Browsing by Author "Ulanova (Igumnova), Viktorija"

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    Pharmacogenetic Aspects of Anti-Tuberculosis Therapy in Latvian Population. Doctoral Thesis
    (Rīga Stradiņš University, 2025) Ulanova (Igumnova), Viktorija; Ranka, Renāte; Bandere, Dace
    Pharmacogenetics (PGx) plays a crucial role in personalised medicine by revealing how genetic variations influence drug response, guiding initial doses, and working in conjunction with therapeutic drug monitoring (TDM) to adjust dosing according to drug metabolism for each individual. Together, PGx and TDM work synergistically to optimise treatment, as using the patient’s PGx profile and up-to-date patient data on drug levels in the systemic circulation enables precision, effectiveness and safety of treatment, moving away from a one-size-fits-all approach to a more individualised strategy. Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which is transmitted between humans through the respiratory tract, most commonly affecting the lungs. TB is a major global public health challenge and social threat worldwide. With the increasing population mobility and travel, TB strains, including drug-resistant variants, are easily disseminated worldwide. The implementation of personalised medicine strategies may help to ensure the effectiveness of existing treatments, promptly identify those patients most likely to develop adverse drug reactions (ADRs), and reduce the likelihood of acquired drug resistance in Mtb, thus playing an important role in the global fight against TB. This Thesis describes the PGx aspects of TB treatment focusing on the Latvian population. Isoniazid (INH) is a cornerstone of the standard regimen for the treatment of drug-susceptible TB (DS-TB). However, the variability in pharmacokinetic (PK) parameters and drug plasma levels may affect drug response and lead to ADRs including a drug-induced hepatotoxicity (DIH). This Thesis primarily investigates the impact of changes in INH PK parameters due to genetic variability in three genes encoding INH-metabolising enzymes, together with a number of patient-related factors, on the response to anti-TB treatment and the risk of DIH in patients with DS-TB. In particular, the N-acetyltransferase 2 (NAT2) haplotype, referred to as acetylator status, and the genotype of glutathione S-transferase M1 class (GSTM1) were assessed in TB patients. Additionally, a new next-generation sequencing-based method for full-length cytochrome P450 family 2 subfamily E member 1 (CYP2E1) gene analysis was designed and evaluated to determine whether CYP2E1 gene variants are of clinical significance. Aminoglycosides (AGs) are potent, broad-spectrum antibiotics, which remain important drugs in the treatment of multidrug-resistant TB. AG-induced hearing loss (AIHL) is a well-recognised ADR with rapid, profound, and irreversible hearing loss that can occur in predisposed individuals. The MT-RNR1 gene, encoding the mitochondrial ribosomal 12S subunit, is particularly susceptible to gene variants associated with AIHL. In this Thesis, the prevalence of AIHL-related MT-RNR1 gene variants was investigated in the Baltic-speaking ethnic Latvian population in comparison to the general population worldwide in order to improve the accuracy and safety of treatment with AGs. This Thesis is presented as a comprehensive compilation of peer-reviewed publications, summarising advancements in personalised TB medicine. Specifically, it focuses on identifying and characterising the factors that contribute to variations in drug response and safety through comprehensive analysis of the PGx and PK data in TB patients. This approach could provide us with an opportunity to advance therapeutic decision-making. The inclusion of profiling of INH and its two main metabolites in clinical studies, together with PGx screening, could be beneficial in determining optimal dosing strategies, tailoring treatment regimens, and fostering a patient-centred healthcare approach for TB patients, challenging the current paradigm of modern public health.
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    Pharmacogenetic Aspects of Anti-Tuberculosis Therapy in Latvian Population. Summary of the Doctoral Thesis
    (Rīga Stradiņš University, 2025) Ulanova (Igumnova), Viktorija; Ranka, Renāte; Bandere, Dace
    Pharmacogenetics (PGx) plays a crucial role in personalised medicine by revealing how genetic variations influence drug response, guiding initial doses, and working in conjunction with therapeutic drug monitoring (TDM) to adjust dosing according to drug metabolism for each individual. Together, PGx and TDM work synergistically to optimise treatment, as using the patient’s PGx profile and up-to-date patient data on drug levels in the systemic circulation enables precision, effectiveness and safety of treatment, moving away from a one-size-fits-all approach to a more individualised strategy. Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which is transmitted between humans through the respiratory tract, most commonly affecting the lungs. TB is a major global public health challenge and social threat worldwide. With the increasing population mobility and travel, TB strains, including drug-resistant variants, are easily disseminated worldwide. The implementation of personalised medicine strategies may help to ensure the effectiveness of existing treatments, promptly identify those patients most likely to develop adverse drug reactions (ADRs), and reduce the likelihood of acquired drug resistance in Mtb, thus playing an important role in the global fight against TB. This Thesis describes the PGx aspects of TB treatment focusing on the Latvian population. Isoniazid (INH) is a cornerstone of the standard regimen for the treatment of drug-susceptible TB (DS-TB). However, the variability in pharmacokinetic (PK) parameters and drug plasma levels may affect drug response and lead to ADRs including a drug-induced hepatotoxicity (DIH). This Thesis primarily investigates the impact of changes in INH PK parameters due to genetic variability in three genes encoding INH-metabolising enzymes, together with a number of patient-related factors, on the response to anti-TB treatment and the risk of DIH in patients with DS-TB. In particular, the N-acetyltransferase 2 (NAT2) haplotype, referred to as acetylator status, and the genotype of glutathione S-transferase M1 class (GSTM1) were assessed in TB patients. Additionally, a new next-generation sequencing-based method for full-length cytochrome P450 family 2 subfamily E member 1 (CYP2E1) gene analysis was designed and evaluated to determine whether CYP2E1 gene variants are of clinical significance. Aminoglycosides (AGs) are potent, broad-spectrum antibiotics, which remain important drugs in the treatment of multidrug-resistant TB. AG-induced hearing loss (AIHL) is a well-recognised ADR with rapid, profound, and irreversible hearing loss that can occur in predisposed individuals. The MT-RNR1 gene, encoding the mitochondrial ribosomal 12S subunit, is particularly susceptible to gene variants associated with AIHL. In this Thesis, the prevalence of AIHL-related MT-RNR1 gene variants was investigated in the Baltic-speaking ethnic Latvian population in comparison to the general population worldwide in order to improve the accuracy and safety of treatment with AGs. This Thesis is presented as a comprehensive compilation of peer-reviewed publications, summarising advancements in personalised TB medicine. Specifically, it focuses on identifying and characterising the factors that contribute to variations in drug response and safety through comprehensive analysis of the PGx and PK data in TB patients. This approach could provide us with an opportunity to advance therapeutic decision-making. The inclusion of profiling of INH and its two main metabolites in clinical studies, together with PGx screening, could be beneficial in determining optimal dosing strategies, tailoring treatment regimens, and fostering a patient-centred healthcare approach for TB patients, challenging the current paradigm of modern public health.
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    Prettuberkulozes terapijas farmakoģenētiskie aspekti Latvijas populācijā. Promocijas darba kopsavilkums
    (Rīgas Stradiņa universitāte, 2025) Ulanova (Igumnova), Viktorija; Ranka, Renāte; Bandere, Dace
    Farmakoģenētikai (angl. PGx) ir izšķiroša nozīme personalizētajā medicīnā, jo tā palīdz atklāt, kā ģenētiskās variācijas ietekmē pacienta reakciju uz zālēm. Tas ļauj precīzāk noteikt sākotnējās zāļu devas, un apvienojot ar zāļu terapeitisko uzraudzību (angl. TDM) pielāgot zāļu devu katram pacientam, balstoties uz viņu individuālo zāļu metabolismu. PGx un TDM darbojas sinerģiski, lai optimizētu ārstēšanu, nodrošinot ārstēšanas precizitāti, efektivitāti un drošumu. Pacienta PGx profila kombinēšana ar aktuāliem datiem par zāļu līmeni sistēmiskajā cirkulācijā ļauj pāriet no pieejas "viens izmērs der visiem" uz individualizētām terapijas stratēģijām. Tuberkuloze (TB) ir infekcijas slimība, ko izraisa mikobaktērija Mycobacterium tuberculosis (Mtb). TB izplatās gaisa pilienu ceļā no cilvēka uz cilvēku un visbiežāk skar plaušas. Šī infekcija ir nozīmīga globāla sabiedrības veselības problēma un sociāls drauds. Pieaugot iedzīvotāju mobilitātei un ceļotāju migrācijai, Mtb celmi, tostarp pret zālēm rezistenti varianti, viegli izplatās visā pasaulē. Personalizētās medicīnas stratēģiju ieviešana var būtiski uzlabot esošās ārstēšanas efektivitāti, savlaicīgi identificējot pacientus ar augstu zāļu nevēlamu blakusparādību (angl. ADRs) risku, kā arī samazināt zāļu rezistences rašanās iespējas pret Mtb. Šāda pieeja spēlē nozīmīgu lomu globālajā cīņā pret TB. Šajā disertācijā ir aprakstīti TB ārstēšanas PGx aspekti ar īpašu uzsvaru uz Latvijas iedzīvotājiem. Izoniazīds (angl. INH) ir standarta ārstēšanas shēmas stūrakmens pret zālēm jūtīgās TB (angl. DS-TB) gadījumos. Tomēr farmakokinētisko (angl. PK) parametru un zāļu līmeņa mainīgums asins plazmā var ietekmēt TB ārstēšanas efektivitāti vai izraisīt ADRs, piemēram, zāļu izraisītu aknu bojājumu (angl. DIH). Šajā promocijas darbā galvenā uzmanība tika pievērsta INH PK parametru izmaiņām, ko izraisa INH metabolizējošo enzīmu kodējošo gēnu ģenētiskā variabilitāte un dažādi ar pacientu saistīti faktori, analizējot to ietekmi uz terapijas atbildes reakciju un DIH attīstības risku pacientiem ar DS-TB. Īpašs uzsvars tika likts uz N-acetiltransferāzes 2 (NAT2) acetilatora statusu, glutationa S-transferāzes M1 klases (GSTM1) genotipu. Turklāt tika izstrādāta un izvērtēta jauna metode, kas balstīta uz nākamās paaudzes sekvencēšanu, lai veiktu pilna garuma citohroma P450 2. saimes E apakšsaimes 1. locekļa (CYP2E1) gēna analīzi. Šī pieeja tika izmantota, lai novērtētu, vai vairāku reģionu CYP2E1 gēna variantiem ir klīniskā nozīme. Aminoglikozīdi (AG) ir spēcīgas plaša spektra antibiotikas, kurām joprojām ir būtiska loma multirezistentās TB ārstēšanā. Tomēr AG izraisīts dzirdes zudums (angl. AIHL) ir labi pazīstama un atzīta ADR. Tas izpaužas kā ātrs, dziļš un neatgriezenisks dzirdes zudums, kas īpaši bieži novērojamas pacientiem ar ģenētisku predispozīciju. MT-RNR1 gēns, kas kodē mitohondriālo ribosomālo 12S apakšvienību, ir īpaši uzņēmīgs pret gēna variantiem, kas saistīti ar AIHL. Šajā promocijas darbā tika pētīta ar AIHL saistītu MT-RNR1 gēna variantu prevalence Latvijas populācijā un salīdzināta ar globālajām populācijām. Pētījuma mērķis bija sekmēt AG lietošanas drošumu un veicināt ārstēšanas precizitāti. Šī disertācija ir veidota kā visaptveroša recenzētu publikāciju kopa, kurā apkopoti pētījumi personalizētās medicīnas jomā. Tajā īpaša uzmanība pievērsta faktoriem, kas ietekmē zāļu atbildes reakcijas un drošuma atšķirības, kā arī šo faktoru identificēšanai un raksturošanai, izmantojot visaptverošu PGx un PK datu analīzi pacientiem ar TB. Šāda pieeja var sniegt nozīmīgu ieguldījumu terapeitisko lēmumu pieņemšanā. INH un tā divu galveno metabolītu koncentrācijas uzraudzība un PGx skrīninga iekļaušana klīniskajos pētījumos varētu būt lietderīga optimālu dozēšanas stratēģiju noteikšanai, ārstēšanas režīmu pielāgošanai un pacientu orientētas veselības aprūpes pieejas veicināšanai pacientiem ar TB. Šis darbs izaicina pašreizējo modernās sabiedrības veselības aprūpes paradigmu, piedāvājot personalizētākas un efektīvākas ārstēšanas iespējas.