternativa selenatu budući da su utjecale na poboljšanje antioksidativnih svojstava rukole i špinata što posljedično može imati blagotvoran utjecaj na zdravlje.Selenium is an essential micronutrient and its insufficient intake has been recorded in Croatia and other parts of the world. Plants absorb selenium from the soil and are responsible for its primary accumulation in the food chain. For this reason, biofortification of plants with selenium is a useful way to ensure optimal intake of selenium in the population. Selenium nanoparticles are relatively novel form of selenium with hypothesized improved bioavailability and reduced toxicity compared to inorganic and organic forms of selenium. Biofortification with selenium can lead to optimal selenium content in plants for human consumption and increased antioxidant content, since it can affect the biosynthesis of phenolic compounds and other secondary metabolites in plants.
In this paper, the antioxidant activity of arugula and spinach extracts biofortified with different chemical forms of selenium was investigated. The highest anti-radical and reductive potential was shown for arugula and spinach extracts biofortified with selenium nanoparticles functionalized with humic acid. All extracts were shown to be biocompatible with HepG2 cells. The protective antioxidant effect of the extract against pro-oxidants has also been proven. It was dependent on the chemical form of selenium used for biofortification. In the case of arugula, the greatest effect was shown for the extract of plants biofortified with selenium nanoparticles functionalized with polysorbate, while in spinach the greatest effect was seen for the extract of plants biofortified with selenium nanoparticles functionalized with humic acid.
Biofortification had an impact on the antioxidative activity of the extracts and it was dependent on the applied chemical form of Se. Nanoparticles can be considered as a potential alternative to selenate in biofortification, since they significantly affected the antioxidant properties of arugula and spinach, which can consequently have a beneficial effect on human health
Detection of potentially inappropriate drugs affecting the gastrointestinal system in residents of nursing homes
No full textCilj istraživanja bio je utvrditi učestalost propisivanja PNL-ova s djelovanjem na gastrointestinalni sustav u starijoj životnoj dobi u domovima za starije i nemoćne osobe. U istraživanju je sudjelovalo 225 korisnika domova za starije i nemoćne osobe na području Dalmacije, Slavonije i Grada Zagreba, a podatci su prikupljani pomoću standardiziranog interRAI upitnika. Na temelju prikupljenih podataka, prikladnost lijekova u terapiji ispitivana je pomoću druge verzije STOPP kriterija koji su definirali četiri kriterija za određivanje PNL-ova s djelovanjem na gastrointestinalni trakt. Otkriveno je ukupno 139 PNL-ova, od čega je najveći udio IPP-ova kod nekompliciranog peptičkog ulkusa ili erozivnog peptičkog ezofagitisa u trajanju dužem od 8 tjedana (N=84), zatim lijekova s potencijalom uzrokovanja konstipacije u pacijenata s kroničnom konstipacijom (N=47), a nešto manja pojavnost bila je oralnog elementarnog željeza u dozama većim od 200 mg dnevno (N=8). Rezultati su pokazali da u ispitivanom uzorku nije bio neprikladno propisan metoklopramid bolesnicima s dijagnozom Parkinsonove bolesti. Otkriveno je ukupno 110 slučajeva PNL-ova s djelovanjem na gastrointestinalni sustav, što čini 48,89% ukupnog broja ispitanika. Među tim slučajevima, 83 ispitanika ispunjavaju jedan kriterij neprikladnog propisivanja, 26 ispitanika ispunjava dva kriterija, dok jedan ispitanik ispunjava sva tri kriterija. Zaključno, ovim istraživanjem pronađena je visoka prevalencija PNL-ova s djelovanjem na gastrointestinalni sustav. Nužno je provoditi mjere te starijim osobama propisivati minimalan potreban broj lijekova kako bi se smanjili rizici od nastanka nuspojava i interakcija među lijekovima što bi posljedično vodilo k racionalnijoj primjeni lijekova, boljoj kvaliteti života osoba starije životne dobi i nižim ukupnim troškovima liječenja.The aim of the research was to determine the frequency of prescribing potentially inappropriate drugs affecting the gastrointestinal system in the older population residing in nursing homes.
The study included 225 residents of nursing homes in the Croatian regions of Dalmatia, Slavonia, and the city of Zagreb. Data were collected using the standardized interRAI questionnaire. Based on the collected data, the appropriateness of medications in therapy was assessed using the second version of the STOPP criteria, which defined four criteria for identifying potentially inappropriate drugs affecting the gastrointestinal tract. A total of 139 potentially inappropriate drugs were identified, with the highest proportion being proton pump inhibitors for uncomplicated peptic ulcer or erosive peptic esophagitis lasting more than 8 weeks (N=84), followed by drugs with potential to cause constipation in patients with chronic constipation (N=47). A slightly lower occurrence was noted for oral elemental iron in doses greater than 200 mg per day (N=8). In the studied sample, metoclopramide was not inappropriately prescribed to patients diagnosed with Parkinson's disease. Overall, potentially inappropriate drugs affecting the gastrointestinal system were found in 48.89% of participants (N=110). Among them, 83 participants met one criterion, 26 met two criteria, and one participant met all three criteria. In conclusion, this study identified a high prevalence of potentially inappropriate drugs affecting the gastrointestinal system. It is essential to implement measures and prescribe the minimum necessary number of medications to the older adults to reduce the risks of side effects and interactions among drugs, potentially leading to a more rational use of medications, improved quality of life, and lower overall treatment costs
Bioslični lijekovi kao terapijska alternativa referentnom biološkom lijeku trastuzumabu
No full textCILJ ISTRAŽIVANJA:
Cilj ovog specijalističkog rada je dati pregled trenutno dostupnih i registriranih trastuzumabu biosličnih lijekova u Europskoj uniji, uz poseban osvrt na zamjenjivost, moguće uštede i dostupnost pacijentima.
Hipoteze istraživanja su:
1. Trastuzumabu bioslični lijekovi omogućuju uštede javnozdravstvenom sustavu;
2. Trastuzumabu bioslični lijekovi i njihova manja nabavna cijena omogućuju veću dostupnost terapije pacijentima;
3. Trastuzumabu bioslični lijekovi mogu se smatrati međusobno zamjenjivima na temelju dosadašnjih pred- i postmarketinških istraživanja i praćenja ovih lijekova u pogledu kvalitete, imunogenosti, učinkovitosti i sigurnosti.
MATERIJAL I METODE
Pri pripremi ovog specijalističkog rada korišteni su elektronički izvori znanstvenih, stručnih i preglednih radova koji su obuhvaćali informacije o biološkim i biosličnim lijekovima koji se koriste za liječenje HER 2 pozitivnog karcinoma, a obuhvaćaju bibliografske baze podataka (PubMed) i baze podataka s cjelovitim tekstom (Science Direct). Također, konzultiran je i registar kliničkih istraživanja za bolji uvid u trenutne aktivnosti po pitanju planiranih i dovršenih kliničkih studija. Za prikupljanje podataka vezanih uz odobrenja biosličnih lijekova korištene su: baza lijekova Agencije za lijekove i medicinske proizvode Republike Hrvatske (HALMED), baza Europske agencije za lijekove (engl. European Medicines Agency, EMA) te Američke Agencije za hranu i lijekove (engl. Food and Drug Administration, FDA). Pravni dokumenti (uredbe, direktive, zakoni, pravilnici) preuzeti su s mrežnih stranica Narodnih novina i Europske komisije.
REZULTATI
Rad daje pregled biosličnih lijekova referentnom biološkom lijeku trastuzumabu koji se koriste u terapiji HER 2 pozitivnog karcinoma.
Do kraja 2022. godine u Europskoj Uniji (EU) šest je biosličnih lijekova referentnog lijeka trastuzumaba dobilo odobrenje za puštanje u promet.
U Sjedinjenim Američkim Državama (SAD) odobrenje za puštanje u promet zaključno s 2022. godinom dobilo je pet biosličnih lijekova referentnom biološkom lijeku trastuzumabu.
U svijetu postoji više biosličnih lijekova referentnom biološkom lijeku trastuzumabu, odobrenih od lokalnih nacionalnih regulatornih tijela prema lokalnim i regionalnim smjernicama. Neki od njih traže svoj put na tržišta EU, europskog gospodarskog prostora i američka tržišta, a niža ponuđena cijena proizvoda ih ovdje čini uvelike konkurentnima te je vidljiv trend povećane primjene biosličnih lijekova u usporedbi na referentni lijek.
ZAKLJUČAK
Biološki lijek trastuzumab koji su 1998. godine odobrile FDA i EMA, unio je revoluciju u pristupu i uspješnosti liječenja HER 2 pozitivnog karcinoma dojke. Nakon njega je uslijedio razvoj i posljedična registracija više bioloških lijekova, monoklonskih protutijela, koji ciljaju ovaj tip raka, no zbog patentne zaštite, zaštite podataka i marketinške zaštite na snazi njihovi bioslični lijekovi se tek očekuju kroz nekoliko sljedećih godina, tako da još nema ni registriranih kliničkih istraživanja koja bi uključivala ove molekule.
Također, primjena trastuzumaba proširena je i na neke druge karcinome koji pokazuju povećanu ekspresiju HER 2, uključujući i karcinom želuca i karcinom gastroezofagealnog spoja.
S druge strane, obzirom na istek perioda zaštite podataka, do kraja 2022. se na tržištu SAD i EU pojavilo pet odnosno šest biosličnih trastuzumaba, od kojih se očekuje proboj na tržišta te time smanjivanje cijene terapije trastuzumabom u zdravstvu.OBJECTIVES
The objective of this work is to give a current overview of both available and registered biosimilar medicinal products of the reference biopharmaceutical trastuzumab with a short commentary on interchangeability, on possible savings and on higher availability to the patients in the world and in Croatia.
Hypothesis of the research are:
1. Trastuzumab biosimilars provide savings to public health care system
2. Trastuzmab biosimilars and their lower costs provide higher therapy availability to the patients
3. Trastuzmab biosimilars can be considered as interchangeable based on pre- and postmarketing research until now and monitoring these medicines in relation to the quality, immunogenicity, efficacy and safety.
MATERIAL AND METHODS
Electronic sources of scientific, professional and review papers that presented information on biologics and biosmilars applied for treatment of HER 2 positive cancer, were reviewed and consulted in preparation of this work. Sources used in provision of aforementioned articles and papers included bibliographical database (PubMed) and the database with full text (Science Direct). Also, clinical research database was consulted in order to better understand
current activities, taking into account both planned and completed clinical studies. Croatian Agency for Medicinal Products, European Medicines Agency and Food and Drug Administration databases were used to collect data on marketing authorization registrations of biosimilars. Legal documents (regulations, directives, laws and ordinances) were adopted from websites of Official Gazette and the European Commission.
RESULTS
Presented work gives an overview of biosimilars of referent biopharmaceutical trastuzumab used in therapy of HER 2 positive cancers.
By the end of year 2022 total of six biosimilars of reference trastuzumab have been granted marketing authorizations in European Union.
In United States of America (USA, US) in 2022 total of five biosimilars of referent biopharmaceutical trastuzumab have been granted marketing authorizations.
There are more trastuzumab biosimilars in the world, approved by local national regulatory authorities, according to local and regional guidelines. Some of these are looking for market share in European Union, European economic area and the United States area, and their lower starting price is making them highly competitive in the market share, establishing and further strengthening a trend of higher use of biosimilars in comparison to the referent biopharmaceutical.
CONCLUSION
Biopharmaceutical trastuzumab, approved by FDA and EMA in 1998, started a revolution in approach and effectiveness of treating HER 2 positive breast cancer. Development and subsequent registration of several other monoclonal antibodies targeting this type of cancer followed the registration of trastuzumab, however due to patent, data and marketing exclusivity periods their biosimilars are expected in the coming years. Therefore there are no registered clinical researches that would include these molecules at the moment.
Also, trastuzumab use was extended to some other types of cancers showing HER 2 overexpression, including gastric cancer and gastro oesophageal junction cancer.
On the other hand, due to expiry of data exclusivity period, 5 and 6 trastuzumab biosimilars were registered in the US and EU, respectively, with expectation of increasing their market share and subsequent reduction the price of trastuzumab therapy in healthcar
Problemi farmakoterapije Parkinsonove bolesti u osoba starije životne dobi
No full textCiljevi istraživanja: Cilj ovog istraživanja je analizirati politerapiju, potencijalno neprikladne lijekove (PNL), potencijalno klinički značajne interakcije (X, D i C) i rizične lijekove s obzirom na oštećenje bubrežne funkcije kod starijih bolesnika s Parkinsonovom bolesti (PB) koji su ambulantno liječeni.
Ispitanici i metode: Provedeno je retrospektivno istraživanje u razdoblju od 1. siječnja 2021. do 31. prosinca 2023. godine u Općoj bolnici Zabok i bolnici hrvatskih veterana. U istraživanju su sudjelovali pacijenti u dobi od 65 ili više godina koji imaju dijagnozu PB i ambulantno su liječeni. Politerapija je definirana kao istovremena primjena 5-9 lijekova, a prekomjerna politerapija kao primjena ≥10 lijekova. EU(7)-PIM lista korištena je za utvrđivanje PNL-ova. Za utvrđivanje potencijalnih klinički značajnih interakcija lijekova (engl. drug-drug interactions, DDI) korištena je baza podataka Lexi-Comp®Online. Oštećenje bubrežne funkcije utvrđeno je na temelju eGFR vrijednosti prema KDIGO klasifikaciji. Za analizu rizičnih lijekova koristili su se Sažetci opisa svojstava lijeka.
Rezultati: Istraživanje je uključilo 50 pacijenata starije životne dobi, prosječne dobi od 75 godina (65-92), od kojih su 56 % bile žene. Kod 34 % pacijenata zabilježena je politerapija, a 62 % pacijenata koristilo je 10 ili više lijekova. Ukupno je 98 % (n=49) ispitanika bilo izloženo PNL-ovima. Kod 100 % pacijenata utvrđena je jedna ili više potencijalno klinički značajnih interakcija lijekova. Ukupno 26 % ispitanika imalo je oslabljenu bubrežnu funkciju, od kojih je 84,6 % imalo jedan ili više propisanih rizičnih lijekova s obzirom na oštećenu bubrežnu funkciju.
Zaključak: U ovom istraživanju utvrđena je visoka učestalost farmakoterapijskih problema kod starijih osoba s PB. Neprepoznati farmakoterapijski problemi mogu uzrokovati slabiju kontrolu bolesti te utjecati na učestalost i težinu nuspojava. Ovo istraživanje ukazuje na važnost kliničkog farmaceuta u analizi farmakoterapije i utvrđivanju farmakoterapijskih problema kod starijih bolesnika oboljelih od PB. Zadaća je kliničkog farmaceuta povećati kvalitetu propisivanja farmakoterapije i optimizirati farmakoterapiju sukladno individualnim potrebama pacijenta.Research Objectives: The aim of this study is to analyze total polytherapy, potentially inappropriate medication (PIM), potentially clinically significant interactions (X, D and C) and renal risk drugs in outpatient treated elderly patients with Parkinson's disease (PD).
Patients and methods: A retrospective study was conducted in the period from January 1, 2021 to December 31, 2023 in Zabok General Hospital and Croatian Veterans Hospital. Patients aged 65 or older, diagnosed with Parkinson's disease and receiving outpatient treatment, participated in the study. Polytherapy is defined as the simultaneous use of 5-9 drugs, and excessive polytherapy as the use of ≥10 drugs. The EU(7)-PIM list was used to determine PNLs. The Lexi-Comp®Online database was used to identify potential clinically significant drug interactions. Impairment of renal function was determined based on the eGFR value according to the KDIGO classification. Summaries of the description of drug properties were used for the analysis of risky drugs.
Results: The study included 50 elderly patients; 56 % of them were female, with a median age of 75 (65-92). Overall, 34 % of patients used 5-9 prescription medications and 62 % used 10 or more medications. PIMs based on EU(7)-PIM criteria occurred in 98 % (n=49) of the participants. In total, 100 % of patients had at least one potential clinically significant DDI. In total, 26 % of patients were found to have eGFR < 60 ml/min/1,73 m2 , of which 84,6 % of patients had one or more inappropriately prescribed renal risk drugs.
Conclusion: This is the first study in Europe to assess the exposure of elderly patients with PD, potential clinically significant interactions, PNLs and renal risk drugs. The research found a high exposure to these pharmacotherapeutic problems in elderly people with Parkinson's disease. This research indicates the importance of the clinical pharmacist in detecting pharmacotherapeutic problems in the elderly
Pyrrolizidine alkaloids as contaminants
No full textPirolizidinski alkaloidi su tvari koje prirodno nalazimo u nekim biljnim vrstama (pretežito vrste porodica Boraginaceae, Compositae/Asteraceae, Leguminosae/Fabaceae, Apocynaceae, Ranunculaceae, Scrophulariaceae), a produkt su njihovog sekundarnog metabolizma i primarno im služe kao obrana od biljojeda. Njihova akutna toksičnost, genotoksičnost i potencijalni karcinogeni učinak na ljude poznati su već jako dugo vremena, a najčešće je toksičnim učinkom u najvećoj mjeri pogođena jetra. Nove spoznaje sve više ukazuju na to da biljke koje prirodno ne sadrže pirolizidinske alkaloide uslijed rasta na istom staništu kao i biljke koje ih sadrže, slučajne kontaminacije ili posljedičnog križanja vrsta, postaju biljke u kojima je moguće naći određeni sadržaj pirolizidinskih alkaloida. Time se povećava sveukupna moguća izloženost pirolizidinskim alkaloidima i to iz više različitih izvora te raste mogućnost ispoljavanja štetnih učinaka po zdravlje, osobito kod redovitih potrošača. Kako bi se ograničila izloženost pirolizidinskim alkaloidma, Komisija Europske unije je donijela odluku da se dozvoljeni sadržaj pirolizidinskih alkaloida dodatno ograniči u proizvodima poput čajeva, biljnih infuzija, biljnih dodatka prehrani, pripravaka na bazi peludi i začinima te provedba te odluke kreće od 1. srpnja 2022. Iako o pirolizidinskim alkaloidima već puno toga znamo, svakodnevno dolazimo do novih spoznaja. Važno je naglasiti da je znanje moć koja nam omogućava da u svjetlu novih spoznaja poduzmemo mjere koje su u našoj moći kako bi se osigurala sigurnost i zdravlje opće populacije u čemu značajnu ulogu ima i sam farmaceut.Pyrrolizidine alkaloids are compounds that naturally occur in some herbal species (mostly species of plant families Boraginaceae, Compositae/Asteraceae, Leguminosae/Fabaceae, Apocynaceae, Ranunculaceae, Scrophulariaceae) and they are products of secondary metabolism that plants have developed as defense mechanism against insect herbivores. The acute toxicity, genotoxicity and carcinogenic potential for humans caused by pyrrolizidine alkaloids have been known for a very long time and usually liver is the most affected by its toxic effects. Recently, it has been shown that a lot of plants that naturally do not contain pyrrolizidine alkaloids are starting to show otherwise. Certain content of pyrrolizidine alkaloids has been found in plants due to the same habitat, contamination or crossbreeding of species. By this appearance, rate of possible exposure to pyrrolizidine alkaloids significantly increases and it is spread to more various sources what presents potential health hazard, especially in regular consumers. In order to restrict pyrrolizidine alkaloid exposure, The European Commission has brought the decision to additionally limit content of pyrrolizidine alkaloids that is allowed in products like tea, herbal infusions, herbal supplements, pollen based products and spices which will be implemented on 1. July 2022. Even though we know a lot about pyrrolizidine alkaloids, regularly we come to the new insights. It is important to emphasize the fact that knowledge is power which allows us to implement measures due to the new insights to ensure safety and preserve health of population in which significant role has the pharmacist
Amide-type harmicines as potential antimalarial agents
No full textU prvom dijelu istraživanja ovog doktorskog rada sintetizirano je četrdeset harmicina amidnoga tipa (7a-h, 13a-h, 19a-h, 22a-h, 25a-f, i-p), hibridnih spojeva harmina/srodnih β-karbolinskih alkaloida i cimetne kiseline/odabranih derivata cimetne kiseline (DCK-a) međusobno povezanih amidnom vezom. U tu svrhu pripravljeni su amini 6, 12, 18, 21 i 24, čime je primarna amino skupina uvedena u pet položaja β-karbolina: 1, 3, 6, 7 i 9. U idućem koraku sintetizirani su harmicini amidnoga tipa reakcijama povezivanja dobivenih amina s cimetnom kiselinom/DCK-ima korištenjem standardnih reakcijskih uvjeta (HATU/DIEA). Harmicini su karakterizirani spektroskopskim (1H, 13C NMR, IR) i spektrometrijskim (MS) tehnikama te im je određeno talište. Svim spojevima ispitano je antiplazmodijsko djelovanje in vitro na eritrocitnu fazu životnog ciklusa dva soja Plasmodium falciparum (Pf3D7 i PfDd2), hepatocitnu fazu životnog ciklusa P. berghei i citotoksičnost na humanu staničnu liniju hepatocelularnog karcinoma (HepG2).
U drugom dijelu istraživanja provedena je analiza kvantitativnog odnosa strukture i djelovanja (engl. quantitative structure-activity relationship, QSAR). Antiplazmodijsko djelovanje harmicina na eritrocitnu fazu Pf3D7 povezano je s pripadajućim izračunatim molekulskim deskriptorima te je primjenom metode višestruke linearne regresije dobiven prediktivni model ovisnosti log IC50 o dvije varijable: izoelektričnoj točki (pI) i Abrahamovom deskriptoru E (Abr E). Model je validiran unutarnjom 10-strukom unakrsnom validacijom.
U trećem dijelu istraživanja, za provedbu vanjske validacije modela predložene su strukture 356 novih harmicina te su im, prema dobivenom modelu, izračunate predviđene IC50 vrijednosti. Potom je odabrano, sintetizirano i karakterizirano ukupno 19 harmicina: šest harmicina amidnoga tipa (25k-p), 11 harmicina karbamatnog tipa (28a-k) i dva harmicina ureidnog tipa (32b,c) u položaju N-9 β-karbolina, te je ispitano njihovo antiplazmodijsko djelovanje in vitro na eritrocitnu fazu životnog ciklusa plazmodija (Pf3D7 i PfDd2). Na temelju dobivenih rezultata izračunate su razlike između eksperimentalnih i predviđenih vrijednosti i srednja apsolutna pogreška predviđanja. Najjače djelovanje, gotovo dva reda veličine jače od harmina, pokazali su harmicini amidnoga tipa u položaju N-9 β-karbolina (25b-e,i,j).
Rezultati ovog doktorskog rada predstavljaju temelj za daljnji razvoj novih harmicina amidnoga tipa s pojačanim antiplazmodijskim djelovanjem.The first part of this thesis includes the synthesis of forty amide-type harmicines (7a-h, 13a-h, 19a-h, 22a-h, 25a-f, i-p), hybrid compounds in which harmine/β-carboline alkaloids and cinnamic acid or cinnamic acid derivatives (CADs) are linked via an amide bond. First, the primary amino group was introduced in five positions of the β-carboline ring: 1, 3, 6, 7 and 9, which resulted in the synthesis of amines 6, 12, 18, 21 and 24. Subsequently, the coupling reaction of amines and cinnamic acid/CADs were preformed using standard conditions (HATU/DIEA). The synthesized compounds were characterized by spectroscopic (1H, 13C NMR, IR) and spectrometric (MS) techniques, as well as determination of their melting points. Finally, we evaluated biological activities of the prepared harmicines, i.e. in vitro antiplasmodial activity against the erythrocytic stage of the Plasmodium falciparum life cycle (Pf3D7 and PfDd2) and hepatic stage of the P. berghei life cycle, as well as cytotoxicity against human hepatocellular carcinoma cell line (HepG2).
In the second part of this thesis quantitative structure-activity relationship (QSAR) analysis was performed using a multiple linear regression technique. A set of molecular descriptors underwent the forward stepwise regression procedure and the predictive model was built by selecting two molecular descriptors: isoelectric point (pI) and Abraham descriptor E (Abr E). The constructed model was internally validated using 10-fold cross-validation.
For the purpose of external validation of the constructed model, in the third part of this thesis 356 novel harmicines were designed and their predicted logIC50 values calculated, followed by the synthesis and characterization of six amide-type harmicines (25k-p), eleven carbamate type-harmicines (28a-k) and two ureido-type harmicines (32b,c) in the position N-9 of the β-carboline. Next, we evaluated in vitro antiplasmodial activity of novel harmicines against the erythrocytic stage of the P. falciparum life cycle (Pf3D7 and PfDd2). Based on the obtained results, the absolute differences between the experimental and predicted values as well as mean absolute error were calculated. The most active compounds, amide-type harmicines in the position N-9 of the β-carboline (25b-e,i,j), displayed at least two orders of magnitude stronger activities than the parent compound, harmine. The results of this doctoral thesis represent the basis for the further development of novel amide-type harmicines with enhanced antiplasmodial activity
