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In vitro effect of fosfomycin combined with other antibiotics on clinical isolates and biofilm of Pseudomonas aeruginosa
No full textPseudomonas aeruginosa (PA) jedan je od vodećih uzročnika bolničkih infekcija. Uzrokuje zabrinutost s obzirom na stalni porast otpornosti na antibiotike i mogućnost stvaranja biofilma. Stari antibiotik fosfomicin sve se češće koristi u terapiji sistemnih infekcija uzrokovanih otpornim bakterijama. Bolja učinkovitost može se postići kombiniranim davanjem antibiotika. Cilj istraživanja bio je odrediti in vitro sinergiju fosfomicina s 8 antibiotika koji se koriste u liječenju PA infekcija na izolatima te bakterije s različitim determinantama rezistencije. Cilj je također bio ispitati postantibiotički učinak fosfomicina samog i u kombinaciji s istim antibioticima i utvrditi učinak kombinacija vršnih koncentracija antibiotika na inhibiciju i razaranje biofilma koji stvaraju otporni izolati te bakterije. Testiranje osjetljivosti na antibiotike provedeno je metodom disk difuzije i određivanjem minimalnih inhibitornih koncentracija. Prisustvo β-laktamaza utvrđeno je fenotipskim testovima i lančanom reakcijom polimeraze. Metodom ukriženih trakica i „time-kill“ metodom ispitana je sinergija. Postantibiotički učinak je određen metodom brojanja poraslih kolonija po uklanjanju antibiotika kojemu su bakterije bile izložene. Stvaranje biofilma, inhibicija formiranja i disrupcija biofilma ispitani su statičkim testom u mikrotitarskim pločicama s kristal violetom. Otpornost na fosfomicin registrirana je kod značajnog dijela kliničkih izolata P. aeruginosa (52,9 %). Najveća stopa sinergije određena metodom ukriženih trakica postignuta je u kombinacijama fosfomicina s ceftazidimom (21,6 %) i gentamicinom (17,7 %), a „time-kill“ metodom s kolistinom i gentamicinom. Iako su sve kombinacije s antibioticima produljile postantibiotički učinak, najbolji rezultat postignut je u kombinaciji s kolistinom. Negativne vrijednosti PAE nisu zabilježene niti s jednom kombinacijom. Prema rezultatima ispitivanja biofilma u mikrotitarskim pločicama svi ispitani sojevi bili su proizvođači biofilma. Predominantno je registriran učinak kombinirane terapije na inhibiciju stvaranja biofilma. Kombinirana terapija bila je učinkovitija u sprječavanju nastanka biofilma od monoterapije, čak i kod izolata otpornih na pojedinačno primijenjene antibiotike. Najviše stope inhibicije stvaranja biofilma zabilježene su u kombinacijama s kolistinom, cefepimom i ceftazidimom. Kombinacije s ispitivanim β-laktamskim antibioticima i kolistinom imale su snažniji učinak na inhibiciju formiranja biofilma od inhibitora sinteze proteina. Rezultati dobiveni u ovoj studiji mogli bi biti klinički značajni u pogledu terapije različito otpornog P. aeruginosa, ali i profilakse stvaranja biofilma kod takvih izolata.Pseudomonas aeruginosa (PA) is one of the leading causes of hospital infections. It is a cause for concern given the rapid antibiotic resistance development and the ability of biofilm formation. Fosfomycin has recently reemerged as an interesting treatment option for antimicrobial-resistant infections, and combination therapy is an important treatment alternative. The aim of this research was to determine in vitro synergy of fosfomycin with 8 antibiotics used for treatment of PA infections on variously resistant PA isolates. The aim was also to examine the postantibiotic effect of fosfomycin alone and in combination with those antibiotics and to determine inhibition and disruption of PA biofilm in the presence of peak plasma concentrations of those antibiotics alone and in combination with fosfomycin. Antibiotic susceptibility was determined using the disk diffusion method and the microdilution method. The presence of β-lactamases was determined using phenotypic tests and polymerase chain reaction. Synergy was determined using the gradient diffusion strip cross method (GDSC) and the "time-kill" method. The post-antibiotic effect was determined by the viable colony counting method after antibiotic removal. Biofilm formation, inhibition of biofilm formation and disruption were determined using the crystal violet microtiter plate assay. Resistance to fosfomycin was registered in a significant part of clinical isolates of P. aeruginosa (52.9 %). The highest synergy rate determined using the GDSC method was observed for combinations with ceftazidime (21.6 %) and gentamicin (17.7 %) and using the "time-kill" method with colistin and gentamicin. Although all antibiotic combinations prolonged the postantibiotic effect, the best result was achieved in combination with colistin. Negative PAE values were not recorded. All tested isolates were biofilm producers. The effect of combination therapy was predominantly registered in prevention of biofilm formation. Combination therapy was more effective in preventing biofilm formation than monotherapy, even in isolates resistant to individually administered antibiotics. The highest inhibition rates of biofilm formation were recorded in combinations with colistin, cefepime and ceftazidime. Combinations with β-lactam antibiotics and colistin had a stronger effect on the inhibition of biofilm formation than protein synthesis inhibitors. The results of this study could be clinically valuable not only regarding treatment of variously resistant P. aeruginosa isolates, but also regaring biofilm formation profilaxis of those isolates
Urban parks biowaste as a sustainable source of new antidiabetics
No full textBiowaste produced in urban parks is composed of large masses of organic matter that is only occasionally used economically. In this work, extracts of six plants widely distributed in urban parks in Central Europe (Achillea millefolium, Cichorium intybus, Malva sylvestris, Medicago sativa, Plantago lanceolata, and Trifolium pratense), prepared using 10 % and 50 % ethanol, were screened for their antidiabetic and related properties. HPLC and UV-Vis analysis revealed the presence of caffeic acid, quercetin, luteolin, and apigenin derivatives. The extracts were active in DPPH antiradical, .-carotene-linoleic acid, ORAC, and reducing power assay. They inhibited lipoxygenase, collagenase, as well as heat-induced ovalbumin coagulation. They were also able to hinder carbohydrate degradation. For example, IC50 of anti-alpha-amylase activity of 10 % and 50 % ethanol extract of M. sativa extracts (204.10 +/- 2.11 mu g mL-1 and 78.27 +/- 0.99 mu g mL-1, respectively) did not statistically differ from the activity of the positive control, acarbose (284.74 +/- 3.81 mu g mL-1). Similar results were observed for their anti-.-glucosidase activity. In most assays, the use of 50 % ethanol was shown to be better suited for the extraction of active metabolites. The results indicate that the biowaste obtained from urban parks represents a potential source of plant material for the preparation of high-value antidiabetic products
Esketamin u liječenju terapijske rezistentne depresije
No full textCILJ ISTRAŽIVANJA
Cilj ovog preglednog rada je opisati i istražiti mehanizam djelovanja, učinak i razinu sigurnosti
upotrebe esketamina u liječenju rezistentne depresije.
MATERIJALI I METODE
U izradi ovog preglednog rada korištena je stručna i znanstvena literatura na temu antidepresiva,
s posebnim naglaskom na upotrebi esketamina u liječenju terapijski rezistentne depresije.
Literatura je pretraživana prema temi i predmetu istraživanja, od općih do specijaliziranih
članaka, pri čemu su odabrani članci relevantni za problematiku ovog specijalističkog rada.
Ciljana pretraga je provedena putem akreditiranih baza podataka kao što su PubMed,
ScienceDirect i Cochrane Library, kao i baza sažetaka opisa svojstava lijekova Agencije za
lijekove i medicinske proizvode (HALMED) i Europske agencije za lijekove (EMA).
REZULTATI
Depresivni poremećaj pogađa oko 4,7 % svjetske populacije. Unatoč širokom spektru
terapijskih opcija razvijenih za liječenje, samo 60-70 % pacijenata postiže zadovoljavajući
odgovor na standardnu terapiju. Trećina pacijenata ne odgovara na standardne terapijske
pristupe. Ovakvi oblici bolesti nazivaju se depresijom otpornom na liječenje te predstavljaju
složen izazov u dijagnostici i planiranju liječenja. Istraživanja pokazuju da intranazalni
esketamin smanjuje rizik od suicida i simptome depresije. Nuspojave kao što su povećan krvni
tlak i disocijacija su prolazne.
ZAKLJUČAK
Tradicionalne opcije liječenja terapijski rezistentne depresije imaju spor početak djelovanja
što ograničava njihovu korist kod najteže pogođenih pacijenata koji mogu biti pod visokim
rizikom od samoubojstva. Stoga je brzodjelujuća terapija bitna. Nazalni esketamin se ističe
kao obećavajući brzodjelujući antidepresiv koji ima potencijal poboljšati simptome teške
depresije već unutar 24 sata od primjene. Ova brza reakcija može biti ključna za pacijente,
pružajući im brzo olakšanje od simptoma i poboljšavajući njihovu kvalitetu života.OBJECTIVES
The goal of this review paper is to describe and explore the mechanism of action, efficacy and
safety level of using esketamine in the treatment of treatment-resistant depression.
MATERIAL AND METHODS
The literature search was done by the subject of research from general to specialized articles
relevant to the questions discussed in this paper. The targeted search was carried out via online
databases such as PubMed, ScienceDirect, and Cochrane Library, summaries of product
characteristics (SmPC) in the database Agency for Medicinal Products and Medical Devices,
and European Medicines Agency.
RESULTS
Depressive disorder affects approximately 4,7 % of the world’s population. Despite a wide
spectrum of therapeutic options developed for treatment, only 60-70 % of patients achieve a
satisfactory response to standard therapy. One-third of patients do not respond to standard
therapeutic approaches. Such forms of the disease are called treatment-resistant depression and
represent a complex challenge in diagnosis and treatment planning. Research shows that
intranasal esketamine reduces the risk of suicide and depressive symptoms. Side effects such
as increased blood pressure and dissociation are transient.
CONCLUSION
Traditional treatment options for treatment-resistant depression often have a slow onset of
action, which limits their effectiveness, especially for severely affected patients who may be at
high risk of suicide. Therefore, the need for rapid-acting therapies is crucial. One promising
rapid-acting antidepressant is intranasal esketamine. It has the potential to improve symptoms
of severe depression within 24 hours of administration. This rapid response can be a key factor
for patients, providing quick relief from symptoms and enhancing their quality of life.. In
summary, while traditional treatments may have limitations, newer approaches like intranasal
esketamine offer hope for more effective and timely relief for those struggling with treatment resistant depression
Synthesis and characterization of novel ureido-type harminechloroquine hybrids
No full textOvaj diplomski rad nastavak je istraživanja na Zavodu za farmaceutsku kemiju Farmaceutsko-biokemijskog fakulteta
Sveučilišta u Zagrebu. Istraživanje obuhvaća dizajniranje, sintezu i ispitivanje biološkog djelovanja derivata harmina s
mogućim antimalarijskim i/ili citostatskim učinkom. Cilj ovog rada bila je sinteza i karakterizacija novih hibrida
klorokina i harmina, spajanjem klorokinskog amina 1 s primarnim aminima (3, 8, 13 i 18) temeljenim na β-karbolinskom
alkaloidu harminu pomoću uree kao poveznice. Sinteza je započeta sintezom pojednostavljenog derivata klorokina,
amina 1. Harminski derivati, amini 3 i 8 dobiveni su iz harmina, amin 13 iz 5-metoksitriptamina, a amin 18 iz metiltriptofanata.
Sinteza urea provedena je korištenjem dviju metoda: korištenjem benotriazolida 5 (BtH metoda) ili coupling
reagensa 1,1'-karbonildiimidazola (CDI metoda). Benzotriazolid harmina 5, tzv. aktivna urea, dobivena je iz amina 3 i
klorida 1-benzotriazol karboksilne kiseline (BtcCl, 4), a aminolizom aktivne uree 5 pomoću amina 1 u bazičnim uvjetima
dobivena je urea 19. CDI metodom iz amina 8, 13 ili 18 te amina 1 mehanizmom nukleofilne supstitucije sintetizirane
su uree 20–22.
Novosintetizirani spojevi karakterizirani su standardnim analitičkim i spektroskopskim metodama: IR, 1H i 13C NMR i
MS te im je određena temperatura tališta, a online platformom SwissADME predviđeni su fizikalno-kemijski parametri
koji utječu na farmakokinetiku novosintetiziranih spojeva. Sva četiri konačna spoja gotovo potpuno zadovoljavaju
Lipinskijeva i Veberova pravila te im web alat SwissADME predviđa dobru oralnu bioraspoloživost. Međutim, uree 19–
22 pokazale su se kao inhibitori CYP enzima te supstrati P-glikoproteina zbog čega je potrebna daljnja optimizacija
strukture spojeva. U daljnjim istraživanjima koja su u tijeku ispituje se citostatsko i antimalarijsko djelovanje
novosintetiziranih spojeva, no ista prelaze okvire ovoga rada.This master’s thesis is a continuation of research at the Department of Medicinal Chemistry, Faculty of Pharmacy and
Biochemistry, University of Zagreb. The research covers the design, synthesis, and evaluation of the biological activity
of harmine derivatives with potential antimalarial and/or cytostatic activity. The aim of this master's thesis was the
synthesis and characterization of novel chloroquine-harmine hybrids prepared by linking chloroquine amine 1 with
primary amines (3, 8, 13, and 18) based on the β-carboline alkaloid harmine using urea as a linker. The synthesis began
with the preparation of a simplified chloroquine derivative, amine 1. Harmine derivatives, amines 3 and 8, were obtained
from harmine, amine 13 from 5-methoxytryptamine, and amine 18 from methyl tryptophanate. Title ureas were obtained
using either benzotriazole 5 (BtH method) or a coupling reagent 1,1'-carbonyldiimidazole (CDI method). The harmine
benzotriazolide 5 (active urea) was synthesized from amine 3 and 1-benzotriazole carboxylic acid chloride (BtcCl, 4).
Urea 19 was obtained by aminolysis of the active urea 5 with amine 1 under basic conditions. Ureas 20–22 were
synthesized using the CDI method from amines 8, 13, or 18 and amine 1 through a mechanism of nucleophilic
substitution.
The newly synthesized compounds were characterized using standard analytical and spectroscopic methods: IR, 1H and
13C NMR, and MS. Their melting points were determined, and physicochemical parameters that could impact the
pharmacokinetics of the newly synthesized compounds were predicted using the SwissADME online platform. All four
final compounds mostly comply with Lipinski's and Veber's rules, and the SwissADME tool predicts good oral
bioavailability. However, further optimization of the compounds’ structures is necessary as ureas 19–22 have been found
to inhibit CYP enzymes and act as P-glycoprotein substrates. Evaluation of the cytostatic and antimalarial activities of
novel ureas is in progress, however, this is beyond the scope of this thesis
Medication reconciliation at hospital admission in elderly patients with cardiovascular diseases
No full textUsklađivanje terapije je proces uspoređivanja najbolje moguće medikacijske povijesti (NMMP) i lijekova koje je propisao liječnik prilikom prijema, premještanja i otpusta bolesnika iz bolnice nakon čega slijedi identificiranje i rješavanje svih odstupanja. NMMP se opisuje kao sveobuhvatna povijest lijekova koje je pacijent koristio prije hospitalizacije, a njeno detaljno prikupljanje predstavlja temelj uspješnog procesa usklađivanja terapije.
Svrha ovog istraživanja bila je utvrditi učestalost nenamjernih odstupanja između lijekova propisanih od liječnika i onih koje su kardiovaskularni bolesnici starije životne dobi koristili prethodno hospitalizaciji, kao i njihov potencijal za izazivanje kliničkog pogoršanja i štete za pacijenta.
Istraživanje je provedeno na Zavodu za bolesti srca i krvnih žila u Kliničkoj bolnici Dubrava. U njemu je sudjelovalo 105 ispitanika starije životne dobi (≥ 65 godina), a većina njih (90,5%) je bila hospitalizirana nakon hitnog prijema. Klinički je farmaceut unutar 24h od prijema prikupio NMMP i usporedio ju s propisanom farmakoterapijom. Nenamjerna odstupanja koju su pritom pronađena podijeljena su prema vrsti u šest skupina. Također, s obzirom na potencijal da izazovu kliničko pogoršanje i štetu pacijentu, odstupanja su klasificirana u tri razreda.
Odstupanja u terapiji pronađena su kod 96 ispitanika, a 10,2% tih odstupanja nije imalo kliničkog opravdanja što znači da su ona bila nenamjerna. Barem jedno takvo odstupanje pojavilo se kod 38 pacijenata (36,2 % svih sudionika). Izostavljanje lijeka je vrsta odstupanja koja je najčešće utvrđena, čineći 70,18% svih nenamjernih odstupanja. Većina njih (71,93%) mogla je izazvati umjereno kliničko pogoršanje, a 10,53% nenamjernih odstupanja imalo je potencijal izazivanja ozbiljnog kliničkog pogoršanja.
Zaključno, usklađivanje terapije je proces koji otkrivajući nenamjerna odstupanja ima veliku ulogu u povećanju sigurnosti prilikom korištenja lijekova. To je od posebne važnosti za pacijente s politerapijom koji su time značajno podložniji riziku od medikacijskih pogrešaka, a to su često osobe starije životne dobi te kardiovaskularni bolesnici. Stoga je potrebno istaknuti ulogu kliničkih farmaceuta koji su se pokazali kao najkompetentniji stručnjaci za dobivanje potpune i točne medikacijske povijesti.Medication reconciliation is a process of comparing the Best Possible Medication History (BPMH) with the medicines prescribed by a physician upon the patient's admission, transfer and discharge from the hospital, followed by the identification and resolution of all discrepancies. The BPMH is described as a comprehensive history of medicines used by a patient prior to hospitalization, and its detailed collection is the basis of successful medication reconciliation process.
The aim of this study was to determine the frequency of unintentional discrepancies between medicines prescribed by a physician and those used by elderly patients with cardiovascular diseases prior to hospitalization, as well as their potential to cause clinical deterioration and harm to the patient.
The study was conducted at the Department of Cardiovascular Diseases at the Dubrava Clinical Hospital. It included 105 elderly examinees (≥ 65 years), and most of them (90.5%) were hospitalized after emergency admission. Within 24 hours of admission, a clinical pharmacist collected BPMH and compared it with the prescribed pharmacotherapy. Unintentional discrepancies found in doing so were divided according to the type into six groups. Also, considering the potential to cause clinical deterioration and harm to the patient, discrepancies are classified into three classes.
Medication discrepancies were found in 96 participants, and 10.2% of these discrepancies had no clinical justification which means that they were unintended. At least one such discrepancie occurred in 38 patients (36.2% of all participants). Omission of the drug is the most frequently detected type of discrepancie, accounting for 70.18% of all unintentional discrepancies. The majority of them (71.93%) were able to cause moderate clinical deterioration, and 10.53% of unintentional discrepancies had the potential to cause serious clinical deterioration.
In conclusion, medication reconciliation is a process that, by detecting uintentional discrepancies, plays a major role in increasing safety when using medicines. This is of particular importance for patients with polytherapy, who are therefore significantly more suspectible to the risk of medication errors, and these are often elderly people and patients with cardiovascular diseases. It is therefore necessary to highlight the role of clinical pharmacist who have proven to be the most competent experts in obtaining a complete and accurate medication history
Kontrola procesa proizvodnje čvrstih farmaceutskih oblika
No full textCilj istraživanja
Cilj ovog specijalističkog rada je dati uvid u aktualna glavna razmatranja o kritičnim procesnim
parametrima, prikazati alate procesne analitičke tehnologije za praćenje procesa proizvodnje u
stvarnom vremenu i osiguranja kritičnih atributa kvalitete gotovog lijeka te kao takav biti
koristan alat za usmjeravanje u daljnje proučavanje literature i primjenu procesne analitičke
tehnologije u proizvodnom procesu. Radom će se posebno osvijestiti važnost kontinuirane
kontrole procesa proizvodnje u svrhu izrade djelotvornih, sigurnih i kvalitetnih lijekova.
Materijali i metode
Istraživanja u okviru specijalističkog rada teorijskog su karaktera. Pretraživanjem odgovarajuće
stručne i znanstvene literature, regulatornih smjernica, zakona i pravilnika, prikupljeni su
podaci o zahtjevima kontrola procesa proizvodnje čvrstih farmaceutskih oblika. Okosnicu
regulatornih zahtjeva čine smjernice dobre proizvođačke prakse (GMP prema engl. Good
Manufacturing Practice), nacionalna legislativa Zakon o lijekovima i popratni pravilnici,
Europska farmakopeja i ICH smjernice (ICH prema engl. International Council for
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use). Bibliografske
baze podataka kao što su PubMed, Science Direct, ResearchGate, National Library of Medicine,
Scopus, Web of Science korištene su za prikupljanje podataka o kritičnim procesnim
parametrima, kritičnim atributima kvalitete, kontrolnoj strategija proizvoda, procesnoj
analitičkoj tehnologiji (PAT) i primjeni iste u farmaceutskoj proizvodnji, kontroli procesa
proizvodnje, NIR spektrometriji, Ramanovoj spektrometriji, kontinuiranoj farmaceutskoj
proizvodnji tableta.
Rezultati
Rezultati su prikazani kroz regulatorne zahtjeve za validacijom proizvodnog procesa,
kontinuiranu proizvodnju i primjenu PAT alata u farmaceutskoj proizvodnji čvrstih oblika.
Regulatorni aspekt prikazuje zahtjev dobre proizvođačke prakse za pristupom validaciji procesa
i kontinuiranoj procesnoj verifikaciji. Također prikazuje zahtjeve kontinuirane farmaceutske
proizvodnje, osiguranje kvalitete gotovog proizvoda, praćenjem i kontrolom proizvodnog
procesa. Prikazani su najčešći kritični procesni parametri te njihov utjecaj na kritične atribute
kvalitete u proizvodnji čvrstih farmaceutskih oblika. Jednako tako opisana je kontrolna
strategija proizvoda i primjene PAT alata, te vrste PAT alata koji se mogu primijeniti u izradi
tableta i filmom obloženih tableta, kao i način regulacije proizvodnog procesa upotrebom
podataka u realnom vremenu.
Zaključak
Za postizanje visoke kvalitete lijeka, ključno je u razvojnoj fazi proučiti kritične atribute
materijala, definirati kritične atribute kvalitete i procesne parametre. Regulativne smjernice
potiču znanstveni pristup razvoju farmaceutskog proizvoda primjenom načela kvalitete
ugrađene dizajnom (engl. Quality by Design, QbD). Validacija procesa ili kontinuirana
procesna verifikacija (engl. Continued process verification, CPV) su neophodni prije puštanja
lijeka na tržište. Hibridni pristup validacije kombinira tradicionalni i kontinuirani pristup.
Korištenje naprednih alata poput PAT-a, uključujući in-line i on-line tehnologije, podržava
praćenje kvalitete u stvarnom vremenu. Kontinuirana farmaceutska proizvodnja se smatra
optimalnim izborom za visoko opasne lijekove, ali zahtijeva posebnu opremu. Pravilna
strategija praćenja procesa i daljnji razvoj tehnologije, uključujući umjetnu inteligenciju, čine
ključne faktore prema Pharma 4.0. temeljenom na QbD.Objectives
The aim of this reasrch is to provide an insight into the current key considerations of critical
process parameters, to present the tools of process analytics to monitor the production process
in real time and to ensure the critical attributes of the quality of the finished drug product, and
thus to be a useful tool for further literature studies and the application of process analytical
technologies in the production process. Most importantly, the work will raise awareness of the
importance of continuous control of the production process for the manufacture of effective,
safe and high quality medicinal products.
Materials and Methods
The research in the context of the technical paper is of a theoretical nature. By searching the
relevant technical and scientific literature, regulatory guidelines, laws and regulations, data was
collected on the control requirements for the production process of solid pharmaceutical forms.
The backbone of the regulatory requirements is formed by the Good Manufacturing Practise
(GMP) guidelines, national legislation, the Medicinal Products Act and associated regulations,
the European Pharmacopoeia and the ICH guidelines (ICH stands for International Council for
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use). Bibliographic
databases such as PubMed, Science Direct, ResearchGate, National Library of Medicine,
Scopus, Web of Science were used to collect data on critical process parameters, critical quality
attributes, product control strategies, process analytical technology (PAT) and its application in
pharmaceutical production, production process control, NIR spectrometry, Raman
spectrometry, continuous pharmaceutical production of tablets.
Results
The results are presented on the basis of the regulatory requirements for validation of the
production process, continuous production and the application of PAT tools in pharmaceutical
production of solid forms. The regulatory aspect shows the requirements of good manufacturing
practise for access to process validation and continuous process verification. It also shows the
requirements for continuous pharmaceutical production, ensuring the quality of the final
product, monitoring and control of the production process. The most common critical process
parameters and their impact on critical quality characteristics in the production of solid
pharmaceutical forms are presented. The product control strategy and the application of PAT
tools and the types of PAT tools that can be used in the production of tablets and film-coated
tablets are described, as well as the regulation of the production process using real-time data.
Conclusion
To achieve high quality of the finished drug product, it is crucial to analyse the critical
properties of the material and define the critical quality characteristics and process parameters
in the development phase. Regulatory guidelines promote a scientific approach to development
of pharmaceutical product using quality by design approach (QbD). Process validation or
continuous process verification (CPV) is necessary before a drug is commercialised. A hybrid
approach to validation combines traditional and continuous approaches. The use of advanced
tools such as PAT, including in-line and on-line technologies, supports real-time quality
monitoring. Continuous pharmaceutical production is considered the optimal choice for highly
hazardous drugs but requires specialised equipment. An appropriate process monitoring
strategy and the further development of technology, including artificial intelligence, are key
factors on the road to Pharma 4.0. based on QbD
The influence of different drying methods on the macronutrient composition of tomato pomace
No full textKomina rajčice je nusproizvod koji nastaje preradom svježe rajčice i u kojem zaostaju brojni vrijedni
nutrijenti i bioaktivne molekule karakteristične za rajčicu. Valorizacija komine rajčice i pronalazak efikasnih
metoda ekstrakcije vrijednih sastojaka imala bi višestruko pozitivne globalne učinke. Za uspješnu ekstrakciju
bioaktivnih sastojaka, od iznimne je važnosti optimirati procese predobrade biljnog materijala koji uključuje
pretpranje, sušenje i mljevenje, s ciljem pripreme stabilnog i homogenog uzorka. Pritom različite metode
sušenja biljnog materijala mogu značajno utjecati na strukturu čestica i posljedično na oslobađanje
bioaktivnih spojeva u procesu ekstrakcije. Stoga je bitno pažljivo odabrati metodu sušenja koja će najbolje
odgovarati potrebama istraživanja i osigurati optimalno oslobađanje bioaktivnih spojeva iz biljnog materijala.
Glavni cilj ovog istraživanja bio je istražiti kako različite metode sušenja utječu na sastav makronutrijenata u
komini rajčice te je određen i uspoređen makronutritivni sadržaj komine rajčice sušene na 70 °C i komine
rajčice sušene liofilizacijom. Rezultati istraživanja pokazali su da su udio vlage i udio lipida veći u uzorcima
sušenim liofilizacijom, dok je udio pepela veći u uzorcima sušenim na 70 °C. Udio proteina, udio svih frakcija
prehrambenih vlakana, udio ugljikohidrata i energetska vrijednost jednaki su u oba uzorka. Komina rajčice
je najbogatija vlaknima, a potom redom ugljikohidratima, proteinima, lipidima i mineralima i mogla bi se
koristiti kao potencijalni izvor vlakana, proteina ili masti. Rezultati ovog istraživanja doprinose saznanjima
o utjecaju metode sušenja na sastav komine rajčice. Također, ova karakterizacija komine rajčice bila je
preduvjet za daljnje analize mikronutrijenata i ostalih komponenti prisutnih u komini rajčice. Rad doprinosi
i ukupnom istraživanju valorizacije komine rajčice i njenom iskorištavanju kao vrijedne sirovine u
prehrambenoj ali i farmaceutskoj, kozmetičkoj i drugim industrijama u kojima komina rajčice može biti jeftin
i lako dostupan izvor bioaktivnih sastavnica.Tomato pomace is a by-product remaining after processing of fresh tomatoes, retaining numerous valuable
nutrients and bioactive molecules characteristic for tomatoes. Valorization of tomato pomace and finding
efficient methods of extracting valuable ingredients would have multiple positive global effects. For
successful extraction of bioactive ingredients, it is crucial to optimize the pre-treatment processes of plant
material, including washing, drying, and grinding, aiming to prepare a stable and homogeneous sample.
Different drying methods of plant material can significantly affect particle structure and consequently the
release of bioactive compounds during the extraction process. Hence, careful selection of a drying method
that best suits the research needs is essential to ensure optimal release of bioactive compounds from the plant
material. The main objective of this research was to investigate how different drying methods affect the
composition of macronutrients in tomato pomace, comparing the macronutrient content of tomato pomace
dried at 70 °C and tomato pomace dried by lyophilization. The research results showed that the moisture and
lipid content were higher in lyophilized samples, while the ash content was higher in samples dried at 70 °C.
The protein content, all fractions of dietary fiber, carbohydrate content, and energy value were equal in both
samples. Tomato pomace is richest in fiber, followed by carbohydrates, proteins, lipids, and minerals, and
could be used as a potential source of fiber, protein, or fat. The results of this research contribute to
understanding the impact of drying methods on the composition of tomato pomace. Additionally, this
characterization of tomato pomace was a prerequisite for further analysis of micronutrients and other
components present in tomato pomace. The study also contributes to overall research on the valorization of
tomato pomace and its utilization as a valuable raw material in not only the food industry but also in
pharmaceutical, cosmetic, and other industries where tomato pomace could serve as an inexpensive and
readily available source of bioactive ingredients
Regulatorni aspekti pripravaka s vitaminom D
No full textCilj istraživanja
Cilj ovog specijalističkog rada je dati sveobuhvatan pregled regulatornih aspekata pripravaka s
vitaminom D s naglaskom na regulatorne specifičnosti pojedine skupine proizvoda (dodaci prehrani i
lijekovi), njihove sličnosti i razlike koje pridonose kakvoći i sigurnosti primjene pripravaka s vitaminom
D.
Materijal i metode
Istraživanje u okviru ovog rada je teorijskog karaktera i uključuje pregled dostupne znanstvene i stručne
literature o predloženoj temi te odgovarajućih zakonodavnih akata i smjernica dostupnih na stranicama
nadležnih regulatornih tijela. Dostupni podaci su kritički razmotreni i sistematično prikazani u obliku
preglednog rada.
Rezultati
Prema podacima iz registra dodatka prehrani i baze lijekova, u Republici Hrvatskoj na tržištu se nalazi
više od 300 pripravaka s vitaminom D, pretežito u kategoriji dodataka prehrani. Osnovne karakteristike
pripravaka s vitaminom D poput količine vitamina D po doznoj jedinici, farmaceutski oblici i namjena
čine dodatke prehrani i lijekove s vitaminom D međusobno usporedivim proizvodima. Dodaci prehrani
s vitaminom D i lijekovi s vitaminom D prolaze različite regulatorne procedure za stavljanje na tržište
te moraju zadovoljiti različite regulatorne zahtjeve kako bi se osigurala kakvoća i sigurnost primjene.
Oba regulatorna okvira imaju međusobne sličnosti s obzirom na svoj osnovni cilj da se na tržištu nalaze
djelotvorni, kvalitetni i sigurni proizvodi, međutim uočene su i prikazane brojne specifične razlike.
Zaključci
Regulatorni zahtjevi iz aspekata kakvoće i sigurnosti primjene koje je potrebno ispuniti da bi dodatak
prehrani s vitaminom D stigao na tržište nisu tako sveobuhvatni kao što je to slučaj za lijekove s
vitaminom D. Krajnja odgovornost za osiguranje kakvoće i zdravstvene ispravnosti dodataka prehrani s
vitaminom D na tržištu Republike Hrvatske, a time i odgovornost za sigurnost potrošača, leži na
poslovnom subjektu koji predmetni dodatak prehrani stavlja na tržište. S druge strane, sustav
regulacije lijekova u Europskoj uniji i Republici Hrvatskoj osigurava visoke standarde sigurnosti,
kvalitete i djelotvornosti lijekova s vitaminom D dostupnih na tržištu Republike Hrvatske.Objectives
The aim of this work is to provide a comprehensive overview of the regulatory aspects of vitamin D
preparations, with an emphasis on the regulatory specificities of each group of products (food
supplements and medicines), their similarities and differences that contribute to the quality and safe
use of vitamin D preparations.
Material and methods
The research within this work is of a theorethical nature and includes a review of the avaliable scientific
and professional literature on the proposed topic and corresponding legal acts and the guidelines
avaliable on the websites of the competent regulatory authorities. The avaliable data were critically
reviewed and systematically presented in the form of an overview paper.
Results
According to data from the register of food supplements and medicinal products database, there are
more than 300 preparations with vitamin D on the market in the Republic of Croatia, predominantly
in the category of food supplements. The basic characteristics of preparations, such as the amount of
vitamin D per dosage unit, pharmaceutical forms and usage, make food supplements and medicines
with vitamin D mutually comparable products. Vitamin D food supplements and vitamin D medicines
are subject to different regulatory procedures before being placed on the market and must comply
with different regulatory requirements to ensure quality and safety. Both regulatory frameworks have
similarities concerning their basic goal of ensuring effective, quality and safe products on the market,
however, numerous specific differences have been observed and presented.
Conclusions
The regulatory requirements in terms of quality and safety that a product must meet to reach the
market are not so comprehensive for a vitamin D food supplement as they are for vitamin D medicines.
The ultimate responsibility for ensuring the quality and health suitability of food supplements with
vitamin D on the market of the Republic of Croatia, and thus the responsibility for consumer safety,
lies with the business operator that places particular food supplement on the market. On the other
hand, the regulatory system for medicines in the European Union and the Republic of Croatia ensures
high standards of safety, quality and effectiveness of vitamin D medicines available on the market of
the Republic of Croatia
Antioxidant status of α-lipoic acid supplemented patients diagnosed with grade 1 and 2 cervical intraepithelial neoplasia
No full textAntioksidativni status organizma ovisi o brojnim čimbenicima životnog stila kao što su indeks tjelesne mase
(ITM), pušenje, karakteristike prehrane, uzimanje dodataka prehrani itd. U okviru ovog istraživanja ispitan
je utjecaj navedenih karakteristika životnog stila i suplementacije α-lipoičnom kiselinom (ALA) (600 mg/dne;
3 mjeseca), na antioksidacijski status 100 pacijentica sa utvrđenom dijagnozom cervikalne intraepitelne
neoplazije stupanj 1 i 2 (CIN1 i CIN2). Antioksidacijski status utvrđen je praćenjem promjene koncentracije
reduciranog glutationa (GSH) u krvnom serumu pacijentica. Utjecaj suplementacije ALA na koncentracije
GSH u serumu istražen je u okviru dvostruko-slijepe randomizirane placebo-kontrolirane studije korištenjem
standardne fluorimetrijske metode, a utjecaj prehrane i karakteristika životnog stila korištenjem validiranog
upitnika o učestalosti konzumacije namirnica. Rezultati ovog istraživanja pokazali su kako ITM, pušenje te
uzimanje dodataka prehrani s antioksidansima nemaju bitan utjecaj na antioksidacijski status pacijentica.
Također, suplementacija α-lipoičnom kiselinom u dozi od 600 mg dnevno kroz 90 dana nije pokazala
značajan utjecaj na antioksidacijski status pacijentica s dijagnozom CIN1 i CIN2. Nasuprot tome, pacijentice
s visokim unosom povrća imale su značajno više koncentracije GSH u serumu. Kako bi se dobili što
relevantniji rezultati i bolji uvid u antioksidacijsku sposobnost α-lipoične kiseline potrebno je provesti daljnja
istraživanja koja uključuju veći broj ispitanica, kao i osjetljivije biomarkere antioksidacijskog statusa ili
kombinaciju istih.The antioxidant status of the organism depends on a number of lifestyle factors such as body mass index
(BMI), smoking, dietary characteristics, taking dietary supplements, etc. The study examined the impact of
these lifestyle characteristics and α-lipoic acid (ALA) supplementation characteristics (600 mg / day; 3
months) on the antioxidant status of 100 patients diagnosed with grade 1 and 2 cervical intraepithelial
neoplasia (CIN1 and CIN2). Antioxidant status was determined by monitoring changes in reduced glutathione
(GSH) levels in the blood serum of patients. The effect of ALA supplementation on serum GSH
concentrations was investigated in a double-blind randomized placebo-controlled study using a standard
fluorimetric method, and the effect of diet and lifestyle characteristics using a validated food consumption
frequency questionnaire. The results of this study showed that BMI, smoking and taking dietary supplements
with antioxidants do not have a significant impact on the antioxidant status of patients. Also, α-lipoic acid
supplementation at a dose of 600 mg daily for 90 days did not show a significant effect on the antioxidant
status of patients diagnosed with CIN1 and CIN2. On the contrary, patients with high vegetable intake had
significantly higher serum GSH concentrations. In order to obtain the most relevant results and better insight
into the antioxidant capacity of α-lipoic acid, it is necessary to conduct further research involving a larger
number of subjects, as well as more sensitive biomarkers of antioxidant status or a combination thereof
The effect of botulinum toxin type A on c-fos activation in spinal cord in inflammatory pain model
No full textBotulinum toksin tipa A (BT-A) više od 30 godina koristi se u terapiji različitih kliničkih stanja praćenih mišićnom spastičnošću. Na različitim eksperimentalnim modelima upalne i neuropatske boli uočeno je njegovo dugotrajno antinociceptivno djelovanje nakon jednokratne periferne primjene, što ga uz malen broj nuspojava razlikuje od ostalih sistemskih analgetika u trenutnoj primjeni. Dosad su provedena brojna pretklinička i klinička istraživanja s ciljem razjašnjavanja točnog mehanizma i mjesta djelovanja toksina, što bi omogućilo proširenje njegovih indikacija na brojna bolna stanja. Usprkos općeprihvaćenoj teoriji o perifernom inhibitornom djelovanju BT-A na egzocitozu neurotransmitora na završetcima senzornih neurona, novija istraživanja ukazuju na središnje djelovanje toksina, najvjerojatnije na razini dorzalnog roga leđne moždine kamo periferno primijenjen BT-A dolazi retrogradnim aksonalnim transportom. Također postoje dokazi o bilateralnom antinociceptivnom djelovanju BT-A nakon njegove unilateralne periferne primjene. Cilj ovog diplomskog rada bio je potvrditi ove navode na modelu bilateralne upalne boli uzrokovane injiciranjem karagenana u stražnje šape mužjaka štakora soja Wistar. Jedna je skupina životinja prethodno tretirana s BT-A u dozi 7 i.j./kg u stražnju desnu šapu, dok je druga skupina uz BT-A primila i antitoksin za BT-A (anti-BT-A). Kontrolnim skupinama injicirana je fiziološka otopina umjesto BT-A, a u jednoj od njih primjenom fiziološke otopine umjesto karagenana izbjegnuto je izazivanje upale. Imunohistokemijski je praćena ekspresija markera neuronalne aktivacije c-Fosa u poprečnim L4/L5 presjecima leđne moždine štakora. Rezultati pokazuju kako, sukladno očekivanjima, karagenan dovodi do bilateralne aktivacije neurona u leđnoj moždini dok unilateralna primjena BT-A smanjuje istu na obje strane leđne moždine. Pritom je statistički značajno smanjenje ekspresije c-Fosa zabilježeno u odnosu na kontrolnu skupinu i na skupinu tretiranu s anti-BT-A na ipsilateralnoj, ali i na kontralateralnoj strani leđne moždine. Ovo je još jedan u nizu dokaza o središnjem mjestu antinociceptivnog djelovanja BT-A, pri čemu se ne može isključiti mogući transinaptički prijenos BT-A u druge neurone/stanice uključene u proces nocicepcije na razini leđne moždine.Botulinum toxin type A (BTX-A) has been used to treat numerous clinical conditions characterised by muscle spasticity for years. Long-term antinociceptive effect of BTX-A after its single peripheal application has been reported in various experimental models of inflammatory and neuropathic pain. This, combined with its low side effects frequency differs BT-A from other currently used systemic painkillers. Until now, many preclinical and clinical studies have been conducted with the goal of discovering BT-A's exact mechanism and site of action in mind, which would allow for the expansion of current indications to many other pain conditions. In contrast to generally accepted theory of BTX-A's peripheral suppression of neurotransmitters release from sensory nerve endings, the results of several recent researches suggest its central site of action, most likely at the dorsal horn of spinal cord level, where peripherally applied BTX-A is delivered by retrograde axonal transport. There is also evidence that BTX-A has bilateral antinociceptive effect after its unilateral peripheral application. The goal of this master's thesis was to confirm these statements using inflammatory pain model where pain is inflicted by carrageenan injection into hindpaws of male Wistar rats. One group of animals was pretreated with a BTX-A dose of 7 i.u./kg, while another group was treated with BTX-A antitoxin (anti-BTX-A) alongside BTX-A. Control groups have received saline injection (0,9 % NaCl) instead of BTX-A and one of them was treated with saline instead of carrageenan in an attempt to avoid inflammation. Expression of c-Fos (neuronal activity marker), which was used as indirect pain indicator, was imunohistochemically examined in L4/L5 cross sections of rat spinal cord. The results show that, in line with our expectations, carrageenan is enabling bilateral activation of spinal neurons while BTX-A reduced this activation on both sides of the spinal cord. Statistically significant reduction of c-Fos expression was recorded in comparison with control group and with experimental group treated with anti-BTX-A on both the ipsilateral and contralateral side of spinal cord. This is just another proof that BTX-A is exerting its antinociceptive effects centrally, with both sides of spinal cord as its site of action