Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
8520 Background: In the randomized, triple-blind, phase 3 PEARLS/KEYNOTE-091 study (NCT02504372), at the second interim analysis, pembrolizumab (pembro) significantly prolonged DFS vs placebo (pbo) in the overall population of patients... more
8520 Background: In the randomized, triple-blind, phase 3 PEARLS/KEYNOTE-091 study (NCT02504372), at the second interim analysis, pembrolizumab (pembro) significantly prolonged DFS vs placebo (pbo) in the overall population of patients (pts) with completely resected stage IB–IIIA NSCLC per AJCC v7 who may or may not have received adjuvant chemotherapy (chemo; up to 4 cycles) as recommended per local guidelines (n = 1177; HR, 0.76 [95% CI, 0.63–0.91]; P = 0.0014). Here we present outcomes for those pts who received 1–4 cycles of prior adjuvant chemo, per protocol. Methods: Eligible adults had pathologically confirmed, completely resected stage IB (T ≥4 cm), II, or IIIA NSCLC (AJCC v7) of any PD-L1 expression, ECOG performance status of 0 or 1, and had not received neoadjuvant radiotherapy or chemo. Pts were randomized 1:1 to pembro 200 mg or pbo Q3W for 18 doses (~1 year); receipt of adjuvant chemo (yes vs no) was one of the stratification factors. Dual primary endpoints were DFS in the ITT and PD-L1 TPS ≥50% populations. No alpha was assigned to this subgroup analysis of pts who received adjuvant chemo for 1–4 cycles per local guidelines. Results: Of 1177 pts in the ITT population, 1010 (85.8%) received adjuvant chemo and were included in this analysis (pembro, n = 506; pbo, n = 504). Pts received a median of 17 and 18 study doses, respectively. As of data cutoff (Sep 20, 2021), 52.6% in the pembro arm vs 64.9% in the pbo arm had completed treatment. Median time from randomization to data cutoff was 37.4 mo. Median (95% CI) DFS was 58.7 mo (39.2 mo–not reached [NR]) in the pembro arm vs 34.9 mo (28.6 mo–NR) in the pbo arm (HR, 0.73 [95% CI, 0.60–0.89]). Estimated 18-mo DFS rates were 73.8% and 63.1%, respectively. In pts with PD-L1 TPS ≥50% (pembro, n = 143; pbo, n = 141), median DFS was NR in both treatment arms (HR, 0.80 [95% CI, 0.54–1.20]). Grade 3–5 adverse events (AEs) occurred in 170 pts (34.3%) in the pembro arm and 128 (25.7%) in the pbo arm (grade 5, 2.2% vs 1.0%). Immune-mediated AEs and infusion reactions occurred in 195 pts (39.3%) in the pembro arm and 69 (13.8%) in the pbo arm. Conclusions: Consistent with the ITT population, pembro substantially improved DFS vs pbo in the subgroup of pts with stage IB (T2a ≥4 cm), II, or IIIA NSCLC who received adjuvant platinum-based chemo following complete resection. Based on these results, pembro was approved for adjuvant treatment in this pt population by the US FDA. Clinical trial information: NCT02504372 .
Research Interests:
Thiopurine S-methyltransferase (TPMT; EC 2.1.1.67) is the key enzyme in the metabolism of thiopurine drugs. Determination of TPMT activity has been used for the individualization of thiopurine dose. We developed HPLC-UV assay for the... more
Thiopurine S-methyltransferase (TPMT; EC 2.1.1.67) is the key enzyme in the metabolism of thiopurine drugs. Determination of TPMT activity has been used for the individualization of thiopurine dose. We developed HPLC-UV assay for the determination of TPMT activity in human erythrocytes using 6-mercaptopurine as a substrate. Various extraction and chromatographic conditions were compared. In-house developed extraction with acetonitrile provided the
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
In comparison with neighbouring Scandinavian countries, the use of digoxin in Estonia is high. The present study was carried out to determine the use pattern of digoxin in Estonia and bioavailability of the local market leader preparation... more
In comparison with neighbouring Scandinavian countries, the use of digoxin in Estonia is high. The present study was carried out to determine the use pattern of digoxin in Estonia and bioavailability of the local market leader preparation in comparison with Lanoxin. Drug use data were evaluated from the annual reports of wholesale companies. For the bioequivalence study, a single-blind cross-over randomised two-way single-dose comparative bioavailability study was performed using 14 healthy volunteers. Digoxin concentrations in serum samples and urine were measured by chemiluminescent competitive immunoassay. The use of digoxin in Estonia has increased by 35% during the period 1994-97. The steady market leader was the local generic drug. No statistically significant differences were found in any pharmacokinetic parameter between the generic preparation and Lanoxin. All parameters showed considerable variability. The total amount of drug excreted was the parameter with lowest inter- individual variation. The present study indicates that the generic digoxin preparation studied is bioequivalent to Lanoxin. The increasing use of digoxin in Estonia is not caused by low bioavailability of the local market leader but by therapeutic traditions.
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Purpose Spironolactone is a potassium sparing diuretic used for decades. Until now, pharmacokinetic (PK) studies of spironolactone have not been conducted in infants and therefore pediatric dosing is based on expert opinion. We aimed to... more
Purpose Spironolactone is a potassium sparing diuretic used for decades. Until now, pharmacokinetic (PK) studies of spironolactone have not been conducted in infants and therefore pediatric dosing is based on expert opinion. We aimed to describe the PK profiles of spironolactone and its main metabolites (7 alpha- thiomethylspironolactone (TMS) and canrenone (CAN)) in infants up to two years of age. Methods The PK of spironolactone and its main metabolites were evaluated following an oral administration of spironolactone (1 mg/kg/dose) to pediatric patients with chronic heart failure, ascites and/or oedema. The plasma concentration of spironolactone and metabolites (TMS and CAN) was determined using an ultra high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Based on rich sampling PK data, the estimation of population PK parameters was performed using nonlinear mixed-effects modelling software Monolix 2018R2. Clinical trial Registration Number 2013-001189-...
Research Interests:
Research Interests:
Research Interests:
Background and aims: Ampicillin is 1 of the most commonly used antibiotics for treatment of early onset sepsis, but its pharmacokinetics (PK) is poorly characterized. We aimed to define the dose of ampicillin for late preterm and term... more
Background and aims: Ampicillin is 1 of the most commonly used antibiotics for treatment of early onset sepsis, but its pharmacokinetics (PK) is poorly characterized. We aimed to define the dose of ampicillin for late preterm and term neonates by evaluating its PK in serum, cerebrospinal (CSF), and epithelial lining fluid. Methods: A prospective study included neonates receiving ampicillin for suspected or proven early onset sepsis and pneumonia. PK samples were collected at steady state, at predose and 5 minutes, 1 hour, 3 hours, 8 hours, and 12 hours after ampicillin 3-minute infusion. Ampicillin concentrations were measured by ultra-high-performance liquid chromatography. Noncompartmental anaysis (NCA) and population pharmacokinetic (pop-PK) modeling were performed and probability of therapeutic target attainment was simulated. Results: In 14 neonates (GA of 32–42 wks; mean BW 2873 g), PK parameters (mean ± SD) in NCA were the following: half-life 7.21 ± 7.97 hours; volume of distribution (Vd) 1.07 ± 0.51 L; clearance (CL) 0.20 ± 0.13 L/h; 24-hour area under the concentration-time curve 348.92 ± 114.86 mg*h/L. In pop-PK analysis, a 2-compartmental model described the data most adequately with the final parameter estimates of CL 15.15 (CV 40.47%) L/h/70kg; central Vd 24.87 (CV 37.91%) L/70kg; intercompartmental CL 0.39 (CV 868.56) L/h and peripheral Vd 1.039 (CV 69.32%) L. Peutic target attainment simulations demonstrated that a dosage of 50 mg/kg q 12 hours attained 100% fT > MIC 0.25 mg/L, group B streptococcal breakpoint. Conclusions: We recommend ampicillin dosage 50 mg/kg q 12 hours for neonates with gestational age ≥32 weeks during the first week of life.
Research Interests:
8512 Background: At the second interim analysis (IA2) of the triple-blind, phase 3 PEARLS/KEYNOTE-091 study (NCT02504372), pembrolizumab significantly improved DFS compared with placebo in patients (pts) with completely resected stage IB... more
8512 Background: At the second interim analysis (IA2) of the triple-blind, phase 3 PEARLS/KEYNOTE-091 study (NCT02504372), pembrolizumab significantly improved DFS compared with placebo in patients (pts) with completely resected stage IB (T ≥4 cm) to IIIA NSCLC per AJCC v7, regardless of PD-L1 expression (N = 1177, HR 0.76, 95% CI 0.63-0.91, P = 0.0014). We present DFS in subgroups related to surgery, disease burden, and adjuvant chemotherapy use. Methods: Pts had pathologically confirmed, completely resected stage IB (T ≥4 cm) to IIIA NSCLC of any PD-L1 expression and ECOG PS 0-1. Systematic complete or lobe-specific mediastinal lymph node dissection was recommended; minimally, the subcarinal and 1 lobe-specific lymph node must have been examined. Adjuvant chemotherapy of ≤4 cycles was given as indicated by local guidelines. Eligible pts were randomized 1:1 to pembrolizumab 200 mg or placebo Q3W for 18 doses (̃1 y). Treatment effects on DFS were assessed in prespecified subgroups o...
Research Interests:
Research Interests:
Immuunsüsteem mängib olulist rolli nii kasvaja arengus kui ka vähivastases ravis. Kasvajarakud on võimelised varjuma immuunsüsteemi eest mitmete kaitsemehhanismide abil. Idee kasutada immuunsüsteemi vähiravis ei ole uus, kuid täpsemad... more
Immuunsüsteem mängib olulist rolli nii kasvaja arengus kui ka vähivastases ravis. Kasvajarakud on võimelised varjuma immuunsüsteemi eest mitmete kaitsemehhanismide abil. Idee kasutada immuunsüsteemi vähiravis ei ole uus, kuid täpsemad teadmised immuunsüsteemi toimimise kohta on loonud lisavõimalusi sihtmärkide mõjutamiseks. Viimastel aastatel on märkimisväärseid tulemusi andnud immuunmoduleerivad antikehad, mis on suunatud T-lümfotsüütide kasvajavastase aktiivsuse suurendamisele ja T-rakke inhibeeriva signaali blokeerimisele. Tsütotoksilise T-lümfotsüüdi antigeen-4 (ingl common T lymphocyte antigene-4, CTLA-4) ja programmeeritud rakusurm-1 (ingl programmed death-1, PD-1) retseptori vastased antikehad on paljude vähipaikmete puhul osutunud tõhusamaks senisest ravist ning immuunravi võib pidada üheks lootustandvamaks vähiravi suunaks onkoloogias. Eesti Arst 2016; 95(6):401–405
Research Interests:
Background: We aimed to study the mortality and intensity of health care in patients with advanced lung cancer assigned to systemic anti-cancer treatment (SACT) compared with patients who were not eligible for SACT (no-SACT). Methods: A... more
Background: We aimed to study the mortality and intensity of health care in patients with advanced lung cancer assigned to systemic anti-cancer treatment (SACT) compared with patients who were not eligible for SACT (no-SACT). Methods: A retrospective cohort of lung cancer patients, who were treated at the North Estonia Medical Centre from 2015–2017, was linked to population-based health care data from the Estonian Health Insurance Fund. We calculated 14- and 30-day mortality after SACT and used a composite measure of intensity of care, comprised from the following: emergency department visit, admission to hospital, admission to intensive care unit, receipt of radiotherapy or systemic treatment. Results: The median overall survival (OS) of patients who received at least one cycle of SACT (n = 489) was 9.1 months and in patients with no-SACT (n = 289) 1.3 months (hazard ratio [HR]=4.23, 95% CI=3.60-5.00). In the SACT group 6.7% and 14.7% of patients died within 14 days and 30 days aft...
Research Interests: Medicine()
()
P-glycoprotein (Pgp) is a m em ber of the A BC-transporter family, and in hum ans, is encoded by th e MDR1 gene. Recently, several single-nucleotide polym orphism s in the MDR1 gene w ere identified. The aim of the present study w as to... more
P-glycoprotein (Pgp) is a m em ber of the A BC-transporter family, and in hum ans, is encoded by th e MDR1 gene. Recently, several single-nucleotide polym orphism s in the MDR1 gene w ere identified. The aim of the present study w as to evaluate the effect of the MDR1 genetic polym orphism s G 2677T and C 3435T on Pgp activity in CD56+ and CD4+ peripheral blood cells. Using flow cytom etry, rhodam ine 123 (R h l2 3 ) efflux w as de term ined in 4 6 m ale h ea lth y volunteers. M edian R h l2 3 fluorescence in contro l sam ple, after baseline dye uptake, w as set as 100% . R h l2 3 fluorescence in efflux sam ples, exposed to different efflux periods, w as used to calculate the percentage of R h l2 3 re ta ined in th e cells in com parison w ith control. There was no significant difference in R h l2 3 efflux in CD56+ cells after 5, 10, 15, and 30 m in efflux betw een individuals w ith different MDR1 genotypes. Also, in CD4+ cells after 15, 30, 60, and 90 m in, R h l2 3 efflux did no t...
Research Interests:
Research Interests:
Background: We aimed to study the mortality and intensity of health care in patients with advanced lung cancer who received systemic anti-cancer treatment (SACT) compared with patients who were not eligible for SACT (no-SACT). Methods: A... more
Background: We aimed to study the mortality and intensity of health care in patients with advanced lung cancer who received systemic anti-cancer treatment (SACT) compared with patients who were not eligible for SACT (no-SACT). Methods: A retrospective cohort of patients with lung cancer, who were treated at the North Estonia Medical Centre from 2015–2017, was linked to population-based health care data from the Estonian Health Insurance Fund. We calculated 14- and 30-day mortality after SACT and used a composite measure of intensity of care, comprised from the following: emergency department visit, admission to hospital, admission to intensive care unit, receipt of radiotherapy or systemic treatment. Results: The median overall survival (OS) of patients who received at least one cycle of SACT (n = 489) was 9.1 months and in patients with no-SACT (n = 289) 1.3 months (hazard ratio [HR]=4.23, 95% CI=3.60-5.00). In the SACT group 6.7% and 14.7% of patients died within 14 days and 30 da...
Research Interests: Medicine()
()
Karbamasepiini, fenobarbitaali, fenutoiini, primidooni, okskarbasepiini, lamotrigiini ja naatriumvalproaadi pikaajaline kasutamine on seotud luutiheduse vahenemisega, mis voib viia osteopeenia, osteoporoosi ja luumurdude tekkeni. Eesti... more
Karbamasepiini, fenobarbitaali, fenutoiini, primidooni, okskarbasepiini, lamotrigiini ja naatriumvalproaadi pikaajaline kasutamine on seotud luutiheduse vahenemisega, mis voib viia osteopeenia, osteoporoosi ja luumurdude tekkeni. Eesti Arst 2012; 91(5):253–255
Keemiaravi korvaltoimena tekkiv luuudi toksiline kahjustus, sealhulgas febriilne neutropeenia (FN) ja selle tusistused, on uheks olulisemaks keemiaravi piiravaks teguriks. Risk FNi tekkeks on koige suurem 7–10 paeva parast keemiaravi. FN... more
Keemiaravi korvaltoimena tekkiv luuudi toksiline kahjustus, sealhulgas febriilne neutropeenia (FN) ja selle tusistused, on uheks olulisemaks keemiaravi piiravaks teguriks. Risk FNi tekkeks on koige suurem 7–10 paeva parast keemiaravi. FN on potentsiaalselt eluohtlik erakorraline seisund onkoloogide tegevuses. Tusistuste tekke riski kliiniline hindamine ja patsiendi kuulumine suure voi vaikse riskiga ruhma on oluline antibakteriaalse ravi valikul. Suremus suure riskiga patsiendiruhmas voib ulatuda kuni 40%-ni, seetottu on oluline laia toimespektriga antibakteriaalse ravi kiire alustamine. Patsiendil, kes kuulub vaikse riski ruhma ning kes vastab kindlatele kriteeriumitele (vt allpool), voib alustada antibakteriaalset ravi kodus suu kaudu. FN voib viia keemiaraviks kasutatavate ravimite annuste vahendamise, ravi edasilukkamise ning isegi ravi lopetamiseni ning koik see voib muuta haiguse kulgu. Eesti Arst 2016; 95(3):188–193
Research Interests:
Dapagliflosiin on glukosuurilise toimega suukaudne antidiabeetiline ravim, mis parsib glukoosi reabsorptsiooni neerutorukeses. Selle tulemusena tekib osmootne diurees, mille efektiivsus soltub neerufunktsioonist (patsiendi hinnanguline... more
Dapagliflosiin on glukosuurilise toimega suukaudne antidiabeetiline ravim, mis parsib glukoosi reabsorptsiooni neerutorukeses. Selle tulemusena tekib osmootne diurees, mille efektiivsus soltub neerufunktsioonist (patsiendi hinnanguline glomerulaarfi ltratsiooni kiirus (eGFR) peab olema vahemalt 60 ml / min / 1,73 m2) ja vere glukoosisisaldusest. Dapagliflosiinravi langetas seerumi glukohemoglobiini (HgA1c) taset keskmiselt 0,5–0,6%, mis on sarnane metformiini ja glipitsiidi maksimaalsete annuste kasutamisel saavutatavaga. Dapagliflosiini kasutamisel vahenes kehakaal (keskmiselt 2–4 kg). Kliinilistes uuringutes 2. tuupi diabeediga patsientidel langetas ravim vahesel maaral nii sustoolset (–4,4 mm Hg) kui ka diastoolset (–2,1 mm Hg) arteriaalset vererohku. Kliiniline uuring arteriaalse hupertensiooniga diabeedipatsientidel on kaimas. Olemasoleva metaanaluusi andmetel ei suurenda ravim kardiovaskulaarset suremust. Kliinilistes uuringutes esines dapagliflosiinigrupis platseebo- ja kontr...
Research Interests:
WHO avaldas 1986. aastal esimest korda nn valuredeli, millest lahtudes valitakse valuvaigisti valutugevuse alusel. Opioidid on naidustatud mooduka voi tugeva valu korral, mis ei allu mittesteroidsetele poletikuvastastele ravimitele.... more
WHO avaldas 1986. aastal esimest korda nn valuredeli, millest lahtudes valitakse valuvaigisti valutugevuse alusel. Opioidid on naidustatud mooduka voi tugeva valu korral, mis ei allu mittesteroidsetele poletikuvastastele ravimitele. Viimasel ajal ollakse siiski seisukohal, et koiki valuravi astmeid ei pea labima ja pahaloomulisest kasvajast pohjustatud valu korral soovitatakse ravi kohe alustada opioidiga. Valu on kasvaja korral uks kardetumaid sumptomeid, mis mojutab nii patsientide kui ka nende lahedaste elukvaliteeti. Kasvaja korral esinev valu voib olla tingitud haiguse progresseerumisest voi kasvaja ravist (kirurgilisest, keemia- voi kiiritusravist). Hoolimata uute valuvaigistite rohkusest ning paljudest ravijuhenditest on kasvaja korral esinev valu alaravitud (1). Ollakse uksmeeles, et opioidid on esmane ravivalik kasvajast tingitud mooduka ja tugeva kroonilise valu korral. Opioidide kasutamine Eestis on viimase nelja aasta jooksul kull monevorra suurenenud, kuid on siiski mit...
Research Interests: Physics()
()
Võtmesõnad: diabeet, tiasolidiindioonid, pioglitasoon, kusepõievähk Euroopa Ravimiamet (EMA) hoiatab, et mitmete epidemioloogiliste uuringute tulemuste alusel on pioglitasooni kasutajatel suurenenud risk kusepõievähi tekkeks (suhteline... more
Võtmesõnad: diabeet, tiasolidiindioonid, pioglitasoon, kusepõievähk Euroopa Ravimiamet (EMA) hoiatab, et mitmete epidemioloogiliste uuringute tulemuste alusel on pioglitasooni kasutajatel suurenenud risk kusepõievähi tekkeks (suhteline risk 1,12–1,33) (1). Pioglitasoon on tiasolidiindioonide rühma kuuluv ravim, mis on näidustatud II tüüpi diabeedi raviks nii monoteraapiana kui ka kombinatsioonis metformiini, sulfonüüluurea derivaatide või/ja insuliiniga. Pioglitasooni algannus on 15 mg või 30 mg üks kord ööpäevas, maksimaalne ööpäevane annus on 45 mg. Pioglitasoon toimib rakutuuma spetsiifi liste peroksisoomi proliferatsiooni aktiveerivate gammaretseptorite aktivatsiooni kaudu, mille tagajärjel väheneb rakkude insuliiniresistentsus. Ravimiameti andmeil kasutab pioglitasooni Eestis ligikaudu 500 patsienti. EMA hindas olemasolevaid andmeid pioglitasooni ja kusepõievähi tekkeriski kohta. Loomkatsetes on näidatud, et kuni 2 aastat pioglitasooniga ravitud rottidel esines sagedamini kusep...
We aimed to study differences in the use of health care resources in relation to time before death in patients with advanced lung cancer who either received systemic anti-cancer treatment (SACT) or were ineligible for SACT. A... more
We aimed to study differences in the use of health care resources in relation to time before death in patients with advanced lung cancer who either received systemic anti-cancer treatment (SACT) or were ineligible for SACT. A retrospective cohort of lung cancer patients (N = 778) diagnosed with advanced disease at North Estonia Medical Centre from 2015–2017 was linked to population-based health care data. We calculated a composite measure of cumulative resource use, comprised from the following: outpatient care, emergency department (ED) visit, inpatient care, admission to intensive care unit, nursing care and prescriptions. Costs were highest in patients who received SACT in the last month before death and decreased in parallel with the time elapsed from the last SACT. Only 20% of SACT patients received nursing care in the final month of life. The no-SACT patients had less time covered by health care services per month, and large differences were seen in the type of service receive...