Pharmacokinetics and Pharmacodynamics of Entacapone and Tolcapone after Acute and Repeated Administration: A Comparative Study in the Rat

ABSTRACT Two catechol-O-methyltransferase (COMT) inhibitors, entacapone and tolcapone, were compared in the rat to elucidate the actual differences between their pharmacokinetics and pharmacodynamics after single and repeated administration. Their inhibitory potencies were also compared in vitro. After intravenous administration (3 mg/kg), the elimination half-life (t 1/2␤ ) of entacapone (0.8 h) was clearly shorter than that of tolcapone (2.9 h). The striatum/serum ratio of tolcapone was 3-fold higher than that of entacapone. After a single oral dose (10 mg/kg), both entacapone and tolcapone produced an equal maximal degree of COMT inhibition in peripheral tissues, but tolcapone inhibited striatal COMT more effectively than did entacapone. After the 7-day treatment (10 mg/kg twice daily), COMT activity had recovered to a level of 67 to 101% of control within 8 h after the last dose of entacapone. In tolcapone-treated animals, there was still extensive COMT inhibition present in peripheral tissues, and the degree of inhibition was higher than that attained after a single dose. The pharmacokinetic-pharmacodynamic modeling revealed that a plateau of COMT inhibition near the maximal attainable inhibition was reached already by plasma concentrations below 2000 ng/ml, both with entacapone and tolcapone. Entacapone and tolcapone inhibited equally rat liver COMT in vitro with K i values of 10.7 and 10.0 nM, respectively. In conclusion, tolcapone has a longer duration of action and a better brain penetration than entacapone. The results also suggest that peripheral COMT is inhibited continuously when tolcapone is dosed at 12-h intervals, but this was not seen with entacapone. The second-generation catechol-O-methyltransferase (COMT, EC 2.1.1.6) inhibitors, entacapone and tolcapone, are indicated as adjuncts to standard levodopa-dopa decarboxylase inhibitor therapy in Parkinson's disease. They increase the bioavailability of levodopa by inhibiting its peripheral metabolism to an inactive metabolite, 3-O-methyldopa. COMT inhibitors improve the efficacy of the levodopa-dopa decarboxylase inhibitor therapy by prolonging the duration of action and the clinical benefit of levodopa Entacapone and tolcapone apparently behave differently both in experimental animals and humans. However, as a rule, entacapone and tolcapone have been studied only individually; their pharmacokinetics and pharmacodynamics have not been compared thoroughly after single and repeated dosing. Actually, very little is known about their pharmacodynamics in different tissues after repeated dosing. Furthermore, only the relationship between the plasma drug concentration and COMT activity in erythrocytes has been studied previously A few available studies on entacapone and tolcapone in rats suggest that entacapone is eliminated faster than tolcapone and its oral bioavailability is lower than that of tolcapone. After intravenous administration of 10 mg/kg tolcapone, the t 1/2 was 0.9 h and total clearance 470 ml ϫ h Ϫ1 ϫ kg Ϫ1 . The oral bioavailability was 48% for 20 mg/kg and 56% for 40 mg/kg The time course of COMT activity in different tissues has ABBREVIATIONS. COMT, catechol-O-methyltransferase; t 1/2␤ , elimination half-life (␤-phase); S-COMT; soluble catechol-O-methyltransferase; MB-COMT, membrane-bound catechol-O-methyltransferase; AUE, area under the effect-time curve; AUC, area under the plasma drug concentration-time curve; C 0 , initial plasma concentration; E 0 , baseline effect; E max , maximum attainable effect

Cumulative contextual risk at birth in relation to adolescent substance use, conduct problems, and risky sex: General and specific predictive associations in a Finnish birth cohort

Background—Research indicates that risk factors cluster in the most vulnerable youth, increasing their susceptibility for adverse developmental outcomes. However, most studies of cumulative risk are cross-sectional or short-term longitudinal, and have been based on data from the United States or the United Kingdom. Using data from the Northern Finland Birth Cohort 1986 Study (NFBC1986), we examined cumulative contextual risk (CCR) at birth as a predictor of adolescent substance use and co-occurring conduct problems and risky sex to determine the degree to which CCR predicts specific outcomes over-and-above its effect on general problem behavior, while testing for moderation of associations by gender. Methods—Analyses of survey data from 6963 participants of the NFBC1986 followed from the prenatal/birth period into adolescence were conducted using structural equation modeling. Results—CCR had long-term positive associations with first-order substance use, conduct problems, and risky sex factors, and, in a separate analysis, with a second-order general problem behavior factor. Further analyses showed that there was a positive specific effect of CCR on risky sex, over-and-above general problem behavior, for girls only. Conclusions—This study, conducted within the Finnish context, showed that CCR at birth had long-term general and specific predictive associations with substance use and co-occurring problem behaviors in adolescence; effects on risky sex were stronger for girls. Results are consistent with the hypothesis that early exposure to CCR can have lasting adverse consequences, suggesting the need for early identification and intervention efforts for vulnerable children

Cumulative contextual risk at birth in relation to adolescent substance use, conduct problems, and risky sex: General and specific predictive associations in a Finnish birth cohort

Background—Research indicates that risk factors cluster in the most vulnerable youth, increasing their susceptibility for adverse developmental outcomes. However, most studies of cumulative risk are cross-sectional or short-term longitudinal, and have been based on data from the United States or the United Kingdom. Using data from the Northern Finland Birth Cohort 1986 Study (NFBC1986), we examined cumulative contextual risk (CCR) at birth as a predictor of adolescent substance use and co-occurring conduct problems and risky sex to determine the degree to which CCR predicts specific outcomes over-and-above its effect on general problem behavior, while testing for moderation of associations by gender. Methods—Analyses of survey data from 6963 participants of the NFBC1986 followed from the prenatal/birth period into adolescence were conducted using structural equation modeling. Results—CCR had long-term positive associations with first-order substance use, conduct problems, and risky sex factors, and, in a separate analysis, with a second-order general problem behavior factor. Further analyses showed that there was a positive specific effect of CCR on risky sex, over-and-above general problem behavior, for girls only. Conclusions—This study, conducted within the Finnish context, showed that CCR at birth had long-term general and specific predictive associations with substance use and co-occurring problem behaviors in adolescence; effects on risky sex were stronger for girls. Results are consistent with the hypothesis that early exposure to CCR can have lasting adverse consequences, suggesting the need for early identification and intervention efforts for vulnerable children

Suomen kuntien kasvihuonekaasupäästöjen laskenta. ALas-mallin menetelmäkuvaus ja laskentojen tuloksia 2005–2018

Kuntien ja alueiden merkitys kasvihuonekaasupäästöjen vähentämisessä on suuri. Valtio osaltaan ohjaa ilmastonmuutosta hillitsevän politiikan toimeenpanoa lainsäädännön tasolla, mutta useat käytännön toimet toteutetaan kunnissa. Kuntien tulee keskimäärin olla hiilineutraaleja vuonna 2035, joka on Suomen itselleen asettama hiilineutraaliuden tavoitevuosi. Useat kunnat, kaupungit sekä jotkin maakunnat tavoittelevat päästövähennyksiä jopa kansallisia ja Euroopan Unionin tavoitteita nopeammin. Yksi keskeisimmistä työkaluista hiilineutraaliuden tavoittelussa on kasvihuonekaasupäästöjen vuosiseuranta, jonka avulla päästövähennystoimenpiteiden vaikuttavuutta voidaan mitata suhteessa asetettuihin tavoitteisiin. Tässä raportissa kuvataan uuden, kuntien ja alueiden kasvihuonekaasupäästöjen laskentaan tarkoitetun Alueellinen Laskenta (ALas) -mallin laskentaperiaatteet sekä luodaan katsaus mallilla laskettuihin Suomen kuntien kasvihuonekaasupäästöihin vuosina 2005–2018. ALas-malli noudattaa kansainvälisen GPC-päästölaskentastandardin (GHG Protocol 2014) ohjeistusta. Mallilla lasketut kuntien päästöt summautuvat IPCC:n (2006) ohjeiden mukaisiin, YK:lle ja EU:lle raportoitaviin Suomen virallisiin päästöihin. Laskentaperiaate on käyttöperusteinen, jossa lähtökohtana ovat alueen tuotantoperusteiset päästöt, mutta osa päästöjä aiheuttavista toiminnoista lasketaan kulutuksen perusteella, riippumatta niiden maantieteellisestä syntypaikasta. ALas sisältää 80 päästösektoria, joiden laskennassa pyritään käyttämään paikallista dataa aina kun mahdollista, mutta joidenkin sektorien kohdalla kansallisia päästötietoja on allokoitu kunnille erilaisin jakoperustein. Päästöistä lasketaan hiilidioksidi-, metaani- ja dityppioksidipäästöt sekä F-kaasut omana kokonaisuutenaan, ja tulokset esitetään hiilidioksidiekvivalentteina. Bioperäiset polttoaineet ovat hiilidioksidin osalta laskennallisesti nollapäästöisiä. Kuntien tavoitteiden seurantaan tarkoitettua oletuslaskentamallia kutsutaan Hinku-laskennaksi. Tällöin seurannan ulkopuolelle jätetään sellaisia päästöjä, joihin kunnassa ei välttämättä pystytä kovin paljon vaikuttamaan. Laskentaan eivät tässä tapauksessa kuulu päästökauppaan kuuluvan teollisuuden polttoaineiden käytön, teollisuuden koko sähkönkulutuksen, teollisuuden jätteiden käsittelyn eivätkä paketti-, linja- ja kuorma-autojen läpiajoliikenteen aiheuttamat päästöt. Lisäksi kunnan alueella tapahtuvasta tuulivoiman tuotannosta lasketaan päästökompensaatio. Hinku-laskennan ohella ALas-mallilla tuotetaan päästötulokset myös ilman kompensaatiota tai muita rajauksia. Päästöjä voidaan lisäksi tarkastella erikseen päästökauppa- ja taakanjakosektoreilla. Kuntien Hinku-laskennan tulokset osoittavat, että lähes kaikissa Suomen kunnissa päästöt ovat vähentyneet vuodesta 2005. Muutos on ollut kunnissa keskimäärin -15 %, mutta kuntien ja alueiden välinen vaihtelu on erittäin suurta. Keskeiset syyt myönteiseen, mutta ilmastotavoitteiden saavuttamisen kannalta toistaiseksi hitaaseen kehitykseen ovat öljylämmityksen väheneminen, muutokset kaukolämmön tuotannon polttoainekäytössä sekä tuulivoiman tuotanto. Myös sähkönkulutuksen, teollisuuden, tieliikenteen ja jätteiden käsittelyn päästöt ovat yleisesti vähentyneet. Sen sijaan maatalouden ja F-kaasujen päästöissä ei ole nähtävissä vastaavaa kehitystä

Absorption Rate Limit Considerations for Oral Phosphate Prodrugs

Purpose . To evaluate the potential of phosphate ester prodrugs to significantly improve the absorptive flux of poorly soluble parent drugs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41498/1/11095_2004_Article_465513.pd

Fabrication and characterization of vacuum deposited fluorescein thin films

Simple vacuum evaporation technique for deposition of dyes on various solid surfaces has been developed. The method is compatible with conventional solvent-free nanofabrication processing enabling fabrication of nanoscale optoelectronic devices. Thin films of fluorescein were deposited on glass, fluorine-tin-oxide (FTO) coated glass with and without atomically layer deposited (ALD) nanocrystalline 20 nm thick anatase TiO2 coating. Surface topology, absorption and emission spectra of the films depends on their thickness and the material of supporting substrate. On a smooth glass surface the dye initially formes islands before merging into a uniform layer after 5 to 10 monolayers. On FTO covered glass the absorption spectra are similar to fluorescein solution in ethanol. Absorption spectra on ALD-TiO2 is red shifted compared to the film deposited on bare FTO. The corresponding emission spectra at {\lambda} = 458 nm excitation show various thickness and substrate dependent features, while the emission of films deposited on TiO2 is quenched due to the effective electron transfer to the semiconductor conduction band.Comment: 24 pages including 5 figure

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Tierakenteen vaurioituminen ja tiestön kunto

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Lääkintätilojen IT-verkon vikakysymykset

Insinöörityössä tutkittiin sairaaloiden lääkintätiloissa käytettävän yksivaiheisen IT-sähkönjakeluverkon vikatilanteita. Tarkoituksena oli selvittää niin sanotun toisen vian tapauksessa vaadittava minimi oikosulkuvirta, jolla syötön automaattisen poiskytkennän kytkentäehto toteutuu. Insinöörityössä selvitetään myös UPS varmennetun IT-verkon oikosulkuvirtojen laskentaan olennaisesti vaikuttavia asioita. Työssä käydään läpi yksivaiheisen IT-sähkönjakeluverkon periaatteellinen rakenne, ja siinä esiintyvät vikatilanteet, ja niiden aikana esiintyvät kosketusjännitteet. Potentiaalintasaus on oleellinen osa lääkintätilojen kosketusjännitesuojausta, joten potentiaalintasausta ja sen vaikutusta kosketusjännitteeseen käsitellään myös laskuesimerkein. Insinöörityö tehtiin perehtymällä IT-verkkoja käsittelevään kirjallisuuteen ja muuhun luotettavaan lähdeaineistoon, sekä haastattelemalla useita aiheen asiantuntijoita. Työ tehtiin Granlund Oy:lle. Työn tuloksena voidaan sanoa, että kun IT-sähkönjakeluverkko tehdään suositusten mukaisesti, ei oikosulkuvirran riittävyys ole sairaalaverkoissa ongelma. Työn tuloksissa havaittiin, että IT-sähkönjakeluverkossa niin sanotun ensimmäisen vian aikana esiintyvä kosketusjännite on hyvin pieni, muutaman millivoltin suuruinen. Tuloksissa havaittiin myös, että potentiaalintasauksella on ratkaiseva merkitys, jotta kosketusjännite voidaan rajoittaa lääkintätiloissa suurimpaan sallittuun 25 volttiin.This final year project studied faults in a single-phase IT electricity distribution network used in hospitals. The purpose was to establish the minimum short-circuit current required for the so-called second fault to switch off the supply. The project also identified factors that affect the calculation of short circuits in a UPS-certified IT network. The study mapped a single-phase IT power grid, its possible faults, and the contact voltages during the faults. Since equipotential bonding is essential for contact space protection of medical spaces, equipotential bonding and its impact on the contact voltage were also discussed. The project included the study of literature on IT networks, and interviews with experts. The thesis showed that when an IT network meets the recommendations, the impedance of a fault circuit is small and the short circuit current is not a problem in hospital networks. It was established that the contact voltage in the IT distribution network during the so-called 1st fault is very small, a few millivolts. Furthermore, equipotential bonding is of crucial importance in order to limit the contact voltage in a medical space to the maximum allowed, 25 volts. This thesis, and its results, can be used to give deeper information and understanding about single phase IT networks to electrical engineers and students

Temmeksen koetien tutkimukset 1996-2001 : yhteenvetoraportti

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