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Opredeluvawe na oligosaharidni angienski determinanti 
od glikoproteini vo periferen nerv i Campylobacter jejuni O:19 
Ana Poceva Panovska
1
, Katerina Brezovska
1
, Aleksandra Grozdanova
1
, 
Slobodan Apostolski
2
, Qubica [uturkova
1
1
Farmacevtski fakultet, Univerzitet Sv. Kiril i Metodij, Vodwanska 17, Skopje, Makedonija
2
Institut za neurologija, Klini~ki Centar na Srbija, Ulica Dr. Suboti}a, Belgrad, Srbija
Vo bolestite na nervniot sistem, imunopatolo{kiot odgovor kon glikokonjugatni strukturi,
osobeno kon glikoproteinite e pole na intenziven nau~en interes. Do denes, izolirani i delumno karak-
terizirani se nekolku jaglehidratni strukturi za koi e utvrdeno deka se celni antigeni vo bolestite na
perifernite nervi. Eksperimentalnite soznanija uka`uvaat na strukturna sli~nost pome|u oligosahard-
ni determinanti od glikoproteinite na perifernite nervi i bakteriski jaglehidratni strukturi {to
upatuva na postoewe na molekularna mimikrija koja ima va`na uloga vo pojavata na nekoi postinfektivni
avtoimuni nevropatii. 
Glikoproteinite od periferen nerv i Campylobacter jejuni O:19 (C. jejuni) koi se vrzuvaat so galakozil
N
-acetilgalaktozamin (Gal(
β1-3)GalNAc) determinantata bea izolirani so afinitetna hromatografija vo
koja e koristen lektinot PNA (Peanut agglutinin). Izoliranite glikoproteini bea doka`ani so imunoblot
analiza koristejki perjodatna oksidacija i biotiniliran PNA. Koristena e ELISA (Enzyme linked immunosor-
bent assay) za da se odredi titarot na antitela kon gangliozidite GM1 i AG1, vo serumi od pacienti so
Guillain-Barre sindrom (GBS). Istite serumi ponatmu se testirani so imunoblot analizi na reaktivnost
kon izoliranite glikoproteini. Pri ovaa analiza odredeni se imunodominantni glikoproteini vo izo-
latite od perifern nerv i C. jejuni. Oddeluvaweto na N-povrzanite glikoproteini (N-glikani) be{e
napraveno so pomo{ na enzimot polipeptidna-N-glikozidaza. Oslobodenite N-glikani bea fluorescent-
no obele`ani i podlo`eni na enzimsko sekvencionirawe so visoko specifi~ni egzoglikozidazi. Vo sekven-
cionira~kiot protokol bea koristeni slednite enzimi: neuraminidaza (NANase III) specifi~na za 
α2-
3,6,8,9 povrzanata N-acetilneuraminska kiselina; 
β-Galaktozidaza (GALase III) specifi~na za β1-4
povrzanata galaktoza; 
βN-acetilheksoaminidaza (HEXase III) specifi~na za β1-2,3,4,6 povrzanata N-acetil-
glukozamin i 
α-manozidaza (MANase II) specifi~na za α1-2,3,6 povrzanata manoza. Produktite od digesti-
jata bea elektroforetski separirani i analizirani softverski. Dobienite monosaharidni strukturi se
odredeni preku sporeduvawe na nivnata migracijata vo odnos na migracijata na glukozniot polimeren
standard.
Od sekvencionira~kite analizi na N-povrzanite glikani izolirani od periferen nerv i C. jejuni
e utvrdeno postoewe na dve galaktozi, dva N-acetilgalaktozamina i dva manozni ostatoci. Postoi raz-
likata vo eden terminalen ostatok na sijalinska kiselina i fukozilirana sr`, prisutni kaj oligosa-
haridite od periferen nerv.
Prisustvoto na strukturno sli~ni oligosaharidni determinanti kaj glikoproteinite vo perifer-
nite nervi i C. jejuni uka`uva na nivnata potencijalna uloga vo molekularnata mimikrija i pokrenuvawe
na imuniot odgovor kon sopstvenite strukturi.
Macedonian pharmaceutical bulletin 53 (1,2) 151-152 (2007)
PP - 68
152
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The effect of intermittent exposure to acute hyperthermia 
on the prostaglandin E2 concentration in Wistar rats
Icko Gjorgoski, Nikola Hadzi-Petrushev
Sts. Cyril and Methodius University, Faculty of Natural Sciences and Mathematics, Institute of Biology, 
Arhimedova 5, 1000 Skopje,Republic of Macedonia
Prostaglandins represent a large group of structurally different lipid mediators with multiple biological activ-
ities. Prostaglandin E
2
(PGE
2
) is formed in a variety of cells from prostaglandin H
2
, which is synthesized from arachi-
donic acid by the enzyme prostaglandin synthetase. PGE
2
produces a broad range of biologic actions in diverse tis-
sues, including vasodilation, both anti- and proinflammatory action, modulation of sleep/wake cycles, and facilitation
of the replication of human immunodeficiency virus. It elevates cAMP levels, stimulates bone resorption, and has
thermoregulatory effects. It has been shown to be a regulator of sodium excretion and renal hemodynamics.
In our experiment we used Wistar rats divided in 4 groups: control male rats, control female rats, exposed male
rats, exposed female rats. The last two groups of animals were exposed to acute hyperthermic stress by spending 90
minutes in climate-controlled chambers at 40 
0
C. After exposure, serum concentrations of PGE
2
were determined for
all experimental animals, using a non-radioactive enzyme-based immunoassay (PGE
2
EIA, Sigma-Aldrich, Inc.).
Using a Student’s T-test, at 95% level of significance, the results have shown that the serum concentration
of PGE
2
in exposed rats is significantly greater than the PGE
2
concentration in the serum samples from non-exposed
rats. The calculated t-value (t = 4.532) for the difference in PGE
2
serum concentration between exposed and non-
exposed (control) male rats is greater than the t-value given in tables (t = 2.110). When comparing the difference in PGE
2
serum concentration between exposed and non-exposed female rats, the calculated t-value is 6.041, again greater
than the value given in tables.
These findings are in favor of the proposed role of PGE
2
in the mechanisms for maintaining temperature
homeostasis. The results lead to a conclusion that the acute hyperthermic stress causes significant increase of the
PGE
2
serum concentration in Wistar rats, probably by boosting the PGE
2
biosynthesis.
Macedonian pharmaceutical bulletin 53 (1,2) 153-154 (2007)
PP - 69
153
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Vlijanie na intermitentnoto eksponirawe 
na akutna hipertermija vrz koncentracijata 
na prostaglandin E
2
kaj Wistar staorci
Icko \orgoski, Nikola Haxi-Petru{ev
Univerzitet „Sv. Kiril i Metodij”, Prirodno-matemati~ki fakultet, Institut za biologija,
„Arhimedova” br. 5, 1000 Skopje, Republika Makedonija
Prostaglandinite pretstavuvaat golema grupa na strukturno razli~ni lipidni medijatori so
mnogubrojni biolo{ki aktivnosti. Prostaglnadin E
2
(PGE
2
) se sozdava vo mnogu tipovi na kletki.
Prekursor vo negovata sinteza e prostaglandin H
2
koj se dobiva od arahidonska kiselina so dejstvo na enz-
imot prostaglandin sintetaza. PGE
2
poka`uva {irok spektar na dejstva vo razli~ni tipovi na tkiva.
Negovite biolo{ki aktivnosti vklu~uvaat: vazodilatacija, anti - i proinflamatorno dejstvo, modulaci-
ja na ciklusot spiewe/budnost i pomagawe na procesot na replikacija na HIV virusot. PGE
2
go poka~uva
nivoto na cAMP, ja stimulira resorpcijata na koskite i ima termoregulaciski efekti. Poka`ano e deka
PGE
2
e regulator na ekskrecijata na natrium i renalnata hemodinamika. 
Vo na{iot eksperiment bea koristeni laboratoriski staorci od sojot Wistar, podeleni vo 4 grupi:
kontrolni ma{ki `ivotni, kontrolni `enski `ivotni, eksponirani ma{ki `ivotni, eksponirani `enski
`ivotni. Poslednite dve grupi na staorci bea izlo`eni na akuten hipertermi~ki stres preku eksponirawe
vo klima komora na 40 
0
C so vremetraewe od 90 minuti. Po ekspozicijata, na site `ivotni im be{e odredena
koncentracijata na PGE
2
vo serum, koristej}i immuno-enzimski metod (PGE
2
EIA, Sigma-Aldrich, Inc.).
So primena na Studentov T-test, pri 95% nivo na verodojstojnost, rezultatite poka`aa deka serum-
skata koncentracija na PGE
2
kaj eksponiranite `ivotni e signifikantno povisoka otkolku koncentraci-
jata na PGE
2
vo serumot na neeksponirani `ivotni od soodvetnite polovi. Imeno, presmetanata t-vred-
nost (t = 4.532) za razlikata vo serumskata koncentracija na PGE
2
kaj eksponirani i neeksponirani ma{ki
staorci e povisoka od tabli~nata t-vrednost (t = 2.110). Pri sporeduvawe na razlikite vo serumskite kon-
centracii na PGE
2
kaj eksponirani i neeksponirani `enski staorci, presmetanata t-vrednost iznesuva
6.041 i povtorno e po-visoka od vrednosta dadena vo tablica.
Ovie rezultati ja potvrduvaat povrzanosta na PGE
2
so mehanizmite za odr`uvawe na temperatur-
nata homeostaza. Toa odi vo prilog na zaklu~okot deka akutniot hipertermi~ki stres doveduva do sig-
nifikantno zgolemuvawe na serumskata koncentracija na PGE
2
kaj Wistar staorci, najverojatno preku zasilu-
vawe na biosintezata na PGE
2
.
Macedonian pharmaceutical bulletin 53 (1,2) 153-154 (2007)
PP - 69
154
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Synthesis, structure and biological activity of some new 3 - substituted
derivates of 4 - Hydroxycoumarin
Davorka Zavrsnik
1
, Selma Spirtovic
1
, Samija Muratovic
1
, Dzenita Softic
2
1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sarajevo, Bosnia and Herzegovina
2
Institute for Quality Control of Medicines, Sarajevo, Bosnia and Herzegovina
Our previous results showed that some of 3-cynnamoyl-4-hydroxycoumarin were found to have very good
antibacterial activity. The series of new 3-cynnamoyl-4-hydroxycoumarin were prepared by the reaction of nucleo-
phylic addition from 3-acetyl-4-hydroxycoumarin acting on appropriate aromatic aldehydes with pyridine and piperi-
dine as catalists. 
R= OH, OCH3, CH3, NO2, Cl, Br, F
The elementary content of the synthesized compounds was confirmed by elementary analysis, and structures
were confirmed with IR-spectrophotometry and 1H-NMR spectrophotometry.
The newly-prepared derivatives have a different supstituents, and according to that, they can exhibit poten-
tial antimicrobial activity, therefore the antimicrobial activity of these derivatives in case of various species of bac-
teria. Using the methods of diffusion, the synthesized derivatives of 3-cynnamoyl-4-hydroxycoumarin were tested
on antimicrobial activity. Namely, the test included six types of bacteria (Pseudomonas aeruginosa ATTC 9027,
Echerichia coli ATCC 8739, Salmonella sp., Bordatella bronchiseptica, Bacillus subtilis ATCC 6633, and
Staphyloccocus aureus ATCC 6538P). The diffusion method showed that compounds have larger or smaller growth
inhibition zones when it comes to Gram-positive aerobe bacteria Bacillus subtilis ATCC 6633 (I mm = 9,0-20,3) and
Staphyloccocus aureus ATCC 6538P (I mm = 11,0-24.5). The tested compounds did not show activity to Gram-neg-
ative types of bacteria Pseudomonas aeruginosa ATTC 9027, Echerichia coli ATCC 8739, Salmonella sp. and
Bordatella bronchiseptica. 
As expected, the compounds that have halogens, chlorine and bromine as substituents showed the best antimi-
crobial activity (I mm = 16.95-24.5). Among the derivatives with halogen substituent, 3-(4-bromphenylcynnamoyl)-
4-hydroxycoumarin had the best ativity. 
Macedonian pharmaceutical bulletin 53 (1,2) 155 (2007)
PP - 70
155
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O
OH
O
POCl
3
CH
3
COOH
O
OH
O
COCH
3
O
OH
O
O
HOC
R
1
2 3
4
R
5
6

Genetic Polymorphism in UGT1A1 and risk of colorectal cancer
M. Hiljadnikova-Bajro
1
, T. Josifovski
2
, Z. Sterjev
1
, A. Kapedanovska
1
, Z. Serafimoska
1
,
N. Matevska
1
, S. Despotovska
1
, N. Petrusevska
3,
M. Panovski
2
, L. Suturkova
1
, A. J. Dimovski
1
1
Institute of Pharmaceutical Chemistry, Faculty of Pharmacy,  
2
Clinic for Abdominal Surgery and 
3
Institute of Radioterapy and Oncology, Faculty of Medicine, 
University “Sts. Cyril and Methodius“, Skopje, Republic of Macedonia
Uridine diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1) is the key hepatic detoxification
enzyme involved in biotransformation of many carcinogens implicated in the development of colon, breast and
prostate cancer in humans. A polymorphism in the UGT1A1 promoter containing a TA repeat element [(TA)
5-8
TAA],
is involved in the modulation of UGT1A1 transcription activity. Wild type activity is associated with the (TA)
6
TAA
allele (UGT1A1*1), whereas UGT1A1 expression decreases with increasing number of TA repeats. We hypothesize
that low activity allele UGT1A1*28 with 7 TA repeats is associated with higher risk for colorectal cancer. Our study
involved 84 patients with histopathologically confirmed colorectal cancer and a control group of 70 individuals older
than 65 (mean age 75) without diagnosis of colorectal cancer. Genomic DNA was isolated from peripheral blood
using Proteinase K digestion / phenol-chlorophorm extraction and ethanol precipitation. Evaluation of the number
of TA repeats was done by fluorescent PCR and capillary gel electrophoresis. Our data indicate that UGT1A1*28
allele is present at a higher frequency than the wild type UGT1A1*1 allele in colorectal cancer patients as compared
to controls (p=0.02; OR = 1.73, CI 1.06-2.81). Consistently, the frequency of genotypes that contain the UGT1A1*28
allele in the homozygous or heterozygous state was greater than the frequency of the wild type UGT1A1*1/*1 geno-
type in colorectal cancer patients as compared to controls (p=0.28, OR = 1.7389, CI 0.63-4.70 and p= 0.001 OR =
3.11, CI 1.53-6.33, respectively). 
To our knowledge this is the first study showing the association between the UGT1A1 length polymorphism
and increased risk of colorectal cancer, and warrants further investigation on the possible interplay between this type
of genetic susceptibility and specific environmental exposures in our population.
Macedonian pharmaceutical bulletin 53 (1,2) 156-157 (2007)
PP - 71
156
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Patients 
(n=84) 
Controls 
(n=70) 
OR 
95% CI 
p 
Allele frequency 
UGT1A1*28 
0.39 
0.27 
1.73 
1.06-2.81 
0.02 
UGT1A1*1 
0.61 
0.73 
 
 
 
Genotype frequency 
UGT1A1*28/*28 
0.13 
0.13 
UGT1A1*1/*28 
0.52 
0.28 
UGT1A1*1/*1 
0.35 
0.59 
2.68
a
 
1.39-5.16
 a
 
0.0028
 a
 

Genetskiot polimorfizam vo UGT1A1 genot kaj pacienti
so kolorektalen karcinom od Makedonija
Hiqadnikova-Bajro M.
1
, Josifovski T.
2
, Sterjev Z.
1
, Kapedanovska A.
1
, Serafimoska Z.
1
, 
Matevska N.
1
, Despotovska S.
1
, Petru{evska N.
3
, Panovski M.
2
, [uturkova Q.
1
, Dimovski, A. J.
1
1
Institut za farmacevtska hemija, Farmacevtski fakultet, 
2
Klinika za Abdominalna hirurgija i
3
Institut za Radioterapija i Onkologija, Medicinski Fakultet, 
Univerzitet ”Sv. Kiril i Metodij”, Skopje, Republika Makedonija
Uridine diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1) e enzim od crniot drob koj igra klu~na
uloga vo detoksifikacita na mnogu kancerogeni supstancii involvirani vo razvojot na karcinomi na
kolonot, dojkata i prostatata. Transkripciskata aktivnosta na UGT1A1 genot e uslovena od TA-polimor-
fizmot vo negoviot promoter, pri {to alelite so pogolem broj na TA povtoruvawa od normalnata sekven-
ca (TA)
6
TAA (UGT1A1*1 alel) se asocirani so namalena aktivnost. Ovaa studija ima{e za cel da ispita
dali nisko aktivniot alel UGT1A1*28 (7 TA povtoruvawa) e asociran so zgolemen rizik kon kolorektal-
en karcinom kaj pacienti od Republika Makedonija. Vo studijata bea vklu~eni 84 pacienti so histopato-
lo{ki potvrden kolorektalen karcinom i kontrolna grupa od 70 zdravi individui >65 godini (sredna
vozrast 75 godini). Genomska DNK be{e izolirana od periferna krv so Proteinaza K digestija /fenol-
hloroform ekstrakcija i etanol precipitacija. Brojot na TA povtoruvawata vo promoterot na UGT1A1
genot be{e utvrdena so fluorescentna polimeraza veri`na reakcija i kapilarna gel elektroforeza.
Dobienite podatoci uka`uvaat na povisoka frekvencija na UGT1A1*28 alelot kaj pacientite so kolorek-
talen karcinom vo odnos na zdravata populacija (p=0.02; OR = 1.73, 95% CI 1.06-2.81). Istovremeno, frekven-
cijata na genotipovite koi go sodr`at UGT1A1*28 alelot vo homozigotna ili heterozigotna forma e povi-
soka od frekvenvijata na UGT1A1*1/*1 genotipot kaj pacintite vo sporedba so kontrolite (p=0.0028, OR
= 2.68, 95% CI 1.39-5.16). 
Spored na{ite soznanija, ova e prva studija koja uka`uva na asocijacija me|u UGT1A1 polimorfiz-
mot i zgolemen rizik od pojava na kolorektalen karcinom. Ovie rezultati mo`e da se objasnat so izlo`e-
nost na odredeni kancerogeni suspstanci ~ija biotranformacija e uslovena od kriti~no nivo na UGT1A1
enzimot, pri {to individuite koi imaat barem eden nisko aktiven UGT1A1*1/*28 alel imaat zgolemen
rizik za razvoj na kolorektalen karcinom. 
Macedonian pharmaceutical bulletin 53 (1,2) 156-157 (2007)
PP - 71
157
^ETVRTI KONGRES NA FARMACIJATA NA MAKEDONIJA SO ME\UNARODNO U^ESTVO
FOURTH CONGRESS OF PHARMACY OF MACEDONIA WITH INTERNATIONAL PARTICIPATION
 
Patients 
(n=84) 
Controls 
(n=70) 
OR 
95% CI 
p 
Allele frequency 
UGT1A1*28 
0.39 
0.27 
UGT1A1*1 
0.61 
0.73 
1.73 
1.06-2.81 
0.02 
Genotype frequency 
UGT1A1*28/*28 
0.13 
0.13 
UGT1A1*1/*28 
0.52 
0.28 
UGT1A1*1/*1 
0.35 
0.59 
 
2.68
a
 
 
1.39-5.16
 a
 
 
0.0028
 a
 

Microsatellite Instabillity and Loss of Heterozygosyty in Colorectal
Cancer Patients from the Republic of Macedonia
M. Hiljadnikova-Bajro
1
, T. Josifovski
2
, Z. Sterjev
1
, A. Kapedanovska
1
, Z. Serafimoska
1
,
N. Matevska
1
, S. Despotovska
1
, N. Petrusevska
3
M. Panovski
2
, L. Suturkova
1
, A. J. Dimovski
1
1
Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, 
2
Clinic for Abdominal Surgery 
and 
3
Institute of Radioterapy and Oncology, Faculty of Medicine, 
University “Sts.Cyril and Methodius“, Skopje, Republic of Macedonia
Genomic instabillity appears to be a key molecular and pathogenetic step in early tumorigenesis creating a
permissive environment for the occurrence of alterations in tumor suppressor genes and oncogenes. At least three
forms of genomic instability have been identified in colon cancer: microsatellite instability (MSI), chromosome insta-
bility i.e. aneusomy, gains and losses of chromosomal regions (CIN), and chromosomal translocations. Elucidation
of the cause and specific role of genomic instability in colon cancer becomes essential for more effective diagnosis,
prognosis and chemotherapy strategies. This study aims at defining the genomic instability patterns i.e. MSI and loss
of heterozygosity (LOH) among 238 randomly selected patients with colorectal cancer from the Republic of Macedonia
who had undergone colectomy at the Clinic of Abdominal Surgery in Skopje. DNA was isolated from peripheral
blood and fresh tumor tissue obtained immediately after surgery with Proteinase K digestion followed by
phenol/chlorophorm extraction and ethanol precipitation. Paired tumor and blood DNA were evaluated for the pres-
ence of MSI or LOH phenotype using fluorescent multiplex PCR followed by capillary gel electrophoresis on
ABIPrism310 Genetic Analyzer. The evaluation includes 14 microsatellite markers located at 1p, 2p, 4q, 5q, 8p, 17p,
17q, 18q, markers from either NCI-recommended panel or located in the regions harboring tumor suppressor genes
or oncogenes (APC, p53, LMYC, EphB2 MSH2 cKIT, SMAD4). MSI was detected in 22/238 cancers (9.2%) and
was more commonly found in tumors located in the proximal colon and with a lower TNM stage. More than half of
the patients (116/208) present with LOH of at least one chromosomal arm, 72% of which had an imbalance in mul-
tiple markers and were assigned a CIN-high status. In 72 patients neither MSI nor CIN was detected. Highest degree
of LOH was detected in chromosome 18q (50%) followed by 1p(35%), 5q(34%),17p(28%), 17q(26%), 8p(24%) and
2p(18%). D18S61 was shown to be the molecular marker mostly affected by loss of heterozygosity among colorec-
tal cancer patients from Macedonia. One third of all cases does not present neither MSI nor LOH suggesting anoth-
er mechanism involved in the genesis of colorectal cancer.
Macedonian pharmaceutical bulletin 53 (1,2) 158-159 (2007)
PP - 72
158
^ETVRTI KONGRES NA FARMACIJATA NA MAKEDONIJA SO ME\UNARODNO U^ESTVO
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