Pharmacophore analysis, design and in vitro testing of multi-target ligands as potentially effective therapeutics of complex neurological and mental disorders

Disfunkcija serotoninske i dopaminske neurotransmisije u mozgu je u osnovi patofiziologijebrojnih neuroloških i mentalnih oboljenja. Definisanje protokola koji integriše in silico i in vitrometode, u cilju prouĉavanja farmakofore multi-potentnih jedinjenja koja deluju na nivou centralnognervnog sistema (CNS), predstavlja vaţan korak u racionalizaciji procesa otkrivanja novih lekova.Primenom simulacija molekulske dinamike i molekulskog dokinga, kao i analize kvantitativnogodnosa strukture i aktivnosti (eng. 3D-Quantitative Structure Activity Relationship, 3D-QSAR)definisane su kljuĉne strukturne karakteristike dualnih antagonista 5-HT2A i D2 receptora, sasmanjenim afinitetom za H1 receptor. Na osnovu dobijenih rezultata izvršeno je pretraţivanje bazafragmenata primenom metode virtuelnog skrininga (eng. Virtual Screening, VS) u cilju dizajniranjapotencijalno bezbednijih i efikasnijih liganada sa višestrukim delovanjem (eng. multi-target),pruţajući smernice za razvoj novih lekova u terapiji sloţenih CNS oboljenja. 3D-QSAR analizombicikliĉnih α-iminofosfonata definisana je struktura farmakofore selektivnih liganadaimidazolinskih I2 receptora, kao potencijalno novih lekova za leĉenje kognitivnih poremećaja. Invitro paralelni test permeabilnosti na veštaĉkim membranama (eng. Parallel Artificial MembranePermeability Assay, PAMPA) je korišćen za odreĊivanje efektivne permeabilnosti (logPe) krozkrvno-moţdanu barijeru (KMB) jedinjenja koja utiĉu na modulaciju aktivnosti serotoninskog idopaminskog sistema u mozgu. Dobijeni rezultati su korišćeni u analizi kvantitativnog odnosastrukture i osobina (eng. Quantitative Structure-Property Relationship, QSPR) u cilju razumevanjastrukturnih karakteristika koje najviše utiĉu na prolazak jedinjenja kroz KMB. Model formiranprimenom metode podrţavajućih vektora (eng. Support-Vector Machine, SVM) i validiranopseţnom statistiĉkom analizom, je korišćen za predviĊanje logPe vrednosti dizajniranih dualnihantagonista i liganada I2 receptora, svrstavajući ih u grupu visoko permeabilnih jedinjenja. Sa ciljemda se dodatno analizira i vizuelizuje proces permeabilnosti centralnodelujućih jedinjenja kroz KMBna molekulskom nivou, korišćene su simulacije usmerene molekulske dinamike (eng. SteeredMolecular Dynamics, SMD).Disturbances in serotoninergic and dopaminergic neurotransmissions in the central nervoussystem (CNS) play a key role in the pathophysiology of various neurological and mental disorders.Developing an integrative approach through application of in silico and in vitro methods, in order toanalyse pharmacophore of multi-target neuroactive compounds, presents a promising strategy inrationalization of drug design process. Molecular dynamics simulations and molecular dockingmethods in combination with 3D-quantitative structure activity relationship analysis (3D-QSAR)were used to evaluate crucial structural features of potent dual antagonists of 5-HT2A i D2 receptors,with lower antagonistic activity on H1 receptors. The virtual screening of the available fragmentlibraries was performed with the aim to design novel multi-target compounds with a more effectiveand safer profile, laying a good foundation for the therapy of complex brain diseases. Moreover,3D-QSAR analysis of bicyclic α-iminophosphonates was used to reveal the pharmacophorestructure of selective imidazoline I2 receptor (I2-IR) ligands, as potentially new drugs for thetreatment of cognitive disorders. In vitro parallel artificial membrane permeability assay (PAMPA)was further employed to examine the effective permeability (logPe) through blood brain barrier(BBB) of compounds that affect serotonin and dopamine levels in the CNS. Based on the obtainedresults, quantitative structure-property relationship (QSPR) analysis was performed with the aim todefine structural features that mostly affect the permeability of compounds through BBB. Support-vector machine (SVM) method was used to create predictable and reliable QSPR model that wasfurther employed to predict logPe values of new designed dual antagonists of 5-HT2A/D2 receptorsand I2-IR ligands, classifying them into a group of highly permeable compounds. Steered moleculardynamics (SMD) simulations have been carried out to additionally explain and visualize the entireBBB permeation pathway at the molecular level

Pharmacophore analysis, design and in vitro testing of multi-target ligands as potentially effective therapeutics of complex neurological and mental disorders

Disfunkcija serotoninske i dopaminske neurotransmisije u mozgu je u osnovi patofiziologije brojnih neuroloških i mentalnih oboljenja. Definisanje protokola koji integriše in silico i in vitro metode, u cilju prouĉavanja farmakofore multi-potentnih jedinjenja koja deluju na nivou centralnog nervnog sistema (CNS), predstavlja vaţan korak u racionalizaciji procesa otkrivanja novih lekova. Primenom simulacija molekulske dinamike i molekulskog dokinga, kao i analize kvantitativnog odnosa strukture i aktivnosti (eng. 3D-Quantitative Structure Activity Relationship, 3D-QSAR) definisane su kljuĉne strukturne karakteristike dualnih antagonista 5-HT2A i D2 receptora, sa smanjenim afinitetom za H1 receptor. Na osnovu dobijenih rezultata izvršeno je pretraţivanje baza fragmenata primenom metode virtuelnog skrininga (eng. Virtual Screening, VS) u cilju dizajniranja potencijalno bezbednijih i efikasnijih liganada sa višestrukim delovanjem (eng. multi-target), pruţajući smernice za razvoj novih lekova u terapiji sloţenih CNS oboljenja. 3D-QSAR analizom bicikliĉnih α-iminofosfonata definisana je struktura farmakofore selektivnih liganada imidazolinskih I2 receptora, kao potencijalno novih lekova za leĉenje kognitivnih poremećaja. In vitro paralelni test permeabilnosti na veštaĉkim membranama (eng. Parallel Artificial Membrane Permeability Assay, PAMPA) je korišćen za odreĊivanje efektivne permeabilnosti (logPe) kroz krvno-moţdanu barijeru (KMB) jedinjenja koja utiĉu na modulaciju aktivnosti serotoninskog i dopaminskog sistema u mozgu. Dobijeni rezultati su korišćeni u analizi kvantitativnog odnosa strukture i osobina (eng. Quantitative Structure-Property Relationship, QSPR) u cilju razumevanja strukturnih karakteristika koje najviše utiĉu na prolazak jedinjenja kroz KMB. Model formiran primenom metode podrţavajućih vektora (eng. Support-Vector Machine, SVM) i validiran opseţnom statistiĉkom analizom, je korišćen za predviĊanje logPe vrednosti dizajniranih dualnih antagonista i liganada I2 receptora, svrstavajući ih u grupu visoko permeabilnih jedinjenja. Sa ciljem da se dodatno analizira i vizuelizuje proces permeabilnosti centralnodelujućih jedinjenja kroz KMB na molekulskom nivou, korišćene su simulacije usmerene molekulske dinamike (eng. Steered Molecular Dynamics, SMD).Disturbances in serotoninergic and dopaminergic neurotransmissions in the central nervous system (CNS) play a key role in the pathophysiology of various neurological and mental disorders. Developing an integrative approach through application of in silico and in vitro methods, in order to analyse pharmacophore of multi-target neuroactive compounds, presents a promising strategy in rationalization of drug design process. Molecular dynamics simulations and molecular docking methods in combination with 3D-quantitative structure activity relationship analysis (3D-QSAR) were used to evaluate crucial structural features of potent dual antagonists of 5-HT2A i D2 receptors, with lower antagonistic activity on H1 receptors. The virtual screening of the available fragment libraries was performed with the aim to design novel multi-target compounds with a more effective and safer profile, laying a good foundation for the therapy of complex brain diseases. Moreover, 3D-QSAR analysis of bicyclic α-iminophosphonates was used to reveal the pharmacophore structure of selective imidazoline I2 receptor (I2-IR) ligands, as potentially new drugs for the treatment of cognitive disorders. In vitro parallel artificial membrane permeability assay (PAMPA) was further employed to examine the effective permeability (logPe) through blood brain barrier (BBB) of compounds that affect serotonin and dopamine levels in the CNS. Based on the obtained results, quantitative structure-property relationship (QSPR) analysis was performed with the aim to define structural features that mostly affect the permeability of compounds through BBB. Support- vector machine (SVM) method was used to create predictable and reliable QSPR model that was further employed to predict logPe values of new designed dual antagonists of 5-HT2A/D2 receptors and I2-IR ligands, classifying them into a group of highly permeable compounds. Steered molecular dynamics (SMD) simulations have been carried out to additionally explain and visualize the entire BBB permeation pathway at the molecular level

Kliničko terapijske specifičnosti shizofrenije s prodromima i ranim početkom - model rizičnog mentalnog stanja i shizofrene vulnerabilnosti

Shizofreniji, kao i drugim psihotičnim oboljenjima, često prethode prodromalne izmjene u ponašanju, koje mogu trajati od nekoliko dana do nekoliko godina, nagovještavajući početak psihoze. Ako bolest počne u ranijem uzrastu, posebno u adolescenciji, prodromalna faza je nespecifična i teža za prepoznavanje i intervencije. Postoji veći broj operacionalnih instrumenata kojima se klinički procjenjuju i kvantificiraju prodromalni simptomi i “rizično mentalno stanje“, kao i prediktivni potencijal za psihozu. U radu je opisana prodromalna faza u razvoju shizofrene psihoze s ranim početkom, s naglaskom na postupnom, višemjesečnom obogaćivanju psihopatologije i evolucijom nespecifičnih i atenuiranih (subklinički) prodromalnih simptoma u floridne shizofrene simptome. Također se ukazuje na optimalne mogućnosti terapijskog tretmana psihoze s ranim početkom u svrhu prevencije težih simptoma i razvijene kliničke slike shizofrenije

3D-QSAR studija i razvoj farmakofore agonista serotoninskih 5-HT2A receptora

All tested compounds show agonistic activity onserotonin5-HT2areceptors, which activation causes neuronal excitations, behavioral changes and platelet aggregation. The main aims of this study were to create 3D-QSAR(3D-Quantitative structure-activity relationship)model, analyse 3D-structure of the pharmacophore, validate the 3D-QSARmodel, and propose structural modification for novel 5-HT2aagonists.3D-QSAR modeling was applied to 51 agonists of 5-HT2areceptors. Dominant forms at physiologic pHof the examined compounds were optimized using the PM3 method and used for QSAR modeling. Data set was divided in two groups, training set of38 compounds, and test set of 13 compounds. Training set was used to build 3D-QSAR model, while test set was examined for the model validation. PLS (Partial Least Square Regression)method was used to develop 3D-QSAR model. Statistical parameters of the created and validated 3D-QSAR model,R2= 0.93, Q2=0.72, RMSEE=0.178, RMSEP=0.190 and R2 pred=0.63, indicate good prognostic capacity of the model.The3D-QSAR model was applied to analyse pharmacophore and to predict activity of other agonists of serotonin 5-HT2areceptors. Information obtained from the 3D-QSAR study indicated that presence of hydrogen bond donor and steric hot spot at a distance 14.80-15.20Å (v477:O-TIP), hydrophobic region and hydrogen bond donor at a distance of 2.40-2.86Å (v226:DRY-O), hydrogen bond donor and hydrogen bond acceptor at a distance of 1.60-2.00Å (v389:O-N1) and two hydrophobic regions at a distance 9.20-9.60Å (v23:DRY-DRY) are essential for agonistic activity on 5-HT2aserotonin receptors.Ispitivana jedinjenja djeluju kao agonisti serotoninskih 5-HT2areceptora, i dovode do neuralne ekscitacije, promjene ponašanja i agregacije trombocita. Cilj ove studije je bio formiranje 3D-QSAR (3D-Quantitative structure-activity relationship) modela i 3D-strukture farmakofore agonista serotoninskih 5-HT2a receptora, validacija formiranog 3D-QSAR modela i definisanje strukturnih modifikacija za dizajn novih agonista serotoninskih 5-HT2areceptora. Iz literature su preuzete strukture i aktivnosti 51 agoniste 5-HT2areceptora. Definisani su dominantni oblici ispitivanih jedinjenja pri fiziološkom pH i optimizovane njihove konformacije primjenom PM3 (Parameterized Model revision 3) metode. Ispitivana jedinjenja su podijeljena u dvije grupe, trening set sa 38 jedinjenja i test set sa 13 jedinjenja. Trening set je korišćen za formiranje jednačine i građenje 3D-QSAR modela, a test set za validaciju 3DQSAR modela. Pomoću PLS (Partial Least Square Regression) metode kreira se novi 3DQSAR model i računaju statistički parametri modela: R2=0,93, Q2=0,72, RMSEE=0,178, RMSEP=0,190 i R2pred=0,63. Formirani i validirani 3D-QSAR model je dalje upotrijebljen za analizu 3D-strukture farmakofore i za predviđanje aktivnosti novih agonista serotoninskih 5-HT2areceptora. Analizom je utvrđeno da je za ispoljavanje agonističke aktivnosti na nivou 5-HT2a serotoninskih receptora neophodno prisustvo donora vodonične veze i sternog centra na rastojanju 14,80-15,20Å (v477:O-TIP), donora i akceptora vodonične veze na rastojanju 1,60- 2,00Å (v389:O-N1), hidrofobnog centra i donora vodonične veze na rastojanju 2,40-2,86Å (v226:DRY-O) i dva hidrofobna centra na rastojanju 9,20-9,60Å (v23:DRY-DRY)

Combined ligand and structure‐based approach in search of 5‐HT2A receptor agonists and antagonists

Serotoninski 5‐HT2A receptori su uključeni u mnogobrojne fiziološke i patofiziološke procese. Strukturno različiti ligandi (agonisti, antagonisti i inverzni agonisti) dovode do različitih konformacionih promena ovih receptora, izazivajući brojne biološke odgovore. Da bi se molekul ponašao kao agonista/antagonista potrebno je da poseduje različite funkcionalne grupe i specifične interakcije sa određenim aminokiselinama u vezujućem mestu receptora. Razumevanje i objašnjavanje različitosti u strukturi i vezivanju za receptor, kod agonista i antagonista, može biti od značaja za racionalni dizajn novih lekova. Za razumevanje strukturnih razlika u farmakoforama, kao i kinetici vezivanja i zmeđu agonista i antagonista korišćeni su ligand‐based i structure‐based pristupi. 3DQSAR (3D‐quantitative structure activity relationship) studije su izvođene na grupama od 79 agonista i 90 antagonista. Uporedo su odrađene četiri simulacije molekularne dinamike: serotoninski 5‐HT2A receptor u kompleksu sa agonistima (serotonin, lorkaserin) i antagonistima (klozapin, ziprazidon). Dobijeni statistički i validacioni parametri za modele agonista i antagonista ukazuju na pouzdanost i dobru predviđajuću moć 3D‐QSAR modela. Najznačajnije varijable formiranih modela daju nam uvid u najvažnije strukturne razlike između njih. Rezultati MD simulacije otkrivaju najvažnije razlike u konformacionim promenama uzrokovane vezivanjem agoniste/antagoniste, kao i interakcije liganada sa ključnim aminokiselinama, odgovornim za vezivanje. Pomoću trajektorije iz MD simulacije izvučeni su modeli, 3D strukture 5‐HT2A receptora u njegovom aktivnom (agonistvezujućem) i inaktivnom (antagonist‐vezujućem) stanju. Na osnovu ovih in silico rezultata moguće je zaključiti da li je jedinjenje agonista ili antagonista. Formirani modeli će dalje biti korišćeni za ligand‐based i structure‐based virtualni skrining i racionalni dizajn novih 5‐HT2A liganada.The serotonin 5‐HT2A receptors have shown a wide range of clinical implications since they are involved in various physiological and pathophysiological processes. Structurally diverse ligands (agonists, antagonists, and inverse agonists) can lead to different biological responses, by provoking different conformational changes of these receptors. To behave like an agonist/antagonist the molecule should have a set of functional groups and specific interactions with certain amino acids in the binding site. Understanding and explaining dissimilarities in agonist/antagonist structure and receptor binding would be beneficial for future rational drug design. To understand structural differences in pharmacophores as well as the binding kinetics of agonists and antagonists, we have combined ligand‐based and structurebased approaches. 3D‐quantitative structure‐activity relationship (3D‐QSAR) studies were performed on a series of 79 agonists and 90 antagonists. Simultaneously, we run four molecular dynamics (MD) simulations: 5‐HT2A in complex with agonists (serotonin, lorcaserin), and antagonists (clozapine and ziprasidone). Obtained statistical and validation parameters for agonists and antagonists model indicated the reliability and good predictive potential of the 3D‐QSAR models. The most influential variables of selected models gave us the insight into major structural dissimilarities between them. Results of MD simulation revealed major differences in conformational changes caused by agonist/antagonist binding, as well as ligand interactions with the key amino acids, responsible for them. Additionally, from MD simulation trajectory, we have extracted 3D structure models of 5‐HT2A in its active (agonist‐bound) and inactive (antagonist‐bound) state. Using these finding we will be able to discriminate whether a compound is agonist or antagonist, in silico. Furthermore, models that we have generated will be further used for ligand‐based and structure‐based virtual screening and rational drug design of novel 5‐HT2A ligands.VII Kongres farmaceuta Srbije sa međunarodnim učešćem Zajedno stvaramo budućnost farmacije Beograd, 10-14. oktobar 201

Combined ligand-based and structure-based approaches in rational drug design of novel 5-HT2A receptor antagonists

Serotonin 5-HT2A receptors (5-HT2AR) are highly expressed in human prefrontal cortex, essential for learning and cognition [1]. Consequently, antagonists of these receptors are effective in treatment of various neuropsychiatric disorders, such as depression, insomnia, schizophrenia, anxiety, and cent progress in molecular modelling studies has led to significant success in drug discovery using ligand and target-based methods. To design novel potent 5-HT2AR antagonists, we report a strategy of combining three-dimensional quantitative structure-activity relationship (3DQSAR) modelling with molecular docking and molecular dynamic (MD) simulation. Based on the common structural features, data set of 75 compounds was divided into three clusters. Firstly, MD simulations were carried out for each cluster representative in complex with 5-HT2AR, providing important molecular level insight into their structure and dynamics. Afterward, to provide more accurate information about binding modes in the active site of the receptor, obtained conformations were used for docking studies and generation of the virtually bioactive conformations of all studied ligands. In addition, 3D-QSAR study, utilizing selected conformers, was carried out to gain further insights into the structural requirements that affect their antagonistic activity. Besides, some commercially available 5-HT2AR antagonists were examined through in vitro PAMPA essay, as well as in silico computational methods not only to improve BBB permeability of new designed compounds, but also to establish promising tool to study their membrane permeability in detail. Overall, these and future results will provide new methodologies that could be used as guidelines for rational drug design of novel 5-HT2AR antagonists

Metode kompjuterski potpomognutog dizajniranja lekova u istraživanju novih potencijalnih terapeutika za neuropsihijatrijske i inflamatorne bolesti

Drug discovery and development is a very challenging, expensive and time-consuming process. Impressive technological advances in computer sciences and molecular biology have made it possible to use computer-aided drug design (CADD) methods in various stages of the drug discovery and development pipeline. Nowadays, CADD presents an efficacious and indispensable tool, widely used in medicinal chemistry, to lead rational drug design and synthesis of novel compounds. In this article, an overview of commonly used CADD approaches from hit identification to lead optimization was presented. Moreover, different aspects of design of multitarget ligands for neuropsychiatric and anti-inflammatory diseases were summarized. Apparently, designing multi-target directed ligands for treatment of various complex diseases may offer better efficacy, and fewer side effects. Antipsychotics that act through aminergic G protein-coupled receptors (GPCRs), especially dopamine D2 and serotonin 5-HT2A receptors, are the best option for treatment of various symptoms associated with neuropsychiatric disorders. Furthermore, multi-target directed cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitors are also a successful approach to aid the discovery of new anti-inflammatory drugs with fewer side effects. Overall, employing CADD approaches in the process of rational drug design provides a great opportunity for future development, allowing rapid identification of compounds with the optimal polypharmacological profile.Proces otkrića i razvoja lekova je veoma zahtevan, skup i dugotrajan. Veliki tehnološki napredak u molekularnoj biologiji i kompjuterskim naukama je omogućio primenu metoda kompjuterski potpomognutog dizajniranja lekova (CADD) u različitim fazama procesa otkrića i razvoja lekova. Danas CADD predstavlja efikasnu i nezamenljivu alatku, koja se široko koristi u medicinskoj hemiji za racionalni dizajn i sintezu novih jedinjenja. U ovom preglednom radu biće prikazani CADD pristupi koji se najčešće koriste od procesa identifikacije hit jedinjenja do optimizacije lead jedinjenja. Pored toga, biće predstavljeni različiti aspekti u dizajnu višeciljnih liganada za neuropsihijatrijske i inflamatorne bolesti. Pokazano je da su ova jedinjenja veoma efikasna u lečenju složenih bolesti zbog veće efikasnosti i manje neželjenih efekata koje izazivaju. Antipsihotici koji deluju preko aminergičnih G-protein spregnutih receptora (GPCR), posebno preko dopaminskih D2 i serotoninskih 5-HT2A receptora, predstavljaju najbolju opcija za lečenje različitih simptoma povezanih sa neuropsihijatrijskim poremećajima. Pored toga, dizajn i sinteza dualnih inhibitora ciklooksigenaze-2 (COX-2) i 5lipoksigenaze (5-LOX) takođe predstavlja uspešan pristup u otkrivanju novih antiinflamatornih lekova sa manje neželjenih efekata. Na kraju se može zaključiti da primena CADD metoda u procesu racionalnog dizajniranja lekova pruža značajnu priliku za dalji napredak jer omogućava brzu identifikaciju jedinjenja sa optimalnim polifarmakološkim profilom

Combined 3D-QSAR modeling, molecular dynamics and molecular docking studies in rational drug design of novel 5-HT2A antagonists

Serotonin 5-HT2A receptors are widely distributed in the human brain where they play a key role in many physiological functions. Numerous neurological disorders caused by 5-HT2A malfunction have made it a very attractive target. Therefore, analysis of 3D-structure of the pharmacophore as well as binding kinetics of 5-HT2A antagonists would be beneficial for future rational drug design. Three dimensional quantitative structure-activity relationship (3D-QSAR) study was combined with molecular docking and molecular dynamic (MD) simulation in order to find crucial structural features responsible for high binding affinity and selectivity of 5-HT2A antagonists. This study was performed on wide range of structurally diverse antagonists that were divided into three different clusters: clozapine, ziprasidone, and CHEMBL240876 derivates. We have used 50ns MD simulations to obtain inactive, antagonist bound, conformations of each cluster representative. Subsequently, these conformations were used as templates for docking studies in order to find virtually bioactive conformations of examined compounds. Selected virtually bioactive conformations were used for generation of specific molecular descriptors (Grid Independent Descriptors- GRIND) and 3D-QSAR model building. The 3D-QSAR approach was used to identify the most important structural determinants responsible for the antagonistic activity and to propose structural modifications for novel antagonists of serotonin 5-HT2A receptors. Furthermore, diverse internal and external validation methods were applied. Obtained statistical parameters indicated the reliability and good predictive potential of the created model. Following these findings we have identified differences and similarities in the binding mode and pharmacophores of structurally diverse 5-HT2A antagonists as well as conformational changes they provoke

Oboljeli od rijetkih bolesti kao vulnerabilni ispitanici u kliničkim studijama

Farmakoterapija rijetkih bolesti suočena je s brojnim etičkim dilemama. Najveći broj oboljelih su djeca, oboljenja su progresivnog tijeka, a liječenje vrlo skupo. Cilj rada bio je ispitati u kojoj mjeri se poštuju principi suvremene bioetike, kada je u pitanju farmakoterapija rijetkih bolesti. Za primjer je uzeta Gaucherova bolest. Pretraživali smo dostupne baze podataka (Cochrane database, MEDLINE i Google) za period od 1996. do 2011. Ključne riječi bile su: Gaucherova bolest, etika/etička pitanja i klinička ispitivanja, a posebno su analizirani učinkovitost, sigurnost i cijena lijekova za ovu bolest. Provedena je i pilot anketa o stavovima liječnika i kliničkih farmaceuta o farmakoterapiji rijetkih bolesti u Srbiji na odabranom uzorku ispitanika (N = 11, Klinika za internu medicinu i Centralna apoteka, KBC „Bežanijska Kosa“ u Beogradu). Na postavljena pitanja odgovoreno je u 97,2 % slučajeva. Uočeni su brojni problemi vezani uz liječenje Gaucherove bolesti: npr. visoka cijena lijekova, nedostatak adekvatne procjene odnosa cijene i učinkovitosti terapije, nedovoljan broj ispitanika u kliničkim studijama i dr. Pilot anketa o rijetkim bolestima ukazuje na nedovoljnu informiranost stručne javnosti (21 %) i komplicirane procedure oko nabave lijekova (21 %). Većina ispitanika (64 %) ocijenila je da je nedovoljno upoznata s postojećom zakonskom regulativom o rijetkim bolestima. Oboljeli od rijetkih bolesti mogu se smatrati vulnerabilnim ispitanicima. Potrebno je formirati registar oboljelih, poboljšati informiranost stručne i šire javnosti i prilagoditi zakonsku regulativu kada su u pitanju rijetke bolesti

Oboljeli od rijetkih bolesti kao vulnerabilni ispitanici u kliničkim studijama

Farmakoterapija rijetkih bolesti suočena je s brojnim etičkim dilemama. Najveći broj oboljelih su djeca, oboljenja su progresivnog tijeka, a liječenje vrlo skupo. Cilj rada bio je ispitati u kojoj mjeri se poštuju principi suvremene bioetike, kada je u pitanju farmakoterapija rijetkih bolesti. Za primjer je uzeta Gaucherova bolest. Pretraživali smo dostupne baze podataka (Cochrane database, MEDLINE i Google) za period od 1996. do 2011. Ključne riječi bile su: Gaucherova bolest, etika/etička pitanja i klinička ispitivanja, a posebno su analizirani učinkovitost, sigurnost i cijena lijekova za ovu bolest. Provedena je i pilot anketa o stavovima liječnika i kliničkih farmaceuta o farmakoterapiji rijetkih bolesti u Srbiji na odabranom uzorku ispitanika (N = 11, Klinika za internu medicinu i Centralna apoteka, KBC „Bežanijska Kosa“ u Beogradu). Na postavljena pitanja odgovoreno je u 97,2 % slučajeva. Uočeni su brojni problemi vezani uz liječenje Gaucherove bolesti: npr. visoka cijena lijekova, nedostatak adekvatne procjene odnosa cijene i učinkovitosti terapije, nedovoljan broj ispitanika u kliničkim studijama i dr. Pilot anketa o rijetkim bolestima ukazuje na nedovoljnu informiranost stručne javnosti (21 %) i komplicirane procedure oko nabave lijekova (21 %). Većina ispitanika (64 %) ocijenila je da je nedovoljno upoznata s postojećom zakonskom regulativom o rijetkim bolestima. Oboljeli od rijetkih bolesti mogu se smatrati vulnerabilnim ispitanicima. Potrebno je formirati registar oboljelih, poboljšati informiranost stručne i šire javnosti i prilagoditi zakonsku regulativu kada su u pitanju rijetke bolesti