Læknablaðið : fylgirit - 05.01.2015, Blaðsíða 31

X V I I V Í S I N D A R Á Ð S T E F N A H Í
F Y L G I R I T 8 2
LÆKNAblaðið/Fylgirit 82 2015/101 31
analyzed by the Higuchi model because the dissolution in the latter case
turns out to be limited.
Conclusion: This work has led to a unified model that can predict the
drug release of a drug loaded matrix systems and also trans-membrane
and transdermal delivery from such systems. Fit with experimental data
has been achieved with the model using various configurations with
donor solution, silicone matrix and skin.
E 73 Virtual screening for new lead compounds for Alzheimer’s
disease with dual mode of action
Natalia M. Pich1, Rikke Bergmann2, Elín S. Ólafsdóttir1, Thomas Balle2
1Faculty of Pharmaceutical Sciences, University of Iceland, 2Department of Drug Design and
Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen
nmp@hi.is
Introduction: Alzheimer’s disease (AD) is the most common form of
dementia. The exact mechanism of the disease is still unknown what
makes development of new drug leads more complicated. First treat-
ment against AD introduced to general use were inhibitors of acetylc-
holinesterase (AChE). The drugs help patients in daily life but are not
able to reverse the progression of the disease and have side effects. New
and safer drugs with multi-target activity are needed. Galanthamine is
a plant alkaloid isolated from Snowdrop (Galanthus sp.) and approved
as a drug for the treatment of AD. It has a dual mode of action - it is an
inhibitor of AChE and an “allosterically potentiating ligand” at nicotinic
acetylcholine receptors (nAChRs). In the search for dual-action enhan-
cers of ACh-mediated neurotransmission natural products database
was screened using high throughput virtual screening (HTVS) on an
X-ray structure of the AChE and on a homology model of the human
α7-nAChR.
Methods and data: A computational model of the human α7-nAChR
was built with Modeller v. 9.9 based on an X-ray structure of an ace-
tylcholine binding protein (AChBP) with galanthamine bound (PDB ID:
2PH9) and AChE crystal structure (PDB ID: 4EY6). Virtual screening
followed a standard workflow in Schrödinger’s software package.
Results: Out of 10 hits tested for AChE inhibitory activity. Three compo-
unds showed high activity of which one is not described in the literature.
Conclusions: Virtual screening brought structures with galanthamine
scaffold as well as new structures what makes it a good method for
searching new drug leads.
E 74 Salicylic acid as a prophylactic treatment of pregnant women
in risk of having preeclampsia
Helga Helgadóttir1,2,3, Maurizio Mandala3, Teresa Tropea3, Kypros Nicolaides4,
Sveinbjörn Gizurarson1,2,
1Faculty of Pharmaceutical Sciences, University of Iceland, 2Hananja plc, 3Department of
Cellular Biology, University of Calabria, 4Fetal Medicine Unit, University College Hospital
heh37@hi.is
Introduction: Although it is 2014, preeclampsia (PE) is still a major
reason for mortality and morbidity of mothers, fetuses and neonate.
For the past three decades, one of the important research questions in
obstetrics has been if prophylactic use of low-dose acetylsalicylic acid
(ASA) may be used to prevent PE. The aim of this work is to study the
effects of ASA and its major metabolite, salicylic acid (SA), on isolated
uterine arteries in rats, with focus on its importance in the widening
and/or preconditioning of the uterine vasculature and possibility to use
it as a prophylactic therapeutic approach.
Methods and data: Isolated arcuate uterine arteries from non-gravid,
and gravid rats at day 14 and 20 of pregnancy were mounted in an
arteriography organ bath and pre-contracted with phenylephrine to
produce 40-50% reduction in baseline. ASA and SA dose response was
then tested by adding the test drugs into the physiological salt solution
superfusing the arteries. Direct vasodilation effect was then recorded
accordingly.
Results: Both ASA and SA induced a direct dose-dependent vasodila-
tion effect on the arteries at different pregnancy state, except ASA did
not induce any vasodilation effect in 20 days pregnant rats.
Conclusions: Results indicate that ASA might have important role in
improving uterine vasculature which is critical for the prevention of PE.
This direct vasodilation effect might be one of main reason that low-dose
ASA therapy has been effective as a prophylactic treatment for PE, but
further studies are needed to confirm the magnitude and mechanism of
ASA and SA on uterine vasculature.
E 75 Áhrif metótrexats á meðferðarárangur TNF-α hemla við iktsýki
Birta Ólafsdóttir1, Pétur S. Gunnarsson1,2, Anna I. Gunnarsdóttir1,2, Þorvarður J.
Löve3,4, Björn Guðbjörnsson3,5
1Lyfjafræðideild Háskóla Íslands, 2sjúkrahúsapóteki Landspítala, 3læknadeild Háskóla Íslands,
4vísinda- og þróunarsviði, 5rannsóknastofu í gigtarsjúkdómum Landspítala
bio3@hi.is
Inngangur: Iktsýki (RA) er algengasti liðbólgusjúkdómurinn og ein-
kennist af samhverfum liðbólgum og sjálfsmótefnum. Ekki er til lækning
við RA en fjöldi lyfja er í boði sem hafa umbreytt langtímahorfum.
Lyfjunum er skipt í þrjá flokka: einkennadempandi (t.d. NSAID), sjúk-
dómsdempandi (t.d. metótrexat) og líftæknilyf (t.d. TNF-α hemlarnir;
adalimumab, etanercept og infliximab). Erlendar rannsóknir benda til
þess að samhliðameðferð TNF-α lyfja og metótrexats gefi betri með-
ferðarárangur en einlyfjameðferð með TNF-α hemili. Þetta hefur ekki
verið skoðað í íslensku þýði.
Efniviður og aðferðir: Notast var við gögn úr ICEBIO-gagnagrunninum.
ICEBIO er kerfisbundin meðferðaskrá yfir gigtarsjúklinga á Íslandi sem
meðhöndlaðir eru með líftæknilyfjum. Í þessari rannsókn var fyrsta
TNF-α hemla meðferð RA-sjúklinga skoðuð (n=206) og meðferðarár-
angur skoðaður með og án metótrexats með tilliti til meðferðasvars.
Klínísk svörun var metin með skilmerkjum amerísku gigtarlæknasam-
takanna (ACR20, ACR50) og evrópsku gigtarsamtakanna (DAS28-CRP).
Sjúkdómsvirkni, sjúkdómshlé og fjöldi sjúklinga á hvorri meðferð sem
hættu á fyrsta meðferðarári, var einnig skoðað. Notuð var lógístísk
aðhvarfsgreining með 95% öryggisbili til að kanna gagnlíkindahlutfall
og skoða mun TNF-α hemla meðferðar með og án samhliðameðferðar
metótrexats.
Niðurstöður: Árangur samhliðameðferðar TNF-α hemils og metótrexats
var betri í flestum mældum útkomum. Ári eftir upphaf meðferðar náðu
68% sjúklinga á samhliðameðferð 50% bata, en 32% sjúklinga á einlyfja-
meðferð með TNF-α hemili (P=0,046). Fleiri sjúklingar á samhliðameð-
ferð náðu góðu meðferðarsvari og sjúkdómshléi ásamt því að sjúkdóms-
virkni var að meðaltali lægri.
Ályktanir: Niðurstöður rannsóknarinnar benda eindregið til þess
að samhliðameðferð metótrexats og TNF-α hemils gefi betri með-
ferðarárangur en einlyfjameðferð með TNF-α hemli meðal íslenskra
RA-sjúklinga.