UKRAINIAN MEDICAL STOMATOLOGICAL ACADEMYUKRAINIAN MEDICAL STOMATOLOGICAL ACADEMY

Professor IGOR SKRYPNYKProfessor IGOR SKRYPNYK

DIAGNOSTIC AND TREATMENT ALGORITHMS OF ULCERATIVE COLITIS

IN UKRAINE

DIAGNOSTIC AND TREATMENT ALGORITHMS OF ULCERATIVE COLITIS

IN UKRAINE

ACTUALITYACTUALITYStandards of diagnostics and treatment of Standards of diagnostics and treatment of ulcerative colitis (UC) in Ukraine are based ulcerative colitis (UC) in Ukraine are based on world generally accepted approaches on world generally accepted approaches and include differentiated stage prescription and include differentiated stage prescription of preparations in dependence on:of preparations in dependence on:

spreading of pathological process;spreading of pathological process;

character of the course of the disease. character of the course of the disease.

PREVENTING RELAPSES

REDUCING DISEASE ACTIVITY

DIMINISHING OF EXPRESSED CLINICALSYMPTOMS

IMPROVING PATIENTS’ QUALITY OF LIFE

The traditional tasks of treatment are:

The traditional tasks of treatment are:

ПЕРЕД НАЧАЛОМЛЕЧЕНИЯ!It is important to estimate

possibilities of therapy taking the following into account:

- localization and gravity of process;- activity of process;- presence of complications;- response to the previously applied therapy.

To present the individual chart of patient’s treatment:- 1-st line of therapy- 2-nd line of therapy

To estimate the prospect of applied therapy

It is important to estimate It is important to estimate possibilities of therapy taking possibilities of therapy taking the following into accountthe following into account::

- localization and gravity of process;- activity of process;- presence of complications;- response to the previously applied therapy.

To present the individual chart of patientTo present the individual chart of patient’’s treatments treatment::- 1-st line of therapy- 2-nd line of therapy

To estimate the prospect of applied therapyTo estimate the prospect of applied therapy

BEFORE THE BEGINNING OF TREATMENT

BEFORE THE BEGINNING OF TREATMENT

AminosalicylatesAminosalicylates (5(5--ААSASA//SPS)SPS)

CorticosteroidsCorticosteroids

ImmunosupImmunosuppresantspresants

((AZA/MTX)AZA/MTX)

Biological Biological therapytherapy ((IFX)IFX)

ООppее--rrааtiontion

II lineline

IIII lineline

T H E R A P YT H E R A P YT H E R A P Y

DIAGNOSISDIAGNOSIS

5-ASA (mildly or moderate course)

Supporting therapy

AbsenceAbsenceof effectof effect

CS

Absence Absence of effectof effect, , increase increase

of activityof activity СS +immunomodula-tors (moderate, severe activity)

More aggressive therapy СSwith/or without

immunomodulators(severe activity)

Immunomo-dulators

Operativetreatment

KornbluthKornbluth A, et alA, et al.Am J Gastroenterol..Am J Gastroenterol.2004:13712004:1371--1385.1385.XuXu CC--T, et al. T, et al. World J GastroenterolWorld J Gastroenterol.2004;10:1416.2004;10:1416--1421.1421.Becker JM. Becker JM. GastroenterolGastroenterol Clinics North AmClinics North Am.1999;28:371.1999;28:371--390.390.

TREATMENT ALGORITHMSTREATMENT ALGORITHMS

DISEASE ACTIVITYDISEASE ACTIVITY

DISEASE ACTIVITYDISEASE ACTIVITY

DIFFICULTIES OF THERAPY ARE:

DIFFICULTIES OF THERAPY ARE:

2525--30% patients are resistant to the 30% patients are resistant to the basic therapy with standard dosesbasic therapy with standard doses

the side effects of systemic the side effects of systemic glucocorticoidsglucocorticoids and and immunosuppressant are forecastedimmunosuppressant are forecasted

BASIC DIAGNOSTIC AND MEDICAL PRINCIPLES OF ULCERATIVE COLITIS

BASIC DIAGNOSTIC AND MEDICAL PRINCIPLES OF ULCERATIVE COLITIS

Detecting localization, activity and

complications

Detecting localization, activity and

complications

Excluding intercurrent

diseases

Excluding intercurrent

diseases

Evaluating the efficiency of the

previously applied therapy

Evaluating the efficiency of the

previously applied therapy

Prescribing preparations having

well-proven efficiency and high safety level

Prescribing preparations having

well-proven efficiency and high safety level

T. Andus, 2003T. Andus, 2003

PRINCIPLESPRINCIPLES

THE ULTIMATE GOAL OF PATIENTS’TREATMENT

THE ULTIMATE GOAL OF PATIENTS’TREATMENT

NOWADAYSNOWADAYSNOWADAYS

Prophylaxis or reducing complications

Prophylaxis or reducing complications

«Convalescence» of mucous membrane

«Convalescence» of mucous membrane

Removing or improving complaints and symptoms

Removing or improving complaints and symptoms

Development of etiotropictherapy

Development of etiotropictherapy

FUTUREFUTUREFUTURE

DESIGN OF INVESTIGATIONDESIGN OF INVESTIGATION25 pts with the moderate course of the active distal 25 pts with the moderate course of the active distal UC (the index of clinical activity 6UC (the index of clinical activity 6--12; 12; endoscopicendoscopicindex index –– 4 according to 4 according to RachmilewitzRachmilewitz, 1989) divided , 1989) divided intointo 3 groups depending on curative complexes: 3 groups depending on curative complexes:

group I (n=9) group I (n=9) –– mesalazinemesalazine (tablets) 3 g/day (tablets) 3 g/day and and budesonidebudesonide 9 mg/day for three taking; 9 mg/day for three taking;

group II (n=8) group II (n=8) –– mesalazinemesalazine ((granulsgranuls) 3 g/day ) 3 g/day and and budesonidebudesonide 9 mg/day for one taking; 9 mg/day for one taking;

group III (n=8) group III (n=8) –– mesalazinemesalazine ((granulsgranuls) 3 g/day ) 3 g/day and and budesonidebudesonide 9 mg/day for one taking and 9 mg/day for one taking and rebamipiderebamipide 300 mg/day300 mg/day

CLINICAL AND ENDOSCOPIC REMISSION

after 8-week treatmentCLINICAL AND ENDOSCOPIC

REMISSION after 8-week treatment

55 (62,5%)(62,5%)

44 (50%)(50%)

3 3 (33,3%)(33,3%)

EndoscopicEndoscopicremissionremission, , numbernumber, %, %

Clinical remission Clinical remission PatientsPatientsgroupsgroups

27,527,5±±1,71,755 (62,5%)(62,5%)Group IIGroup II

30,730,7±±1,81,866 (75%)(75%)Group IIIGroup III

23,723,7±±1,41,45 5 (55,6%)(55,6%)Group IGroup I

durationduration, , daysdaysnumbernumber, %, %

mmоl

/l

BloodBlood

0

1

2

3

І ІІ ІІІ

– normal– before treatment– after treatment

mm

ol/2

4 ho

urs

NАNА concentrationin UC pts

NАNА concentrationin UC pts

UrineUrine

0

1

2

3

4

І ІІ ІІІ

mmоl

/l

BloodBlood

0

0,2

0,4

0,6

І ІІ ІІІ– normal– before treatment – after treatment

mm

ol/2

4 ho

urs

FUCOSE CONCENTRATIONin UC pts

FUCOSE CONCENTRATIONin UC pts

UrineUrine

0

0,5

1

1,5

І ІІ ІІІ

Rebamipide enema versus 5-ASA enema for distal UC: a randomized controlled trialRebamipide enema versus 5-ASA enema

for distal UC: a randomized controlled trial

1,651,65±±0,580,581,651,65±±0,480,48before treatmentbefore treatmentEndoscopicEndoscopicgrading scalegrading scale 1,21,2±±0,690,691,151,15±±0,480,48after treatmentafter treatment

9,69,6±±1,461,461010,,6565±±0,870,87before treatmentbefore treatmentDisease Disease activity indexactivity index 6,056,05±±3,773,776,66,6±±3,2*3,2*after treatmentafter treatment

7,17,1±±2,022,028,058,05±±2,012,01before treatmentbefore treatmentEndoscopicEndoscopicindex scoreindex score 5,055,05±±2,92,96,06,0±±2,382,38after treatmentafter treatment

6,66,6±±1,691,697,857,85±±1,561,56

55--ASA ASA enemaenema

7,87,8±±1,731,73before treatmentbefore treatmentBiopsy scoreBiopsy score 6,36,3±±1,651,65after treatmentafter treatment

RebamipideRebamipideenemaenema

40 pts with mildly to moderately active distal UC: 40 pts with mildly to moderately active distal UC: group I (n=20) group I (n=20) –– rebamipiderebamipide enema; enema; group II (n=20) group II (n=20) –– 55--ASA enema. ASA enema.

Once a day for 4 weeks.Once a day for 4 weeks.

The efficacy of RE was The efficacy of RE was similar to that of 5similar to that of 5--ASA.ASA. M. Miyata et al., 2006M. Miyata et al., 2006M. Miyata et al., 2006

Efficacy and safety of rebamipideenemas for active UC pts

(a randomized, multicentre pilot study)

Efficacy and safety of rebamipideenemas for active UC pts

(a randomized, multicentre pilot study)19 pts with mild to moderate active distal US19 pts with mild to moderate active distal US

44--week once a day treatmentweek once a day treatmentI groupI group (n=9)(n=9)

1 g of 1 g of mesalazinemesalazine enemaenema+ baseline treatment+ baseline treatment

II groupII group (n=10)(n=10)150 mg of 150 mg of rebamipiderebamipide enemaenema

H. Ogata et al., 2006H. Ogata et al., 2006H. Ogata et al., 2006

The efficacy and safety of RE treatment appears to be The efficacy and safety of RE treatment appears to be egualegual to ME for active distal UC.to ME for active distal UC.R. increase regeneration by enhancing expressionR. increase regeneration by enhancing expressionof intercellular claudinof intercellular claudin--11in colonic epithelial cells.in colonic epithelial cells.

0,160,162,32,3±±1,31,35,85,8±±1,01,0

after after treatmenttreatment

0,080,082,82,8±±1,21,266,,1+1+1,01,0

before before treatmenttreatment

DiseaseDisease activityactivity indexindex Results of treatmentResults of treatmentPatient groupsPatient groups

5 5 (50%)(50%)4 4 (40%)(40%)IIII –– rebamipiderebamipideP.P.

5 5 (55,6%)(55,6%)3 3 (33,3%)(33,3%)ll –– mesalazinemesalazine

clinical clinical improvementimprovement

clinical clinical remissionremission

Increase Increase of of PgEPgE22 in IMMin IMM

Induction of Induction of the the CCООGG--22expressionexpression

Improvement ofImprovement ofmicrocirculation in IMMmicrocirculation in IMM

Stimulation of regeneration of intestine mucous membrane

Improvement of EGFImprovement of EGF andandEGFEGF--receptor expressionreceptor expression

ImprovementImprovementof claudinof claudin--11expressionexpression

↓↓ POLPOLin IMM in IMM

Suppression of Suppression of neutrophilneutrophil functionsfunctions

↑↑ resistance of resistance of IMMIMM

((citoprotectioncitoprotection))

MECHANISMS OF CITOPROTECTIVE EFFECT OF

REBAMIPIDE IN UC pts

MECHANISMS OF CITOPROTECTIVE EFFECT OF

REBAMIPIDE IN UC pts

BUDESONIDE FOR THE TREATMENT OF ACTIVE

DISTAL UC BUDESONIDE

FOR THE TREATMENT OF ACTIVE DISTAL UC

Study designStudy design –– open,randomizedopen,randomized, , multicentermulticenterDurationDuration –– 8 8 weeksweeks

DosageDosage group Igroup I :: 3 3 ccааpsps. 3 . 3 mgmg 3 3 times atimes a dayday ((nn==77))group II group II :: 3 3 capscaps. (9. (9mgmg) 1) 1time a daytime a day ((nn==88))

0,3150,31555 (71%)(71%)33 (38%)(38%)

0,0260,02677 (57%)(57%)

00

Improve of clinical Improve of clinical activity index activity index

Remission Remission

44 (57%)(57%)44 (57%)(57%)Group IIGroup II0,6190,6190,026*0,026*РР

33 (38%)(38%)00Group lGroup l5656--thth dayday2828--thth dayday

Prescribing B. in a dose of 9 mg one-time has an

advantage in comparison with taking 1 caps. 3 times a day.

Prescribing B. in a dose Prescribing B. in a dose of 9 mg oneof 9 mg one--time has an time has an

advantage in comparison with advantage in comparison with taking 1 caps. 3 times a day.taking 1 caps. 3 times a day.

* * -- statistic reliablestatistic reliable

Kolkman et al., 2004KolkmanKolkman et al., 2004et al., 2004

PROTECTIVE EFFECT OF MELATONINE IN COLITIS PROTECTIVE EFFECT OF MELATONINE IN COLITIS

A. Akсan et al., 2008A. Akсan et al., 2008

antioxidant effectimproving the microcirculationstimulating the repair of intestinal epithelium

antioxidant effectimproving the microcirculationstimulating the repair of intestinal epithelium

0

50

100

150

0

10

20

30

40

0

50

100

150

ControlControl ColitisColitis Colitis+Colitis+melatoninemelatonine

nmol

nmol

// mg

mg //

min

min

albu

min

albu

min

UAUA .

/./ grgr

tissu

etis

sue

ControlControl ColitisColitis Colitis+Colitis+melatoninemelatonine

piko

grpi

kogr

/ml

/ml

ControlControl ColitisColitis Colitis+Colitis+melatoninemelatonine

TNF-αendotoxineTNF-αendotoxine

TNF-α and endotoxine, blood serum

TNF-α and endotoxine, blood serum

Caspase-3 activityCaspase-3 activity

Myeloperoxidase activityMyeloperoxidase activity

BASIC FUNCTIONS OFESSENTIAL PHOSPHOLIPIDS

BASIC FUNCTIONS OFESSENTIAL PHOSPHOLIPIDS ААntioxydativentioxydative effecteffectDesagregationalDesagregational effecteffectImmunomodulationImmunomodulation in a cellular levelin a cellular levelRestore of the damaged Restore of the damaged membrane structures of the cellmembrane structures of the cellIncrease of prostaglandins synthesisIncrease of prostaglandins synthesis

HepatoprotectiveHepatoprotective effecteffectStimulation of Stimulation of endogenicendogenicphospholipids synthesisphospholipids synthesis

DEPROTEINATED HEMODERIVATE–removal of tissue hypoxia and improvement

of circulation of blood in to the mucous membrane of intestine

DEPROTEINATED HEMODERIVATE–removal of tissue hypoxia and improvement

of circulation of blood in to the mucous membrane of intestine

increase of energetic potential of cells increase of energetic potential of cells (increase in 5 times of cell consumption (increase in 5 times of cell consumption of glucose)of glucose)

diminishes inflammatorydiminishes inflammatory--cellular cellular infiltration, anabolism actioninfiltration, anabolism action

improves blood supply, removes tissue improves blood supply, removes tissue hypoxiahypoxia

CONCLUSIONCONCLUSION

1. Optimization of the curative 1. Optimization of the curative complexes with the substitution of the complexes with the substitution of the MesalazineMesalazine in tablets on granules, in tablets on granules, especially with additional especially with additional RebamipideRebamipideprescription, in one time daily taking of prescription, in one time daily taking of BudesonideBudesonide leads to rising of the leads to rising of the effectiveness of treatment and effectiveness of treatment and improvement of life spending quality in UC improvement of life spending quality in UC patients. patients.

MODERN APPROACHES TO UC TREATMENT

MODERN APPROACHES TO UC TREATMENT

citoprotectorcitoprotector ((RebamipideRebamipide))bilious acids (bilious acids (UrsodeoxycholicUrsodeoxycholic acid)acid)endogenous matters (Melatonin)endogenous matters (Melatonin)stabilization of membranes stabilization of membranes ((phosphatidilcholinephosphatidilcholine))antihypoxantsantihypoxants (deproteinated hemoderivate)correction of correction of microbiocenosismicrobiocenosis disordersdisorders

Basic therapyBasic therapy «Convalescence»of mucous membrane↑↑ resistance mucous resistance mucous

barrier of intestinebarrier of intestine