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Polymorphisms of genes for coagulation and fibrinolysis factors, platelet membrane glycoproteins and intermediate risk factors in children with ischemic stroke
No full textIshemijski moždani udar (IMU) u djece je relativno rijedak poremećaj miješane etiologije koja je nerazjašnjena u približno 30 % slučajeva. Protrombotički poremećaji prepoznati su kao rizični čimbenik za nastanak IMU-a u
djece, ali su potencijalne pozadinske genske varijacije analizirane u oskudnom broju studija u specifičnim populacijama ili u odraslih, dok u djece rijetko ili uopće nisu analizirane. Kako se povezanost protrombotičkih
polimorfizama s IMU-om može razlikovati ovisno o geografskoj i etničkoj pripadnosti ispitivane populacije, a poznato je dodatno povećanje rizika u prisutnosti više od jednoga protrombotičkog rizičnog čimbenika, cilj ovoga istraživanja jest ispitati povezanost pojedinačnih polimorfizama u genima za čimbenike zgrušavanja, glikoproteinima trombocitne membrane i intermedijarne rizične čimbenike te potencijal zajedničke povezanosti s pojavom IMU-a u djece u Hrvatskoj ovisno o tipu, dobi nastanka i lokalizaciji IMU-a. Genotipizacija 21 polimorfizma u 13 gena kandidata provedena je iz uzorka DNA leukocita dobivenih nakon prikupljanja uzoraka ostatne periferne krvi od 185 djece starosne dobi do 18 godina s potvrđenom dijagnozom arterijskog IMU-a ili tromboze venskih sinusa mozga (CSVT) i 185 zdrave djece podudarne po dobi i spolu djeci s IMU-om. Dobiveni rezultati potvrdili su veću zastupljenost dječaka u svim podtipovima bolesti, osim perinatalnog
arterijskog IMU-a i CSVT-a te različite genetičke čimbenike za karakterizaciju različitih podtipova IMU-a u
djece. Na temelju dobivenih rezultata predložen je i algoritam ispitanih genetičkih čimbenika za IMU u djece za razlikovanje rizika nastanka podtipova bolesti te je uspostavljena baza podataka djece s IMU-om u Hrvatskoj. Rezultati predloženog istraživanja proširili su dosadašnja saznanja o potencijalnoj ulozi ispitanih genskih
varijacija u etiologiji IMU-a u djece u Hrvatskoj, ali i u općoj populaciji.Ischemic paediattric stroke (IPS) is a relatively rare disorder of mixed aetiology that is unexplained in
approximately 30% of cases. Prothrombotic disorders are recognized as a risk factor for the development of IPS, but potential genetic variations in prothrombotic risk factors have been analysed in a limited number of studies in
specific populations or in adults, while in children they have been scarcely analysed or they have not been analysed at all. As the association of prothrombotic polymorphisms with IPS can differ depending on the geographic and ethnic categorisation of the population studied, and an additional increased risk is known in the presence of more than one prothrombotic risk factor, the aim of this study is to examine the association of individual polymorphisms in the genes coding clotting factors, platelet membrane glycoproteins and intermediate risk factors, and the potential of their joint association with the occurrence of IPS in children in Croatia depending on the type of IPS, age of onset and localization of the lesion. Genotyping of 21 polymorphisms in 13
candidate genes was performed in a DNA samples obtained from leukocytes after collecting residual peripheral blood samples from 185 children aged up to 18 years with confirmed diagnosis of arterial IPS (AIS) or cerebral venous sinus thrombosis (CSVT) and 185 healthy children matched by age and gender to children with IPS. Obtained results confirmed a higher frequency of AIS in boys and other subtypes, but not in perinatal AIS and CSVT. Also, it has been proven that different subtypes of IPS are caracterised by different genetic factors. Based
on the obtained results, an algorithm of tested genetic risk factors for IPS was proposed to distinguish the risk of subtypes of the disease, which established a database of children with IPS in Croatia. The results of the proposed
research expanded the previous knowledge about the potential role of the examined genetic variations in the aetiology of IPS in Croatia, with translational potential to the adult population
Primjena antipsihotika u neodobrenim indikacijama
No full textistraživanja: Cilj ovog rada je pregledno opisati primjenu antipsihotika u neodobrenim
indikacijama s aspekta prevalencije, razine dokaza o učinkovitosti u pojedinim indikacijama,
rizicima primjene u općoj populaciji te osobitostima primjene u djece i starijih osoba.
Materijali i metode: U tu svrhu napravljen je sustavni i retrospektivni pregled znanstvene i
stručne literature. Pretraženi su relevantni terapijski priručnici, trenutno važeće terapijske
smjernice, publikacije stručnih udruga i institucija, baze lijekova te drugi raspoloživi izvori.
Rezultati: Utvrđeni su antipsihotici s najvišom prevalencijom off-label primjene u općoj i
posebnim populacijama. Identificirane su najznačajnije off-label indikacije i prikazana razina
dokaza o učinkovitosti i sigurnosti za pojedini antipsihotik. Opisane su koristi i rizici off-label
primjene antipsihotika te osobitosti iste u djece i starijih osoba.
Zaključak: Off-label primjena antipsihotika visoko je prevalentna u kliničkoj praksi unatoč
činjenici da djelotvornost i sigurnost ovako primijenjenog lijeka nisu odgovarajuće
evaluirane. Nedvojbeno postoje kliničke situacije u kojima je racionalno primijeniti
antipsihotik u off-label indikaciji, ali pri tome uvijek vodeći se medicinskim dokazima.
Postoji manji broj indikacija koje posjeduju relativno snažne dokaze no za većinu su isti
ograničeni. Ranjive skupine pacijenata, djeca i starije osobe, osobito su izložene
neutemeljenoj off-label primjeni antipsihotika odnosno pod povećanim su rizikom s upitnom
terapijskom koristi. Potrebno je unutar procesa off-label primjene rutinski i sustavno
prikupljati podatke kako bismo s većom pouzdanošću mogli utvrditi omjer koristi i rizika za
buduće pacijente te prikladnost izbora ovakvog terapijskog pristupa.Objectives: The aim of this paper is to clearly describe the use of antipsychotics in off-label
indications in terms of prevalence, the level of evidence of efficacy in individual indications,
risks of use in the general population and the specifics of use in children and the elderly.
Material and Methods: For the purposes of this research, a systematic and retrospective
review of scientific and professional literature was made. Relevant therapeutic manuals,
currently valid therapeutic guidelines, publications of professional associations and
institutions, drug databases and other available sources were searched.
Results: Antipsychotics with the highest prevalence of off-label use in general and special
populations have been identified. The most significant off-label indications were identified
and the level of evidence of efficacy and safety for each antipsychotic was presented. The
benefits and risks of off-label use of antipsychotics and its specifics in children and the elderly
are described.
Conclusion: The off-label use of antipsychotics is highly prevalent in clinical practice despite
the fact that the efficacy and safety have not been adequately evaluated. Undoubtedly, there
are clinical situations in which it is rational to use an antipsychotic in the off-label indication,
but always guided by medical evidence. There are small number of indications that have
relatively strong evidence but for most they are limited. Vulnerable groups of patients,
children and the elderly, are particularly exposed to unjustified off-label use of antipsychotics
and are at increased risk with questionable therapeutic benefits. It is necessary to routinely
and systematically collect data within the off-label application process in order to be able to
determine, with greater reliability, the ratio of benefits and risks for future patients and the
appropriateness of choosing such therapeutic approach
The role of probiotics, vitamin D and omega-3 fatty acids in pathophysiology, prevention and treatment of atopic dermatitis
No full textBased on the review of data regarding the pathophysiology of atopic dermatitis, this research aims to
evaluate the efficacy of using probiotics, omega-3 fatty acids, and vitamin D in prevention and
treatment of this condition. Hypothetically, if omega-3 fatty acids, vitamin D, and probiotics are timely
recommended to patients with atopic dermatitis and families planning a pregnancy but are
predisposed to this disease - the symptoms of atopic dermatitis can be alleviated, the cost of
treatment reduced, and in some cases, even the manifestation of the disease might be prevented.
Material and methods
The research was conducted electronically using digital books and journals, a bibliographic database
(PubMed), a full-text database (Science Direct), and Cochrane Library. The data from clinical studies,
meta-analyses, and review articles were thoroughly analysed and selected. Relevant items were
studied analytically and critically regarding the definition of the role of probiotics, omega-3 fatty acids,
and vitamin D in the treatment and prevention of atopic dermatitis.
Results
Omega-3 fatty acids, probiotics, and vitamin D supplementation open new avenues for safe and
effective preventive measures in atopic dermatitis, although the results of the research are still
ambiguous.
Evidence from different research groups show that probiotics could have a positive effect on
prevention of atopic dermatitis. Nevertheless, there is still a lack of evidence regarding multiple
factors, like the type of probiotic used, timing of dosage, and duration of exposure to recommend
probiotic use as a treatment for atopic dermatitis.
The use of omega-3 fatty acids could provide a potential way to prevent allergic disorders. Studies
conducted to date, indicate that supplementation with these preparations have a positive effect on
children with AD, up to 1-year-olds. Likewise, omega-3 fatty acids consumption during pregnancy can
decrease sensitization to common food allergens and can protect infants from developing atopic
dermatitis during their first year of life. To confirm positive effects and address long-term outcomes,
a larger randomized, placebo-controlled study should be conducted.
It was found that serum Vitamin D levels and atopic dermatitis severity exhibited an inverse
correlation, as reported in most published literature. Moreover, Vitamin D acts on immunity, the
proliferation of skin keratinocytes, and the production of antimicrobial peptides in the skin. The
research observed that people with atopic dermatitis have lower levels of Vitamin D than the general
population. However, Vitamin D supplementation have not been well investigated, maybe due to lack
of a well-established dose regimen demonstrating its benefits.
Conclusion
According to the results of clinical studies, supplementation of certain strains of probiotics in atopic
dermatitis has a positive treatment effect. However, the level of evidence for the effectiveness of
probiotics' use for the treatment and prevention of atopic dermatitis is still low. Therefore, there are
currently no official recommendations on the use of probiotics in the treatment or prevention of
atopic dermatitis.
Supplementation with long-chain omega-3 fatty acids appear promising, although not fully examined
as a preventative approach for atopic dermatitis. More randomized controlled intervention studies
are required to establish the long-chain omega-3 fatty acid administration concept in a therapeutic
setting.
As reported in most published sources, serum vitamin D levels and the severity of atopic dermatitis
exhibit an inverse correlation. Numerous studies have demonstrated that vitamin D
supplementation can reduce the severity of atopic dermatitis and have confirmed that correcting
vitamin D deficiency can improve the clinical development of atopic dermatitis by reducing immune
responses, by its effect on skin keratinocyte proliferation, and by production of antimicrobial
peptides in the skin. However, further studies with different vitamin D dosing regimens are needed
to include vitamin D therapy in an official therapeutic setting of atopic dermatitis treatment.Ciljevi
Na temelju pregleda podataka o patofiziologiji atopijskog dermatitisa, ovim istraživanjem želi se
procijeniti učinkovitost primjene probiotika, omega-3 masnih kiselina i vitamina D u prevenciji i
liječenju ovog stanja. Hipotetski, ako se oboljelima od atopijskog dermatitisa i obiteljima koje
planiraju trudnoću na vrijeme preporuče omega-3 masne kiseline, vitamin D i probiotici, a imaju
predispozicije za ovu bolest - mogu se ublažiti simptomi atopijskog dermatitisa, smanjiti troškovi
liječenja i u nekim slučajevima, može se i spriječiti manifestacija bolesti.
Materijal i metode
Istraživanje je provedeno elektroničkim putem, korištenjem digitalnih knjiga i časopisa, bibliografske
baze podataka (PubMed), baze podataka punog teksta (Science Direct) i „Cochraneove knjižnice“.
Temeljito su analizirani i odabrani podaci iz kliničkih studija, meta-analiza i preglednih članaka.
Relevantne stavke u vezi definiranja uloge probiotika, omega-3 masnih kiselina i vitamina D u
liječenju i prevenciji atopijskog dermatitisa proučavane su analitički i kritički.
Rezultati
Omega-3 masne kiseline, probiotici i suplementacija vitaminom D otvaraju nove puteve za sigurnu i
učinkovitu prevenciju atopijskog dermatitisa, iako su rezultati istraživanja još uvijek nejasni.
Različite skupine istraživača dokazuju da bi probiotici mogli imati pozitivan učinak na prevenciju
atopijskog dermatitisa. Unatoč tome, da bi se preporučila uporaba probiotika za liječenje atopijskog
dermatitisa, još uvijek nedostaju dokazi koji se odnose na više čimbenika, poput vrste korištenog
probiotika, vremena doziranja i trajanja izloženosti istome.
Korištenje omega-3 masnih kiselina moglo bi predstavljati potencijalni način prevencije alergijskih
poremećaja. Dosadašnja istraživanja pokazuju da suplementacija ovim pripravcima pozitivno djeluje
na djecu s AD-om do 1 godine starosti. Također, konzumacija omega-3 masnih kiselina tijekom
trudnoće može smanjiti osjetljivost na uobičajene alergene iz hrane i može zaštititi dojenčad od
razvoja atopijskog dermatitisa tijekom prve godine života. Kako bi se potvrdili pozitivni učinci i riješili
dugoročni ishodi, potrebno je provesti veću, slučajnu, placebom kontroliranu studiju.
Utvrđeno je da razine vitamina D u serumu i težina atopijskog dermatitisa pokazuju obrnutu
korelaciju, kao što je priopćeno u većini objavljenih literatura. Štoviše, vitamin D djeluje na imunitet,
proliferaciju kožnih keratinocita i proizvodnju antimikrobnih peptida u koži. Istraživanje je pokazalo
da ljudi s atopijskim dermatitisom imaju niže razine vitamina D od opće populacije. Međutim,
suplementacija vitaminom D nije dobro istražena, vjerojatno zbog nedovoljno dobro uspostavljenog
režima doziranja, koji bi pokazao njegove prednosti.
Zaključak
Prema rezultatima kliničkih studija, suplementacija određenih sojeva probiotika kod atopijskog
dermatitisa ima pozitivan učinak liječenja. Međutim, razina dokaza o učinkovitosti primjene istih u
liječenju i prevenciji atopijskog dermatitisa još uvijek je niska. Stoga, trenutno ne postoje službene
preporuke o korištenju probiotika u liječenju ili prevenciji atopijskog dermatitisa.
Suplementacija s dugolančanim omega-3 masnim kiselinama čini se obećavajućom, iako nije u
potpunosti ispitana kao preventivni pristup za atopijski dermatitis. Potrebno je više slučajnih,
kontroliranih intervencijskih studija da bi se uspostavio koncept primjene dugolančanih omega-3
masnih kiselina u terapeutskom okruženju.
Kao što je navedeno u većini objavljenih izvora, razine vitamina D u serumu i ozbiljnost atopijskog
dermatitisa pokazuju obrnutu korelaciju. Brojne su studije pokazale da dodatak vitamina D može
smanjiti ozbiljnost atopijskog dermatitisa i potvrdile da nadomještanje vitamina D može poboljšati
klinički razvoj atopijskog dermatitisa - smanjenjem imunoloških odgovora, učinkom na proliferaciju
keratinocita kože i proizvodnjom antimikrobnih peptida u koži. Međutim, da bi se terapija vitaminom
D uključila u službenu terapijsku postavku liječenja atopijskog dermatitisa, potrebna su daljnja
istraživanja s različitim režimima doziranja spomenutog vitamina
Determination of H69/V70 deletion in SARS-CoV-2 virus using TaqPath reagents
No full textVirus SARS-CoV-2 velikom se brzinom proširio cijelim svijetom 2020. godine te uzrokovao globalnu pandemiju. Podložan je brojnim mutacijama koje na različite načine utječu na njegova svojstva kao i na rezultate molekularne analize RT-PCR kojom se potvrđuje infekcija ovim virusom. Cilj ovog diplomskog rada bio je usporediti rezultate RT-PCR testiranja uzoraka nazofaringealnih briseva na prisutnost virusa SARS-CoV-2 korištenjem komercijalnog test paketa koji detektira prisutnost više virusnih gena (ORF1ab, N i S protein) s rezultatima sekvenciranja različitih uzoraka kod kojih je RT-PCR metodom dokazana i kod kojih nije dokazana prisutnost S gena. Za provođenje testiranja korišten je TaqPathTM COVID-19 CE-IVD RT-PCR Kit, a sekvenciranje je provedeno NGS metodom u laboratoriju Eurofins Genomics Europe. Rezultati su potvrdili postojanje delecije H69/V70 kod svih uzoraka kod kojih RT-PCR metodom nije detektiran S gen. Utvrđeno je da postojanje delecije H69/V70 na S genu onemogućuje njegovu detekciju. S obzirom na to da se određuje prisutnost druga dva gena, lažno negativni rezultati za S gen ne znače odsustvo virusa nego ukazuju na potencijalno prisustvo ove mutacije u soju virusa koji kruži u populaciji.The SARS-CoV-2 virus spread rapidly throughout the world and caused a global pandemic in 2020. The virus is susceptible to numerous mutations that affect to its properties in different ways. Mutations also affect to the results of the RT-PCR molecular analysis which is used to confirm virus infection. The aim of this study was to compare RT-PCR results of nasopharyngeal swab samples which were analyzed to detect the presence of the SARS-CoV-2 virus using a commercial test package that detects the presence of several viral genes (ORF1ab, N and S protein) with different sequencing results of samples where the presence of S protein was confirmed and samples where the presence of S protein was not confirmed using RT-PCR. The TaqPathTM COVID-19 CE-IVD RT-PCR Kit was used for testing and the sequencing was performed using the NGS method in the Eurofins Genomics Europe laboratory. The results confirmed deletion H69/V70 in every sample where the S gene was not detected using RT-PCR It was found that H69/V70 S gene deletion prevents S gene to be detected while PCR testing. False-negative results for S gene presence should not indicate the absence of the virus because there are two other gens which presence is detected. But negative S gene results can indicate the potential presence of this virus mutation and its spreading through population
MicroRNA - new biomarker for early detection and monitoring of patients with type 2 diabetes
No full textŠećerna bolest tipa 2 jedno je od najčešćih oboljenja i najvećih izazova suvremene medicine. Glavne karakteristike T2DM su nesposobnost tkiva osjetljivih na inzulin da na odgovarajući način reagiraju na inzulin (inzulinska rezistencija), smanjena funkcija β stanica Langerhansovih otočića te smanjena sekrecija inzulina. Definitivan i konačan uzrok smanjene funkcije β-stanica u T2DM je zasad nepoznat a smatra se da ulogu imaju genetski i okolišni čimbenici. T2DM je jako komplicirana bolest sa multiorganskim efektima a glavni simptomi koji se javljaju su povećani osjećaji gladi i žeđi, učestalo mokrenje, gubitak na tjelesnoj masi, pretjerani umor te je glavni uzročnik ovih simptoma hiperglikemija. Javlja se potreba za biomarkerima koji će nam pomoći da ranije otkrijemo bolest i kvalitetnije pratimo učinak terapije. MikroRNA (miRNA) su male nekodirajuće RNA molekule koje su duge oko 21-25 nukleotida te funkcioniraju kao translacijski represori. MiRNA su danas univerzalno prepoznate kao glavni regulatori genske ekspresije i kao ključni kontrolori nekoliko bioloških i patoloških procesa. MiRNA nemaju samo funkciju regulacije gena unutar stanica u kojoj nastaju, već se mogu naći i u tjelesnim tekućinama poput krvi, zajedno sa proteinima, mikrovezikulama ili lipoproteinskim kompleksima. Neke značajke miRNA koje ih čine dobrim biomarkerima su da se osim u krvi, nalaze se i u drugim tjelesnim tekućinama koje možemo analizirati kao što su slina, urin, majčino mlijeko i amnionska tekućina, mogu se određivati visokoosjetljivim i specifičnim kvantitativnim PCR metodama, zdravi donori nemaju značajnije varijacije miRNA profila tijekom dana te se mogu mjeriti i u serumu i u plazmi. Ono što je jako važno je da se profil ekspresije miRNA u β-stanicama i ciljanim tkivima inzulina mijenjaju i u T1DM i T2DM što najvjerojatnije pridonosi oštećenju funkcija ovih tkiva. Iako teoretski dobar biomarker za šećernu bolest tipa 2, istraživanja su pokazala da je samo mali broj pouzdanih miRNA profila ekspresije konzistentan. Zbog tehnoloških problema u rukovanju uzorcima, mjerenju miRNA i interpretaciji podataka, moguće je propustiti značaj miRNA. MiRNA koje bi se koristile trebale bi zamijeniti ili dopuniti postojeće standardne biomarkere. Stoga je potrebno sustavno uspoređivati njihovu sposobnost predviđanja pojave šećerne bolesti ili njenih posljedica s onima već postojećih biomarkera.Type 2 diabetes is one of the most common diseases and the greatest challenges of modern medicine. The main characteristics of T2DM are the inability of insulin-sensitive tissues to respond appropriately to insulin (insulin resistance), reduced β-cell function of the islets of Langerhans, and reduced insulin secretion. The definitive and definitive cause of reduced β-cell function in T2DM is currently unknown, and it is believed that genetic and environmental factors play a role. T2DM is a very complicated disease with multiorgan effects, and the main symptoms that occur are increased feelings of hunger and thirst, frequent urination, weight loss, excessive fatigue, and the main cause of these symptoms is hyperglycemia. There is a need for biomarkers that will help us detect the disease earlier and better monitor the effect of therapy. MicroRNAs (miRNAs) are small non-coding RNA molecules that are about 21-25 nucleotides long and function as translational repressors. MiRNAs are now universally recognized as the main regulators of gene expression and as key controllers of several biological and pathological processes. MiRNAs not only have the function of gene regulation inside the cells in which they are produced, but can also be found in body fluids such as blood, together with proteins, microvesicles or lipoprotein complexes. Some features of miRNAs that make them good biomarkers are that apart from blood, they are also found in other body fluids that we can analyze such as saliva, urine, breast milk and amniotic fluid, they can be determined by highly sensitive and specific quantitative PCR methods, healthy donors do not have more significant variations of the miRNA profile during the day and can be measured in both serum and plasma. What is very important is that the expression profile of miRNAs in β-cells and target tissues of insulin are changed in both T1DM and T2DM, which most likely contributes to the impairment of the functions of these tissues. Although theoretically a good biomarker for type 2 diabetes, research has shown that only a small number of reliable miRNA expression profiles are consistent. Due to technological problems in sample handling, miRNA measurement and data interpretation, it is possible to miss the significance of miRNAs. The miRNAs that would be used should replace or complement existing standard biomarkers. Therefore, it is necessary to systematically compare their ability to predict the onset of diabetes or its consequences with those of already existing biomarkers
Trends in drug research and development - new medicines in 2021
No full textOvaj pregledni diplomski rad sažeto prikazuje lijekove koji su odobreni u 2021. godini od strane američke i europske regulatorne agencije za lijekove (FDA i EMA), te naglašava važnost daljnjeg ulaganja u razvoj novih lijekova. Ovim diplomski radom nisu obuhvaćeni lijekovi za liječenje malignih bolesti, kao niti cjepiva . Razvoj novih lijekova u svrhu unaprjeđivanja zdravstvene skrbi oboljelih uključuje multidisciplinarni pristup i suradnju znanstvenika različitih profila, od molekularnih biologa, genetičara, kemičara, biostatičara, do farmakologa, liječnika i farmaceuta. Od 50 odobrenih lijekova u SAD-u, najviše ima malih molekula, zatim bioloških lijekova, od čega su najzastupljenija monoklonska protutijela, a od terapijskih područja najzastupljeniji su onkološki lijekovi . U 2021. godini odobren je lijek koji je mala inteferirajuća RNA, čime se otvara prostor za post-transkripcijsko utišavanje gena kao terapijski pristup u liječenju određenih bolesti i stanja. Odobreni su i četiri bioslična lijeka te tako ti lijekovi postaju dostupniji većem broju pacijenata. Ovaj broj od 50 novih lijekova govori u prilog ulaganja u prevenciju, liječenje i unaprjeđenje skrbi o bolesnicima. Lijek koji je dostupan svima, učinkovit i siguran, težnja je svih uključenih u skrb o oboljelima.The review thesis summarizes the drugs approved in 2021 by the US and European Medicines Regulatory Agency (FDA and EMA). It highlights the importance of further investment in the development of new drugs. Medicines for the treatment of malignant diseases, as well as vaccines were not included in this thesis. Development of new drugs for the purpose of improving health care of patients involves a multidisciplinary approach and cooperation of scientists of various profiles, from molecular biologists, geneticists, chemists, biostatisticians, to pharmacologists, doctors and pharmacists. Of the 50 approved drugs in the USA, the most represented are small molecules, followed by biological drugs of which monoclonal antibodies are the most represented, of therapeutic areas oncology drugs are the most represented. In 2021 a small interfering RNA drug was approved, which opens the way for post transcriptional gene silencing as therapeutic approach in the treatment of certain diseases and conditions. Four biosimilar drugs have also been approved, making these drugs more accesssible to a larger number of patients. This number of 50 new medicines speaks in favor of investment in prevention, treatment and improvement of patient care. Medicine that is available to everyone effective and safe is the aspiration of everyone involved in the care of patients
Racionalna primjena ehinaceje u pedijatrijskoj populaciji
No full textCilj istraživanja
Cilj ovog specijalističkog rada je dati sveobuhvatan pregled dosadašnjih znanstvenih spoznaja
o kliničkoj učinkovitosti i sigurnosti primjene ehinaceje u pedijatrijskoj populaciji s obzirom
da one predstavljaju temelj racionalne i na dokazima utemeljene primjene ove biljne droge u
suvremenoj farmaciji i medicini.
Materijal i metode
Istraživanja u okviru ovog specijalističkog rada teorijskog su karaktera i obuhvaćaju pregled
znanstvene literature o dosad provedenim kliničkim studijama koje su uključivale primjenu
ehinaceje. Pretraživane su dostupne elektroničke bibliografske baze podataka kao što su
PubMed (Medline), Embase, Current Contents Connect, Cochrane Library i Google Scholar
te baze registriranih kliničkih studija (clinicaltrials.gov i WHO ICTRP) korištenjem ključnih
riječi vezanih za temu rada kao i mrežne stranice relevantnih hrvatskih i europskih institucija
(Agencija za lijekove i medicinske proizvode u Hrvatskoj i Europska agencija za lijekove).
Rezultati
Učinkovitost primjene fitopreparata ehinaceje u djece vrednovana je u šest kliničkih studija.
Istraživana je primjena ehinaceje u prevenciji akutne upale srednjeg uha, tonzilofaringitisa, i
općenito liječenju virusnih infekcija dišnog sustava. Rezultati četiriju studija potvrđuju
pozitivan učinak suplementacije, dok kod dvije studije nije uočeno poboljšanje nakon
primjene ehinaceje. Posebno je izražena učinkovitost ehinaceje u prevenciji virusnih infekcija
dišnog sustava, što ukazuje na veliki potencijal njezine primjene kao profilaktičkog tretmana.
Zaključak
Kliničke studije o učinkovitosti primjene ehinaceje u pedijatrijskoj populaciji su još uvijek
malobrojne, a dobiveni rezultati nekonzistentni. Iako većina dosad objavljenih studija ukazuje
na značajan potencijal u prevenciji i liječenju, potrebne su dodatne studije na većem broju
ispitanika, sa standardiziranim fitopreparatima ehinaceje koji će pružiti dovoljnu snagu
dokaza za njenu sigurnu i učinkovitu kliničku primjenu u djece.Objectives
The aim of this thesis is to provide a comprehensive overview of current scientific knowledge
on the clinical efficacy and safety of echinacea in the pediatric population, considering that
they represent the basis of the rational and evidence-based use of this herbal drug in modern
pharmacy and medicine.
Material and Methods
Research within the thesis is of a theoretical nature and includes a review of scientific
literature on clinical studies conducted so far that included the use of echinacea. Available
electronic bibliographic databases such as PubMed (Medline), Embase, Current Contents
Connect, Cochrane Library and Google Scholar and databases of registered clinical studies
(clinicaltrials.gov and WHO ICTRP) were searched using keywords related to the topic of the
work as well as web pages of relevant Croatian and European institutions (Agency for
Medicines and Medical Products in Croatia and European Medicines Agency).
Results
The effectiveness of echinacea herbal products in children has been evaluated in six clinical
studies. The use of echinacea in the prevention of acute otitis media, tonsillopharyngitis, and
in the general treatment of viral respiratory infections was investigated. The results of four
studies confirm the positive effect of supplementation, while in two studies no improvement
was observed after the use of echinacea. The effectiveness of echinacea in the prevention of
viral respiratory infections is particularly pronounced, which indicates the great potential of
its use as a prophylactic treatment.
Conclusion
There are still few clinical studies on the effectiveness of echinacea in the pediatric population,
and the results obtained are inconsistent. Although most of the studies published so far
indicate a significant potential in prevention and treatment, additional studies are needed on a
larger number of subjects, with standardized echinacea phytopreparations that will provide
sufficient evidence for its safe and effective clinical use in children
Upotreba postojećih lijekova u farmakoterapiji bolesti COVID-19
No full textCilj istraživanja: Cilj ovog rada je pregledno prikazati glavne specifičnosti primjene određenih
postojećih lijekova u farmakoterapiji COVID-19.
Ispitanici i metode: U tu svrhu korištena je najnovija znanstvena i stručna literatura, trenutno
važeće terapijske smjernice, publikacije stručnih udruga i institucija, baza lijekova Agencije za
lijekove i medicinske proizvode i Europske agencije za lijekove te drugi raspoloživi izvori.
Rezultati: Pregledno su prikazani lijekovi koji se trenutno najčešće koriste u ublažavanju
simptoma i liječenju COVID-19: monoklonska protutijela, kortikosteroidi, antivirotici te ostali
lijekovi.
Zaključak: Primjena postojećih lijekova koji su se u ovoj pandemiji počeli koristiti u svrhu
liječenja COVID-19 od samog početka pokazala se izazovnom. Unatoč složenoj situaciji s
kojom su se kliničari susreli i dalje je ostalo jednako važno voditi brigu o dovoljnoj količini
relevantnih znanstvenih dokaza koji bi opravdali primjenu tih lijekova u liječenju ove bolesti.
Također, važno je i spriječiti situaciju u kojoj bi takva primjena postojećih lijekova mogla
dovesti do nestašice za pacijente koji su ih koristili u do sada odobrenim indikacijama te
dodatne opterećenosti zdravstvenog sustava koji bi nastao kao posljedica toga. Dobro
poznavanje kliničkih manifestacija bolesti i općenito patofiziologije COVID-19 je važno za
odluku o ključnim parametrima koji definiraju učinak farmakoterapije: vrijeme primjene lijeka
(s obzirom na stadij uznapredovalosti bolesti) i vrsta lijeka. Magistri farmacije, kao
visokoobrazovani stručnjaci koji posjeduju široko znanje o mehanizmu djelovanja lijekova,
mogu pomoći identificirati terapijske probleme te doprinijeti pozitivnim ishodima liječenja.The goal of this research: The goal of this thesis is to present the main aspects of the use of
some of the existing medications in COVID-19 pharmacotherapy.
Research methods: For this purpose, a variety of latest scientific and professional literature,
current guidelines, publications by professional associations and institutions, the Croatian
Agency for Medicinal Products and Medical Devices database, the European Medicines
Agency database and other available sources were examined.
Results: Most commonly used medications (to this moment) for treating COVID-19:
monoclonal antibodies, corticosteroids, antivirotics and others were presented in one place.
Conclusion: From the very beginning of this pandemic the use of existing medications for
treating COVID-19 has proved to be very challenging. Despite the complex situation
clinicians had to face, it is still important to provide a sufficient amount of relevant scientific
evidence to justify the use of these medications in the treatment of this disease. It is also
important to prevent a situation in which such use of existing medications could lead to
shortages for patients who have used them in so far approved indications. This could also be
an additional burden on the healthcare system. Good knowledge of the clinical manifestations
and pathophysiology of COVID-19 in general is important to decide on the key parameters
that define the effect of the pharmacotherapy: the time of drug administration (with respect to
the stage of disease progression) and the type of drug. Pharmacists, as highly educated experts
who have extensive knowledge of the mechanism of action of drugs, can help identify
therapeutic problems and contribute to positive outcome
Syntheses and mechanisms of ethanolysis of benzyl bromide derivatives
No full textRazličito supstituirani benzil-bromidi su sintetizirani bromiranjem odgovarajućih
benzilnih alkohola. Spojevi 3,4-dimetilbenzil-bromid, 3,5-dimetilbenzil-bromid, 4-
fenoksibenzil-bromid, 4-(metiltio)benzil-bromid, 4-tert-butilbenzil-bromid, 4-metilbenzilbromid i 4-fenilbenzil-bromid sintetizirani su uz fosforov tribromid, a 4-metoksibenzil-bromid
uz acetil-bromid. Kako bi utvrdili čistoću spojeva provedene su nuklearna magnetska rezonancija (NMR) i
tankoslojna tekućinska kromatografija (TLC). Konduktometrijski su određene konstante
brzine solvolize sintetiziranih benzil-bromida u etanolu na 25 °C. Spojevima koji se zbog
manje reaktivnosti nisu mogli mjeriti na 25 °C su konstante brzine solvolize izmjerene na
povišenim temperaturama i naknadno ekstrapolirane na 25 °C. Logaritmi izmjerenih konstanti
brzina solvolize korelirani su sa σ + – vrijednostima odgovarajućih supstituenata prema
Hammett-Brownovoj korelacijskoj analizi. Dobivena su dva pravca različitih nagiba pri čemu
prvi pravac čine točke koje pripadaju 4-metoksibenzil-bromidu i 4-(metiltio)benzil-bromidu, a
drugi je definiran točkama koje pripadaju ostalim spojevima (redom 4-fenoksibenzil-bromid,
3,4-dimetilbenzil-bromid, 4-metilbenzil-bromid, 4-tert-butilbenzil-bromid, 4-fenilbenzilbromid, 3,5-dimetilbenzil-bromid). Svaki pravac predstavlja zaseban mehanizam nukleofilne
supstitucije u solvolizi ove serije bromida. Iznos reakcijske konstante ρ + (nagib pravaca) daje
nam prikaz promjene naboja na reakcijskom centru benzila. Nagibi oba pravca negativnog su
predznaka što upućuje na nastanak pozitivnog naboja na reakcijskom centru. Negativnija
vrijednost ρ + benzila lijevog pravca (ρ1 + = −6,30) upućuje na nastajanje stabilnog karbokationa
u prvom stupnju SN1 reakcije. Manje negativan nagib desnog pravca (ρ2 + = −2,34) sugerira
SN2 mehanizam pripadajućih benzil-bromida. Dakle, eksperimentom je dokazano da 4-metoksibenzil-bromid i 4-(metiltio)benzil-bromid u etanolu solvoliziraju SN1 mehanizmom, dok 4-fenoksibenzil-bromid, 3,4-dimetilbenzilbromid, 4-metilbenzil-bromid, 4-tert-butilbenzil-bromid, 4-fenilbenzil-bromid i 3,5- dimetilbenzil-bromid solvoliziraju SN2 mehanizmom. Budući da 4-metoksibenzil-bromid ima najveći apsolutan iznos σ + vrijednosti supstituenta i najveću konstantu brzine reakcije, dokazana je početna pretpostavka da reakcija solvolize spojeva s jačim elektron-donorskim supstituentima teče brže.Differently substituted benzyl bromides were synthesized by bromination from adequate
benzyl alcohols. Compounds 3,4-dimethylbenzyl bromide, 3,5-dimethylbenzyl bromide, 4-
phenoxybenzyl bromide, 4-(methylthio)benzyl bromide, 4-tert-butylbenzyl bromide, 4-
methylbenzyl bromide and 4-phenylbenzyl bromide were synthesized with phosphorus
tribromide, while 4-methoxybenzyl bromide was synthesized with acetyl bromide.
Nuclear magnetic resonance (NMR) and Thin-layer chromatography (TLC) were carried
out to determine the purity of the compounds. The solvolysis rate constants of synthesized
benzyl bromides were determined conductometrically in ethanol at 25 °C. Solvolysis reaction
constants for compounds which couldn`t be measured at 25 °C because od their lesser
reactivity were determined at higher temperatures and later extrapolated to 25 °C. The
measured values of the logarithms of reaction constants of solvolysis were correlated with the
σ + -values of adequate substituents according to the Hammett-Brown correlation analysis. Two
plots with different slopes were obtained where the first plot includes data for 4-metoxybenzyl
bromide and 4-(methylthio)benzyl bromide, while the second plot is defined by the data which
belongs to other compounds (4-phenoxybenzyl bromide, 3,4-dimethylbenzyl bromide, 4-
methylbenzyl bromide, 4-tert-butylbenzyl bromide, 4-phenylbenzyl bromide and 3,5-
dimethylbenzyl bromide). Each plot represents a separate mechanism of nucleophilic
substitution in solvolysis of this bromide series. The value of the reaction constant ρ
+ (the slope of the plots) gives us a display of the charge change on the benzyl reaction site. The
slopes of both plots have negative value which indicates a formation of a positive charge on
the reaction center. The more negative value of ρ + for benzyls on the left plot (ρ1
+ = −6,30) indicates the formation of a stable carbocation in the first step of an SN1 reaction. Lesser
negative slope of the right plot (ρ2 + = −2,34) suggests an SN2 mechanism of belonging benzyl
bromides. Therefore, the experiment has proven that 4-methoxybenzyl bromide and 4-
(methylthio)benzyl bromide solvolyze in ethanol by SN1 mechanism, while 4-phenoxybenzyl
bromide, 3,4-dimethylbenzyl bromide, 4-methylbenzyl bromide, 4-tert- butylbenzyl bromide,
4-phenylbenzyl bromide and 3,5-dimethylbenzyl bromide solvolyze by SN2 mechanism. Since
4-methoxybenzyl bromide has the highest absolute substituent σ + value and the highest
reaction rate constant, the inital assumption that the solvolysis reaction of compounds with
stronger electron-donating substitutents happens faster, was proven
Retinoids in the treatment of skin diseases
No full textRetinoidi su prirodni i sintetski analozi vitamina A, esencijalnog nutrijenta ljudskog organizma. Retinoidi se obzirom
na strukturne značajke dijele u četri generacije, no biološka aktivnost unutar generacija je ista. Retinoidi uglavnom svoje
djelovanje ostvaruju vežući se za nuklearne receptore steroidne/tiroidne superporodice. Dvije su vrste receptora na koje
djeluju – RAR te RXR. Prilikom ulaska u stanicu i jezgru, retinoidi potiču biološke učinke nakon vezanja za određenu
izoformu receptora što potiče konformacijske promjene genoma i dovodi do pojačane ekspresije ili inhibicije
transkripcije gena. Svoj negenomski učinak mogu ispoljavati i aktivacijom kaskade kinaza što dovodi do
posttrasnalcijskih promjena na unutarstaničnim proteinima. Genomskim učinkom na transkripciju dovode do raznih
učinaka na organizam, a posebno utječu na keratinocite i hiperpigmentacije. Zbog ovog učinka indicirani su za liječenje
hiperkeratoznih dermatoloških promjena na koži i poremećaja hiperpigmetacije. Koriste se za liječenje akni, psorijaze,
ihtioze, promjena povezanih sa fotostarenjem (bore, melazma, posinflamatorne hiperpigmentacije), Darierove bolesti i
kutanog limfoma T stanica. Fiziološki učinak retinoida dovodi do normalizacije diferencijacije keratinizacije i
epitelizacije epidermisa, normaliziraju povećanu proliferaciju keratinocita te djeluju antiinflamatorno, antimikrobno i
protuupalno. Dodatno, u određenim stanjima mogu djelovati i antitumorski potičući apoptozu prokancerogenih
keratinocita. Najčešće sistemske nuspojave oralno primijenjenih retinoida obuhvaćaju teratogenost, hiperlipidemiju,
hiperkolesterolemiju i suhoću sluzokože. Žene reproduktivne dobi treba informirati o teratogenom djelovanju sistemski
primijenjenog retinoida. Nužno je primijeniti odgovarajući režim kontracepcije za vrijeme terapije. Topikalna primjena
može izazvati pruritis, svrbež, crvenilo, eritrem te perutanje kože na mjestu primjene. Pacijentima se preporuča pravilna
uporaba krema sa SPF faktorom tokom korištenja terapije kako bi se umanjile neželjene reacije.Retinoids are natural and synthetic analogues of vitamin A, an essential nutrient of the human body. Retinoids are
divided into four generations due to their structural features, but the biological activity within the generations is the
same. Retinoids spend most of their effect binding to steroid / thyroid superfamily nuclear receptors. There are two
types of receptors they act on - RAR and RXR. Upon entering the cell and nucleus, retinoids promote biological effects
upon binding to a particular receptor isoform which induces conformational changes in the genome and leads to
enhanced expression or inhibition of gene transcription. They can also exert their non-genomic effect by activating the
kinase cascade, which leads to posttransnal changes in intracellular proteins. The genomic effect on transcription leads
to various effects on the organism, and in particular affects keratinocytes and hyperpigmentation. Due to this effect, they
are indicated for the treatment of hyperkeratotic dermatological changes in the skin and hyperpigmentation disorders.
They are used to treat acne, psoriasis, ichthyosis, changes associated with photoaging (wrinkles, melasma, postinflammatory hyperpigmentation), Darier's disease and cutaneous T-cell lymphoma. The physiological effect of
retinoids leads to the normalization of the differentiation of keratinization and epithelialization of the epidermis,
normalize the increased proliferation of keratinocytes and have anti-inflammatory, antimicrobial and anti-inflammatory
effects. In addition, in certain conditions, they may have antitumor activity by stimulating the apoptosis of
procarcinogenic keratinocytes. The most common systemic side effects of orally administered retinoids include
teratogenicity, hyperlipidemia, hypercholesterolemia, and mucosal dryness. Women of childbearing potential should be
informed of the teratogenic effects of systemically administered retinoids. It is necessary to apply an appropriate
contraceptive regimen during therapy. Topical application may cause pruritus, redness, erythema and flaking of the skin
at the site of application. Patients are recommended to use SPF factor creams correctly during the use of therapy in order
to reduce side effects