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Uloga farmakogenetike i polimorfizma gena za dihidropirimidin-dehidrogenazu (DPYD) u personaliziranom liječenju 5-fluorouracilom
No full textCilj istraživanja: Cilj ovog rada jest sistematično i pregledno prikazati farmakogenetiku 5-fluorouracila (5-FU-a) i polimorfizme gena za dihidropirimidin-dehidrogenazu (DPYD) koji utječu na učinkovitost i sigurnost terapije 5-FU-om. Time bi se zdravstvenim djelatnicima olakšala odluka o odbacivanju ili odabiru i individualizaciji terapije 5-FU-om prema određenom genotipu onkološkog pacijenta kojem je potrebno liječenje 5-FU-om, a sve u svrhu sigurnog liječenja i prevencije teških nuspojava i smrti.
Materijali i metode: Pretražena je znanstvena literatura objavljena u bazama podataka Medline i PubMed u posljednjih 10 godina. Također su pretražene publikacije stručnih udruga i institucija, baze lijekova te ostali znanstveni izvori. Komentirane su terapijske smjernice za primjenu i individualizaciju terapije 5-FU-om (polimorfizmi gena DPYD-a c.1905+1G>A, c.1679T>G, c.2846A>T i c.1236G>A). Opisana je i moguća važnost drugih polimorfizama DPYD-a (c.496A>G, c.85T>C i c.2194G>A) te su navedene i međuetničke i međurasne razlike u učestalosti nekih polimorfizama DPYD-a. Izneseni su i podaci o mogućnostima individualizacije terapije 5-FU-om u Hrvatskoj, tj. informacije o laboratorijima koji provode genotipizaciju DPYD-a. Rezultati: Aktivnost enzima dihidropirimidin-dehidrogenaze (DPD) ograničavajući je faktor brzine metabolizma 5-FU-a i podliježe velikoj varijabilnosti stoga su bolesnici s nedostatkom DPD-a pod povećanim rizikom od toksičnosti povezane s fluoropirimidinima. Smjernice za genotipizaciju DPYD-a i doziranje fluoropirimidina izdane od strane CPIC-a (Clinical Pharmacogenetics Implementiation Consortium) uključuju 4 varijante gena DPYD za koje je dokazano da smanjuju aktivnost DPD-a (c.1905+1G>A, c.1679T>G, c.2846A>T i c.1236G>A). Proučavani su i drugi polimorfizmi (c.496A>G, c.85T>C i c.2194G>A) te većina rezultata govori u prilog smanjene aktivnosti enzima DPD-a uslijed njihove prisutnosti. U talijanskoj randomiziranoj studiji Three or six colon adjuvant (TOSCA) ozbiljne i
teške nuspojave zabilježene su u 38,2 % ispitanika (nositelji mutacija c.2194G˃A, c.1905+1G˃A i c.496A˃G). Kliničko ispitivanje Pan-European Trials in an Alimentary Tract Cancer (PETACC-8) također potvrđuje gore navedeno jer je u istom utvrđeno da su se ozbiljne nuspojave javljale u 85,7 % nositelja mutacije c.2846A˃T i 60,8 % nositelja mutacije c.2194G˃A. Božina i suradnici su zabilježili ozbiljne nuspojave u čak 56,3 % ispitanika (nositelji varijanti c.496A>G ili c.2194G>A) dok mutacija c.85T>C nije bila povezana s razvojem ozbiljnih nuspojava. U radu Henricks i suradnika pokazano je da je predterapijsko testiranje isplativo ili barem ne predstavlja dodatni trošak za zdravstveni sustav. Zaključak: Nositelji inaktivirajućih alela DPYD-a imaju značajno veći rizik ozbiljnih nuspojava. Zbog toga su izdane preporuke za obavljanje genetičkog testiranja DPYD-a ili mjerenja aktivnosti DPD-a prije primjene lijeka. Time se olakšava odluka o odabiru 5-FU-a i doze prema pacijentovom genetičkom profilu te se smanjuju troškovi zdravstvene zaštite jer se poboljšava liječenje i smanjuju rizici koji, osim što predstavljaju teško stanje i patnju za pacijenta, za zdravstveni sustav predstavljaju i trošak u zbrinjavanju nuspojava liječenja.Objectives: This thesis aim is to systematically and clearly present the pharmacogenetics of 5-fluorouracil (5-FU) and DPYD gene polymorphisms that affects the efficacy and safety of 5-FU therapy. Healthcare professionals would find it easier to decide whether to reject or select and individualize 5-FU therapy according to the specific genotype of an oncology patient in need of 5-FU treatment, thus providing the safe treatment and prevention of severe side effects and death.
Materials and methods: The scientific literature in databases Medline and PubMed in the last 10 years has been searched. Publications of professional associations and institutions, drug databases and other scientific sources also were searched. Therapeutic guidelines for the application and individualization of 5-FU therapy are commented (the most important polymorphisms of the DPYD gene c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A). The possible importance of other DPYD polymorphisms (c.496A>G, c.85T>C and c.2194G>A) is also described, and interethnic and interracial differences in the frequency of some DPYD polymorphisms are listed. Information on laboratories that perform DPYD genotyping and the possibilities of individualization of 5-FU therapy in Croatia are also presented.
Results: DPD activity is a limiting factor in the rate of 5-FU metabolism and is subject to high variability, therefore patients with DPD deficiency are at increased risk of toxicity related to fluoropyrimidines. Guidelines for DPYD genotyping and fluoropyrimidine dosing were published by CPIC (Clinical Pharmacogenetics Implementation Consortium), which include 4 variants that have been shown to reduce DPD activity (c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G A). Other polymorphisms (c.496A>G, c.85T>C and c.2194G>A) have been studied in various studies and most of the results speak in favor of reduced activity of DPD enzymes due to their presence. In the Italian randomized study Three or six colon adjuvant (TOSCA), serious and severe side effects were reported in 38.2 % of subjects (carriers of mutations c.2194G˃A, c.1905+1G˃A and c.496A˃G). Clinical trial Pan-European Trials in an Alimentary
Tract Cancer (PETACC-8) also confirms the above mentioned as it was found that serious side effects occurred in 85.7 % of carriers of mutation c.2846A˃T and 60.8 % of carriers of mutation c.2194G˃А. Božina and co-workers reported serious side effects in 56.3 % of subjects (carriers of c.496A>G or c.2194G>A) while c.85T>C mutation was not associated with the development of serious side effects. The work of Henricks and co-workers has shown that pre-therapy testing is cost-effective or at least does not represent an additional cost to the health care system.
Conclusion: Carriers of DPYD inactivating alleles have a significantly higher risk of serious side effects. Therefore, recommendations have been issued to perform genetic testing for DPYD or to measure DPD activity prior to drug administration. This facilitates the decision on the choice of 5-FU and dose individualization according to the patient's genetic profile and reduces health care costs because it improves treatment and reduces risks that represents suffering for the patient and cost the health system
Challenges and opportunities in amphetamine use
No full textU ovom diplomskom radu prikazan je povijesni pregled upotrebe amfetamina od njihovog otkrića pa sve do danas. Nakon njihovog otkrića, širu primjenu su našli za vrijeme 2. Svjetskog rata kada su davani primjenjivani vojnicima kao psihostimulansi. Zbog potencijala zlouporabe i rizika za razvoj ovisnosti, danas je njihova primjena strogo regulirana.Krajem četrdesetih godina prošlog stoljeća došlo je do spoznaja o potencijalu amfetamina za razvijanje ovisnosti. Iz tog razloga uvedena je stroga regulativa propisivanja i njihove upotrebe.
Bez obzira na sve to,rizike, oni su našli svoju primjenu u liječenju ADHD-a, narkolepsije i pretilosti. Amfetamin je po kemijskom sastavu α-metilfenetilamini, a dolazi kao racemična smjesa. Dokazano je da d-amfetamin ima veću farmakološku aktivnost od l-amfetamina. Općenito amfetamini pokazuju brzu apsorpciju i dosežu maksimalnu koncentraciju lijeka u krvi nakon 1-3 sata pri oralnoj primjeni, a poluvrijeme eliminacije iznosi 9-11 sati. Da bi se smanjila učestalnost doziranja lijeka i povećavala adherencija na terapiju, posebno kod djece, razvijeni su novi terapijski sustavi s produljenim oslobađanjem lijeka te prolijek lisdeksamfetamin, kompleks d-amfetamina i l-lizina koji se razgrađuje u eritrocitima i oslobađa aktivnu komponentu d-amfetamina. Novi terapijski sustavi s produljenim oslobađanjem također su razvijeni da bi smanjili mogućnost zloupotrebe koja je bila više izražena kod oblika s trenutnim oslobađanjem.
Iako amfetamini imaju svoje pozitivne učinke, njihova zloupotreba može dovesti do razvoja ovisnosti te ozbiljnih kardiovaskularnih, cerebrovaskularnih i psihičkih nuspojava.
Dosadašnja istraživanja rađena su na manjem broju ispitanika, uglavnom zdravih odraslih osoba, u kraćem vremenskom periodu, te se nameće potreba za daljnjim istraživanjima koja bi uključila kroničnu primjenu lijeka s amfetaminima te procjenjivala akutnu i odgođenu korist i rizike primjene, posebice one od razvoja ovisnosti i kardiovaskularnih te psihičkih komplikacija, s naglaskom na dječju i adolescentsku populaciju.This Bachelor's Thesis presents a historic review of amphetamine use from discovery until today. After their discovery, they found wider usage during World War II when they were given to soldiers as psychostimulants. The knowledge about amphetamine abuse potential has been recognized in the late 1940s. Therefore, a more strict regulatory control has been implented in prescription and use. Nevertheless, amphetamines have been used in treatment of ADHD, narcolepsy and obesity. Amphetamine is an α-methylphenethylamine and comes in the form of racemic mixture. It was confirmed that d-amphetamine shows higher pharmacological activity than l-amphetamine. Pharmacokinetic studies show their fast absorption with maximal blood concentration after 1-3 hours in oral application, with half-life of 9-11 hours. In order to decrease frequency of drug application and increase adherency, especially in child population, new therapeutic systems have been developed with prolonged release and a prodrug lisdexamphetamine, complex of d-amphetamine and l-lysine, which converts to the active d-amphetamine component in red blood cells. New therapeutic systems with prolonged release have also been developed to decrease abuse potential which occured at immediate release dosage forms.
Although aphetamines show positive therapeutic effects, their recreational abuse can cause addiction and lead to serious cardiovascular, cerebrovascular and psychiatric side effects.
Clinical studies have been performed on limited number of subjects so far, mainly on heatlhy volunteers and in shorter period of time. Therefore, there is a need for larger studies that would include populations with chronic amphetamine therapy and that would enable conclusions of acute and delayed usage and risks of application like development of addiction, cardiovascular and psychiatric complications, especially in children and adolescent population
Treatment options for cluster headache
No full textCluster glavobolja je najbolnija primarna glavobolja koja se ubraja u trigeminalne autonomne cefalgije (TAC).
Karakterizirana je snažnim jednostranim napadajima koji se javljaju u nakupinama (tzv. klasterima) između kojih su
razdoblja remisije. Napadaj boli traje 15 do 180 minuta te je praćen lakrimacijom, rinorejom i crvenilom oka. Ovisno o
trajanju remisije između napadaja, cluster glavobolja se dijeli na epizodičnu i kroničnu cluster glavobolju.
Patofiziologija cluster glavobolje je složena i još uvijek nije u potpunosti razjašnjena. Prema dosadašnjim saznanjima
u patogenezu cluster glavobolje uključeni su trigeminovaskularni sustav, autonomni sustav i hipotalamus. Također,
važnu ulogu u patogenezi imaju neuropeptidi kao što su CGRP, PACAP-38 i VIP.
Liječenje cluster glavobolje može biti usmjereno na prekidanje akutnog napadaja ili na prevenciju napadaja. Za akutno
liječenje najčešće se koriste kisik i triptani, a za profilaktičko liječenje verapamil i litij. Kortikosteroidi su se pokazali
korisnima na početku epizodične cluster glavobolje dok dugoročna prevencija ne postane učinkovita. Galkanezumab se
pokazao učinkovitim u profilaktičkom liječenju kod pacijenata s epizodičnom cluster glavoboljom. U liječenju i
prevenciji važnu ulogu imaju i neurostimulacijske tehnike kao što su neinvazivna stimulacija živca vagusa, duboka
mozgovna stimulacija, stimulacija sfenopalatinskog ganglija i invazivna stimulacija okcipitalnog živca.
Cilj akutnog liječenja cluster glavobolje je olakšati simptome i skratiti trajanje boli, dok se preventivnim liječenjem
nastoji smanjiti frekvencija napadaja, kao i njihov intenzitet. Kako bi se postigli željeni terapijski ciljevi, nužno je
pacijente s cluster glavoboljom educirati o samoj bolesti i pravilnoj primjeni lijekova. Upravo u tome važnu ulogu imaju
farmaceuti kao educirani posrednici između liječnika i pacijenata.Cluster headache is the most painful primary headache that is included in trigeminal autonomic cephalgias (TACs). It is
characterized by strong unilateral attacks that occur in clusters between periods of remission. The pain attack lasts 15
to 180 minutes and is accompanied by lacrimation, rhinorrhea and redness of the eye. Depending on the duration of the
remission between attacks, cluster headache is divided into episodic and chronic cluster headache.
The pathophysiology of cluster headache is complicated and not yet fully understood. According to current knowledge,
the trigeminovascular system, the autonomic system and the hypothalamus are involved in the pathogenesis of cluster
headaches. Neuropeptides such as CGRP, PACAP-38 and VIP are also an important part of pathogenesis.
Treatment of cluster headache can be aimed at terminating an acute attack or at preventing it. Oxygen and triptans are
most often used for acute treatment, while verapamil and lithium are used for prophylactic treatment. Corticosteroids
were shown useful at the onset of episodic cluster headache until long-term prevention becomes effective. Galcanezumab
was shown effective in the prophylactic treatment of patients with episodic cluster headache. Neurostimulation
techniques such as non-invasive vagus nerve stimulation, deep brain stimulation, sphenopalatine ganglion stimulation
and invasive occipital nerve stimulation also play an important role in treatment and prevention.
The goal of acute treatment of cluster headache is to relieve symptoms and shorten the duration of pain, while preventive
treatment aims to reduce the frequency of attacks, as well as their intensity. To achieve the desired therapeutic goals, it
is necessary to educate patients with cluster headaches about the disease itself and the proper use of medications. This
is exactly where pharmacists play an important role as educated mediators between doctors and patients
In vitro characterisation of nasal powder delivery system of sodium dexamethasone phosphate using Calu-3 respiratory epithelial cell model
No full textNazalna primjena lijekova istraţuje se u svrhu izravne dostave u središnji ţivčani sustav. Razvijanjem novih praškastih terapijskih sustava poboljšava se efikasnost takve primjene. U ranoj fazi razvoja ispituju se biokompatibilnost i utjecaj sustava na permeabilnost lijeka na in vitro modelima.
Cilj rada bio je pripremiti praškaste sustave mikrosfera s uklopljenim natrijevim deksametazon fosfatom (NDF-om) i inertnog nosača (laktoze i manitola) te odrediti osmolalnost disperzije sustava, kao i biokompatibilnost sustava te permeabilnost uklopljenog NDF-a korištenjem Calu-3 staničnog modela nazalnog epitela.
Metodom sušenja raspršivanjem uspješno su pripravljene mikrosfere graĎene od pektina i hipromeloze, sa sadrţajem uklopljenog NDF-a od 31,6 ± 1,5 %. Miješanjem mikrosfera s inertnim nosačem (laktozom i manitolom) u omjeru 1:9 (m/m) uspješno su pripravljeni praškasti sustavi. OdreĎena je osmolalnost disperzije sustava nakon suspendiranja u smjesi pročišćene vode i HBSS-Ca2+ (1:1, V/V). Vijabilnost Calu-3 staničnog modela nakon izlaganja ispitivanim sustavima bila je u rasponu od 81,5 ± 5,4 % do 113,8 ± 1,6 %. Manitol je pokazao bolja svojstva kao nosač u odnosu na laktozu. Za praškaste sustave s manitolom zabiljeţeno je reverzibilno smanjenje transepitelnog električnog otpora staničnog monosloja tijekom ispitivanja permeabilnosti te značajno veći prividni koeficijent permeabilnosti (Papp) NDF-a kroz Calu-3 stanični monosloj u odnosu na Papp NDF-a iz otopine.
Zaključno, pripravljeni praškasti sustav mikrosfera s uklopljenim NDF-om i manitolom kao inertnim nosačem pokazao je potencijal za nazalnu primjenu prema utvrĎenoj biokompatibilnosti i permeabilnosti lijeka in vitro.Nasal drug administration is being examined as a direct delivery path to the central nervous system. The development of new powder drug delivery systems improves the effectiveness of such applications. Biompatibility and impact of system on drug permeability are evaluated early in the development using in vitro models.
The aim of this study was to prepare powder systems of microspheres with entrapped sodium dexamethasone phosphate (NDF) and inert carrier (lactose and mannitol), and to determine the osmolality of the dispersion of the systems, their biocompatibility and permeability of the incorporated NDF using a Calu-3 cell model of the nasal epithelium.
Microspheres made of pectin and hypromellose with a drug loading of 31.6 ± 1.5 %, were successfully prepared by spray-drying. Powder systems were successfully prepared by mixing microspheres with lactose and mannitol in ratio of 1:9 (w/w). The osmolality of the dispersion of powder systems was determined after suspending in a mixture of purified water and HBSS-Ca2+ (1:1, V/V). Calu-3 cell viability after exposure to the systems ranged from 81.5 ± 5.4 % to 113.8 ± 1.6 %. Mannitol showed better properties as the carrier compared to lactose. For systems with mannitol, a reversible decrease in transepithelial electrical resistance of the cell monolayer and significantly higher apparent permeability coefficient (Papp) of NDF across the Calu-3 monolayer in comparison to Papp of NDF in solution were observed.
In conclusion, prepared powder system composed of NDF loaded microspheres and mannitol showed potential for nasal administration considering determined in vitro biocompatibility and drug permeability
Regulativni zahtjevi za odobravanje cjepiva protiv bolesti COVID-19 u Europskoj uniji
No full textCilj istraživanja
Cilj istraživanja je detaljnije objasniti ulogu nadležnih institucija, postupke i vrste davanja
odobrenja za cjepiva protiv bolesti COVID-19.
Hipoteze istraživanja temelje se na utvrđenim propisima i postupcima nadležnih institucija u
Europskoj uniji kako bi se čim prije proizveli i odobrili lijekovi i cjepiva protiv bolesti COVID19 u svrhu sprječavanja širenja bolesti. Također, prate se i načini i posljedice cijepljenja na nivou
Europske unije kako bi se skupilo što više informacija o bolesti COVID-19.
Materijali i metode
Provedeno je detaljno istraživanje postojeće literature i svih službeno dostupnih podataka koja se
odnose na odobravanje cjepiva unutar Europske unije, s posebnim naglaskom na ubrzani postupak
davanja odobrenja. U svrhu boljeg razumijevanja potrebe za hitnim odobrenjem cjepiva, također
je istražena odobrena i dostupna literatura koja se odnosi na porijeklo i nastanak bolesti COVID19. Ovaj dio istraživanja proveden je pretraživanjem objavljenih zakona, uredbi i pravilnika na
stranicama Europske agencije za lijekove (EMA), Europske komisije (EK), Hrvatske agencije za
lijekove i medicinske proizvode (HALMED), Hrvatskog zavoda za javno zdravstvo kao i
akreditiranih baza podataka npr. ScienceDirect, PubMed, Elsevier koristeći sljedeće pojmove:
COVID-19, koronavirus, SARS-CoV-2, COVID-19 cjepivo i sl. Nadalje, pojašnjene su razlike
Regulativni zahtjevi za odobravanje cjepiva protiv bolesti COVID-19 u Europskoj uniji
odobrenih cjepiva protiv bolesti COVID-19 u Europskoj uniji iz regulativne perspektive kao i
predložene strategije i plan distribucije istih.
Rezultati
Ovo istraživanje osigurava detaljan uvid u stroge zahtjeve farmaceutske kakvoće, sigurnosti
primjene i djelotvornosti kako bi se odobrilo cjepivo protiv bolesti COVID-19 po ubrzanom
postupku u svrhu sprečavanje daljnjeg širenja zaraze. Također, istraživanje je prikazalo i
analiziralo najnovije prikupljene podatke o odobrenim cjepivima te daljnje korake regulativnih
institucija u Europskoj uniji.
Zaključak
Trenutačno pandemijsko širenje bolesti COVID-19 predstavlja globalnu krizu s velikim
zdravstvenim, socijalnim i ekonomskim utjecajem. Stoga je bilo potrebno uložiti iznimne napore
u razvoj i proučavanje cjepiva protiv bolesti COVID-19 kako bi učinkovita cjepiva ispunila
zahtjeve za ishođenje odobrenja i bila što prije dostupna. Trenutno su u Europskoj uniji odobrena
sljedeća cjepiva protiv bolesti COVID-19 različitih proizvođača: Comirnaty, Spikevax (prijašnji
naziv: COVID-19 Vaccine Moderna), Vaxzevria (prijašnji naziv: COVID-19 Vaccine
AstraZeneca) i COVID-19 Vaccine Janssen. Također, nastavno na dogovorene strategije i plan
cijepljenja u Europskoj uniji, EMA prikuplja sve nuspojave odobrenih cjepiva, dok Europski
centar za prevenciju i kontrolu bolesti prati učinkovitost cjepiva protiv bolesti COVID-19. Time
Regulativni zahtjevi za odobravanje cjepiva protiv bolesti COVID-19 u Europskoj uniji
se omogućuje identifikacija i procjena novih informacija kojima se osigurava otkrivanje
potencijalnih rizika te njihove prevencije.Objectives
The aim of the study is to explain in more detail the role of competent institutions, procedures and
marketing authorisation types for COVID-19 vaccines. The research hypotheses are based on the
established rules and procedures of the competent institutions in the European Union in order to
produce and approve COVID-19 medicinal products and vaccines as soon as possible to prevent
the spread of disease. The vaccination administration and consequences of vaccination at the level
of the European Union are also monitored to gather as much information as possible about
COVID-19.
Material and Methods
Detailed study of the existing literature and any officially available data concerning the vaccine
authorisations within the European Union has been carried out, with a particular focus on the
conditional marketing authorisation procedure. For the purposes of a better understanding of the
need for an urgent fast-track vaccine approvals, the approved and available literature relating to
the origin and emergence of COVID-19 disease has also been investigated. This part of the
research was carried out by searching published laws, regulations and ordinances on the pages of
the European Medicines Agency (EMA), the European Commission (EC), the Croatian Agency
for Medicinal Products and Medical Devices (HALMED), the Croatian Public Health Agency as
well as accredited databases, e.g. ScienceDirect, PubMed, Elsevier using the following terms:
COVID-19 disease, coronavirus, SARS-CoV-2, COVID-19 vaccine, etc. Furthermore, the
Regulativni zahtjevi za odobravanje cjepiva protiv bolesti COVID-19 u Europskoj uniji
differences of the approved COVID-19 vaccines in European Union from the regulatory
perspective and the proposed strategies and the distribution plan have been clarified.
Results
This research provides a detailed insight into the strict pharmaceutical quality requirements, safety
and efficacy requirements in order to approve COVID-19 vaccines following urgent fast-track
vaccine approvals procedures to prevent further contagion spread. The research also presented and
analysed the most recent data about approved vaccines and further steps of the regulatory
institutions in the European Union.
Conclusion
The current pandemic COVID-19 disease spread is a global crisis with a major health, social and
economic impact. Therefore, it was necessary to make exceptional efforts to study and develop
vaccines against COVID-19 in order to meet the requirements for marketing authorisation and
availability as soon as possible. The following COVID-19 vaccines of different producers are
currently authorised in the European Union: Comirnaty, Spikevax (previous product name:
COVID-19 Vaccine Moderna), Vaxzevria and COVID-19 Vaccine Janssen. In addition, following
the agreed strategy and vaccination plan in the European Union, the EMA shall collect all side
effects of authorised vaccines, while the European Centre for Disease Prevention and Control shall
monitor the efficacy of COVID-19 vaccines. Above written enables identification and assessment
of new information to ensure the detection of potential risks and their prevention
Primjena peroralnih preparata željeza u prevenciji i liječenju sideropenične anemije u dječjoj dobi
No full textSideropenična anemija ili anemija nastala uslijed nedostatka željeza u organizmu javlja se kad je
smanjen unos željeza prehranom, kad postoji poremećaj u apsorpciji željeza u probavnom traktu, zbog
gubitka krvi ili zbog povećanih potreba organizma za željezom. Procjenjuje se da od sideropenične
anemije pati oko 30% svjetske populacije od čega je više od 40% zastupljenost među predškolskom
djecom. U prevenciji nastanka sideropenične anemije značajna je edukacija roditelja i populacije
općenito o važnosti pravilne prehrane i unosu željeza u organizam putem hrane, s posebnim naglaskom
na potrebu za dodatkom željeza u adaptirane mliječne formule za dojenčad i malu djecu.
U liječenju je najznačajnije pronaći i liječiti uzrok zbog kojeg je to stanje nastalo, a cilj liječenja je
normalizacija krvne slike, serumskog željeza i transferina, ali najvažnije je popuniti rezerve željeza.
Liječenje sideropenične anemije se provodi peroralnim preparatima željeza koji su po svome sastavu
organske ili anorganske soli željeza u dvovalentnom (fero) ili trovalentnom (feri) obliku.
Ovaj rad ima za cilj dati sustavni pregled aktualnih smjernica, preporuka i postupaka koji se koriste u
svrhu prevencije i liječenja sideopenične anemije u pedijatrijskoj populaciji. Također, dati će se pregled
peroralnih preparata željeza registriranih kao lijekovi i kao dodaci prehrani zastupljeni na hrvatskom
tržištu kao i početnih dojenačkih formula.
Prilikom izrade ovog teorijskog rada korišteni su preglednici znanstvene literature kao što su
internetske baze podataka, udžbenik iz područja hematologije, smjernice stručnih društava te važeći
zakoni i pravilnici iz područja istraživanja. Za teorijsku analizu lijekova, dodataka prehrani i početnih
dojenačkih formula dostupnih na hrvatskom tržištu pretraživana je internetska baza lijekova Hrvatske
agencije za lijekove i medicinske proizvode, registar dodataka prehrani i hrane za posebne
prehrambene potrebe kao i mrežne stranice nositelja odobrenja za proizvode koji su u ovom radu
analizirani.
Rezultati ispitivanja ovog rada daju analizu dostupnih lijekova i dodataka prehrani na hrvatskom tržištu
kojima se može uspješno prevenirati i/ili liječiti sideropenična anemija u pedijatrijskoj populaciji; njihov
sastav, farmaceutski oblik i potrebnu dozu. Dostupni preparati na hrvatskom tržištu registrirani kao
lijekovi imaju jasno definiran udio elementarnog željeza po mililitru pripravka, a ono se nalazi u obliku
sulfata, hidroksida, proteinsukcinilata i glicin sulfata. Peroralnih preparata registriranih kao dodaci
prehrani na tržištu Republike Hrvatske ima znatno više nego preparata registriranih kao lijekovi. Veći
broj pripravaka sadrži željezo u dvovalentoj formi fumarata, laktata, glukonata i bisglicinata kao i
trovalentno mikrokapsulirano željezo.
Iz podataka dobivenih uspoređivanjem sastava i udjela željeza u adaptiranim mliječnim formulama
dostupnim na hrvatskom tržištu može se zaključiti da svi pripravci namjenjeni djeci od rođenja do 6.
mjeseca života sadrže željezo te da u njima prevladava željezov (II) sulfat.
Zaključno, sideropenična anemija predstavlja velik javnozdravstveni problem u dječjoj populaciji te je
važna uloga ljekarnika u edukaciji roditelja o unosu željeza prehranom i suplementaciji željezom koja
je ograničena nuspojavama preparata željeza te prekratkim trajanjem terapije. Razlog loše adherencije
uglavnom su gastrointestinalne nuspojave standardnih oblika peroralnog željeza, dok su kod novijih
peroralnih oblika željeza te nuspojave smanjene, a njihova šira primjena ograničena još uvijek visokom
cijenom.Sideropenic anemia or anemia caused by iron deficiency occurs because of lower intake of dietary iron,
gastrointestinal tract iron absorption disorder, blood loss or increased iron inquirements.
It is estimated that about 30% of world population is affected by sideropenic anemia, more than 40%
of them are preschool children.
Educating parents and population in general about importance of the right diet and dietary iron intake
particularly focusing on iron-fortified infant formula is significant in prevention of sideropenic anemia.
The most significant part of treatment is to find and cure the source that caused the condition and the
goal of treatment is normalization of blood test, serum iron and transferrin but the most important is
to fill the iron body iron stores.
Oral organic or inorganic (bivalent or trivalent) iron supplements are used for treating sideropenic
anemia.
On Croatian market there are oral iron supplements registrated as medications and as food
supplements.
The aim of this paper is to give the systematic review of the current guidelines, recommendations
and procedures that are being used in prevention and treatment of sideropenic anemia in pediatric
population. There will also be a review of peroral iron supplements registered as medications and as
food supplements available on Croatian market as well as infant formulas.
Scientific literature browsers have been used while writing this paper, e.g. internet data base,
haematology textbook, guidelines of professional societies and rulebooks of the research field. The
internet data base of agency for medicinal products and medical devices of Croatia, food
supplements and food for particular nutritional uses registry as well as websites of product license
holder that are analysed in this paper have been searched for theoretical analysis of medications,
food supplements and infant formulas available on Croatian market.
This paperʼs research results give the analysis of available medications and food supplements on
Croatian market that can successfully prevent and/or treat sideropenic anemia in pediatric
population; their ingredients, pharmaceutical shape and necessary dosage.
Research results are showing that products available on Croatian market registrated as medicines have
well-defined percentage of elementary iron per product mililiter and it can be in the form of sulfate,
hydroxide, protein succinylate and glycine sulfate. On Croatian market there are more oral supplement
that are registrated as food supplements then as medicines. More supplements contain iron (II)
components of fumarate, lactate, gluconate and bisglycinate as well as trivalent microencapsulated
iron.
Comparing the composition and percentage of iron in adapted formulas available on Croatian market
it can be concluded that all the products for newborn children up to six months of age contain iron and
it is mostly iron (II) sulfate.
In conclusion, sideropenic anemia is a large public health problem for children and the role of a
pharmacist is very important in educating the parents about dietary iron intake and supplementation
which is limited by iron supplements side-effects and short-term duration of therapy. The reason of
poor adherence are mostly gastrointestinal side-effects of standard forms of oral iron whereas new
forms of oral iron have less side-effects but their broader use is still limited because of high price
Method optimisation for determining heavy metals in samples of spices by flame atomic absorption spectroscopy
No full textTeški metali predstavljaju značajnu sirovinu za brojne industrijske grane, neki od njih su neophodni za žive organizme, za produktivnost poljoprivrede, dok su neki od njih zagađivači životne sredine.
Cilj ovog rada bio je provesti validaciju metode za kvantitativnu analizu teških metala iz uzoraka začina pomoću plamene atomske apsorpcijske spektroskopije. U tu svrhu ispitani su validacijski parametri kao što su linearnost, ponovljivost, LOD, LOQ te je optimiziranom metodom provedena kvantitativna analiza teških metala u uzorcima origana i peršina.
Provedeno ispitivanje pokazalo je da u ispitivanom području metoda ima prihvatljivu linearnost, (Zn)2 = 0,9994, (Cu)2 = 0,9994, (Mn)2 = 0,9939, (Fe)2 = 0,9996. Ponovljivost metode izražena kao relativna standardna devijacija (RSD) bila je u rasponu od 0,86 % do 1,72% za Fe, od 0,41% do 1,21% za Mn, od 1,15% do 10,44% za Cu i od 1,88% do 4,43% za Zn, što ukazuje na prihvatljivu ponovljivost. Dobiveni analitički prinos bio je u rasponu od 92,4% do 109.2% što ukazuje ne zadovoljavajuću točnost metode. Najniža granica dokazivana (LOD) iznosila je 0,0619 / za Cu, dok je najviša LOD iznosila 2,2484 / za Mn. Najniža granica određivanja (LOQ) iznosila je 0,1878 / za Cu, dok je najviša LOQ iznosila = 6,8134 / za Mn. Iz navedenih podataka može se zaključiti da validirana metoda ima zadovoljavajuću selektivnost i osjetljivost. Nakon optimizacije metode, izmjerene su koncentracije teških metala u uzorcima. PCA i klasterska analiza pokazale su moguću korelaciju između ispitivanih elemenata i istaknuti su potencijalni izvori metala u ispitivanom materijalu. Ovo istraživanje pokazalo je da se različiti začini mogu grupirati prema sadržaju elemenata u njima što može biti od velike koristi pri analizi kontrole kvalitete.Heavy metals are an important raw material for many industries, some of them are necessary for living organisms, others for agricultural productivity, while some of them are environmental pollutants.
The aim of this work was to validate the method for quantitative analysis of heavy metals from spice samples using flame atomic absorption spectroscopy. For this purpose, validation parameters such as linearity, repeatability, LOD, LOQ were examined, and a quantitative analysis of heavy metals in oregano and parsley samples was performed using an optimized method.
The performed study showed that the method has acceptable linearity in studied range, (Zu) 2 = 0.9994, (Cu) 2 = 0.9994, (Mn) 2 = 0.9939, (Fe) 2 = 0.9996. Method repeatability expressed as relative standard deviation (RSD) ranged from 0.86% to 1.72% for Fe, from 0.41% to 1.21% for Mn, from 1.15% to 10.44% for Cu and from 1.88% to 4.43% for Zn, indicating acceptable repeatability. Recovery results between 92,4% and 109.2% show acceptable accuracy of the method. The lowest limit of detection (LOD) was 0.0619 / for Cu, while the highest LOD was 2.2484 mg/L for Mn. The lowest limit of quantification (LOQ) was 0.1878 / for Cu, while the highest LOQ was 6.8134 / for Mn. After optimization of the method, the concentrations of heavy metals in the samples were measured. PCA and cluster analysis showed a possible correlation between the tested elements and possible sources of metals in the material were highlighted. This study showed that different spices can be grouped according to their content of elements, which can be very useful for quality control analysis
Pharmacologic properties of drugs used in irritable bowel syndrome therapy
No full textSindrom iritabilnog crijeva (engl. irritable bowel syndrome, IBS) najčešći je funkcionalni poremećaj crijeva koji zahvaća 11 % svjetske populacije. Kompleksni poremećaj rezultat je složenog međudjelovanja različitih patofizioloških mehanizama koji uključuju poremećaj u komunikaciji središnjeg i mijenteričkog živčanog sustava, poremećaj u sastavu i funkciji crijevne mikrobiote, visceralnu preosjetljivost i poremećaj motiliteta. IBS se prema kliničkoj slici dijeli u podskupine: IBS s dominantnom dijarejom, IBS s dominantnom konstipacijom i miješani oblik IBS-a. Liječenje IBS-a zahtjevan je proces zbog složene patofiziologije u kojem ne postoji jedan uzrok koji bi bio glavna meta liječenja. Promjenjiva priroda bolesti otežava praćenje liječenja i učinkovitosti primijenjenih metoda i lijekova. Terapija IBS-a trebala bi uključivati i nefarmakološke i farmakološke mjere, od kojih je farmakološka terapija u fokusu ovog rada. U farmakološkoj terapiji najvažnije mjesto zauzimaju laksativi i antidijaroici kao prva linija liječenja, zatim spazmolitici, lijekovi s djelovanjem na serotoninski sustav, antibiotici i antidepresivi u težim oblicima bolesti. Pristup liječenju bolesnika s IBS-om mora biti individualan koliko je to moguće. Izbor lijekova, doza i trajanje liječenja moraju se prilagoditi svakom pacijentu. Pregled najvažnijih karakteristika lijekova ukazuje da većina imaju povoljan farmakološki i sigurnosni profil, pogotovo lijekovi novije generacije. Najnoviji lijekovi su dalje usmjereni na nove mete uz poboljšanje farmakokinetskog i sigurnosnog profila u odnosu na starije lijekove. Korištenje antidepresiva u liječenju IBS-a zahtjeva poseban oprez i praćenje, jer su to lijekovi s najviše nuspojava, uz odgođeni terapijski učinak. Većina lijekova iz ostalih skupina svoje djelovanje ispoljava izravno u crijevima i ima minimalne sistemske nuspojave. Važno je naglasiti da su lijekovi koji se koriste u terapiji IBS-a vrlo raznoliki, djeluju različitim mehanizmima, ali dijele većinu nuspojava. Nuspojave su uglavnom vezane za GI trakt, a uključuju nadutost, mučninu, povraćanje, abdominalnu bol. Uloga farmaceuta iznimno je važna u povećanju kvalitete života pacijenata koji boluju od IBS-a. Klinički farmaceut kroz edukacije o bolesti, lijekovima, provođenju terapije i prilagodbi životnog stila može značajno povećati adherenciju na terapiju i utjecati na postizanje željenih ishoda liječenja. Ljekarnik ima važnu ulogu u praćenju pacijenta i prikladnom savjetovanju ovisno o tijeku bolesti te odabiru lijekova u bezreceptnom režimu.Irritable bowel syndrome is the most common functional bowel disorder, affecting 11 % of the world's population. This complicated disorder is the result of complex interaction of various pathophysiological mechanisms that include central and mienteric nervous system communication disorder, intestinal microbiota composition and function disorder, visceral hypersensitivity, and motility disorder. According to the clinical manifestations, IBS is divided into subgroups: diarrhoea predominant IBS, constipation predominant IBS and mixed form of IBS. The treatment of IBS is a demanding process due to the complex pathophysiology in which there is no one paticular cause that would be the main target of treatment. The unpredictable nature of the disease makes it difficult to monitor the treatment and effectiveness of the therapy. IBS therapy should include both nonphamacological and pharmacological measures, of which pharmacological therapy is the focus of this paper. In pharmacological therapy the most important place is taken by laxatives and antidiarrhoeals as the first line of treatment, followed by antispasmodics, drugs that affect the serotonin system, antibiotics and antidepressants in severe forms of IBS. Therapeutic approach must be as individual as possible. The choice of medication, dose and duration of treatment must be adjusted to each patient. An overview of the most important drug characteristics indicates that most of them have a favorable pharmacological and safety profile, especially newer generations of drugs. The use of antidepressants ih the treatment of IBS requires special caution and monitoring because these drugs have the most side effects, with delayed therapeutic effect. Most drugs from other therapeutic groups affect their targets in the gut directly and have minimal systemic side effects. It is important to emphasize that the drugs used in treatment of IBS have heterogeneous mechanisms of action, but share most of side effects. Most side effects are related to the GI tract, and are manifested as bloating, nausea, vomiting, and abdominal pain. The role of pharmacists is extremely important in increasing the quality of life of IBS patients. A clinical pharmacist can significantly increase therapy adherence and achieve better treatment outcomes trough education about the illness, medications, therapy, and lifestyle adjustments. A pharmacist has an important role in monitoring the patient and presenting appropriate counseling depending on the current condition and the choice of OTC medications
Association of extracellular molecules heat shock protein 70 and adenosine triphosphate with systemic inflammatory response in patients with chronic obstructive pulmonary disease
No full textKronična opstrukcijska plućna bolest (KOPB) kompleksna je i heterogena bolest s kroničnom upalom. Sustavni upalni odgovor vidljiv je u povećanju koncentracije općih upalnih biljega poput C-reaktivnog proteina (CRP), fibrinogena (Fbg), ukupnog broja leukocita (lkc) i upalnih citokina. Uslijed upalnih reakcija i oštećenja stanica u KOPB-u, povećava se koncentracija izvanstaničnog proteina toplinskoga šoka 70 (eHsp70) i izvanstaničnog adenozin-trifosfata (eATP). U ovom istraživanju određene su plazmatske koncentracije eHsp70 i eATP-a u 137 pacijenata sa stabilnim KOPB-om i uspoređene s koncentracijama u 95 kontrolnih ispitanika. Ispitano je postoji li povezanost ovih parametara sa stupnjem plućne opstrukcije, simptomima i povijesti egzacerbacija te pušačkim statusom. Određena je relativna razina ekspresije gena HSP70, TLR2 i TLR4 (dva receptora za eHsp70) te P2X7R i P2Y2R (dva receptora za eATP) te genotipizacija polimorfizama u genima HSP70, TLR2 i TLR4. eHsp70 i eATP povezani su s KOPB-om, sa stupnjom plućne opstrukcije i progresijom simptoma. Također, koncentracije eHsp70 i eATP-a veće su u skupini zdravih pušača nego u zdravih nepušača što ukazuje na pojavu upalnih procesa prilikom izlaganja cigaretnom dimu prije pojave bolesti. Značajna povezanost uočena je između IL-1β, IL-6, TNF-α, CRP-a, Fbg-a, eHsp70 i eATP-a u pacijenata s KOPB-om, a hijerarhijskom klasterskom analizom potvrđena je heterogenost i kompleksnost bolesti. Model sastavljen od IL-1β, eHsp70 i eATP-a pokazao je veliku predikcijsku vrijednost. Značajno povećanje relativne genske ekspresije u pacijenata s KOPB-om u odnosu na zdrave ispitanike opaženo je za HSP70, TLR2 i P2Y2R gene, dok je analiza polimorfizama ukazala da postoji povezanost između rizika od KOPB-a i polimorfizma rs6457452 u promotorskom dijelu gena HSP70. eHsp70 i eATP biljezi su sustavnog upalnog odgovora u KOPB-u i dio su patogeneze KOPB-a, a u kombinaciji s IL-1β čine model s velikim predikcijskim potencijalom. Dodatni doprinos istraživanja postignut je analizom genske ekspresije i polimorfizama koje pružaju bolje razumijevanje mehanizama i patogeneze KOPB-a.Chronic obstructive pulmonary disease (COPD) is a complex and heterogenous disease with chronic inflammation. Systemic inflammatory response is followed by increased concentration of common inflammatory biomarkers as C-reactive protein (CRP), total count of leukocytes (lkc), fibrinogen (Fbg) and inflammatory cytokines. There is an increase in extracellular heat shock protein 70 (eHsp70) and extracellular adenosine triphosphate (eATP) due to inflammatory response and cell damage in COPD. In this thesis, eHsp70 and eATP were determined in 137 patients with stable COPD and compared with the concentrations in 95 controls. It was assessed if there is the association between eHsp70 and eATP and the severity of the airflow limitation, symptoms burden and history of excerbations as well as smoking status. The relative gene expression HSP70, TLR2 and TLR4 (eHsp70 receptors) as well as P2X7R and P2Y2R (eATP receptors) was determined. Moreover, selected HSP70, TLR2 i TLR4 polymorphisms were genotyped. There was an association of eHsp70 and eATP with COPD compared to healthy subjects, airflow limitation and symptoms severity. eHsp70 and eATP were increased in control smokers compared to non-smoking controls which indicates there is an inflammatory response due to the expose of cigarette smoke even before the disease occurs. Significant association was observed between IL-1β, IL-6, TNF-α, CRP, Fbg, eHsp70 and eATP in COPD patients, while hierarchical cluster analysis confirmed heterogeneity and complexity of COPD. Based on logistic regression analysis, combination of IL-1β, eHsp70 and eATP-a showed significant predictive potential in identifying COPD subjects. There was a significant increase in the relative gene expression of HSP70, TLR2 and P2Y2R genes in COPD patients, while the analysis of single nucleotide polymorphisms showed an association of rs6457452 in the promoter region of HSP70 with the risk of COPD. In conclusion, eHsp70 and eATP are biomarkers of systemic inflammatory response in COPD and it seems they might be useful as prognostic biomarkers, especially in a combination with IL-1β. This thesis contributed with the data at genetic level which could be useful for better understanding of the COPD pathogenesis
Impact of microalgae Pseudo-nitzschia metabolites on oxidative stress parameters in blood cells
No full textMikroalge roda Pseudo-nitzschia prisutne su u gotovo svim morskim i estuarijskim ekosustavima te čine bazu hranidbenoga lanca. Pojedine vrste roda Pseudo-nitzschia izlučuju neurotoksin, domoičnu kiselinu (DK). Poremećaj koji se razvija u ljudi koji su hranom unijeli u organizam DK naziva se amnezijsko trovanje školjkašima. Oksidacijski stres predstavlja neravnotežu u oksido-redukcijskim reakcijama u organizmu te se povezuje s razvojem niza bolesti u ljudi. Cilj ovoga istraživanja bio je ispitati oksidacijski stres kao mehanizam toksičnosti metabolita pojedinih vrsta roda Pseudo-nitzschia u ljudskim stanicama krvi. Prvo su uzgojene tri vrste roda Pseudo-nitzschie, P. delicatissima (PN1), P. pseudodelicatissima (PN2) i P. calliantha (PN3) te je sakupljen hranjivi medij u kojem su rasle mikroalge. Potom su uzorci krvi zdravih dobrovoljnih davatelja tretirani medijem u kojem su rasle Pseudo-nitzschia PN1, PN2 i PN3 te morem i morem i medijem (kontrole) u razdoblju od 4 i 24 sata. Nakon tretmana u uzorcima krvi određene su koncentracije: glutationa (GSH), mjera anti-oksidacijske obrane, malondialdehida (MDA), pokazatelj lipidne peroksidacije te proteinskih karbonili (PC), pokazatelji oksidacijskog oštećenja proteina, spektrofotometrijski. Dobiveni rezultati statistički su obrađeni Studentovim t-testom (Excel, MS Office), a razina značajnosti postavljena je na p ≤ 0,05.
Tretman krvi (4 i 24 sata) s medijem u kojem su rasle Pseudo-nitzschie PN1, PN2 i PN3 doveo je do porasta koncentracije GSH, ali je samo nakon 24-satnog tretmana s P. pseudodelicatissima (PN2) zabilježena značajno viša koncentracija GSH u odnosu na kontrolu (p ≤ 0,05). Tretman hranjivim medijem Pseudo-nitzschie snizio je koncentraciju MDA, a značajan pad koncentracije MDA u krvi u odnosu na kontrolnu skupinu zabilježen je nakon 24-satnog tretmana medijem u kojem je rasla P. delicatissima (PN1) (p ≤ 0,05). Tretman krvi medijem u kojem su rasle PN1, PN2 i PN3 doveo je do pada koncentracije PC, no taj pad nije bio značajan u odnosu na kontrolu. Zabilježeni porast koncentracije GSH nakon tretmana medijem u kojem su rasle Pseudo-nitzschie pokazuje da je došlo do aktivacije obrane od oksidacijskog stresa. Sniženje koncentracija MDA i PC može se povezati s povećanom koncentracijom GSH koja je spriječila oksidacijska oštećenja lipida i proteina. Konačno, može se zaključiti da ispitivane vrste Pseudo-nitzschie u hranjivi medij izlučuju metabolit(e) koji mogu izazvati oksidacijski stres u stanicama krvi.Microalgae of the genus Pseudo-nitzschia are present in almost all marine and estuarine ecosystems and are the basis of the food chain. Some species of the genus Pseudo-nitzschia produce neurotoxin, domoic acid (DA). Individuals who have consumed food containing DA develop disorder called amnesic shellfish poisoning. Oxidative stress is result of an imbalance in oxido-reduction reactions in the body and in humans is associated with the development of numerous diseases. The aim of this study was to explore on human blood cells oxidative stress as a mechanism of toxicity of metabolites of some Pseudo-nitzschia species. In the first step of the study three species of the genus Pseudo-nitzschie were grown: P. delicatissima (PN1), P. pseudodelicatissima (PN2) and P. calliantha (PN3), and the nutrient medium in which the microalgae grew was collected. In the next step blood samples from healthy voluntary donors were treated with collected medium as well as with sea and sea and media (that served as controls) for 4 and 24 hours. After treatment in blood samples glutathione (GSH) as marker of anti-oxidative defence, malondialdehyde (MDA) as marker of lipid peroxidation and protein carbonyls (PC) as marker of oxidative damage to proteins were determined spectrophotometrically. For statistical analysis Student t-test (Excel, MS Office) was used, and the significance level was set at p ≤ 0.05.
In blood samples exposed for 4- and 24-hours to medium in which Pseudo-nitzschie PN1, PN2 and PN3 grew an increase in GSH level was observed. However, only in blood samples exposed for 24-hours to medium in which P. pseudodelicatissima (PN2) grew significantly higher GSH level in comparison to control is recorded (p ≤ 0.05). Exposure to medium in which Pseudo-nitzschie grew decreased MDA level in blood samples. After 24-hour exposure of blood cells to medium in which P. delicatissima (PN1) was grown, a significant decrease in MDA concentration compared to the control group was observed (p ≤ 0.05). 4- and 24-hour exposure of blood cells to medium in which PN1, PN2 and PN3 were grown led to a decrease in PC level, however, the decrease was not significant compared to control. The observed increase in GSH level in blood samples exposed to the medium in which Pseudo-nitzschie grew indicate that in blood cells activation of the defence against oxidative stress occurred. Decrease in MDA and PC level may be explained with increased GSH level that prevented oxidative damage to lipids and proteins. Therefore, it can be concluded that the tested Pseudo-nitzschie species into the nutrient medium secrete metabolite(s), which can induce oxidative stress in human blood cells