**13. Appendix 2**

520 New Advances in the Basic and Clinical Gastroenterology

detection of ADRs. Also, the review of prescription by pharmacists can achieve a diminution

It´s also important to recognize people specially susceptible to ADRs: elderly, women, polipharmacy, renal insufficiency and presence of drug-drug interactions. In this special

Adverse drug reactions is a very frequent problem that affects specially the gastrointestinal tract, being GI bleeding the most common adverse drug reaction causing hospital admission. Patients predisposed to suffer ADRs are elderly, women, renal insufficiency, polipharmacy and drug-drug interactions. Drugs used for treat gastrointestinal disease are quite sure but can b e implicated in ADRs as IBPs, imunosupre4ssants used for autoimmune hepatitis or inflammatory bowel disease. Recognition of this problem is increasing in frequency and new drugs can be responsible for new ADRs. Collaboration between

ICH Guideline on E2D post-approval drug safety defined an adverse drug reaction (ADR)

An adverse drug reaction, as established by regional regulations, guidance and practices, is concern noxious and unintended responses to a medicinal product. The phrase "responses to a medicinal product" means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility (refer to the ICH E2A guideline). A reaction, in contrast to an event, is characterized by the fact that a causal relationship between the drug and the occurrence is suspected. For regulatory reporting purposes, if an event is spontaneously reported, even if the relationship is unknown or unstated, it meets

Serious adverse event /ADR. In accordance with ICH E2A guideline, a serious adverse

 is life-threatening (NOTE: The term "life-threatening" in the definition of "serious" refers to an event/reaction in which the patient was at risk of death at the time of the event/reaction; it does not refer to an event/reaction which hypothetically might have

Medical and scientific judgment should be exercised in deciding whether other situations should be considered serious, such as important medical events that might not be immediately life-threatening or result in death or hospitalization but might jeopardize the patient or might require intervention to prevent one of the other outcomes listed in the definition above. Examples of such events are intensive treatment in a emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in

event or reaction is any untoward medical occurrence that at any dose:

hospitalization or development of drug dependency or drug abuse.

population we have to be careful with prescription of new drugs and its dosing.

clinician, pharmacists and pharmacology specialists is needed.

and a serious adverse drug reactions (SADR) as follows:

the definition of an adverse drug reaction".

caused death if it were more severe), is a congenital anomaly/birth defect, is a medically important event or reaction.

in the appearance of adverse drug reactions.

**11. Conclusions** 

**12. Appendix 1** 

Results in death


Reprinted from Toxicologic Pathology, 33, Lee, W.M. & Senior, J.R., Recognizing drug-induced liver injury: current problems, possible solutions, pp.155-64, copyright © 2005 by the Society of Toxicologic Pathology. Reprinted by Permission of SAGE Publications.

Table 1. RUCAM Hepatocellular Injury Scale

Adverse Reactions and Gastrointestinal Tract 523

• More than or equal to twofold elevation above the ULN for alkaline phosphatase (ALP) (particularly with accompanying elevations in concentrations of 5′-nucleotidase or γ-glutamyl transpeptidase in the

Box 1. clinical chemistry criteria for drug-induced liver injury (DILI) (adapted from Aithal et

• Pattern of liver injury is based on earliest identified liver chemistry elevations that qualify as DILI

estimation of alanine aminotransferase (ALT) (aspartate transaminase is used when ALT is

unavailable) and alkaline phosphatase (ALP) from the same serum sample

• Pattern of liver injury is defined using R value where R =(ALT/ULN)/(ALP/ULN). This will require

• ALT activity = patient's ALT/upper limit of normal (ULN); ALP activity = patient's ALP/ULN; R =

• Histological summary should be recorded separately (if liver biopsy has been performed). However, the liver biopsy interpretation will generally not replace the R value for purposes of classification

Box 2. criteria for classifying the clinical pattern of drug induced liver injury (DILI) (adapted

1 Mild Elevated alanine aminotransferase/alkaline phosphatase

2 Moderate Elevated ALT/ALP concentration reaching criteria for DILI\*

3 Severe Elevated ALT/ALP concentration reaching criteria for DILI\*,

4 Fatal or transplantation Death or transplantation due to DILI

Box 3. DILI severity index (adapted from Aithal et al. 2011)

• International normalized ratio ≥1.5

weeks, and absence of underlying cirrhosis31 • Other organ failure considered to be due to DILI

(ALT/ALP) concentration reaching criteria for DILI\* but bilirubin concentration <2× upper limit of normal (ULN)

and bilirubin concentration ≥2× ULN, or symptomatic hepatitis

bilirubin concentration ≥2× ULN, and one of the following:

• Ascites73 and/or encephalopathy, disease duration <26

• More than or equal to fivefold elevation above the upper limit of normal (ULN) for alanine

• More than or equal to threefold elevation in ALT concentration and simultaneous elevation of

Any one of the following:

aminotransferase (ALT)

ALT activity/ALP activity

from Aithal et al. 2011)

• Hepatocellular pattern of DILI = R ≥ 5 • Mixed pattern of DILI = R > 2 and < 5 • Cholestatic pattern of DILI = R ≤ 2

Level of evidence: 2b (retrospective cohort studies)

Category Severity Description

al. 2011)

(Box 1)

absence of known bone pathology driving the rise in ALP level)

bilirubin concentration exceeding 2× ULN

Level of evidence: 2b (exploratory/retrospective cohort studies)


Reprinted from the Journal of Clinical Epidemiology, 46 (11), Danan, B. & Benichou, C., Causality assessment of adverse reactions to drugs--I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries, pp.1323-1330, copyright © 1993 by Pergamon Press Ltd. Reprinted with Permission from Elsevier.

Table 2. RUCAM Cholestatic or Mixed Liver Injury Scale

Any one of the following:

522 New Advances in the Basic and Clinical Gastroenterology

1. Temporal relationship of start of drug to ALP>2x ULN Score Initial treatment 5–90 days; subsequent treatment course: 1–90 days 2 Initial treatment <5 or >90 days; subsequent treatment course: >90 days 1 From cessation of drug: <30 days, or <30 days after subsequent treatment 1 Otherwise 0

Decreases >50% within 180 days 2 Decreases <50% within 180 days 1 Persistence or increase or no information 0 If drug is continued – inconclusive 0

No alcohol use 0 Alcohol use 1 Age <55 years 0 Age >55 years 1

No concomitant drug administered 0 Concomitant drug with suggestive or compatible time of onset -1 Concomitant known hepatotoxin with suggestive or compatible time of onset -2 Concomitant drug with positive rechallenge or validated diagnostic test -3 5. Nondrug causes: Six are primary: recent hepatitis A, B, or C, biliary obstruction, acute

All primary and secondary causes reasonably ruled out: 2 All 6 primary causes ruled out 1 4 or 5 primary causes ruled out 0 < 4 primary causes ruled out (max. negative score for items 4 and 5: –4) -2 Nondrug cause highly probable -3

Package insert or labelling mention 2 Published case reports but not in label 1 Reaction unknown 0

Positive (ALT doubles with drug in question alone) 3 Compatible (ALT doubles with same drugs as given before initial reaction) +1 1

reaction occurred) -2 Not done, or indeterminate result 0

Reprinted from the Journal of Clinical Epidemiology, 46 (11), Danan, B. & Benichou, C., Causality assessment of adverse reactions to drugs--I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries, pp.1323-1330, copyright © 1993 by

Secondary group: Underlying other disease; possible CMV, EBV or HSV infection

2. After drug cessation - difference between peak ALP or total bilirubin and ULN

Subject Information

3. Risk factors

4. Concomitant drug

7. Rechallenge

alcoholic hepatitis (AST > 2x ALT), recent hypotension

6. Previous information on hepatotoxicity of the drug in question

Negative (Increase in ALT but <2x ULN, same conditions as when

Score Interpretation: Highly probable >8; Probable 6–8;

Pergamon Press Ltd. Reprinted with Permission from Elsevier. Table 2. RUCAM Cholestatic or Mixed Liver Injury Scale

Total (range of algebraic sum: –8 to +14)

Possible 3–5; Unlikely 1–2; Excluded <0

• More than or equal to fivefold elevation above the upper limit of normal (ULN) for alanine aminotransferase (ALT)

• More than or equal to twofold elevation above the ULN for alkaline phosphatase (ALP) (particularly with accompanying elevations in concentrations of 5′-nucleotidase or γ-glutamyl transpeptidase in the absence of known bone pathology

driving the rise in ALP level)

• More than or equal to threefold elevation in ALT concentration and simultaneous elevation of bilirubin concentration exceeding 2× ULN

Level of evidence: 2b (exploratory/retrospective cohort studies)

Box 1. clinical chemistry criteria for drug-induced liver injury (DILI) (adapted from Aithal et al. 2011)

• Pattern of liver injury is based on earliest identified liver chemistry elevations that qualify as DILI (Box 1)

• Pattern of liver injury is defined using R value where R =(ALT/ULN)/(ALP/ULN). This will require estimation of alanine aminotransferase (ALT) (aspartate transaminase is used when ALT is unavailable) and alkaline phosphatase (ALP) from the same serum sample

• ALT activity = patient's ALT/upper limit of normal (ULN); ALP activity = patient's ALP/ULN; R = ALT activity/ALP activity


• Histological summary should be recorded separately (if liver biopsy has been performed). However, the liver biopsy interpretation will generally not replace the R value for purposes of classification Level of evidence: 2b (retrospective cohort studies)

Box 2. criteria for classifying the clinical pattern of drug induced liver injury (DILI) (adapted from Aithal et al. 2011)


Box 3. DILI severity index (adapted from Aithal et al. 2011)

Adverse Reactions and Gastrointestinal Tract 525

Aithal GP, Day CP. Hepatic adverse drug reactions. En: Pharmacovigilance. Chichester:

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Aronson, J.K. Adverse drug reactions—no farewell to harms. Br J Clin Pharmacol. ;63(2):131-

Balani AR, Grendell JH.Drug Saf. 2008;31(10):823-37.Drug-induced pancreatitis : incidence,

Bates, D.W., Spell, N., Cullen, D.J., Birdick, E., Laird, N., Petersen, L.A., Small, S.D., Boddie,

Benichou C, Danan G, Flahault A. Causality assessment of adverse reactions to drugs--II. An

Björnsson E. Review article: drug-induced liver injury in clinical practice. Aliment

Budnitz, D.S., Pollock, D.A., Weidenbach, K.N., Mendelsohn, A.B., Schoeder, T.J., Annest,

Carrasco-Garrido P\*, López de Andrés A, Hernández Barrera V, Gil de Miguel A, Jiménez

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Cheng, C.M. Hospital systems for detection and prevention of adverse drug events. Clin

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to drug-induced liver injuries. J Clin Epidemiol. 1993 Nov;46(11):1323-1330.

with positive rechallenge. J Clin Epidemiol. 1993 Nov;46(11):1331-1336 Beppu K, Osada T, Shibuya T, Watanabe SPathogenic mechanism of NSAIDs-induced mucosal injury in lower gastrointestinal tract. Nihon Rinsho. 2011 Jun;69(6):1083-7 Björnsson, E., Jerlstad, P., Bergqvist, A. & Olsson, R. Fulminant drug-induced hepatic failure

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management and prevention.

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**14. References** 

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• The Roussel Uclaf Causality Assessment Method (RUCAM) scale should be used for causality assessment (Appendix 2)

• If more than one drug is suspected to be causing DILI, the RUCAM scale should be applied to each drug separately. If such assessments are not practical (e.g., antituberculosis medications), all the drugs involved may be implicated as a single entity.

• If more than one drug is rated "possible" or higher by RUCAM, evaluation should be sought by a specialist to rank the drugs by order of likelihood of causing DILI. This may be done on the basis of the signature pattern of DILI and a review of the literature.

Level of evidence: 1b (validating cohort studies)

Box 4. DILI causality assessment (adapted from Aithal et al. 2011)

• Initial clinical episode met the criteria to qualify as acute DILI (Box 1)

• Initial episode on causality assessment has been considered possible, probable, or highly probable DILI on the basis of Roussel Uclaf Causality Assessment Method scoring criteria (Appendix 2). Persistent DILI is defined as evidence of continued liver injury after withdrawal of the causative agent, beyond 3 months of follow-up for hepatocellular and mixed DILI, and beyond 6 months for cholestatic DILI

• Chronic DILI is defined as evidence of continued liver injury after withdrawal of the causative agent beyond 12 months of follow-up, regardless of the classification of DILI

• There is no new risk factor other than exposure to the suspect drug that would explain the persistence of liver injury, and other causes of chronic liver diseases have been excluded Level of evidence: 4 (prognostic cohort studies of modest quality)

Box 5. Characteristics of persistent and chronic druginduced liver injury (DILI) (adapted from Aithal et al. 2011)

• Evidence of chronic liver disease is established on the basis of validated methods such as clinical evidence of cirrhosis, histological evidence of chronic liver disease, and imaging in cases of vascular disorder and tumours, as appropriate

• Evidence of drug intake for an appropriate duration preceding the appearance of symptoms, signs, or test results suggestive of chronic liver disease

• Exclusion of other etiologies of chronic disease (outlined in Supplementary Appendix 2, table S3) Level of evidence: 1b (prospective/validating cohort studies with good follow-up)

Box 6. characteristics of drug-associated chronic liver disease (adapted from Aithal et al. 2011)

• The score is ≥6 points on simplified diagnostic criteria for AIH (scores >6 points with the simplified criteria can be obtained if liver biopsy is performed. Hennes *et al*.()consider a probable diagnostic score to be ≥6)

• Injury resolves on withdrawal of medication that triggered the AIH, with or without immunosuppressive therapy to induce remission

• No relapse within a period of 1 year after withdrawal of all immunosuppressants. This criterion needs further confirmation and cannot be considered pathognomonic because it is quite variable depending on the cohorts analyzed

Level of evidence: 2b (exploratory cohort study)

Box 7. Characteristics of drug-induced autoimmune hepatitis (AIH) (adapted from Aithal et al. 2011)

#### **14. References**

524 New Advances in the Basic and Clinical Gastroenterology

• The Roussel Uclaf Causality Assessment Method (RUCAM) scale should be used for causality

• If more than one drug is suspected to be causing DILI, the RUCAM scale should be applied to each drug separately. If such assessments are not practical (e.g., antituberculosis medications), all the drugs

• If more than one drug is rated "possible" or higher by RUCAM, evaluation should be sought by a specialist to rank the drugs by order of likelihood of causing DILI. This may be done on the basis of the

• Initial episode on causality assessment has been considered possible, probable, or highly probable DILI on the basis of Roussel Uclaf Causality Assessment Method scoring criteria (Appendix 2). Persistent DILI is defined as evidence of continued liver injury after withdrawal of the causative agent, beyond 3 months of follow-up for hepatocellular and mixed DILI, and beyond 6 months for cholestatic

• Chronic DILI is defined as evidence of continued liver injury after withdrawal of the causative agent

Box 5. Characteristics of persistent and chronic druginduced liver injury (DILI) (adapted

• Evidence of chronic liver disease is established on the basis of validated methods such as clinical evidence of cirrhosis, histological evidence of chronic liver disease, and imaging in cases of vascular

• Evidence of drug intake for an appropriate duration preceding the appearance of symptoms, signs,

• Exclusion of other etiologies of chronic disease (outlined in Supplementary Appendix 2, table S3)

Box 6. characteristics of drug-associated chronic liver disease (adapted from Aithal et al.

• The score is ≥6 points on simplified diagnostic criteria for AIH (scores >6 points with the simplified criteria can be obtained if liver biopsy is performed. Hennes *et al*.()consider a probable diagnostic score

• No relapse within a period of 1 year after withdrawal of all immunosuppressants. This criterion needs further confirmation and cannot be considered pathognomonic because it is quite variable

Box 7. Characteristics of drug-induced autoimmune hepatitis (AIH) (adapted from Aithal et

Level of evidence: 1b (prospective/validating cohort studies with good follow-up)

• Injury resolves on withdrawal of medication that triggered the AIH, with or without

• There is no new risk factor other than exposure to the suspect drug that would explain the persistence of liver injury, and other causes of chronic liver diseases have been excluded

assessment (Appendix 2)

from Aithal et al. 2011)

disorder and tumours, as appropriate

or test results suggestive of chronic liver disease

immunosuppressive therapy to induce remission

Level of evidence: 2b (exploratory cohort study)

depending on the cohorts analyzed

DILI

2011)

to be ≥6)

al. 2011)

involved may be implicated as a single entity.

signature pattern of DILI and a review of the literature. Level of evidence: 1b (validating cohort studies)

Box 4. DILI causality assessment (adapted from Aithal et al. 2011)

• Initial clinical episode met the criteria to qualify as acute DILI (Box 1)

beyond 12 months of follow-up, regardless of the classification of DILI

Level of evidence: 4 (prognostic cohort studies of modest quality)


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**26** 

*Sweden* 

Elisabeth Rakus-Andersson *Blekinge Institute of Technology* 

**Selected Algorithms of Computational** 

**Intelligence in Gastric Cancer Decision Making** 

Due to the latest research (Engelbrecht, 2007; Rutkowski, 2008) the subject of Computational Intelligence has been divided into five main regions, namely, neural networks, evolutionary

Our attention has been attracted by the possibilities of medical applications provided by immunological computation algorithms. Immunological computation systems are based on immune reactions of the living organisms in order to defend the bodies from pathological substances. Especially, the mechanisms of the T-cell reactions to detect strangers have been

Immunological systems have been developed in scientific books and reports appearing during the two last decades (de Castro & Timmis, 2002; Dasgupta & Nino, 2008; Engelbrecht, 2007; Forrest et al., 1997). The basic negative selection algorithm NS was invented by Stefanie Forrest (Forrest et al., 1997) to give rise to some technical applications. We can note such applications of NS as computer virus detection (Antunes & Correia, 2011; Harmer et al., 2002; Zhang & Zhao, 2010), reduction of noise effect (Igawa & Ohashi, 2010), communication of autonomous agents (Ishida, 2004) or identification of time varying systems (Wakizono et al., 2006). Even a trial of connection between a computer and biological systems has been proved by means of immunological computation (Cohen, 2006). Hybrids made between different fields can provide researchers with richer results; therefore associations between immunological systems and neural networks (Gao et al., 2008) have

In the current chapter we propose another hybrid between the NS algorithm and chosen solutions coming from fuzzy systems (Rakus-Andersson, 2007, 2009, 2010a, 2010b, 2011; Rakus-Andersson & Jain, 2009). This hybrid constitutes the own model of adapting the NS algorithm to the operation decisions "operate" contra "do not operate" in gastric cancer surgery. The choice between two possibilities to treat patients is identified with the partition of a decision region in self and non-self, which is similar to the action of the NS algorithm. The partition is accomplished on the basis of patient data strings/vectors that contain codes of states concerning some essential biological markers. To be able to identify the strings that characterize the "operate" decision we add the own method of computing the patients' characteristics as real values. The evaluation of the patients' characteristics is supported by

algorithms, swarm intelligence, immunological systems and fuzzy systems.

converted into artificial numerical algorithms.

**1. Introduction** 

been developed as well.

