1,721,141 research outputs found
Challenges in migraine therapy: new therapeutic possibilities with action on the calcitonin gene related peptide system
No full textMigrena je kronični neurološki poremećaj koji se manifestira napadima umjerene ili jake glavobolje te reverzibilnim
neurološkim i sistemskim simptomima. Procjenjuje se da je ukupna prevalencija migrene u zapadnim zemljama 6-8%
kod muškaraca i 15-25% kod žena.
Patofiziologija migrene je kompleksna, te je i dalje predmet intenzivnih istraživanja. Prema trigeminovaskularnoj
teoriji, vazodilatacija ekstracerebralnih krvnih žila i neurogena upala dure najvažnije su patofiziološke značajke
migrenozne glavobolje.
Farmakološka terapija migrene tradicionalno se dijeli na akutnu i preventivnu. Akutno liječenje namijenjeno je
smanjenju boli i pridruženih simptoma migrene te onesposobljenja bolesnika tijekom samog napadaja. Preventivno
liječenje koristi se u svrhu smanjenja učestalosti i težine očekivanih napada u osoba s intenzivnim i čestim
glavoboljama.
Trenutno se akutni napadi migrene liječe neopioidnim analgeticima, triptanima (agonisti 5-HT1B/1D receptora) ili
nazalnim dihidroergotaminom. Međutim, glavni nedostaci ove terapije su neučinkovitost kod 20-30% pacijenata i
nuspojave. Preventivna terapija je nespecifična i uključuje empirijsku primjenu lijekova iz različitih
farmakoterapijskih skupina te ne postiže zadovoljavajuće učinke kod većine pacijenata.
Cilj ovog rada je dati pregled novih specifičnih lijekova za migrenu koji su razvijeni kako bi se postigla veća
učinkovitost te bolja podnošljivost i sigurnost u odnosu na dosadašnje terapijske opcije, a s konačnim ciljem povećanja
kvalitete života i olakšanja svakodnevnog funkcioniranja pacijenata s migrenom.
Intenzivna istraživanja patofiziologije migrene ukazala su na nove terapijske mete i mogućnost razvoja novih
generacija lijekova. Istraživanjem farmakologije serotonina razvili su se agonisti 5-HT1F receptora, a prvi u skupini
koji je odobren za akutnu migrenu je lasmiditan. Nadalje, rasvjetljavanje važne uloge CGRP sustava u migrenskoj
patofiziologiji dovelo je do razvoja antagonista CGRP receptora, tzv. gepanta i monoklonskih protutijela usmjerenih
na CGRP ligand ili CGRP receptor. Ubrogepant i rimegepant su prva dva odobrena antagonista receptora za akutnu
terapiju migrene, dok su monoklonska protutijela namijenjena uporabi u profilaktičkoj terapiji epizodične i kronične
migrene.Migraine is a chronic neurological disorder that is characterized by an attack of moderate or severe headache and
reversible neurological and systemic symptoms. It is estimated that the overall prevalence of migraine in Western
countries is 6-8% in men and 15-25% in women.
The pathophysiology of migraine is complex and it is still the subject of intensive research. According to the
trigeminovascular theory, vasodilation of extracerebral blood vessels and neurogenic inflammation of the dura are the
most important pathophysiological features of migraine headaches.
Pharmacological therapy of migraine is traditionally divided into acute and preventive. Acute treatment aims to reduce
pain and accompanied symptoms, as well as the disability of patients during a migraine attack. Preventive treatment is
used to reduce the frequency and severity of expected attacks for people with intense and frequent headaches.
Currently, acute migraine attacks are treated with non-opioid analgesics, triptans (5-HT1B/1D receptor agonists), or
nasal dihydroergotamine. However, the main disadvantages of this therapy are ineffectiveness in 20-30% of patients
and side effects. Preventive therapy is non-specific and involves the empirical administration of drugs from different
pharmacotherapeutic groups and does not achieve satisfactory effects in most patients.
This diploma thesis gives an overview of new specific migraine drugs that are developed to achieve better efficiency
and better, tolerability, and safety compared to previous therapeutic options, with the final goal in increasing the
quality of life of patients suffering from migraine. Intensive research on the pathophysiology of migraine has
indicated new therapeutic targets and opportunities for the development of new generations of drugs. Based on the
understanding of serotonin system pharmacology, 5-HT1F receptor agonists were developed, and the first in class for
acute migraine treatment is lasmiditan. Furthermore, clarification of the important role of the CGRP system in
migraine pathophysiology has led to the development of CGRP receptor antagonists, the so-called gepants, and
monoclonal antibodies targeting the CGRP ligand or CGRP receptor. Ubrogepant and rimegepant were the first two
approved receptor antagonists for acute migraine therapy, while monoclonal antibodies are intended for use in the
prophylactic therapy of episodic and chronic migraine
Polycystic ovary syndrome - challenges and opportunities
No full textU ovom teorijskom diplomskom radu opisane su patofiziološke karakteristike te mogućnosti nefarmakološkog i farmakološkog liječenja sindroma policističnih jajnika. PCOS je najčešći endokrini i metabolički poremećaj u žena reproduktivne dobi. Smatra se da je riječ o multigenetskom poremećaju sa snažnim utjecajem okolišnih čimbenika. Poremećaji u komunikaciji između hipotalamusa, hipofize i jajnika, inzulinska rezistencija, pretilost i adrenokortikalna disfunkcija osnova su patofiziologije PCOS-a. Biokemijski i klinički hiperandrogenizam, (oligo)anovulacija i policistična morfologija jajnika predstavljaju glavne reproduktivne značajke PCOS-a. Nadalje, pacijentice s PCOS-om imaju povećan rizik razvoja intolerancije glukoze, dijabetesa tipa 2, dislipidemije, hipertenzije i kardiovaskularnih bolesti. Navedene značajke PCOS-a rezultiraju smanjenom kvalitetom života povezanom sa zdravljem ovih pacijentica. Zabilježena je povećana prevalencija depresije i anksioznosti, psihoseksualne disfunkcije i poremećaja hranjenja. Cilj je kombinacijom nefarmakoloških mjera s odgovarajućim farmakološkim liječenjem postići optimalan tretman pacijentica. Od nefarmakoloških mjera, svakako valja istaknuti uvođenje hipokalorijske dijete i fizičke aktivnosti. Prvu liniju liječenja hiperandrogenizma, ukoliko pacijentica ne planira trudnoću, predstavljaju kombinirani oralni hormonski kontraceptivi, a kao druga linija razmatra se uvođenje antiandrogena. Medroksiprogesteron acetat, intrauterini sustav s levonorgestrelom, kao i prethodno navedeni kombinirani oralni hormonski kontraceptivi pružaju dobru regulaciju menstrualnog ciklusa, a time i zaštitu od hiperplazije i karcinoma endometrija. Za liječenje metaboličkih nepravilnosti obično se koristi metformin, dok klomifen citrat predstavlja prvu liniju za indukciju ovulacije kod anovulatornih pacijentica s PCOS-om.The pathophysiological characteristics and the possibilities of non-pharmacological and pharmacological treatment of polycystic ovarian syndrome are described in this theoretical diploma thesis. PCOS is the most common endocrine and metabolic disorder in women of reproductive age. It is considered to be multigenetic disorder with strong environmental influences. Communication disorders between hypothalamus, pituitary gland and ovaries, insulin resistance, obesity and andrenocortical disfunction are the basis of PCOS pathophysiology. Biochemical and clinical hyperandrogenism, (oligo)anovulation and polycystic ovarian morphology represent the main PCOS reproductive features. Furthermore, patients with PCOS are at high risk of developing glucose intolerance, type 2 diabetes, dyslipidemia, hypertension and cardiovascular diseases. The listed PCOS features result in decreased health related quality of life of these patients. Increased prevalence of depression, anxiety and eating disorders has been noticed. The therapeutic goal is to achieve the optimal treatment for patients by combining non-pharmacological measures with appropriate pharmacological treatment. Of non-pharmacological measures, it is important to emphasize the introduction of hypocaloric diet and physical activity. The first-line therapy for hyperandrogenism is combined oral hormonal contraceptives if patient do not plan for pregnancy, while it is considered to introduce antiandrogens as the second-line therapy. Medroxyprogesterone acetate, levonorgestrel intrauterine system, as well as previously mentioned combined oral hormonal contraceptives ensure effective regulation of menstrual cycle and thus protection against the development of endometrial hyperplasia or carcinoma. Metformin is usually used to treat the metabolic irregularities, while clomiphene citrate is the first-line therapy to induce ovulation in anovulatory PCOS patients
Immunomodulatory effect of Echinacea species
Get PDFEchinacea je zbog svog izražnog imunomodulacijskog učinka jedna od najistraživanijih biljaka današnjice. Unatoč brojnim istraživanjima kemizma, mehanizma djelovanja pojedinih sastavnica, malo je relevantnih na dokazima-utemeljenih podataka o učinkovitosti i sigurnosti iz kliničkih studija. Cilj ovog rada bio je istražiti utemeljenost tvrdnji o imunomodulacijskom djelovanju te istražiti mehanizam istog, prikazati metabolizam, nuspojave i interakcije koje mogu nastati prilikom korištenja preparata koji sadrže Echinaceu, prikazati važnost kontrole kvalitete biljnih droga koje se koriste u kliničkoj primjeni. Mehanizam imunomodulacijskog djelovanja temelji se na povećanju fagocitoze, mobilnosti T limfocita i povećane respiratorne aktivnosti. Protuupalno djelovanje bazirano je na povećanju lučenja protuupalnih, a smanjenja lučenja proupalnih citokina. Metabolizam glavnih aktivnih sastavnica odvija se putem citokroma P450, a zbog inhibicijskog djelovanja na CYP3A4 moguće su interakcije s lijekovima koje taj enzim metabolizira.Terapijski potencijal ove zanimljive biljne vrste temelji se na rezultatima pretkliničkih, ali i sve većeg broja kliničkih studija koje govore u prilog imunomodulacijskog djelovanja. Kako bi se maksimalno iskoristio terapijski potencijal Echinaceae vrsta, a minimalizirao rizik nuspojava i interakcija s drugim lijekovima, potrebno je kontrolirati pripravke koji dolaze na tržište s obzirom na sastav, količinu i kvalitetu sastavnica koje sadrže.Because of it's expressed immunommodulatory effect Echinacea is one of the most investigated medicinal plants. Despite numerous studies of it's chemistry, mechanism of action of main constituents, there is little evidence from clinical studies related to it's efficiency and safety. The main goal of this diploma thesis was to investigate the mechanism of immunomodulatory effect of Echinaceae species. Additionally, aims were to: explain metabolism, describe side effects and interactions which can emerge during usage of preparations which contain Echinacea and to show importance of quality control of herbal medicine used in clinical practice. The mechanism of immunomodulatory effect is based on increased phagocytosis, increased mobility of the T-lymphocytes and increased respiratory activity. Anti-inflammatory effect is based on up-regulation of anti-inflammatory cytokines and down-regulation of pro-inflammatory cytokines. Metabolism of main active components involves reactions catalyzed by cytocrome P450. Because of it's inhibitory effect on CYP3A4, interactions with drugs which are substrates of this enzyme are possible. Therapeutic potential of this interesting plant is based on results from numerous preclinical and growing number of clinial trials which are going in favor oEchinacae immunomodulatory effect. To maximize therapeutic potential of Echinacea and to minimize side effects and interactions we need better quality control of available preparations considering quantity, quality and type of constituents
The effect of botulinum toxin type A on neuronal activation in hypothalamus in experimental inflammatory pain
Get PDFBotulinum toksin tipa A (BT-A) je neurotoksin kojeg proizvodi anaerobna bakterija Clostridium botulinum. Smatra se
jednim od najpotentnijih bioloških toksina, no pročišćeni farmakološki pripravak u pikomolarnim dozama koristi se
liječenju različitih kliničkih stanja praćenih povećanom kontraktilnošću mišića. Dugotrajno djelovanje nakon
jednokratne primjene koje traje do nekoliko mjeseci daje mu prednost nad poznatim analgeticima te se sve više koristi
u liječenju određenih tipova kronične boli, primjerice migrene. Brojna istraživanja bave se njegovim
antinociceptivnim djelovanjem s ciljem otkrivanja mehanizma, kako bi se što bolje iskoristio u terapijske svrhe.
Nasuprot općeprihvaćenoj teoriji o djelovanju BT-A na inhibiciju egzocitoze neurotransmitora na perifernim
završecima osjetnih neurona, rezultati brojnih istraživanja ukazuju na središnje mjesto djelovanja, najvjerojatnije na
razini dorzalnog roga kralježnične moždine gdje periferno primijenjen BT-A dolazi retrogradnim aksonalnim
transportom. Ovim radom istraženo je potencijalno mjesto središnjeg djelovanja BT-A injiciranjem toksina u moždane
komore (intracerebroventrikularno, i.c.v.) na modelu formalinom uzrokovane periferne upalne boli, promatrajući
ekspresiju c-Fos proteina kao markera aktivacije neurona. Ispitivanja su provedena na tkivu mozga mužjaka štakora
soja Wistar. BT-A je primijenjen i.c.v. u dozi od 1 i.j./kg, a kontrolnoj je skupini i.c.v. injicirana fiziološka otopina u
odgovarajućem volumenu. Imunohistokemijskom metodom analizirana je ekspresija c-Fos proteina u hipotalamusu,
regiji mozga koja sudjeluje u modulaciji boli. Rezultati kvantitativne analize ekspresije c-Fos proteina očekivano
pokazuju aktivaciju ove regije nakon uzrokovanja upalne boli perifernom injekcijom formalina. Međutim, učinak BTA
nakon primjene u moždane komore (i.c.v.) je izostao, što se očituje podjednakim brojem aktiviranih neurona kod
ispitivanih i kontrolnih uzoraka tkiva. Ovi rezultati u skladu su s hipotezom o središnjem segmentalnom
antinociceptivnom djelovanju BT-A na spinalnoj razini, tj. razini kralježnične moždine na bol perifernog porijekla te
isključuju antinociceptivno djelovanje BT-A na supraspinalnoj razini. Međutim, potrebna su daljna istraživanja kako
bi se otkrilo primarno mjesto središnjeg djelovanja BT-A.Botulinum toxin type A (BTX-A) is a neurotoxin produced by anaerobic bacteria Clostridium botulinum. It is
considered as one of the most potent biological toxins, but purified pharmacological preparation in picomolar doses is
used to treat various clinical conditions followed by increased muscular contractility. Long-term duration of effects
after its single administration represents a special clinical value among known analgesics, so it is widely used in the
treatment of certain types of cronic pain, such as migraine. Numerous researches are based on its antinociceptive
action to find out the mechanism and improve its clinical use. In contrast to generally accepted theory of BTX-A
activity on inhibition of neurotransmitters release on peripheral endings of sensory neurons, the results of numerous
researches point to its central site of action, most likely at the dorsal spinal cord level where peripherally applied BTXA
occurs by retrograde axonal transport. This study investigated the potentially central site of BTX-A action after
supraspinal administration (intracerebroventricular, i.c.v.) in inflammatory pain model induced by formalin injection,
by observing c-Fos protein expression as a marker of neuronal activation. Experiment was performed on brain tissue
of male Wistar rats. BTX-A was injected into the lateral cerebral ventricles (i.c.v.) in a dose of 1 U/kg. Control
animals received 0,9% saline in the appropriate volumes. C-Fos expression was imunohistochemically examined in
hypothalamus, a brain region involved in pain modulation. The results of the quantitative analysis of c-Fos protein
expression show activation of this region because of inflammatory pain induced by peripheal formalin injection.
However, BTX-A application into lateral cerebral ventricles failed to affect pain induced by formalin injection which
is manifested by an equal number of activated neurons in the examined and control tissue samples. These results are
following the hypothesis of the central segmental antinociceptive action of BTX-A at spinal level, i.e. spinal cord level
on the pain of peripheal origin and exclude antinociceptive action of BTX-A on supraspinal level. However, further
research is needed to investigate the primary location of BT-A's central activity
Therapy of visceral hypersensitivity in irritable bowel syndrome
No full textVisceralna preosjetljivost je važna komponenta sindroma iritabilnog crijeva, a pogađa 30-60% pacijenata, pretežito mlađe dobi i ženskog spola. Patofiziološka podloga visceralne preosjetljivosti nije još do kraja objašnjena, no smatra se da razni periferni i središnji faktori, poput psihološkog stresa i poremećaja crijevne permeabilnosti, mogu uzrokovati promjenu dvosmjerne signalizacije osi crijeva-mozak i povećanu senzitizaciju perifernog (enteričkog) i središnjeg živčanog sustava. Spazmolitici kao periferni neuromodulatori koriste se za smanjenje spazama i abdominalne boli. Antidepresivi se danas najčešće koriste kao središnji neuromodulatori, a istražuju se i atipični antipsihotici. Ovi lijekovi svojim kompleksnim djelovanjem na serotoninski i druge neurotransmitorske sustave djeluju izravno i posredno na neke patofiziološke komponente u podlozi visceralne preosjetljivosti, a posebno su korisni kod pacijenata s psihičkim poremećajima u anamnezi. U raznim studijama, tvari prirodnog porijekla poput berberina i kurkumina, kao i probiotici, pokazuju učinkovitost u smanjenju visceralne preosjetljivosti, što zahtijeva daljnja istraživanja. Istraživanja ukazuju na širok spektar medijatora i receptora uključenih u transmisiju, percepciju i modulaciju bolnih signala porijeklom iz gastrointestinalnog trakta, posebice na razini komunikacije crijeva-mozak, koji se istražuju kao potencijalne nove mete za specifičnije lijekove s neuromodulatornim djelovanjem na visceralnu preosjetljivost.Visceral hypersensitivity is an important component of irritable bowel syndrome, and affects 30-60% of patients, mostly younger and female. The pathophysiological basis of visceral hypersensitivity has not yet been fully explained, but it is believed that various peripheral and central factors, such as psychological stress and disorders of intestinal permeability, can cause a change in the bidirectional signaling of the gut-brain axis and increased sensitization of the peripheral (enteric) and central nervous system. Antispasmodics as peripheral neuromodulators are used to reduce spasms and abdominal pain. Today, antidepressants are most often used as central neuromodulators, and atypical antipsychotics are also being investigated. With their complex action on serotonin and other neurotransmitter systems, these drugs act directly and indirectly on some pathophysiological components underlying visceral hypersensitivity, and are especially useful in patients with a history of mental disorders. In various studies, substances of natural origin such as berberine and curcumin, as well as probiotics, show efficacy in reducing visceral hypersensitivity, which requires further research. Research indicates a wide spectrum of mediators and receptors involved in the transmission, perception and modulation of pain signals originating from the gastrointestinal tract, especially at the level of gut-brain communication, which are being investigated as potential new targets for more specific drugs with neuromodulatory effects on visceral hypersensitivity
Utjecaj koronavirusa na crijevnu mikrobiotu
No full textCilj istraživanja: Ravnoteža crijevne mikrobiote od velike je važnosti za očuvanje zdravlja ljudi. Stanje kada je ravnoteža među komponentama mikrobiote narušena, naziva se disbioza. Godine 2019. u kineskom gradu Wuhan izbijala je bolest teškog akutnog respiratornog sindroma nazvana COVID-19, koja je uzrokovana novim koronavirusom SARS-CoV-2. Osim infekcije respiratornog sustava, SARS-CoV-2 također inficira gastrointestinalni trakt, gdje se intenzivno razmnožava. Cilj ovog rada je pružiti uvid u promjene sastava crijevne mikrobiote kod pacijenata s COVID-19 i kod osoba koje su se oporavile od COVID-19, kao i uvid u terapijske intervencije koje utječu na promjenu sastava crijevne mikrobiote u pacijenata s COVID-19.
Metode: Za izradu ovog preglednog rada pretraživana je dostupna znanstvena literatura na temu crijevne mikrobiote, COVID-19, analize crijevne mikrobiote u COVID-19 pacijenata te utjecaja probiotika i prehrane na crijevnu mikrobiotu kod COVID-19 pacijenata.
Rezultati: Sastav crijevne mikrobiote COVID-19 pacijenata te osoba koje su se oporavile od COVID-19 pokazuje značajnu disbiozu u usporedbi sa zdravim kontrolama. Dokazano je smanjenje mikrobne raznolikosti i mikrobnog bogatstva, kao i promjene u sastavu crijevne mikrobiote u obliku gubitka korisnih bakterija i povećanja brojnosti patogenih bakterija. Disbioza crijeva usko je povezana s gastrointestinalnim simptomima i težinom bolesti COVID-19.
Zaključak: Za utvrđivanje odražavaju li te promjene u sastavu crijevne mikrobiote uzrok ili posljedicu COVID-19, potrebno je provesti dodatna istraživanja. Terapijska intervencija na mikrobiotu putem probiotika, prebiotika i fekalne transplantacije je jedna od obećavajućih strategija za liječenje COVID-19 u budućnosti, ali neophodna su daljnja istraživanjaObjectives: The intestinal microbiota balance is of great importance for maintaining human health. The condition when the balance in the microbial community is disturbed is called dysbiosis. In 2019, a severe acute respiratory syndrome disease called COVID-19 broke out in the Chinese city of Wuhan. It is an infectious disease caused by the new coronavirus SARS-CoV-2. In addition to infection of the respiratory system, SARS-CoV-2 also infects the gastrointestinal tract, where it multiplies intensively. The aim of this work is to provide insight into changes in the intestinal microbiota compostion in patients with COVID-19 and in people who have recovered from COVID-19, as well as insight into therapeutic interventions that affect changes in the intestinal microbiota composition in patients with COVID-19.
Methods: The methods included a review of available scientific literature on the topic of intestinal microbiota, COVID-19, analysis of intestinal microbiota in COVID-19 patients, and the impact of probiotics and nutrition on intestinal microbiota in COVID-19 patients.
Results: The composition of the intestinal microbiota of COVID-19 patients and persons who have recovered from COVID-19 shows significant dysbiosis compared to healthy controls. A decrease in microbial diversity and richness, as well as changes in the composition of the intestinal microbiota in the form of a loss of beneficial bacteria and an increase in the number of pathogenic bacteria, have been proven. Gut dysbiosis is closely related to gastrointestinal symptoms and the severity of the disease of COVID-19.
Conclusion: To determine whether these changes in the composition of the intestinal microbiota reflect the cause or effect of COVID-19, it is necessary to perform additional research. Therapeutic intervention on the microbiota through probiotics, prebiotics and fecal transplantation is one of the promising strategies for the treatment of COVID-19 in the future, but further research is necessary
Pharmacological therapy of stable angina pectoris
No full textStabilna angina pektoris predstavlja najčešću kliničku manifestaciju ishemijske bolesti srca, a povezana je s narušenom kvalitetom života i povećanim rizikom od štetnih kardiovaskularnih događaja. Važno je prepoznati njezine simptome i započeti s liječenjem koje ima dva glavna cilja. Prvi od njih je sprječavanje ili smanjenje pojave anginoznih simptoma te poboljšanje kvalitete života, dok je drugi cilj prevencija ozbiljnih kardiovaskularnih događaja. Patofiziološku podlogu čini prisutna opstruktivna koronarna arterijska bolest, odnosno prisutnost aterosklerotskih plakova u epikardijalnim koronarnim arterijama zbog čega se javlja neravnoteža između potrebe srca za kisikom i opskrbe srca kisikom. Farmakološka terapija stabilne angine uključuje primjenu antiishemijskih lijekova, kojima se nastoji uspostaviti ravnoteža između opskrbe srca kisikom i potrebe srca za kisikom, te lijekova koji preveniraju kardiovaskularne događaje. Među antiishemijskim lijekovima razlikuju se lijekovi prve i druge linije liječenja, pri čemu se u prvu liniju ubrajaju β-blokatori, blokatori kalcijevih kanala i kratkodjelujući nitrati. Uz dugodjelujuće nitrate, lijekovima druge linije smatraju se nikorandil, ranolazin, trimetazidin i ivabradin. Lijekovi druge linije se koriste u slučaju prisutnih kontraindikacija na lijekove iz prve linije, u slučaju njihove nepodnošljivosti ili ako se prvom linijom ne može postići dobra kontrola simptoma. Pri tome je važno istaknuti kako ne postoje usporedbe između prve i druge linije koje bi pokazale superiornost jedne skupine nad drugom u pogledu učinkovitosti. Od lijekova koji preveniraju kardiovaskularne događaje značajni su antiagregacijski lijekovi (acetilsalicilna kiselina, P2Y12 antagonisti), statini i ACE inhibitori. Revaskularizacija miokarda može se razmotriti kod bolesnika koji imaju prognostički značajne lezije ili simptome unatoč optimalnoj farmakološkoj terapiji, pri čemu je moguće izvesti perkutanu koronarnu intervenciju, premoštenje koronarnih arterija ili oboje.Stable angina pectoris represents the most common clinical manifestation of ischemic heart disease, and is associated with impaired quality of life and increased risk of adverse cardiovascular events. It is important to recognize its symptoms and start treatment, which has two main goals. The first of them is the prevention and reduction of anginal symptoms and the improvement of quality of life, while the second goal is the prevention of serious cardiovascular events. The pathophysiological basis is the presence of obstructive coronary artery disease, that is, the presence of atherosclerotic plaques in the epicardial coronary arteries, which causes an imbalance between the heart's need for oxygen and the heart's oxygen supply. Pharmacological therapy of stable angina pectoris includes use of anti-ischemic drugs which try to restore balance between the heart's oxygen supply and the heart's need for oxygen, and drugs that prevent cardiovascular events. Among anti-ischemic drugs, first- and second-line drugs are distinguished, whereby β-blockers, calcium channel blockers and short-acting nitrates are included in the first line. In addition to long-acting nitrates, second-line drugs include nicorandil, ranolazine, trimetazidine, and ivabradine. Second-line drugs are used in case of contraindications for first-line drugs, in case of their intolerance or if good control of symptoms cannot be achieved with the first-line drug. It is important to point out that there are no comparisons between the first- and second-line drugs that would show the superiority of one group over the other in terms of effectiveness. Among the drugs that prevent cardiovascular events, antiplatelet drugs (acetylsalicylic acid, P2Y12 antagonists), statins and ACE inhibitors are important. Myocardial revascularization may be considered in patients who have prognostically significant lesions or symptoms despite optimal pharmacology therapy, where percutaneous coronary intervention, coronary artery bypass grafting or both can be performed
The pharmacological characteristics of diuretics and their misuse
No full textDiuretici su lijekovi koji smanjuju volumen ekstracelularne tekućine povećavanjem izlučivanja soli i vode putem bubrega. Međusobno se razlikuju po strukturi, fizikalno-kemijskim svojstvima, mehanizmu i mjestu djelovanja zbog čega se svrstavaju u nekoliko skupina. Raznolikost diureticima omogućava široku primjenu za niz indikacija, kao što su arterijska hipertenzija i srčano zatajivanje. Međutim, zbog brzog smanjenja kilograma i prikrivanja prisutnosti drugih zabranjenih supstanci, često se koriste kao doping sredstvo u sportu. Nalaze se na Listi zabranjenih supstanci Svjetske antidoping agencije više od 30 godina te je njihova upotreba zabranjena i u samom natjecanju i izvan natjecanja. Posljedice njihove nekontrolirane primjene s jedne strane mogu biti stroge kazne koje mogu značajno obiljeţiti karijeru sportaša, a s druge strane direktni nepovoljni učinci na organizam sportaša te je potreban veliki oprez kod (zlo)upotrebe diuretika.Diuretics are drugs that reduce volume of extracellular fluid by increasing the excretion of salt and water by the kidneys. They can be differentiated by structure, physical and chemical properties, mechanism, together with, the place of action, which is why we classify them in several groups. The diversity of diuretics enables wide application for a number of indications such as arterial hypertension and heart failure. However, due to the rapid weight loss and the concealment of the presence of other prohibited substances, they are often used as a doping agent in sports. They have been on the List of Prohibited Substances of the World Anti-Doping Agency for more than 30 years, and their use is prohibited both in and out of competition. Aftermath of uncontrolled intake and usage of diuretics can result in severe penalties that can significantly and negatively mark an athlete´s career, as well as direct adverse effect they have on the athlete´s body, and it is necessary to be weary and precautious when (mis)using diuretics
Therapeutic challenges in the treatment of polycystic ovary syndrome
No full textU ovom teorijskom diplomskom radu obrađena je tema sindroma policističnih jajnika, od opisa kliničke slike,
etiologije i patofiziologije do terapijskih mogućnosti s fokusom na farmakološka svojstva i rizike lijekova i
dodataka prehrani te učinkovitost nefarmakoloških mjera koje podupiru ishode farmakološkog liječenja. PCOS
predstavlja ozbiljan javnozdravstveni problem koji je visoko prevalentan u žena reproduktivne dobi. Osim što je
vodeći uzrok ženske neplodnosti, povezan je s nizom drugih ozbiljnih zdravstvenih komplikacija, uključujući
inzulinsku rezistenciju, pretilost, povišeni kardiovaskularni rizik i mentalne poremećaje. Unatoč visokoj
prevalenciji, većini žena s PCOS-om nije postavljena dijagnoza pa izostaje i odgovarajuće liječenje koje bi postiglo
kontrolu simptoma i popravilo kvalitetu života. Liječenje PCOS-a treba započeti promjenom načina života
usvajanjem zdravih prehrambenih navika i redovitom fizičkom aktivnošću. Zdravi način života temelj je za
učinkovitije djelovanje farmakološke terapije koju najčešće čine kombinirani oralni kontraceptivi kao prva linija
liječenja. Osim njih koriste se i metformin, antiandrogeni i lijekovi za smanjenje tjelesne težine, koji se mogu
primjenjivati u kombinaciji s oralnim kontraceptivima ili samostalno u slučaju kontraindiciranosti ili slabog
podnošenja kombinacije estrogena i progestina. Za induciranje ovulacije preporučuje se letrozol kao prva linija, a
u istu se svrhu mogu koristiti i klomifen citrat ili egzogeni gonadotropini. Od dodataka prehrani najviše dokaza o
koristi primjene imaju inozitoli, no mnoštvo je drugih suplemenata s obećavajućim pozitivnim učincima na
endokrine i metaboličke parametre koji rijetko izazivaju nuspojave i sigurni su čak i u trudnoći. Lijekovi koji se
koriste za kontrolu simptoma i smanjenje rizika od komorbiditeta primjenjuju se off-label na temelju kliničkog
iskustva, no još uvijek nedostaju opsežna istraživanja na području patofiziologije i terapijskih mogućnosti koja bi
nam donijela sveobuhvatniju sliku o uzrocima ovoga stanja kao i odgovarajuću terapiju koja bi osim kontrole
simptoma djelovala i na sam uzrok i trajno popravila endokrino i metaboličko zdravlje pogođenih žena.This theoretical diploma thesis deals with the topic of polycystic ovary syndrome, from the description of the
clinical features, etiology and pathophysiology to therapeutic options with a focus on the mechanisms of action
and side effects of drugs and dietary supplements, as well as non-pharmacological interventions that support the
outcomes of pharmacological treatment. PCOS is a serious public health problem that is highly prevalent in women
of reproductive age. In addition to being the leading cause of female infertility, it is associated with a number of
other serious health complications, including insulin resistance, obesity, increased cardiovascular risk and mental
disorders. Despite its high prevalence, most women with PCOS are not diagnosed and therefore do not receive
appropriate treatment that would achieve symptom control and improve their quality of life. Treatment of PCOS
should begin with lifestyle changes by adopting healthy eating habits and regular physical activity. A healthy
lifestyle is the basis for more effective pharmacological therapy, which most often consists of combined oral
contraceptives as the first line of treatment. Metformin, antiandrogens and weight loss drugs can be also used, in
combination with combined oral contraceptives or alone in case of contraindications or poor tolerance to the
combination of estrogen and progestin. Letrozole is recommended as the first line for ovulation induction, and
clomiphene citrate or exogenous gonadotropins can be used for the same purpose. Among dietary supplements,
inositol has the most evidence of benefits, but there are many other supplements with promising beneficial effects
on endocrine and metabolic parameters that rarely cause side effects and are very safe even during pregnancy.
Medicines used to control symptoms and reduce the risk of comorbidities are being used off-label based on clinical
experience, but there is still a lack of extensive research into the pathophysiology and therapeutic options that
would bring us a more comprehensive picture of the causes of this condition, as well as adequate therapy that, in
addition to controlling symptoms, would also act on the cause itself and permanently improve the endocrine and
metabolic health of affected women
Distribution of botulinum toxin in the central nervous system
No full textBotulinum toksin tipa A je neurotoksični protein koji proizvodi anaerobna bakterija Clostridium botulinum,
te predstavja jedan od najsmrtonosnijih otrova u prirodi. Mehanizam djelovanja BoNT/A uključuje
cijepanje proteina SNAP-25 koji ima ključnu ulogu u egzocitozi acetilkolina na krajevima aksona, te
posljedično svoje djelovanje manifestira nastankom mlohane paralize mišića. Tijekom godina bazičnih
istraživanja, pokazano je da toksin osim na motoričke neurone, također djeluje i na senzorne neurone te
tako interferira s prijenosom bolnih signala, što za posljedicu može imati izniman klinički značaj.
Kontroliranom primjenom u pikomolarnim dozama toksin se koristi u terapiji stanja koja su uzrokovana
hiperaktivnosti mišića, kao što su cervikalna distonija, strabizam, hiperhidroza, ali i u terapiji kroničnih
migrena. Brojna istraživanja su rađena istražujući dodatne mogućnosti primjene BoNT/A u kliničke svrhe,
između ostalog i u terapiji kronične boli, čije je liječenje do sad predstavljalo veliki izazov. Cilj ovog
diplomksog rada bio je ispitati distribuciju botulinum toksina u različitim regijama mozga nakon njegove
primjene u cisternu magnu. Eksperimenti su provedeni na mužjacima štakora Wistar na Zavodu za
farmakologiju Medicinskog fakulteta Sveučilišta u Zagrebu u skladu s s aktualim propisima i Zakonom o
zaštiti životinja. Nakon iniciranja 5 i.j./kg BoNT/A u cisternu magnu, prikupljeni su uzorci tkiva mozgova i
pripremljeni za imunohistokemijsku analizu. Pratila se prisutnost pocijepanog SNAP-25 proteina kao
pokazatelja prisutnost toksina, u različitim regijama mozga.Dobiveni rezultati ukazuju na prisutnost toksina
u neposrednoj blizini mjesta iniciranja, u područjima trigeminalnog nucleus caudalisaihipokampusa, ali i u
udaljenim regijama mozga. Ovi nalazi zahtjevaju daljnja istraživanja kako bi se objasnili načini distribucije
toksina u udaljenija područja te njihovo značenje za djelovanje toksina, posebice u kliničkom okruženju.Botulinum toxin type A is a neurotoxic protein produced by the anaerobic bacterium Clostridium
botulinum, and is one of the deadliest poisons in nature. The mechanism of action of BoNT/A involves the
cleavage of the SNAP-25 protein, which plays a key role in the exocytosis of acetylcholine at the ends of
axons, and consequently manifests its action in the occurrence of flaccid muscle paralysis. During the years
of basic research, it was shown that the toxin not only acts on motor neurons, but also on sensory neurons
and thus interferes with the transmission of pain signals, which as a result can have exceptional clinical
significance. With controlled application in picomolar doses, the toxin is used in the treatment of conditions
caused by muscle hyperactivity, such as cervical dystonia, strabismus, hyperhidrosis, but also in the
treatment of chronic migraines. Numerous studies have been conducted investigating the additional
possibilities of using BoNT/A for clinical purposes, among others in the therapy of chronic pain, the
treatment of which has been a great challenge so far. The aim of this thesis was to examine the distribution
of botulinum toxin in different regions of the brain after its application to the cisterna magna. The
experiments were conducted on male Wistar rats at the Department of Pharmacology, Faculty of Medicine,
University of Zagreb, in accordance with current regulations and the Animal Protection Act. After the
initiation of 5 IU/kg BoNT/A into the cisterna magna, brain tissue samples were collected and prepared for
immunohistochemical analysis. The presence of cleaved SNAP-25 protein was monitored as an indicator of
the presence of toxins in different regions of the brain. The obtained results indicate the presence of toxins
in the immediate vicinity of the initiation site, in the areas of the trigeminal nucleus of the caudalis and
hippocampus, but also in distant regions of the brain. These findings require further research to explain the
ways of toxin distribution to more distant areas and their significance for the action of the toxin, especially
in the clinical setting
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