\r\n\tAnimal food additives are products used in animal nutrition for purposes of improving the quality of feed or to improve the animal’s performance and health. Other additives can be used to enhance digestibility or even flavour of feed materials. In addition, feed additives are known which improve the quality of compound feed production; consequently e.g. they improve the quality of the granulated mixed diet.
\r\n
\r\n\tGenerally feed additives could be divided into five groups: \r\n\t1.Technological additives which influence the technological aspects of the diet to improve its handling or hygiene characteristics. \r\n\t2. Sensory additives which improve the palatability of a diet by stimulating appetite, usually through the effect these products have on the flavour or colour. \r\n\t3. Nutritional additives, such additives are specific nutrient(s) required by the animal for optimal production. \r\n\t4.Zootechnical additives which improve the nutrient status of the animal, not by providing specific nutrients, but by enabling more efficient use of the nutrients present in the diet, in other words, it increases the efficiency of production. \r\n\t5. In poultry nutrition: Coccidiostats and Histomonostats which widely used to control intestinal health of poultry through direct effects on the parasitic organism concerned.
\r\n
\r\n\tThe aim of the book is to present the impact of the most important feed additives on the animal production, to demonstrate their mode of action, to show their effect on intermediate metabolism and heath status of livestock and to suggest how to use the different feed additives in animal nutrition to produce high quality and safety animal origin foodstuffs for human consumer.
",isbn:"978-1-83969-404-2",printIsbn:"978-1-83969-403-5",pdfIsbn:"978-1-83969-405-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"8ffe43a82ac48b309abc3632bbf3efd0",bookSignature:"Prof. László Babinszky",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10496.jpg",keywords:"Technological Feed Additives, Feed Industry, Quality of Compound Feed, Non-Antibiotic Growth Promoter, Product Quality, Additive Enzymes, Digestibility of Nutrients, NSP Enzymes, Farm Animals, Livestock, Immunity, Microbiome",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 24th 2020",dateEndSecondStepPublish:"December 22nd 2020",dateEndThirdStepPublish:"February 20th 2021",dateEndFourthStepPublish:"May 11th 2021",dateEndFifthStepPublish:"July 10th 2021",remainingDaysToSecondStep:"a month",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Professor Emeritus from the University of Debrecen, Hungary who authored 297 publications (papers, book chapters) and edited 3 books. Member of various committees and chairman of the World Conference of Innovative Animal Nutrition and Feeding (WIANF).",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"53998",title:"Prof.",name:"László",middleName:null,surname:"Babinszky",slug:"laszlo-babinszky",fullName:"László Babinszky",profilePictureURL:"https://mts.intechopen.com/storage/users/53998/images/system/53998.jpg",biography:"László Babinszky is Professor Emeritus of animal nutrition at the University of Debrecen, Hungary. From 1984 to 1985 he worked at the Agricultural University in Wageningen and in the Institute for Livestock Feeding and Nutrition in Lelystad (the Netherlands). He also worked at the Agricultural University of Vienna in the Institute for Animal Breeding and Nutrition (Austria) and in the Oscar Kellner Research Institute in Rostock (Germany). 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1. Introduction
When asked what developmental stage is diagnosed with conduct disorder the primary answer would be adolescent. However, based on research the greatest damage to society is the result of actions by delinquent adolescents but conduct disorder begins below the age of 7 (Scott, 2007). The researcher hypothesis suggests conduct disorder has a multi-factorial causation which includes biologic, psychosocial and numerous facets of the family unit. The research reveals a negative combination of these factors may predispose young children to exhibit symptoms of conduct disorder. The following questions will hopefully be answered: (1) What causes conduct disorder? (2) Can conduct disorder be prevented or predicted? (3) Does parenting style promote symptoms of conduct disorder? and (4) What are the intervention programmes that can be used to manage conduct disorder in adolescents.
2. Definition of conduct disorder
According to Evans (2003) conduct disorder is a steady pattern of harming others or their property, lying, stealing, or breaking societal rules of behaviour. Remote instances of acute behaviour, running away, or vandalism is not enough to merit a diagnosis of conduct disorder. Most children exhibit instances of poor judgment and bad behaviour at least one time in their childhood. The distinction is children with conduct disorder break the rules over and over again, exhibit aggressive behaviour, and show no regard for others. The behaviour is not considered conduct disorder until the symptoms are displayed for one year or more. The disturbances in behaviour result in significant clinical impairment with social skills, academics and occupational functioning (American Psychiatric Association, 1994).
Conduct disorder is differentiated from other psychiatric disorders diagnosed in children by the following criteria: “persistent pattern of behavior in which the basic rights of others or major age-appropriate societal norms or rules are violated” American Psychiatric Association (as cited from Tehama, 2007). According to them conduct disorder is a psychiatric syndrome occurring in childhood and adolescence which characterized by a longstanding pattern of violations of rules and antisocial behaviors. They interpret conduct disorder as:
Conduct disorder is a common childhood psychiatric problem that has increased incidence in adolescence. The primary diagnostic features of conduct disorder include aggression, theft, vandalism, violation of rules and/or lying. For a diagnosis these behaviors must occur for a least a six-month period.
3. Causes conduct disorder
The conditions that contribute to the development of conduct disorder are considered to be multifactorial, with many factors (multifactorial) contributing to the cause. Neuropsychological testing has shown that children and adolescents with conduct disorders seem to have an impairment in the frontal lobe of the brain that interferes with their ability to plan, avoid harm, and learn from negative experiences. Childhood temperament is considered to have a genetic basis. Children or adolescents who are considered to have a difficult temperament are more likely to develop behaviour problems. Children or adolescents from disadvantaged, dysfunctional, and disorganized home environments are more likely to develop conduct disorders. Social problems and peer group rejection have been found to contribute to delinquency (Salaam 1992). Low socioeconomic status has been associated with conduct disorders (Busari & Adejumobi 2012). Children and adolescents exhibiting delinquent and aggressive behaviours have distinctive cognitive and psychological profiles when compared to children with other mental health problems and control groups (Aderanti 2006). All of the possible contributing factors influence how children and adolescents interact with other people.
The etiology of conduct disorder consists of the correlation of genetic, family and social factors. The child may inherit limited baseline autonomic nervous system activity, resulting in a need for greater stimulation to attain optimal arousal. This hereditary aspect may explain the high level of sensation-seeking activity associated with the disorder (Johnson et al., 2002). Several studies have revealed the role of autonomic under-arousal in conduct-disordered adolescents (Crowell et al., 2006). According to McBurnett&Lahey, 1994 & Scrapa & Raine, 1997 (as cited in Crowell et al., 2006) conduct disorder and antisocial behaviour in adulthood are marked by autonomic under-arousal which included reduced electro-dermal responding (EDR) and heart rate. Beauchaine, 2003 (as cited in Crowell et al., 2006) revealed both elementary children and adolescents have reduced sympathetic and parasympathetic linked cardiac activity when diagnosed with conduct disorder.
The importance of this research is evident when considering the critical period of preschool when noradrenergic, serotonergic, and dopaminergic systems which administer behavioural control are susceptible to long-term changes in functioning Bremner&Vermetten, 2001 (as cited in Crowell et al., 2006). Parasympathetic nervous system (PNS)-linked cardiac activity has been associated with emotional regulation capabilities Porges, 1995 (as cited in Crowell et al., 2006) in contrast to deficiencies in sympathetic nervous system (SNS)-linked cardiac activity have been linked with reward inconsiderateness.
During gestation the brain is vulnerable to the effects of environmental stressors; this statement applies to both prenatal and postnatal development Hulzink et al., 2004 (as cited in Van Goozen et al., 2007). Environmental factors which can affect brain development are:
Poor nutrition
Maternal psychopathology
Atypical child interaction from a depressed mother
Baumrind (as cited in Marsiglia et al., 2007) classified three parenting styles: authoritarian, authoritative, and permissive. For the purpose of this research authoritarian parenting styles will be discussed. The characteristics of an authoritarian parent according to this researcher, are extremely restrictive and demanding rules. Parents who utilize this style tend to hamper children’s autonomy and force them to follow stringent rules by threatening harsh punishment. This type of parenting may lead children to believe they are not responsible for their actions; by contrast, when actions are questions they assume it is not their fault. According to numerous psychological theories parent-child relationship can generate psychological disorders such as anxiety, identity confusion and conduct disorder (Dwairy, et al., 2006). Hoeve et al., (2008) concluded from their study a strong link between parenting styles and delinquency trajectories; therefore, they recommended future research include parenting styles in measuring serious behaviours which are classified as conduct disorders.
The link between exposure to violence in the home and community is a crucial risk factor for conduct disorder according to research by Elze et al., 1999; Fergusson &Horwood, 1998; ; Kaplan et al., 1998 (as cited in McCabe et al., 2005). Violence exposure can take place in many places within the child’s environment including: (1) victimization and witnessing child abuse; (2) community violence; (3) parental abuse (McCabe et al., 2005).
Culture and societal norms make up the macro-system which is seen as the most distant factors; the eco-system is seen as a midlevel factor; and the micro-system is seen as the most proximal position to the child. Lynch &Cicchetti, 1998 (as cited in McCabe, et al., 2005) stress risk factors which have the most impact are the factors which are more proximal to the child. Family stresses: (1) substance abuse; (2) violence; and (3) social isolation etc. increase a child’s risk of conduct disorder or other mental health disorders. Garrison et al., 1992 (as cited in Baker et al., 2007) reveals several studies have documented the relationship between childhood psychosocial issues and primary care visits. Pediatricians consistently under identify mental health problems in children. Behavioural problems have been linked to an increase in family stressors: (1) divorce; (2) relocation; and (3) financial issues Lavigne et al., 1998 (as cited in Baker et al., 2007). Pediatrician should be aware of these factors when addressing repetitive visits to the office or the emergency room for treatment.
Parental psychopathology and parenting behaviour may be potentially important risk or protective factors in developmental outcomes for these children with concurrent conduct problems. Parental stress and maladaptive parenting may foster the development of conduct disorder Johnson & Mash, 2001 (as cited by Chronis et al., 2007). The researchers propose maternal smoking is a significant factor in conduct disorder because nicotine may interrupt fetal brain development. According to them, “Our study suggests that cigarette smoking may be one of the first prenatal risk factors for this very serious disorder” (University of Chicago Medical Center, 1997).
According to the ecological-transactional model child abuse has the greatest impact on child functioning. Kaplan et al., 1998 states several studies have correlated child maltreatment to an increase risk of conduct disorder (as cited in McCabe et al., 2005). A study at University of Chicago Medical Center (1997) reveals a link between smoking during pregnancy and the likelihood of having a son with conduct disorder. The researchers analyzed records of 177, 7-12 year-old boys who were referred for outpatient treatment for behavioural problems. The study indicated 24 percent of the mothers who reported smoking more than a half-pack of cigarettes per day during pregnancy, 80% of their sons had conduct disorder. This was in contrast to conduct disorder in 50% of the boys whose mothers did not smoke (University of Chicago Medical Center, 1997). According to the researcher “Our study indicates that regardless of other factors, smoking during pregnancy can have serious behavioural outcomes in children” (University of Chicago Medical Center, 1997).
The longitudinal and experimental studies on children who are raised in orphanages, children’s homes, and foster homes have established the adverse effects of long-term institutional care on children’s personality development according to the American Academy of Child and Adolescent Psychiatry, 2005 (as cited in Chronis et al., 2007). Consistent research has shown a correlation between institutional child rearing and hyperactivity and inattention (Busari & Ojo 2011). Both of these symptoms are precursors of conduct disorder Roy et al., 2000 (as cited in Chronis et al., 2007).
The research repeatedly exposes children who are diagnosed with ADHD and conduct disorder are predisposed for (1) risky sexual behaviour; (2) substance abuse; (3) delinquency; and (4) driving risks Barkley et al., 1993 (as cited in Chronis et al., 2007). The most disturbing fact is children who are diagnosed with ADHD and conduct disorder are at a greater risk of chronic criminal offenses Lyman, 1998 (as cited in Chronis et al., 2007). They identified children with conduct disorder at a greater jeopardy for continual offending and explained their perseverance by the correlation of their behaviour, neuropsychological and physiological deficits are comparable to adult psychopaths.
Childhood conduct disorder is a major risk factor for adult disorders especially anti-social behaviour. The key to diagnosing these children is to identify the origin of antisocial behaviour which is found in (1) difficult temperament and (2) ineffective socialization (Van Goozen et al., 2007). Conduct disorder in childhood which persists through adolescence is associated with co-morbidity, recurrence and resistance to treatment Moffit(2005). The study shows children and adolescence who struggle with signs and symptoms of conduct disorder continue to struggle throughout adulthood with psychosocial problems. The trajectories of antisocial behaviour influence these children throughout adulthood and influence the childrearing environment (Jafee et al., 2006).
The influences of individual factors are multifaceted and confusion. Family dysfunction is repetitively identified as one of the crucial factor for conduct disorder in adolescence. Poor parental supervision is the preeminent predictor of violence and vandalism committed by boys. Psychosocial disturbances in children and adolescence bring together a comprehensive range of research to shed light on these young people who become parents of tomorrow; these parents who were diagnosed with conduct disorder predispose their child to the same disorder (Pearce, 1996).
The public debate concerning the relationship between family characteristics and children with conduct disorder continues to raise questions which researchers hope to answer. A longitudinal survey of children suggests ineffective parenting style is the strongest predictor of delinquent behaviour in children between the ages of 8 and 11 years. In addition, aversion tactics, low socioeconomic status and the number of siblings in the home are associated with higher probability of children exhibiting delinquent behaviour and conduct disorder (Busari&Adejumobi 2012). Somerstein (2007) reveals the common family dynamic in many individuals’ histories of male terrorist is authoritarian parents.
4. Symptoms of conduct disorder
The clinical features of Conduct Disorder are:
aggression or serious threats of harm to people or animals;
deliberate property damage or destruction (i.e. fire setting);
repeated violation of household or school rules, laws or both; and
persistent lying to avoid consequences or to obtain tangible goods or privileges
The American Psychiatric Association (1994) provides further symptoms which support the clinician in diagnosis of conduct disorder. The child will often bully, threaten or intimidate others. They may intentionally set fires with the objective of harming others. The violation of rules would include: (1) often staying out late at night regardless of parental prohibitions which can begin before the age of 13; (2) has run away from home more than two times; and (3) the child is often truant from school which usually begins before the age of 13.
Additional features of conduct disorder include an indifference to the welfare of others and little if any remorse about harming others. Adolescents often verbalize outward remorse to avoid punishment but do not exhibit any guilt. They do not require an objective basis to conclude others are a threat to them. Because of this demeanor they may lash out aggressively without being provoked (Scott., 2007). During normal child development aggression and fighting is pertinent for defensive issues which do not escalate into anti-social behaviours; but, persistent anti-social behaviour collectively handicaps during childhood and leads to deprived adjustment during adulthood. The child often endures negative responses by their peers and high levels of disapproval from their parents (Scott, 2007).
Children who are diagnosed with conduct disorder judge the world as an antagonistic and intimidating place. They may tattle on friends or blame others for the harm they have caused. They have few if any friends because of their limited interpersonal skills. Peers and family members may view them as irritating because of their indifference to their actions. They often have low self-esteem internally but externally they appear tough, cocky or self-assured (Evans, 2003).
5. Prevalence of conduct disorder among the adolescents
Conduct disorder has become a major health and social problem; it is the most common psychiatric problem diagnosed among children. Around the world the prevalence of conduct disorder is 5% (Scott, 2007). A study conducted by Sujit et al., (2006) reveals 4.58% of boys and 4.5% of girls are diagnosed with conduct disorder worldwide. In their study of 240 students in four schools in Kanke childhood conduct disorder was found in 73% and in adolescent 27%. Mild conduct disorder was found in 36%, moderate in 64% and severe conduct disorder in none. Lying, bullying and cruelty to animals were the primary symptoms (Sujit, 2006).
Conduct disorder affects 1 to 4 percent of 9- to 17-year olds in the United States. The disorder is more predominate in boys than girls and more common in cities than in rural areas (U.S. Department of Health and Human Services, 1999). Between 6 to 16 percent of boys and 2 to 9 percent of girls meet the criteria to be diagnosed with conduct disorder. It is estimated 40 percent of these children will grow up to be adults with antisocial personality disorder (Searight, 2001).
Epidemiological studies state approximately 2% of girls and 9% of boys are afflicted with this disorder. Adolescents with more external signs and symptoms would amplify the percentage to one third or one half of all children and adolescent clinic referrals Kazdin et al., 1992 (as cited by McCabe et at., 2005).
6. What are the symptoms of conduct disorder?
Most symptoms seen in children with conduct disorder also occur at times in children without this disorder. However, in children with conduct disorder, these symptoms occur more frequently and interfere with learning, school adjustment, and, sometimes, with the child\'s relationships with others.
The following are the most common symptoms of conduct disorder. However, each child may experience symptoms differently. The four main groups of behaviours include the following:
Aggressive conduct. Aggressive conduct causes or threatens physical harm to others and may include the following:
Intimidating behaviour
Bullying
Physical fights
Cruelty to others or animals
Use of a weapon(s)
Forcing someone into sexual activity, rape, molestation
Destructive conduct. Destructive conduct may include the following:
Vandalism; intentional destruction to property
Arson
Deceitfulness. Deceitful behaviour may include the following:
Lying
Theft
Shoplifting
Delinquency
Violation of rules. Violation of ordinary rules of conduct or age-appropriate norms may include the following:
Truancy (failure to attend school)
Running away
Pranks
Mischief
Very early sexual activity
The symptoms of conduct disorder may resemble other medical conditions or behavioural problems.
7. How is conduct disorder diagnosed?
A child psychiatrist or a qualified mental health professional usually diagnoses conduct disorders in children and adolescents. A detailed history of the child\'s behaviour from parents and teachers, observations of the child\'s behaviour, and, sometimes, psychological testing contribute to the diagnosis. Parents who note symptoms of conduct disorder in their child or teen can help by seeking an evaluation and treatment early. Early treatment can often prevent future problems. Further, conduct disorder often coexists with other mental health disorders, including mood disorders, anxiety disorders, posttraumatic stress disorder, substance abuse, attention-deficit/hyperactivity disorder, and learning disorders, increasing the need for early diagnosis and treatment. Parents should consult their child\'s doctor for more information.
8. Prevention of conduct disorder in childhood
As with oppositional defiant disorder (ODD), some experts believe that a developmental sequence of experiences occurs in the development of conduct disorder. This sequence may start with ineffective parenting practices, followed by academic failure, and poor peer interactions. These experiences then often lead to depressed mood and involvement in a deviant peer group. Other experts, however, believe that many factors, including child abuse, genetic susceptibility, history of academic failure, brain damage, and/or a traumatic experience influence the expression of conduct disorder. Early detection and intervention into negative family and social experiences may be helpful in disrupting the development of the sequence of experiences that lead to more disruptive and aggressive behaviour
9. Relationship between conduct disorder, depression and opposition disorder
Many studies have shown that conduct disorder (CD) and depression often co-occur in late childhood and adolescence and have historically been regarded as the primary point of comorbidity between internalizing and behavioral disorders. On the other hand, recent evidence suggests that oppositional defiant disorder (ODD), and not CD, may best explain the comorbidity between disruptive behaviour disorders and depression. ODD typically onsets before CD and depression, changes in ODD symptoms predict changes in symptoms of CD and depression from one year to the next, and ODD in childhood and adolescence predicts depression in adulthood. Emerging evidence suggests that there are affective and behavioural dimensions of ODD symptoms, and those affective ODD symptoms (and not the behavioural symptoms) best predict later depression.
These results are highly relevant not only for our understanding of the etiology of the disorders, but also for optimizing early interventions aimed at reducing irritability in some ODD children. The new findings also stimulate new questions to be addressed with future research. In this review, the comorbidity between disruptive behaviour disorders (oppositional defiant disorder [ODD] and conduct disorder [CD] ) and depression will be considered. The term comorbidity is used to indicate the concurrent co-occurrence of two disorders, but like Angold, Costello, and Erkanli (1999), the researcher do not use concurrent to imply that the two disorders onset or terminate at exactly the same time. In addition, the researcher is primarily interested in the heterotypic comorbidity (e.g., Angold et al., 1999) involving the disruptive behaviour disorders and depression. The term heterotypic continuity is used to refer to the continuity of psychopathology in different forms over time, such as children with ODD being more likely to become depressed in adulthood (e.g., Copeland, Shanahan, Costello, &Angold, 2009). This is in contrast to homotypic continuity, which refers to the continuity of the same type of psychopathology over time, such as depression in adolescence showing continuity in the form of depression in adulthood.
10. What is cognitive therapy?
Cognitive therapy is an active, structured form of psychotherapy that is designed to rapidly and effectively reduce and eliminate psychological symptoms. Cognitive is simply a fancy word that means thoughts. Cognitive behaviour therapy, sometimes known as CBT is a form of psychological treatment that focuses on the thoughts and behaviours that accompany psychological distress.
Traditionally, CBT has been relatively brief treatment compared to other types of psychotherapy. CBT is focused on achieving defined and measurable treatment goals. Progress towards these goals is regularly assessed to ensure that treatment is progressing in an efficient and effective manner.
There is a significant amount of scientific evidence demonstrating that CBT is effective in treating a wide variety of psychological difficulties including depression, anxiety, panic attacks, phobias, obsessive compulsive disorder, social anxiety and shyness, and post- traumatic stress disorder. The evidence suggests that CBT is not only effective in helping people get better but it is also effective in minimizing relapse or helping people stay better. Cognitive behaviour therapists (CBT) emphasise the process of learning in improving and maintaining behaviour. The client is encouraged to identify connections between thoughts and their responses to social situations.
CBT often involves problem solving skills training. This type of training has been widely evaluated and there is evidence for its efficacy in the short term in treating aggression and conduct disorders in children. CBT is used for a range of problems for children and adults. It places emphasis on certain cognitive techniques that are designed to produce changes in thinking and therefore changes in behaviour or mood (Busari & Uwakwe 2001). CBT also emphasises the learning process and the ways in which external environments can change both cognition and behaviour. CBT for children and adolescents usually includes a range of behaviour performance-based procedures, and often involve the family or school in therapy. It may include individual work, group sessions, or both. The length of treatment varies considerably and depends on the severity of difficulties experienced.
For children with conduct disorder CBT usually has a strong focus on social cognitions and interpersonal problem-solving. Programmes are often quite long and may take up to 25 or 30 weekly sessions. The therapist is active and involved and tries to develop a collaborative relationship that stimulates the child to think for him or herself. The approach aims to give the child the opportunity to try things out and develop new skills
11. Problem solving skills training
A basic ingredient in CBT is to improve the problem-solving abilities of children and adolescents with conduct disorder. The training helps them to deal with external problems that may provoke behaviours. The child is first encouraged to generate potential solutions to a problem. The child and the therapist then decide on the best solution and identify steps in implementing it. The child practices these steps, and finally the whole process is evaluated.
There is some evidence that suggests that clients that develop new ways of thinking get better from psychological difficulties. When clients develop skills that enable them to identify, evaluate and change their thoughts they are likely to get better. In fact, there is proof, in the form of research studies that suggests that when clients develop these new thinking skills that they tend to get better and stay better, or have a lower chance of relapse (Busari 2012).
Cognitive behaviour therapy aims at changing clients’ beliefs by treating beliefs as testable hypothesis to be examined through behavioural experiments jointly agreed upon by the clients and the therapists. The therapist does not tell the client that his belief is wrong but rather asks questions to elicit the meaning, function, usefulness, and consequences of clients’ beliefs (Busari, 2000).
Cognitive behaviour therapy also challenges adolescents to make conscious choices and to accept full responsibility for their choices (Martye 2004). Cognitive behaviour therapy has been found to be very effective in the treatment of all forms of antisocial behaviours such as stealing (Obalowo, 2004), socially undesirable behavior, faulty thinking.frustration, recidivism and delinquent behaviour (Busari & Adejumo 2012). Cognitive Behaviour Therapy also involves self-management which explains the self- which believes that individuals have potential for self-actualization. The proponent of this theory believed that human beings have inherent tendency to develop their “self” in the process of interpersonal and social experiences, which they have in the environment (Chauman 2000). Since individual has the potential for self-actualization, self-management techniques will make the delinquent individual take part in the management of his own behaviour. Research work cited in Juvenile Justice Bulletin (1999), Gardner 2003), revealed that self-management is effective in modifying deviant behaviours. The present study therefore investigates the effectiveness of cognitive – behaviour programme in the management of adolescents conduct disorder.
12. Hypotheses
The following four null hypotheses were formulated and tested to guide this study at 0.05 level of significant.
Ho1: There is no significant difference in the level of reduction of conduct disorder of participants in the experimental and those in the control group
Ho2: There is no significant difference in the level of reduction of conduct disorder of participants based on gender after exposure to therapeutic treatment
Ho3: There is no significant difference in the level of reduction of conduct disorder of participants from separated and those from intact homes exposed to cognitive behaviour intervention
Ho4: There is no significant difference in the level of reduction of conduct disorder exhibited by participants form polygamous and those from monogamous home after therapeutic treatment
13. Methodology
13.1. Design
The design adopted for this study was a two group (experimental vs control) pretest-post -test design with dependent variable (conduct disorder) and independent variable (Cognitive Behaviour Therapy). Participants were assigned to either experimental or control group by randomly alternating sign-up at counter balanced times.
13.2. Participants
The participants of is study were 350 adolescents pre-selected using conduct disorder questionnaire. The participant’s ages between 10-19 years from five secondary schools selected through stratified random sampling techniques in Ibadan metropolis of Oyo State, Nigeria. Out of 350 (72%) 252 were males while (28%) 98 were females 58% (203) were from monogamous home while (42%) 147 were from polygamous homes. (84%) 294 were from intact family while (16%) 56 were form separated family.
13.3. Instrument
The instrument used for collecting data was conduct disorder questionnaire (CDQ) designed by the researcher. It consists of two sections with section A consisting of Demographic data such as age, sex, religion, type of home, type of family, class, etc. while section B consists of 37 items eliciting information on conduct disorder of the participants. These items requires the participants to indicate their degree of agreement with each item on a five point likert type scale ranging from 1 (most unlike me) to 5 (very much like me). Total scores range thus from 37 to 185. High score indicate highest level of conduct disorder. These instrument (conduct disorder questionnaire) was cross-validated with two other instruments (Juvenile Delinquency Questionnaire and Anti-social Behaviour Scale) in a pilot study among randomly selected adolescents in the Junior secondary School, different form the participants (n= 150). The result when correlated with conduct disorder questionnaire was (.763) at 0.01. A test-retest method was used to establish the reliability of the instrument. A reliability coefficient of 0.83 was obtained, thus indicating that the instrument was highly reliable. Some of the items in the instrument (conduct disorder questionnaire) include:
Fighting is okay, so far you are not caught
Running away from school to avoid punishment is okay
Stealing is not bad so far you don’t exceed what you need
Rules are not meant to be strictly obeyed
13.4. Procedure
This study was carried out in three phases. In the first phase, the participants were screened through conduct disorder questionnaire (CDQ). In the second phase, the participants were randomly assigned to the treatment group (cognitive behaviour therapy) and the control group respectively. At phase three, the experimental group went through eight weeks (1 hour a week) of intensive training consisting of discussion/lecture, discussion of the previous assignment given to the participants, summary and given of assignment for the next session. Instructions and explanations on the task involved in the experimental group such as lectures, discussion and assignment were given to all participants.
In the first session, participants introduced themselves to one another and the therapist familiarized them with the entire programme, she also created a good climate for discussion sessions. Pre-test questionnaire was administered to the participants. A contract was then made between the therapist and the participants such as agreeing on the venue, and time of meeting for the next eight sessions. The participants were encouraged to participate actively in the discussions and to do hoe work/assignments.
The second session witnessed conceptualization of Cognitive Behaviour Therapy (CBT) which was discussed with participants as an active, structured form of psychotherapy designed to rapidly and effectively reduce and eliminate psychological symptoms. The participants were taught that CBT is a form of psychological treatment that focuses on the thoughts and behaviours that accompany psychological distress.
In the third session the participants and the therapist discussed negative effects of conduct disorder to include school drop- out, inferiority complex, low self-esteem, lack of ambition, lack of decision making skills, inability to set goals and make plans inability to clarify values, feelings of guilt, unhappiness etc.
During the fourth session participants were asked to write down various conduct disorder experienced. Among the conduct disorder experienced as mentioned by the participants include truancy, aggression, theft, violation of rules, stealing, disobedience to parents and teachers etc.
The fifth session witnessed, teaching of various personal skills needed by the adolescents to make life meaningful to them. Various personal skills taught the adolescents include decision making goal setting, values of honest, honour, respect, self-control, responsibility, equality, social justice etc. others include communication skills, assertiveness, negotiation. When asked why they engage in conduct disorder the participants mentioned cruelity by parents, teachers and other siblings, inadequate provision of needed materials, lack of love and affection by relations, etc.
In the sixth session participants were taught to replace negative conducts, behaviours and feelings with positive ones; for example they were asked to substitute statement like
Rules are not meant to be strictly obeyed with
To avoid punishment rules must be strictly obeyed. In this session the process of learning in improving and maintain behaviour was emphasized. The participants were encouraged to identify connections between thoughts and their responses to social situations.
During the seventh session the participants were taught that the various negative thoughts and behaviors were learned and therefore can be unlearned. They were therefore trained in the emphasis of certain cognitive techniques that are deigned to produce changes in thinking and therefore changes in behavior or mood. They were taught on how learning process and the ways in which external environments can change both cognition and behaviour. They were taught how to strongly focus on social cognitions and inter-personal problem-solving techniques.
Session eight witnessed review of previous session activities rehearsal, role play and administration of post-test instrument.
The control group were given a brief educational review in conduct disorder but no treatment was applied to them both the pre and post -test measures were also administered on them.
Follow-up: Six weeks after the treatment programme, conduct disorder questionnaire was administered on the participants. The results obtained from the data indicates that cognitive behaviour therapy was effective in the management of conduct disorder among adolescent.
Data analysis: The data obtained from this study was analysed using analysis of co-variance (ANCOVA).
14. Results
In order to estimate the effects of the independent variable in the observed differences in the pre- and post- treatment scores of the participants on the dependent measures,an Analysis of Covariance (ANCOVA) was ran, using the pre- test scores as covariates and the post- test scores a criterion. ANCOVA is used to adjust for the initial differences that existed between the groups, since they were randomly selected. Thus, this study adopted ANCOVA to test the hypotheses formulated.
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tSource of variation \n\t\t\t
\n\t\t\t
\n\t\t\t\tDF\n\t\t\t
\n\t\t\t
\n\t\t\t\tSS\n\t\t\t
\n\t\t\t
\n\t\t\t\tMS\n\t\t\t
\n\t\t\t
F-ratio Obs.
\n\t\t\t
F-ratio Crit.
\n\t\t\t
\n\t\t\t\tTest decision\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
Between group
\n\t\t\t
7
\n\t\t\t
6376.44
\n\t\t\t
910.92
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
18.74
\n\t\t\t
2.81
\n\t\t\t
Reject Ho
\n\t\t
\n\t\t
\n\t\t\t
Within group
\n\t\t\t
342
\n\t\t\t
17681.4
\n\t\t\t
51.7
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
Total
\n\t\t\t
349
\n\t\t\t
24057.84
\n\t\t\t
962.62
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t
\n\t
Table 1.
Post-treatment Comparison of Cognitive Behaviour Therapy (CBT) and the Control Group using ANCOVA.
Critical value F (7,342 = 18.74; P>0.05
With regard to between group differences, there was a significant main effect of treatment(Cognitive Behaviour Therapy) on participants’ mean level of conduct disorder (Dependent Variable)scores, F(7,342=18.74;p>0.05.Treatment was found to have contributed significantly to variations in participants’ conduct disorder scores.
As shown in table 1, the computed outcome of pre and post treatment evaluation revealed that the null hypothesis was not confirmed at 0.05 alpha level. The finding showed that the critical value F (7,342) = 18.74 has P>0.05 and thus simultaneously indicated that a statistical significant difference existed in the investigated conditions.
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tSource of variation \n\t\t\t
\n\t\t\t
\n\t\t\t\tDF\n\t\t\t
\n\t\t\t
\n\t\t\t\tSS\n\t\t\t
\n\t\t\t
\n\t\t\t\tMS\n\t\t\t
\n\t\t\t
F-ratio Obs.
\n\t\t\t
F-ratio Crit.
\n\t\t\t
\n\t\t\t\tTest decision\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
Between group
\n\t\t\t
3
\n\t\t\t
54948.3
\n\t\t\t
18316.1
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
47.91
\n\t\t\t
3.72
\n\t\t\t
Reject Ho
\n\t\t
\n\t\t
\n\t\t\t
Within group
\n\t\t\t
346
\n\t\t\t
156911.0
\n\t\t\t
453.5
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
Total
\n\t\t\t
349
\n\t\t\t
211859.3
\n\t\t\t
18769.6
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t
\n\t
Table 2.
Pre and post-treatment comparison of male and female participants using ANCOVA.
Critical value F (7,346 = 47.91; P>0.05
A significant main effect of treatment (Cognitive Behaviour Therapy) on participants’ mean level of conduct disorder (Dependent Variable) was evident F(3, 346,=47.91;p>0.05.Post treatment comparison outcome of pre and post -test indicates treatment was found to have contributed significantly to variations in participants’ conduct disorder scores.
As shown in table 2, the compared pre and post-treatment outcome with the critical value F (3,346) = 47.91 and P>0.05 showed that there was statistical significant difference between male and female participants exposed to cognitive behaviour therapy. The null hypothesis therefore was not supported.
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t\tSource of variation \n\t\t\t
\n\t\t\t
\n\t\t\t\tDF\n\t\t\t
\n\t\t\t
\n\t\t\t\tSS\n\t\t\t
\n\t\t\t
\n\t\t\t\tMS\n\t\t\t
\n\t\t\t
F-ratio Obs.
\n\t\t\t
F-ratio Crit.
\n\t\t\t
\n\t\t\t\tTest decision\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
Between group
\n\t\t\t
5
\n\t\t\t
156528.0
\n\t\t\t
31305.6
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
194.57
\n\t\t\t
2.72
\n\t\t\t
Reject Ho
\n\t\t
\n\t\t
\n\t\t\t
Within group
\n\t\t\t
344
\n\t\t\t
107293.6
\n\t\t\t
311.9
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
Total
\n\t\t\t
349
\n\t\t\t
263821.6
\n\t\t\t
31617.5
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t
\n\t
Table 3.
Pre and post-treatment comparison participants from intact and those form separate family using ANCOVA.
Critical value F(5,344 = 194.57; P>0.05
The between group differences, shows that a main significant effect of treatment (Cognitive Behaviour Therapy)on participants’ mean level of conduct disorder (Dependent Variable) scores existed F(5,344=194.57;p>0.05. Treatment was found to have contributed significantly to variations in participants’ conduct disorder scores.
As indicated in table 3, the outcome of pre and post treatment details among participants from intact and those form separated family showed that there was statistical significant difference in the results obtained contrary to the postulated null hypothesis. Consequently, therefore, the null hypothesis was rejected at 0.05 level of significance.
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t\t
Source of variation
\n\t\t\t
\n\t\t\t\tDF\n\t\t\t
\n\t\t\t
\n\t\t\t\tSS\n\t\t\t
\n\t\t\t
\n\t\t\t\tMS\n\t\t\t
\n\t\t\t
F-ratio Obs.
\n\t\t\t
F-ratio Crit.
\n\t\t\t
\n\t\t\t\tTest decision\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
Between group
\n\t\t\t
5
\n\t\t\t
78299.5
\n\t\t\t
15659.9
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t\t
125.9
\n\t\t\t
2.72
\n\t\t\t
Reject Ho
\n\t\t
\n\t\t
\n\t\t\t
Within group
\n\t\t\t
344
\n\t\t\t
1836157.6
\n\t\t\t
5337.65
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t
\n\t\t
\n\t\t\t
Total
\n\t\t\t
349
\n\t\t\t
1914451.1
\n\t\t\t
20997.55
\n\t\t\t
\n\t\t\t
\n\t\t\t
\n\t\t
\n\t
Table 4.
Pre and Post-treatment comparison of participants from Monogamous and those from Polygamous Homes using ANCOVA.
Critical value F(5,344 = 125.9; P>0.05
There was a significant main effect of treatment (Cognitive Behaviour Therapy) on participants’ mean level of conduct disorder scores (Dependent Variable) F(5,344=125.9;p>0.05.Post treatment comparisons revealed its significant contribution to variations in participants’ conduct disorder scores.
In table 4, the compared computed pre-and post –treatment outcome of participants from monogamous and polygamous homes showed that there was statistical significant difference following the alpha level of 0.05. The findings revealed that the critical value of F(5,344)=125.9; P>0.05 evidently failed to support the predicted null hypothesis.
15. Discussion of the findings
The result of the first hypothesis shows that there was a significant difference in the level of reduction of conduct disorder of participants in the experimental and those in the control group.
This result corroborates the findings of Wolinsky and Miller (2006) when they found that cognitive training would affect the cognitive ability targeted by that training and these effects would be maintained over time. It also indicates that maintained on improvements in cognitive ability would have a positive transfer effect on everyday function.
Gardner (2003) also confirms the effectiveness of cognitive behaviour therapy in treating rebelliousness, delinquency and conduct disorder. According to him, cognitive factors play an important and well documented roles in these undesirable behaviors since the way people think has a controlling effect on their action and that replacement of negative habits with positive ones and rethinking will help individual to generate more adaptive behaviour. Moreover, an individual cognition is important in the acquisition of a new behaviour.
Results emanated from hypothesis two indicates that there exists significant difference in the level of reduction of conduct disorder of male and female participants.
This finding agrees with that of Rathus (1996) who suggested that females who have become involved in criminality must somehow be more male-like than their law abiding counterparts. Some researchers have suggested that where the females have been involved in crime, they have typically played a more passive compliance role, their male counterparts are actually responsible for the planning and execution of the crime. Moreover, it was observed that females restricted their criminal activities to such female crimes as shoplifting, incorrigibility, sex offences or running away whereas males participates in offences like homicide, forcible rape, aggravated assault, robbery, burglary, and auto-theft.
The findings from the result of hypothesis three reveals that there exist significant difference in the response to treatment of participants form intact and those from separated homes. Parents are responsible for the upbringing and development of their children and make provision for their basic needs such as food, education, shelter, protection etc. the family integrates the child into the community. Families raise children to learn the cultural norms. They are the teacher of the rules which in most cases are not written down but may be passed from one generation to another through the process of socialization. In a situation where the two parents are not living together proper upbringing of the children might be impossible. Actions and behaviours which do not promote positive development and growth of the children are likely to be the end product of separated parents whereas the opposite is find in the intact homes (Busari & Adejumobi, 2012).
Results from the findings of the fourth and the last hypothesis indicates that there was significant difference in the level of education of conduct disorder of participants form monogamous and those from polygamous homes after exposure to treatment.
This findings is in line with the findings of Mathye (2004) which reveals that family size is a variable which makes major contribution to the explanation of degree of participation of children in anti-social behaviour such as delinquent acts, rebelliousness, conduct disorder etc. He further expantiate that large family is believed to be negatively related to high rate of anti-social behaviours and that as family increases a child’s undesirable behaviour increases. The findings also appear to be consistent with the finding that poor living conditions may slow down growth and maturity among growing children and thrown them off their “programmed curve” that is off the curve that they normally follow under optimal conditions.
16. Conclusion / recommendation
The main objective of this study was to investigate the effects of cognitive behaviour therapy on the management of conduct disorder among adolescents. This study provided substantial evidence to support the fact that cognitive behaviour therapy was effective in the reduction of conduct disorder among the adolescents.
Clearly the research reveals the correlation of diverse factors which promote conduct disorder. Parenting styles play a key role in promoting an environment which is conductive to this disorder. It follows therefore that therapist need to educate their clients, public, parents, families etc. on the negative effects authoritarian parenting styles have on their children.
The research suggests that children with conduct disorder become adults with anti-social behaviour and other psychological problems. The disorder is more than a fussy child it is a serious issue which parents, teachers and the mental health professionals needs to address.
Another aspect to consider is the link between nicotine and conduct disorder. Pregnant women need to be warned against smoking during and after pregnancy. There are significant risks with cigarette smoking during pregnancy.
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/41674.pdf",chapterXML:"https://mts.intechopen.com/source/xml/41674.xml",downloadPdfUrl:"/chapter/pdf-download/41674",previewPdfUrl:"/chapter/pdf-preview/41674",totalDownloads:3772,totalViews:2047,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,dateSubmitted:"May 9th 2012",dateReviewed:"September 4th 2012",datePrePublished:null,datePublished:"January 16th 2013",dateFinished:null,readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/41674",risUrl:"/chapter/ris/41674",book:{slug:"mental-disorders-theoretical-and-empirical-perspectives"},signatures:"Afusat Olanike Busari",authors:[{id:"159003",title:"Dr.",name:"Afusat",middleName:null,surname:"Busari",fullName:"Afusat Busari",slug:"afusat-busari",email:"olanikebusari@yahoo.com",position:null,institution:{name:"Federal College of Education",institutionURL:null,country:{name:"Nigeria"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Definition of conduct disorder",level:"1"},{id:"sec_3",title:"3. Causes conduct disorder ",level:"1"},{id:"sec_4",title:"4. Symptoms of conduct disorder",level:"1"},{id:"sec_5",title:"5. Prevalence of conduct disorder among the adolescents",level:"1"},{id:"sec_6",title:"6. What are the symptoms of conduct disorder?",level:"1"},{id:"sec_7",title:"7. How is conduct disorder diagnosed?",level:"1"},{id:"sec_8",title:"8. Prevention of conduct disorder in childhood",level:"1"},{id:"sec_9",title:"9. Relationship between conduct disorder, depression and opposition disorder",level:"1"},{id:"sec_10",title:"10. What is cognitive therapy?",level:"1"},{id:"sec_11",title:"11. Problem solving skills training",level:"1"},{id:"sec_12",title:"12. Hypotheses",level:"1"},{id:"sec_13",title:"13. Methodology",level:"1"},{id:"sec_13_2",title:"13.1. Design",level:"2"},{id:"sec_14_2",title:"13.2. Participants",level:"2"},{id:"sec_15_2",title:"13.3. Instrument",level:"2"},{id:"sec_16_2",title:"13.4. Procedure",level:"2"},{id:"sec_18",title:"14. Results",level:"1"},{id:"sec_19",title:"15. Discussion of the findings",level:"1"},{id:"sec_20",title:"16. Conclusion / recommendation",level:"1"}],chapterReferences:[{id:"B1",body:'AderantiR. A.2006Prevalent of adolescents’ delinquent behavioral patterns: An issue in counseling psychology and implications for national development. A paper presented at the 1st National Conference of Colelge of Applied education and Vocaitoanl Technology. Tai Solarin University of Education, Ijagun (unpublished)'},{id:"B2",body:'American Psychiatric Association.2000Diagnostic and statistical manual of mental disorders (4th ed. Text Revision). Washington D.C.: Author.'},{id:"B3",body:'BartonA.et al.2007Functional Family Therapy: blueprint for violence Prevention.Institute of Behavioral Science. Retrieved June 19, 2011 from http:www.colorado.edu/cspv/blueprints/model/programs/FFT.html'},{id:"B4",body:'Functional Family Therapy Website.2007http://www.fftinc.om'},{id:"B5",body:'BusariA. O.2000Stress Inculcation Training and Self Statement Monitoring Techniques in the Reduction of Test Anxiety Among Adolescent Under Achievers in Ibadan Metropolis, Nigeria. An unpublished Ph.D Thesis, University of Ibadan 309\n\t\t\t'},{id:"B6",body:'BusariA. O. .UwakweC. B. U.2001The Effects of Stress Inoculation TrainingTechniques in the Management of Worry as a self Handicapping Strategy in IntellectualPerformance. Nigerian Journal of Emotional Psychology and Sport Ethics 3:612\n\t\t\t'},{id:"B7",body:'BusariA. O.OjoR. A.2011Empowering Youth in Remand Home Against Risk Taking Behaviours for Effective Transition to Independence. Ethno Medicine. 5(3)217222India'},{id:"B8",body:'BusariA. O.2012Cognitive Training Intervention and Daily Functioning Improvement among the Retirees of University of Ibadan, Nigeria. European Journal of Globalization and Development Research.3(1) 143153'},{id:"B9",body:'Busari & Adejumobi2012Cognitive Behaviour Therapy in the Management of Juvenile Delinquency; being a paper presented at the International Conference on Sustainable Development in Africa. Held at R.S. Amegashie Auditorium University of Ghana, Legon, Accra, Ghana between 25th- 27th July.'},{id:"B10",body:'EdelsonS. M.2004Self-management center for autism. Retrieved from the web November 22, 2011 http://www.ojdpncjrs.org'},{id:"B11",body:'GarnerJ. R.2003Cognitive Rehabilitation. Retrieved from the web November 22, 2010\n\t\t\t'},{id:"B12",body:'Hoeve et al.2008Trajectories of delinquency and parenting styles.Journal of Abnormal Child Psychology, 36 (2), 223-235. Retrieved May 23, 2011 from http://www.pubmedcentral.nih.gov/'},{id:"B13",body:'HoagwoodK.et al.2007Empirically-based school interventions targeted at academic and mental health functioningJournal of emotional and behavioral disorders66 EOF92 EOF'},{id:"B14",body:'Marsiglia et al.2007Impact of parenting styles and locus of control on emerging psychosocial success. Journal of Education and Human Development, 1. Retrieved April 29, 2012 from: http://www.scientificjournals.org'},{id:"B15",body:'MathyeL. V.2004Therapeutic techniques for treatment of adolescents with rebellious behavior.\n\t\t\t'},{id:"B16",body:'National Institute for Health & Clinical Excellence.2007Conduct disorder programs {Electronic Version}. Community Care, 167216723233Retrieved June 22, 2012 http://www.nice.org.uk/page.aspx?0=529846'},{id:"B17",body:'ObalowoY. O.2004Cognitive restructuring and contigency management in the treatment of stealing behavior among some Nigerian adolescents. Unpublished Ph.D Thesis, Olabisi Onabanjo University, Ago-Iwoye.'},{id:"B18",body:'RayD.2007Two counseling interventions to reduce teacher-child relationship Stress {Electronic version}. Professional School Counseling, 10(4), 428-440. http://www.goliath.ecnext.com/coms2.\n\t\t\t'},{id:"B19",body:'SalaamA. O.1990Screening for Signs and Symptoms of Juvenile Delinquency in Secondary School Students.In Kajola Local Government area of Oyo State.An Unpublished B.Ed Project, University of Ibadan 127\n\t\t\t'},{id:"B20",body:'ScottS.2007Conduct disorder in children.BMJ 2007. Retrieved July 13, 2012 from http://www.bmj.com/cgi/content/full/334/7595/646'},{id:"B21",body:'SomersteinL.2007I came with a sword on judgment day: a psychoanalytic look at terrorist enactments. Psychoanalytic Review, 94 (5).'},{id:"B22",body:'StevensonK.1999Family characteristics of problem kids.Canadian Social Trends.'},{id:"B23",body:'U.S.Department of Health and Human Services. (1999Mental Health: A report of the Surgeon General {Electronic Version}.Rockville, MD. Retrieved July 13, 2010 from http://mentalhealth.samsha.gov/publications\n\t\t\t'},{id:"B24",body:'U.S. Department of Justice.2000Juvenile Justice Bulletin. Washington, D.C.'},{id:"B25",body:'Van Goozen et al.2007The evidence for a neurobiological model of childhood antisocial behaviorPsychological Bulletin149182\n\t\t\t'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Afusat Olanike Busari",address:null,affiliation:'
University of Ibadan, Ibadan, Nigeria
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1. Introduction
Multidrug resistance (MDR) is one of the major factors contributing to a failure of doxorubicin for cancer treatment. Typically, the loss of cell sensitivity to chemotherapy is not limit to only doxorubicin and anthracycline derivatives. The MDR phenomenon evidently extends across various structurally-unrelated anticancer drugs, regardless of their molecular targets [1, 2, 3]. Hence, MDR development in cancer cells can simultaneously reduce the effectiveness of several cytotoxic drugs, leading to chemotherapeutic failure. Consequently, patients need higher doses of the anticancer agents to achieve therapeutic success. Either intrinsic or acquired resistance to doxorubicin-based chemotherapy has been attributed to various mechanisms including high expression of the drug efflux transporters, alteration of cell cycle checkpoints and apoptotic signals, increased drug detoxification and DNA repair processes [4, 5, 6]. Regarding this, MDR reversal can be one of the strategic approaches to enhance the efficacy, without increased adverse events, of doxorubicin.
This chapter focused on the most studied drug efflux transporter P-glycoprotein (P-gp) and its role in doxorubicin resistance in chemotherapy. In addition, some strategic approaches to conquer P-gp-based MDR in cancer treatment were also described.
2. The drug efflux transporter: P-glycoprotein
Drug transporters can be grouped, according to their transport direction, into uptake and efflux pumps. Most of the known efflux transporters particularly P-glycoprotein (P-gp or MDR1; encoded by ABCB1), multidrug resistance protein 1 (MRP1, encoded by ABCC1), multidrug resistance protein 2 (MRP2, encoded by ABCC2) and breast cancer resistance protein (BCRP; encoded by ABCG2) are members of the adenosine triphosphate (ATP)-binding cassette (ABC) superfamily. The ABC transporters require ATP hydrolysis for their transport activity across plasma membrane in the secretive direction. These efflux transporters share similar structural assembly across plasma membrane, composing of a membrane-spanning α-helix structure as a transmembrane domain (TMD) and a relatively hydrophilic ATP-binding site in nucleotide binding domain (NBD). High activity and expression of these ABC drug efflux pumps is a major contributing factor for development of MDR phenomenon in cancer cells [1, 4].
Among the ABC efflux transporters, P-gp is the first and most studied transporter for MDR development in chemotherapy and drug-transporter-related interaction issues. This transporter was first identified from its involvement with multidrug-resistance in cancer cells. Particularly, overexpression of P-gp in cancer cells, either intrinsic or acquired, has been strongly associated with MDR occurrence, thereby P-gp becomes a promising target for development of chemosensitizers.
2.1 Overview of P-gp (structure, function, location, expression, and MDR)
P-gp (MW approximately 170 kDa) is a single polypeptide with 1280 amino acids arranging in two duplicated units of a 6 α-helix structure hydrophobic TMD with linkage to a hydrophilic NBD (Figure 1) [1, 2, 7]. These two TMD with the total of 12 helices forms together into one channel as the membrane crossing passage. A substrate binds to the drug-binding site in the TMD whereas an ATP binds to the NBD. After ATP binding, ATP undergoes hydrolysis into ADP for energy to activate P-gp action through protein conformational alteration [7, 8]. This transporter, then, is able to move its substrates across lipid bilayer structure of plasma membrane to extracellular environment.
Figure 1.
The key ABC drug efflux transporters and their selected anticancer drug substrates.
2.1.1 P-gp and its normal physiological functions
P-gp is constitutively located in the apical surface of either epithelial or endothelial linings of various normal tissues/organs such as adrenal glands, intestine, liver, kidney, pancreas, placenta, capillary vessels in the brain and testes [2, 7, 8, 9, 10]. Some organs such as prostate, skin, heart and skeletal muscle have low constitutive expression of P-gp. It should be noting that expression level of P-gp varies in each organ. For example, the numbers of P-gp in colon and ileum are higher than those in jejunum, duodenum and stomach [11, 12]. The tissue distribution of P-gp indicates that this transporter normally serves as an intrinsic determinant of oral drug bioavailability and drug disposition [13, 14, 15, 16, 17, 18]. Intestinal P-gp can influence the absorptive amount of its drug substrates, except those in BCS class I (i.e., high permeability and high solubility drugs such as verapamil), into the body after orally taken [13, 19, 20, 21]. The constitutive expression of P-gp at the mucosal surface in the lower gastrointestinal (GI) tract (i.e. jejunum, ileum, and colon) may prevent an uptake of its substrate, and perhaps also facilitate GI excretion. Moreover, the interplay between P-gp and the major phase I drug metabolizing enzymes (e.g. cytochrome P450, CYP450) can be anticipated due to their substrate similarity [22]. As such, P-gp and CYP3A4 act in concert to affect metabolic biotransformation of their substrates such as paclitaxel in intestine and liver, influencing the oral drug bioavailability [22, 23, 24]. Localization of P-gp in the blood-organ barriers such as brain or testis prevents drug penetration into such organ systems such as brain, testes [13, 23, 25, 26]. The presence of P-gp on the brush border of nephron proximal tubule and hepatocytes involve with excretion of drugs and endogenous substrates into the urine and bile [13, 27]. To this end, P-gp can be considered as the protective mechanism against xenobiotics as well as pharmacokinetic influencer particularly on absorption, distribution and disposition.
2.1.2 P-gp expression and signaling pathways
Expression of P-gp at plasma membrane involves several cellular processes that linking to P-gp mRNA and protein expression. The regulatory mechanisms have been largely associated with (1) activation or inactivation of oncogenes (e.g., Ras, c-Raf) and transcriptional process, (2) MDR1 translation into P-gp and post translational modification, protein trafficking, and (3) P-gp turn over. It has been reported that the dysregulated microRNA levels (e.g., miR-21, -27a, -451, -130a, -298) could cause MDR development in various cancer cells [28, 29, 30, 31, 32, 33, 34]. For example, miR-130 was correlated to MDR1/P-gp overexpression, and cisplatin resistance in SKOV3/CIS cells [32]. Overexpression of miR-27a and miR-451 was linked to increased MDR1 expression and MDR phenotype in resistant cancer cells A2780DX5 and KB-V1 [28].
Overexpression of P-gp particularly in MDR phenomenon has been evidently connected to up-regulation of MDR1 gene through alteration of various signaling pathways and transcription factors. Example of the transcriptional factors involving in MDR1 transcription are nuclear factor-κB (NF-𝂻) [35, 36], Y-box binding protein-1 (YB-1) [37, 38], activator protein-1 (AP-1) [39], and hypoxia-inducible factor-1 (HIF-1) [38, 40]. The activities of these transcription factors have been linked to various signal transduction pathways, particularly the two major cell survival signaling cascades i.e. (1) the mitogen-activated protein kinase (MAPK) [37, 41], and (2) the phosphatidylinositol 3-kinase (PI3K) pathways [42, 43] It has been shown that hyperactivation of either MAPK/ERK1/2 or PI3K/Akt/NF-𝂻 signaling pathways results in overexpression of P-gp in doxorubicin-resistant cells such as lung, breast and ovarian cancer cells [44, 45, 46, 47, 48, 49]. An up-regulation of P-gp expression in vincristine-resistant human gastric cancer cells was associated with activation of the p-38/MAPK pathway [50].
After activation and translocation into nucleus, transcription factors such as NF-kB and YB-1 (Y-box binding protein) bind to MDR1 promoter region, leading to initiation of MDR1 transcription. Increase in YB-1 nuclear activity is related to P-gp-mediated development of MDR in several cancers including breast cancer, lung cancer, ovarian cancer, colorectal cancer, prostate cancer and osteosarcoma [38]. In response to cell stress such as hyperthermia, viral infection and chemical assault, the survival Akt and MAPKs signaling would be activated, and subsequently increase YB-1 expression and translocation into nucleus for its MDR1-transcription activity [51]. Doxorubicin is a known P-gp inducer in various cancer cells. Doxorubicin up-regulates MDR1 gene expression via the MAPK/ERK1/2 signaling that linked to activation of YB-1 in B-cell lymphoma [37]. Moreover, upregulation of P-gp has been reported after prolonged exposure to various functional unrelated compounds, leading to the loss of drug efficacy and safety [52]. Examples of the known P-gp inducers include anticancer (e.g., cisplatin, doxorubicin, etoposide vinblastine), antidepressants (e.g., trazodone, St. John’s Wort), anticonvulsants (e.g., carbamazepine, phenytoin), anti-HIV (e.g., saquinavir, indinarvir, tenofovir), immunosuppressants (e.g., cyclosporine, tacrolimus), steroids (e.g., dexamethasone) [52, 53, 54]. It is worth noting that certain CYP450 inducers such as rifampin and St. John’s Wort are able to up-regulate P-gp expression, possible sharing through the PXR regulation [55, 56]. Prolonged exposure to rifampin and St. John’s Wort in human led to increased intestinal P-gp level, and increased digoxin absorption [57, 58]. Since, P-gp-mediated MDR in cancer is largely due to up-regulation of P-gp expression, better understanding of the signaling proteins and transcription factors will provide a promising targets in overcoming MDR for anticancer chemotherapy.
2.1.3 P-gp and multi-drug resistance in cancer
Overexpression of P-gp has been strongly correlated with chemo-resistance and cancer relapses in several cancer patients such as breast cancer, adult acute myeloid leukemia, pheochromocytoma patients, leading to poor prognosis from therapeutic failure in patients receiving chemotherapy [1, 59, 60, 61, 62]. Accordingly, P-gp is intrinsically expressed in various cancer types, particularly those derived from tissues with high basal MDR1 expression levels such as colon, kidney and liver tissues. Being a transmembrane efflux pump, P-gp serves as a cellular defense mechanism against drug assault by limiting intracellular drug accumulation up to toxic threshold level. Regarding this, the susceptibility of cancer to anticancer drugs being P-gp substrate varies, depending on intrinsic expressed P-gp levels. Certain types of cancers may be classified as poor responder showing their unresponsiveness to chemotherapy regimens containing P-gp substrates. For example, prostate cancer appears to be better responder to chemotherapy, as compared to colorectal or renal cancers [63, 64]. Moreover, some cancers such as leukemia, lymphoma and breast cancer having low levels of intrinsic P-gp expression, and thus initially respond well to chemotherapy. Later, after repeated treatment, the expression level of P-gp markedly increases, and those cancers display multi-drug resistance (MDR) phenotype [1, 65, 66]. This acquired MDR phenomenon can be viewed as cellular adaptive survival response to cytotoxic challenge.
2.2 Substrates and modulators
Examples of substrates and modulators of P-gp are listed in Table 1.
Selected substrates, inducers and modulators of P-gp.
2.2.1 Substrates
Human ABC efflux transporters demonstrate their broad substrate specificity toward structurally diverse lipophilic compounds. Most of their substrates are weakly amphipathic and hydrophobic planar structure with aromatic ring and positively charged nitrogen atom [52, 54, 67, 68]. Examples of P-gp substrates are anticancer drugs (vinca alkaloids, anthracyclines, and epipodophyllotoxins), cardiovascular drugs (e.g., digoxin, quinidine, talinolol, diltiazem, losartan, verapamil), anti-microbial agents (e.g., doxycycline, erythromycin, itraconazole, rifampin), anti-viral drugs (e.g., indinavir), anticonvulsants (e.g., phenytoin), acid blockers (e.g., cimetidine), immunosuppressants (e.g., cyclosporine, tacrolimus), steroids (e.g., aldosterone, cortisol, dexamethasone), opioids (loperamide, morphine).
2.2.2 Modulators
Modulators suppress P-gp activity through either (1) direct inhibition of P-gp function by either competitive or non-competitive inhibitors; or (2) suppression of P-gp expression levels by interferences with either transcription, translation/post-translation, and degradation processes.
2.2.2.1 Direct inhibition of functionally active P-gp
The direct inhibition of active P-gp can be attributed to the interaction between chemicals and P-gp at either TMB or NBD [67, 68, 69]. Any compound such as tyrosine Kinase Inhibitors interferes with ATP binding or hydrolysis in NBD site can reduce P-gp transport action [70]. Chemicals identified as small molecule P-gp inhibitors such as amiodarone, diltiazem, verapamil bind to substrate binding sites or allosteric sites in TMB, resulting in interference on substrate binding and transport. It has been reported that certain compounds such as cyclosporine A could exert their inhibitory action by interfering with substrate recognition and ATP hydrolysis [8, 67, 68, 69]. It is not surprising that these TMB type inhibitors and substrates share many common molecular features such as hydrophobic planar structure. In addition, due to the diversity in chemical structure of P-gp inhibitors, establishment of the structure activity relationship (SAR) of P-gp inhibitors is very challenging. The structure pattern of the inhibitors contains planar rings and basic nitrogen atom within an extended side chain of the aromatic ring. The presence of tertiary amino groups, in comparison with primary and secondary amine, increases the anti-MDR potency considerably. Furthermore, the presence of nitrogen atom in non-aromatic ring apparently increases inhibitory action of the compounds [71]. Examples of P-gp inhibitors are calcium channel blockers (verapamil, diltiazem), and various phytochemicals such as flavonoid and steroidal compounds (e.g., quercetin, resveratrol), indole alkaloids and polycyclic compounds (e.g., capsaicin, piperine, rhinacanthin C) [66, 72, 73, 74].
Ideally, the P-gp inhibitors should be potent and selective to P-gp function at target cells/tissues, with no systemic side effects. To date, there are four generations of small molecule inhibitors. The first generation inhibitors are known drug substrates of the ABC transporters such as verapamil, cyclosporine A, tamoxifen and quinidine [75]. They were not specifically designed to be P-gp inhibitors, and could not display good clinical outcomes in their MDR reversal activity. The clinical disappointment could be due to their weak inhibitory potency against the MDR transporters including P-gp, and their pharmacokinetic interactions with chemotherapeutic agents, leading to the need of high doses and intolerable adverse effects [1, 76]. Next, the second generation inhibitors such as valspodar (cyclosporine A derivative) were developed, based on structure activity relationships of the first generation compounds, in order to improve potency, specificity, and to reduce systemic toxicity. Although this group of inhibitors demonstrated their improvement in inhibitory potency, their clinical outcomes were still unsatisfied due to their pharmacokinetic interaction with the anti-cancer drugs via inhibition of cytochrome P450, and their severe toxicity [75, 77]. Subsequently, the third generation P-gp inhibitors such as elacridar, tariquidar and zosuquidar were developed in order to address the limitations of the second generation compounds. These inhibitors elicit no effect on CYP P450 metabolism, therefore they are unlikely to affect the plasma concentrations of anti-cancer drugs. They were also more potent and selective P-gp inhibitors, effectively working in nanomolar concentration range. However, the potent P-gp inhibitor tariquidar can be either substrate or inhibitor of P-gp depending on its given dose [78]. To date, the clinical efficacy for MDR reversal of this generation has yet completely satisfied, its effectiveness possibly also depends on given dosage and intrinsic tumor properties.
Currently, phytochemicals or natural compounds with MDR reversal activity have been subject of interest in searching for new effective chemo-sensitizer against cancer. This group of inhibitors obtained from natural sources is classified as the fourth generation inhibitor. Numerous phytochemical researches on pharmacological activities and pharmacokinetics have revealed that plant-based compounds elicit a broad spectrum of pharmacological actions such as anti-cancer, anti-oxidant, anti-microbial, anti-inflammation, etc. In addition, these plant-based compounds, depending upon its molecular structure, may interfere with P-gp and metabolizing enzymes, leading to the concerning issues in drug bioavailability and pharmacokinetic drug interactions. The advantages of the fourth generation inhibitors in part rely on their natural origin with long history of uses in dietary or health supplements and in traditional medicine. It may be able to presume that this group of inhibitors derived from known edible products possessed less toxicity and more tolerable than those of the previous generation compounds. Evidently, even vegetables (e.g., bitter melon), spices (e.g., black pepper, turmeric) or fruits (e.g., orange, grapefruit) also contain substances that could inhibit P-gp and other efflux transporters in the ABC superfamily [72, 73, 74, 75, 77, 79, 80, 81, 82]. Their competitive inhibition against the efflux transporters enhance cytotoxicity of anticancer drugs such as doxorubicin and vinblastine, leading to potential MDR reversal in various cancer cells. However, the inhibitory potency of these plant-based compounds against P-gp activity might be low. Their IC50 values obtained from the in vitro cell culture models appear to be in micromolar range. Thus, this group of inhibitors is unlikely a good MDR reversing agent through direct P-gp inhibition at MDR cancer cells in clinical setting. In addition, the interference of P-gp activity of these compounds in pharmacokinetic aspect may influence on P-gp-related ADME and bioavailability of chemotherapeutic drugs that concomitantly given. Nevertheless, the opportunities of further development into effective chemosensitizers cannot be excluded. Better understanding of QSAR may enable to facilitate chemical modification of these identified plant-based P-gp inhibitors to generate more potent and high selective P-gp inhibitors. Furthermore, several plant-based compounds (e.g, curcumin, resveratrol, quercetin) have been demonstrated their potential in down-regulation of P-gp and other key regulators in transporter-independent MDR mechanisms [75, 82, 83, 84, 85, 86].
In addition to small molecule inhibitors, monoclonal antibodies can be another alternative approach in inhibiting P-gp activity. Theoretically, any agents that specifically affect lipid-protein interactions or protein structure of targeted P-gp can be developed into P-gp inhibitor. Typically, monoclonal antibody can be developed to specifically recognize and bind to its target protein, leading to inhibition of changes in protein conformation. Regarding this, human P-gp-specific antibodies UIC2, MRK-16 and 4E3 reacted specifically to the extracellular loop of both halves of P-gp, and disabled P-gp transport activity [87]. Consequently, treatment cancer cells with these antibodies resulted in increased concentrations of anticancer drugs (e.g., vincristine, actinomycin D, doxorubicin, paclitaxel) within the cells, and improve drug effectiveness [87, 88, 89, 90, 91]. In athymic mice model, MRK16 was demonstrated its ability to significantly reduce tumor mass [92]. Further clinical studies of human P-gp-specific antibodies are needed to conduct in terms of safety and efficacy.
2.2.2.2 Suppressor of P-gp expression
In addition to direct inhibition, reduction of P-gp activity can arise from decrease of protein expression at plasma membrane. Interference on transcription and translation of MDR1 gene, resulting in reduction of P-gp expression, can be another approach to overcome MDR in cancer. Several innovative tools targeting at MDR transcription or mRNA including small molecules, antisense oligonucleotides, hammerhead ribozymes and RNA interference strategies have been employed.
2.2.2.2.1 MicroRNA and RNA interference (RNAi) technologies
Application of microRNA and RNAi technologies with either small-interfering RNA (siRNA) or small hairpin RNA (shRNA) to specific silence MDR1 expression in cancer cells with MDR phenotype has been demonstrated their effectiveness in down-regulation of MDR1 and P gp expression with paralleled increases drug accumulation and improved sensitivity to treatment. MicroRNAs (miRNAs) are small non-coding RNA molecules that can inhibit ABCB1 mRNA translation processes [93, 94]. A number of miRNAs have been studied on their ability to down-regulate P-gp expression and restore cell sensitivity to P-gp drug substrates in drug resistant cells [34]. For example, miRNA-4539 could increase doxorubicin-mediated cell death in MDA-MB-231 breast cancer cells [93, 94].
The RNAi technologies involve either transient gene-silencing by siRNA or stable inhibition by MDR1 shRNA-transfected on plasmid DNA of MDR cancer cells. Treatment with siRNA against MDR1 increases drug-mediated cytotoxicity in various MDR cancer cells such as paclitaxel in MDR1 ovarian cancer cells and doxorubicin in doxorubicin-resistant breast cancer cells [95]. In addition, siRNA was able to significant reduced size of doxorubicin-resistant xenograft in a mouse model [96]. MDR1 ShRNA transfected in taxol-resistant human ovarian cancer cell line A2780 effectively down-regulated P-gp expression, and enhanced paclitaxel-mediated toxicity in this cells [97].
Selective suppression of P-gp/MDR1 expression with either microRNA or RNAi technologies offers the novel approach to specifically combat P-gp-based MDR in cancer, and re-sensitize the MDR cells to chemotherapeutic agents. However, for their therapeutic applications, there are several challenges required especially the effective miR/RNAi delivery to target cancer cells, design of expression vectors for shRNA, systemic stability and degradation, and safety of patients.
2.2.2.2.2 Small molecules as P-gp down-regulator
Numerous small molecules particularly those in the fourth generation of P-gp inhibitors such as curcumin, ginsenoside, quercetin and resveratrol have been demonstrated their ability to reduce P-gp function in the MDR cancer cells via down-regulation of P-gp expression [83, 84, 85]. By targeting at the signaling pathways related to transcription process of MDR1, several plant-based compounds suppress P-gp expression in the resistance cells and improve chemo-sensitivity to anticancer drugs. For instance, the P-gp modulating effect of asiatic acid, ginsenoside, isoquinoline alkaloids (e.g. cepharantine, tetrandine) resulted from their blockade of MAPK/ERK1/2 or PI3K/Akt pathways in MDR cancer cells [86, 98, 99, 100, 101]. Another isoquinoline alkaloid berberine inhibited P-gp expression and enhanced doxorubicin-mediated toxicity in MCF-7 cells through down-regulation of AMPK-HIF1α signaling cascade [102]. Anti-MDR property of natural curcuminoids (e.g., curcumin, bisdemethoxycurcumin) involved with inhibition of human MDR1 gene expression in MDR cervical carcinoma KB-V1 cells [103]. In addition, certain compounds such as a natural marine product Et743 inhibit MDR1 transcription via blocking its promoter activation [104].
3. Doxorubicin and P-gp
Doxorubicin is one of the most effective cytotoxic anticancer drugs. This drug has been used for combating various types of cancers such as cancers of breast, ovary, prostate, stomach, thyroid; small cell cancer of lung; squamous cell cancer of head and neck; multiple myeloma; Hodgkin’s disease; lymphomas; acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML). Unfortunately, the uses of doxorubicin can be limited because of its dose-related toxicity (e.g., nausea, vomiting, hair loss, leucopenia, cardiomyopathy, heart failure) and high MDR incidence [105, 106]. Despite the good clinical therapeutic responses are seen in patients receiving doxorubicin in the earliest stage of treatment, multi-drug resistance may later develop and lead to treatment failure.
One of the major mechanisms responsible for doxorubicin-induced MDR is up-regulation of MDR1/P-gp expression. Doxorubicin is an anthracycline derivative with a four-membered ring system containing an anthraquinone chromophore, and an aminoglycoside (Figure 1). This molecular structure accommodates its interaction with major MDR efflux transporters in the ABC superfamily proteins. It has been well established that doxorubicin and other anthracycline derivatives are P-gp substrates with ability to up-regulate P-gp/MDR1 expression after repeated exposure in various cancer cells such as breast and lung cancers as well as in vivo and in clinical settings [66, 107, 108]. For instance, lung perfusion with doxorubicin resulted in an increase of MDR1 RNA in patients with sarcoma pulmonary metastases [18]. The P-gp-overexpressed cancer cells would have intracellular doxorubicin concentration below its effective threshold level. Consequently, cancer cells increasingly survive from doxorubicin-mediated cytotoxity. In this circumstance, titrating dose up to overcome MDR may not enable to achieve a successful outcome due to dose-limiting toxicity. Because the adverse effects of doxorubicin and other anti-cancer drugs are mostly concentration-dependent, increasing doses can produce higher degree of severity and unendurable adverse events, leading to patient’s intolerability and even fatal outcome. Addition of other cytotoxic drugs into doxorubicin-based regimens may not also enable to obtain a chemotherapeutic success, if those drugs are also substrates of the MDR transporters.
Generally, clinical efficacy of doxorubicin depends on its pharmacokinetics after systemic exposure influencing (1) the therapeutic concentration at target organs, and (2) the homogeneity of drug distribution in the cancerous tissues particularly solid tumor. In addition, it is very critical that doxorubicin accumulates within the targeted cancer cells at the level greater than its cytotoxic threshold to elicit its pharmacological actions.
3.1 P-gp effects on doxorubicin’s Pharmacokinetics aspect
Doxorubicin is poorly absorbed through GI with low bioavailability (approximately 5%) after orally taken, due to its instability in stomach acidic pH and CYP450 biotransformation in liver. In addition, doxorubicin can induce cytotoxicity in normal tissue. Currently, doxorubicin is commercially available for cancer treatment in injection dosage form. Due to its lipophilicity, doxorubicin moves through plasma membrane into the cells via passive diffusion, and its extent of tissues/cellular permeation and cellular retention can be limit by the existence of efflux transporters particularly P-gp. Apparently, doxorubicin is extensively distributed to several organs such as liver, heart, kidney after injection. Being the efflux transporters, P-gp has a significant impact on doxorubicin distribution to certain target tissues such as brain, testes [109, 110]. Certain P-gp inhibitors such as PSC-833, piperine capsaicin, resveratrol, silymarin and quercetin were reported their influence on the pharmacokinetics and tissue distribution of doxorubicin in animal models [85, 110]. Capsaicin was reported to significantly increase the extent of doxorubicin accumulation in mice brain after iv injection probably through inhibition of P-gp at blood brain barrier [110]. In addition, piperine and capsaincin, through P-gp inhibition, reduced drug excretion into bile and urine, leading to increased drug levels in liver and kidney [110].
3.2 P-gp effects on doxorubicin’s Pharmacodynamic aspects
Critically, overexpression of P-gp on the plasma membrane of cancer cells is a major determinant in preventing intracellular doxorubicin accumulation up to its cytotoxic level. Doxorubicin resistant cancer cells clearly display significant lower intracellular doxorubicin retention with more tolerable to doxorubicin exposure than their parental sensitive cells [65, 66]. Thus, P-gp can be a potential therapeutic target for either MDR reversal or bio-enhancing effect in cancer therapy. The presence of P-gp modulators clearly demonstrates their abilities to restore doxorubicin-mediated killing effect in various cancer cells by increasing intracellular level of doxorubicin [66, 111]. Several plant-based compounds such as limonin, quercetin, resveratrol, curcumin and rhinacanthin-C at their non-cytotoxic concentration have been reported to significantly enhance doxorubicin-mediated cytotoxicity in various cancer resistance cells through modulation of P-gp function [66, 112]. These phytochemical P-gp modulators may suppress P-gp function either by direct inhibition of activity or down-regulation of protein expression.
Moreover, the influence of P-gp on clinical resistance to doxorubicin-based treatment has been reported in cancer patients [113, 114, 115, 116]. In order to improve drug efficacy and patient tolerability, several approaches targeting at the P-gp function and expression have been introduced to increase cellular doxorubicin drug level and restore drug sensitivity without the need of higher concentration or additional chemotherapeutic drugs in the therapeutic regimen.
4. Strategic approaches to overcome P-gp mediated resistance to doxorubicin
Taken that doxorubicin is a known substrate of P-gp, the drug efflux transporters in the ATP binding cassette (ABC) family. Hence, any approaches target at the function of these transporters can be presumed to increase therapeutic success for doxorubicin-based chemotherapeutic regimens. Regarding this, the strategies are as follows:
Increases in dose of doxorubicin or number of cytotoxic drugs to achieve therapeutic success. This has not been a satisfactory approach due to drug toxicity and patients’ intolerability.
Utilization of P-gp modulators to inhibit either function or expression.
Development of better drug delivery platforms to bypass P-gp activity, leading to increase intracellular retention of doxorubicin within target cells.
The current MDR reversal strategy has been exploited P-gp modulators that either directly inhibit P-gp activity or down-regulate P-gp expression in order to restore cell chemo-sensitivity to doxorubicin [107]. With the encapsulation technology, P-gp modulators can be co-administered with doxorubicin in the same drug delivery platform, and enhance intracellular doxorubicin accumulation. This approach can be accomplished if the potent, non-cytotoxic P-gp modulators that specifically target at cancer cells are implemented. In addition, the P-gp modulators that also target at non-transporter based resistance such as activation of cellular survival pathways can exert potentially synergistic impact on MDR reversal effect and better response to doxorubicin treatment. Collectively, the combined doxorubicin and P-gp modulators with multiple-hit targets is a promising strategy to achieve chemotherapeutic efficacy without the need of high dose or additional cytotoxic drugs in the therapeutic regimen.
4.1 Synergy with P-gp modulators
This approach aims to suppress P-gp activity at plasma membrane of target cancer cells. Several P-gp modulators in combination with anti-cancer drugs have been evaluated for safety and efficacy in clinical trials. The clinical outcomes from the first three generations of ABC inhibitors such as quinine, verapamil, cyclosporine-A, tariquitor, PSC 833, LY335979, and GF120918 were quite disappointed, partly because of their dose-limiting adverse events. Most of the P-gp inhibitors required high doses for their clinical MDR reversal effects. In addition, their interference on the P-gp or other ABC transporters at non-target tissues such as brain and kidney could adversely increase accumulation of cytotoxic drugs in these tissues.
The fourth generation of P-gp modulators which are mostly natural products have gained a great interest as potential chemosensitizers in MDR cancer treatment. The advantages of being natural products with long history of use are inclined to the known safety profiles in human and potential hit multiple targets that can restore cell sensitivity to doxorubicin. In addition to direct inhibition of P-gp activity, a number of the natural compounds at non-cytotoxic concentration elicit their chemo sensitizing effects through down-regulation of MDR1 and signaling proteins in cell adaptive survival mechanisms. The higher degree of synergism between doxorubicin and a P-gp modulator can be anticipated with potential therapeutic success. Synergistic outcomes between doxorubicin and natural compounds such as resveratrol, quercetin, silymarin, gallic acid, curcumin, epigallocatechin-3-gallate have been demonstrated in various cancer cell models [82, 83, 103, 111, 117, 118, 119, 120]. In addition to P-gp modulatory activity (inhibiting both P-gp function and expression), these natural compounds have a broad spectrum of pharmacological activities such as antioxidant, anticancer, anti-inflammation, possible through multiple signaling pathways. For example, the biological effects of curcumin have been related to multiple signaling pathways including NF-kB, Akt, MAPK, Nrf2, AMPK, JAK/STAT that involve in MDR1 expression, cell inflammation, and apoptosis [121]. Co-administration of doxorubicin and curcumin significantly improved doxorubicin-mediated cytotoxicity in vitro cell models and in vivo hepatic xenograft mice model, compared with doxorubicin alone [121, 122, 123, 124, 125].
In addition to chemical-based modulators, the uses of specific antibody against P-gp or RNA interference (RNAi) technology to silence P-gp expression may be effective approach to suppress P-gp activity and restore chemo-sensitivity to doxorubicin treatment. Clinical studies on these MDR reversing methods should be extensively conducted to support their uses and benefits in cancer patients.
4.2 Drug delivery system and formulation
This approach aims to develop targeted delivery platforms for improving the permeation of doxorubicin/P-gp modulators/ chemo-sensitizers (e.g., antibodies against ABCB1, siRNA) into target cancer cells, leading to an increased intracellular doxorubicin concentration [3, 89, 96, 126, 127, 128]. Various nano-drug delivery platforms such as polymeric and solid lipid nanoparticle (SLNs), liposomes, micelles, mesoporous silica nanoparticles, nanostructured lipid carriers, dendrimers have been constructed to better targeting drug delivery to site of action. This approach in couple with utilization of P-gp modulators can overcome MDR and enhance therapeutic efficacy of doxorubicin. Furthermore, with cancer-targeting ability, this target specific delivery would limit the adverse effect to normal tissues. With the encapsulation technology, nanoparticles (NPs) loaded with doxorubicin and P-gp modulators or other molecules (e.g., siRNAs) has been reported their effectiveness in target delivery into the cells. For examples, aerosol OT (AOT)-alginate NPs enhanced cellular delivery of doxorubicin in MCF-7 cells [129]. Lipid-modified dextran-based NPs loaded with doxorubicin and MDR1 siRNA significantly increased intracellular doxorubicin and reduced P-gp expression levels in osteosarcoma cell line, as compared to doxorubicin alone [130]. Doxorubicin-curcumin composite NPs (e.g., NanoDoxCurc, pegylated-DOX-CUR NPs) could enhance effects of doxorubicin both in vitro and in vivo models of DOX-resistant cancers (e.g., multiple myeloma, acute leukemia, prostate and ovarian cancers). In addition, doxorubicin-curcumin NPs did not cause cardiac toxicity and bone marrow suppression in mice model [131].
5. Conclusion
Doxorubicin is an effective anti-cancer drug that has high MDR incidence. High expression of an efflux transporter P-gp is one established mechanism responsible for the loss of drug effectiveness and MDR development. This can be due to the P-gp function in preventing intracellular accumulation of doxorubicin up to its effective level. Several approaches have been introduced in order to increase the efficacy of doxorubicin-based chemotherapy and overcome MDR. The combination of doxorubicin and non-cytotoxic P-gp modulators, particularly when given to the specific target cancer can be a promising approach to increase cancer sensitivity to doxorubicin through suppression of P-gp function. With the novel encapsulation technologies, it is very possible to develop the drug delivery platforms with specific targeted cancer cells as well as improvement of doxorubicin delivery into the cells. By these means, enhancement of doxorubicin-mediated cytotoxicity can be achieved with minimal dosing of the anti-cancer drugs. After clinically approval, it will provide a great benefit to patients receiving doxorubicin-based chemotherapy.
Acknowledgments
The author gratefully thanks IntechOpen Limited for the sponsorship program in publishing this work.
Conflict of interest
The Author declares no conflicts of interest.
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Moreover, these P-gp-overexpressed cells display multi-drug resistance (MDR) phenotype. Regarding this, application of P-gp modulators (suppressor of P-gp activity and expression) is likely to reverse MDR and restore cell sensitivity to doxorubicin treatment. In searching for potential chemo-sensitizer against resistant cancer, a number of phytochemicals or dietary compounds have been studied extensively for their P-gp modulating effects. Furthermore, combination between doxorubicin and P-gp modulators (e.g., plant-derived compounds, siRNA) given through specific target delivery platforms have been an effective strategic approach for MDR reversal and restore doxorubicin effectiveness for cancer treatment.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/74811",risUrl:"/chapter/ris/74811",signatures:"Suree Jianmongkol",book:{id:"10194",title:"Overview of Doxorubicin - Clinical Use, Resistance, Side Effects, and Palliative Care",subtitle:null,fullTitle:"Overview of Doxorubicin - Clinical Use, Resistance, Side Effects, and Palliative Care",slug:null,publishedDate:null,bookSignature:"Dr. Bassam Abdul Rasool Hassan",coverURL:"https://cdn.intechopen.com/books/images_new/10194.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"155124",title:"Dr.",name:"Bassam",middleName:"Abdul Rasool",surname:"Hassan",slug:"bassam-hassan",fullName:"Bassam Hassan"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. The drug efflux transporter: P-glycoprotein",level:"1"},{id:"sec_2_2",title:"2.1 Overview of P-gp (structure, function, location, expression, and MDR)",level:"2"},{id:"sec_2_3",title:"2.1.1 P-gp and its normal physiological functions",level:"3"},{id:"sec_3_3",title:"2.1.2 P-gp expression and signaling pathways",level:"3"},{id:"sec_4_3",title:"2.1.3 P-gp and multi-drug resistance in cancer",level:"3"},{id:"sec_6_2",title:"2.2 Substrates and modulators",level:"2"},{id:"sec_6_3",title:"2.2.1 Substrates",level:"3"},{id:"sec_7_3",title:"2.2.2 Modulators",level:"3"},{id:"sec_7_4",title:"2.2.2.1 Direct inhibition of functionally active P-gp",level:"4"},{id:"sec_8_4",title:"2.2.2.2 Suppressor of P-gp expression",level:"4"},{id:"sec_8_5",title:"2.2.2.2.1 MicroRNA and RNA interference (RNAi) technologies",level:"5"},{id:"sec_9_5",title:"2.2.2.2.2 Small molecules as P-gp down-regulator",level:"5"},{id:"sec_14",title:"3. Doxorubicin and P-gp",level:"1"},{id:"sec_14_2",title:"3.1 P-gp effects on doxorubicin’s Pharmacokinetics aspect",level:"2"},{id:"sec_15_2",title:"3.2 P-gp effects on doxorubicin’s Pharmacodynamic aspects",level:"2"},{id:"sec_17",title:"4. Strategic approaches to overcome P-gp mediated resistance to doxorubicin",level:"1"},{id:"sec_17_2",title:"4.1 Synergy with P-gp modulators",level:"2"},{id:"sec_18_2",title:"4.2 Drug delivery system and formulation",level:"2"},{id:"sec_20",title:"5. Conclusion",level:"1"},{id:"sec_21",title:"Acknowledgments",level:"1"},{id:"sec_24",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Robey RW, Pluchino KM, Hall MD, Fojo AT, Bates SE. and Gottesman MM. (2018). Revisiting the role of ABC transporters in multidrug-resistant cancer. Nature reviews Cancer 18(7): 452-464.'},{id:"B2",body:'Liu X. (2019). ABC Family Transporters. 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PD-L1 monoclonal antibody-decorated nanoliposomes loaded with Paclitaxel and P-gp transport inhibitor for the synergistic chemotherapy against multidrug resistant gastric cancers. Nanoscale Res Lett 15(1):59.'},{id:"B129",body:'Chavanpatil MD, Khdair A, and Panyam J. (2007). Surfactant-polymer Nanoparticles: A Novel Platform for Sustained and Enhanced Cellular Delivery of Water-soluble Molecules. Pharmaceutical Research 24(4):8.3-810.'},{id:"B130",body:'Susa M, Iyer AK, Ryu K, Choy E, Hornicek FJ, Mankin H, Milane L, Amiji MM, and Duan Z. (2010). Inhibition of ABCB1 (MDR1) Expression by an siRNA Nanoparticulate Delivery System to Overcome Drug Resistance in Osteosarcoma. PLoS One. 5(5): e10764.'},{id:"B131",body:'Pramanik D, Campbell NR, Das S, Gupta S, Chenna V, Bisht S, Sysa-Shah P, Bedja D, Karikari C, Steenbergen C, Gabrielson KL, Maitra A, and Maitra A. (2012). A composite polymer nanoparticle overcomes multidrug resistance and ameliorates doxorubicin-associated cardiomyopathy. 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