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The major limitation of microsomes is that inhibition parameters may not accu- rately reflect the situation in vivo buy quetiapine 100 mg lowest price medications known to cause tinnitus, since the contribution of drug transport is not considered. The best picture of a potential drug-drug interaction can be obtained in metabolically competent hepatocytes. Human hepatocytes in primary culture respond well to enzyme inducers during the first few days; this ability is lost thereafter. Hepatoma cell lines respond poorly to inducers, although the induction of a few isoenzymes has been reported. Primary cultured hepatocytes are still the unique in vitro model that allows global examination of the inductive potential of a drug. Genetically manipulated cell lines that express enzymes and respond to inducers would be more suitable for this purpose as an alternative to the use of human hepatocytes. Universal Free E-Book Store Role of Pharmacogenetics in Pharmaceutical Industry 111 Polymorphism of Drug Transporters Transporters are involved in the transport of proteins, peptides, amino acids, ions and certain drugs. Transport proteins have an important role in regulating the absorption, distribution, and excretion of many medications. Disorders associated with defects in solute transporters, such as severe diarrhea in glucose/galactose malabsorption and pri- mary bile acid malabsorption may be associated with pronounced general changes in drug absorption. Several investigations are aimed at clarifying the role of trans- porters in drug absorption, disposition, and targeting. Another important gene family is the biogenic amine transporters, which regu- late neurotransmitter levels in synaptic transmission, with a number of documented variants that may affect function. These transporters are the direct target receptors for numerous drugs, including antidepressants and cocaine. Allelic variations, in particular of the serotonin transporter, are associated with the modulation of com- plex behavior and may play a significant role in therapy with specific serotonin transporter inhibitors. Variation in neurotransmitter receptors can also be the cause of treatment failure. Genetic polymorphism of the β2-adrenoreceptor can alter the process of signal transduction by these receptors. Polymorphisms in drug target genes that can influence drug response are listed in Table 4. Protein kinases are coded by more than 2,000 genes and thus constitute the largest single enzyme family in the human genome. Amplicon modeling, primer design and assay vali- dation have been established for over 1,600 amplicons within 92 different kinase genes. Kinase mutation mapping can be used to pinpoint responder populations and facilitate the development of person- alized medicine. Effect of Genetic Polymorphisms on Disease Response to Drugs Genetic polymorphism of genes and gene products may influence the disease- modifying effects of drugs. It offers 1,936 high value, biologically relevant markers in 225 drug metabolism enzyme, trans- porter, and transferase genes. Such informa- tion is useful in identifying the responders to drugs and is discussed further in sub- sequent chapters. Ethnic Differences in Drug Metabolism Ethnic differences in drug metabolism are well documented for a number of drugs. The molecular mechanisms responsible for ethnic differences in drug metabolism have been partly clarified because of the advances in molecular biology. Genotype analysis indicates a different frequency for the mutant alleles in different ethnic populations, which results in variations in the frequency of subjects who are homo- zygous for the mutant allele among the extensive metabolizers in different ethnic populations. Ethnic differences in drug metabolism may result from differences in distribution of a polymorphic trait and mutations, which code for enzymes with abnormal activity which occur with altered frequency in different ethnic groups. Ethnic factors, therefore, are an important consideration in individualization of therapy. Gender Differences in Pharmacogenetics There are gender-related differences in pharmacokinetics, which may be related to pharmacogenetic differences in to drug-metabolizing enzymes. Other gender differences in pharmacokinetics may be due to fluctuations in hormone levels in women with menstruation and pregnancy.
Gram-positive bacteria with thick external cell walls are particularly susceptible generic 300 mg quetiapine medications medicaid covers. The genes for b-lactamases can be transmitted during conjugation or as small plasmids (minus conjugation genes) via transduction. Common organisms capable of producing penicillinase include Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Neisseria gonorrhoeae, and Bacillus, Proteus, and Bacteroides species. Selected drugs and their therapeutic uses (Table 11-1) (1) Penicillin G and penicillin V are mainly used to treat infections with the following organisms (resistant strains of bacteria are being isolated more frequently): (a) Gram-positive cocci (aerobic): Pneumococci, streptococci (except S. This group represents the most common pathogens for which first-generation penicillins are used today. Pro- benicid, a uricosuric agent that blocks renal secretion of penicillin, is used rarely for this purpose. Chapter 11 Drugs Used in Treatment of Infectious Diseases 255 (3) Penicillinase-resistant penicillins (oxacillin, dicloxacillin, and nafcillin) are used pre- dominantly for penicillinase-producing staphylococcal infections. Ampicillin is useful for infections caused by Haemophilus influenzae, Streptococcus pneumonia, Streptococcus pyrogenes, Neisseria meningitides, Pro- teus mirabilis, and Enterococcus faecalis. Amox- icillin is commonly used for endocarditis prophylaxis before major procedures. Piperacillin/tazobactam is effective against most gram-negative organisms, including Pseudomonas spp. Adverse effects (1) Penicillins cause hypersensitivity reactions in nearly 10% of patients. All types of reac- tions, from a simple rash to anaphylaxis, can be observed within 2 minutes or up to 3 days following administration. Endocarditis prophylaxis (1) Endocarditis prophylaxis is indicated for patients with prosthetic heart valves; those who have previously been diagnosed with endocarditis; patients born with cyanotic heart disease; and patients with surgically constructed systemic pulmonary shunts. Patients with intermediate risk for endocarditis are those who were born with other con- genital cardiac abnormalities; those with acquired valvular dysfunction; and patients with hypertrophic cardiomyopathy. Structure and mechanism of action (1) Cephalosporins consist of a 7-aminocephalosporanic acid nucleus and a b-lactam ring linked to a dihydrothiazine ring (see Fig. Third-generation cephalosporins are sensitive to another class of b-lactamase, the cephalosporinases (genes are generally located on chromosomes as opposed to plasmids). They are used in treatment of streptococcal infections as well as infections Chapter 11 Drugs Used in Treatment of Infectious Diseases 257 caused by E. Ceftriaxone is used for sexually trans- mitted infections caused by gonorrhea, as well as in empiric therapy for commu- nity-acquired meningitis. Adverse effects and drug interactions (1) Cephalosporins most commonly cause hypersensitivity reactions (2%–5%); 5%–10% of penicillin-sensitive persons are also hypersensitive to cephalosporins. Aztreonam (Azactam) (1) Aztreonam is a naturally occurring monobactam lacking the thiazolidine ring that is highly resistant to b-lactamases. Vancomycin (Vancocin, Vancoled) (1) Vancomycin is a tricyclic glycopeptide that binds to the terminal end of growing pepti- doglycan to prevent further elongation and cross-linking; this results in decreased cell membrane activity and increased cell lysis. Rapid infusion may cause anaphylactoid reactions and ‘‘red neck’’ syndrome (flushing caused by release of histamine). Bacitracin (1) Bacitracin inhibits dephosphorylation and reuse of the phospholipid required for accep- tance of N-acetylmuramic acid pentapeptide, the building block of the peptidoglycan complex. Cycloserine (Seromycin) (1) Cycloserine is an amino acid analogue that inhibits alanine racemase and the incorpo- ration of alanine into the peptidoglycan pentapeptide. Daptomycin (Cubicin) (1) Daptomycin is a bactericidal agent that binds to and depolarizes the cell membrane resulting in loss of membrane potential and rapid cell death. Fosfomycin (Monural) (1) Fosfomycin inhibits the enzyme enolpyruvate transferase and therby interferes down- stream with the formation of bacterial cell wall specific N-acetylmuramic acid. Structure and mechanism of action (1) Aminoglycosides are amino sugars in glycosidic linkage to a hexoseaminocyclitol. Transport across the inner membrane requires active uptake that is dependent on electron transport (gram- negative aerobes only), the so-called energy dependent phase I transport. This ‘‘freezes’’ the initiation complex and leads to a buildup of monosomes; it also causes translation errors. Selected drugs and their therapeutic uses (1) The role for aminoglycosides has decreased substantially due to their narrow spectrum of activity and toxicity, and the availability of other agents. Adverse effects (1) Aminoglycosides have a narrow therapeutic index; it may be necessary to monitor se- rum concentrations and individualize the dose.
Genetic Polymorphism and Management of Alcoholism Several gene variants have been identified as risk or protective factors in alcoholism generic quetiapine 100 mg online symptoms enlarged spleen. The genes coding for dopamine receptors, serotonin transporters, and dehydroge- nases represent susceptibility loci for addictive behavior. The presence of the L versus the S allele on a serotonin transporter gene has been found to influence responses to ondansetron. Alcoholics with the L-allele have greater alcohol craving than those with the S-allele, and polymorphisms in another receptor result in differences in sensitivity to benzodiazepines used to treat early stage alcohol withdrawal systems. Alcoholism is a complex psychiatric disorder caused by multiple factors, both genetic and environmental. Furthermore, there are probably different subtypes of alcoholism each with a distinct genetic background, which require different thera- peutic approaches. However, gene polymorphisms are not only responsible for a predisposition to alcoholism, but also for the way an individual responds to treat- ment. Because of the genetic heterogeneity between alcoholics there is no one drug that works in all patients, which has made it necessary to provide multiple treatment options that clinicians can use to find which ones work. A personalized treatment that matches specific interventions to the individual, particularly to an individual’s genetic profile, is more efficient. Topiramate has been shown to reduce drinking and heavy drinking in individuals with alcohol dependence whose goal is to stop drinking. A randomized study has evaluated the efficacy and tolerability of topiramate in heavy drinkers whose treat- ment goal is to reduce drinking to safe levels (Kranzler et al. The moderator effect of rs2832407, if validated, would facilitate the identification of heavy drinkers who are likely to respond well to topiramate treatment and provide an important Universal Free E-Book Store Personalized Approach to Addiction 475 Table 13. New treatment strategies focusing on genes contribut- ing to drug and alcohol dependence (such as gene therapy) have been examined in animal models and clinical trials have been conducted with drugs. However, further research is required before these developments will consider- ably change today’s clinical handling of alcoholism on an individual basis. Various human and animal studies can help to determine the full range of genetic variation affecting the pharmacodynamic and pharmacokinetic parameters that result in altered drug efficacy and toxicity. Sequencing technologies to identify variations in candidate genes that may play a role in drug responses, use of pharmacogenetic testing to examine genetic variability in side effects from medi- cation, and use of gene expression profiling to determine transcriptomics changes associated with drug response. Personalized Therapy for Smoking Cessation The evidence to date is very consistent with respect to the significance of genetic contributions to smoking behavior. Variants in the genes encoding the α5-α3-β4 nico- tinic receptor subunits most strongly contribute to differences in the risk for develop- ing nicotine dependence among smokers and a differential response to pharmacologic treatment for smoking cessation (Bierut et al. As the field of genetics and smoking research progresses, increasing attention is being devoted to gene-environ- ment interactions, with particular attention to the identification of genetic variants that may modify the effects of pharmacological treatment for smoking. Universal Free E-Book Store 476 13 Personalized Management of Psychiatric Disorders With advances in molecular biology and genomics technology, individualization of smoking cessation therapy according to genotype is within our grasp. Such research has the potential to improve treatment outcome, thereby reducing morbid- ity and mortality from smoking-related disease. A dopamine receptor gene polymorphism appears to influence the response of cigarette smokers to smoking cessation therapy that includes an antidepressant medicine − venlafaxine. A clinical trial showed no significant difference between the active and placebo treatments for the smokers with the A1 allele in terms of reduction in negative affect during their attempt to quit but those with the A2 allele receiving venlafaxine have 25 % lower score on testing for negative affect. This demonstrates the value of genotyping in designing a spe- cific smoking cessation therapy for a subgroup of patients. Effectiveness of Nicotine Patches in Relation to Genotype In women the effectiveness of nicotine patches seems to be related to genotype. The increased effectiveness reflected a tendency to a higher quit rate with the active patches and a lower quit rate with placebo patches. The overall effectiveness of nicotine replacement therapy could be greater if the therapy were targeted at those most likely to respond. Future Prospects of Personalized Psychiatry Limited number of applications of personalized medicine approach in psychiatry has shown the usefulness of this approach and identified this as an area for further development. Pre-emptive approaches are an important part of personalized medi- cine and preventive psychiatry requires predictive tools that are currently not ade- quate. Biomarkers are needed to develop a clinical staging model for psychiatric disorders.
A hypothesis has been presented generic 100mg quetiapine with mastercard medications gabapentin, which states that commonly-used pharmaceutical drugs can cause such persistent epigenetic changes (Csoka and Szyf 2009). An example of an indirectly acting drug is isotretinoin, which has transcription factor activity. A two-tier mechanism is Universal Free E-Book Store 146 4 Pharmacogenetics postulated for indirect effects in which acute exposure to a drug influences signaling pathways that may lead to an alteration of transcription factor activity at gene promoters. This stimulation results in the altered expression of receptors, signaling molecules, and other proteins necessary to alter genetic regulatory circuits. Therefore, any epigen- etic side-effect caused by a drug may persist after the drug is discontinued. It is further proposed that some iatrogenic diseases such as tardive dyskinesia and drug- induced systemic lupus erythematosus are epigenetic in nature. If this hypothesis is correct the consequences for modern medicine are profound, since it would imply that our current understanding of pharmacology is an oversimplification. Thus epi- genetic side-effects of pharmaceuticals may be involved in the etiology of heart disease, cancer, neurological and cognitive disorders, obesity, diabetes, infertility, and sexual dysfunction. It is suggested that a systems biology approach employing microarray analyses of gene expression and methylation patterns can lead to a better understanding of long-term side-effects of drugs, and that in the future, epigenetic assays should be incorporated into the safety assessment of all pharmaceutical drugs. The impact of pharmacoepigenomics may be equal to or greater than that of pharmacogenetics. Future Role of Pharmacogenetics in Personalized Medicine The number of polymorphisms identified in genes encoding drug metabolizing enzymes, drug transporters, and receptors is rapidly increasing. In many cases, these genetic factors have a major impact on the pharmacokinetics and pharmaco- dynamics of a particular drug and thereby influence the sensitivity to such drug in an individual patient with a certain genotype. Many of the genes examined in early studies were linked to highly penetrant, single-gene traits, but future advances hinge on the more difficult challenge of elucidating multi-gene determinants of drug response. In order to apply the increasing amount of pharmacogenetic knowledge to clini- cal practice, specific dosage recommendations based on genotypes will have to be developed to guide the clinician, and these recommendations will have to be evalu- ated in prospective clinical studies. Such development will lead to personalized medicines, which hopefully would be more efficient and will result in fewer adverse drug reactions. Epigenetic side-effects of common pharmaceuticals: a potential new field in medicine and pharmacology. Pharmacogenomic biomarker information in drug labels approved by the United States food and drug administration: prevalence of related drug use. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Investigating drug-induced mitochondrial toxicity: a biosensor to increase drug safety? A preliminary pharmacogenetic investigation of adverse events from topiramate in heavy drinkers. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent place- ment. Establishing the characteristics of an effective pharmaco- genetic test for clozapine induced agranulocytosis. Currently, it is estimated that there are approximately 19,000 genes in the human organism. Several new technologies have been devel- oped to study the genome and new terms have been derived from genomics, the best known of which is pharmacogenomics. Completion of sequencing of the human genome has opened a new era for improved understanding of the genetic basis of human diseases and to provide new targets for drug discovery. Pharmacogenomics is an important basis for the development of personalized medicines. Pharmacogenomics implies the use of genetic sequence and genomics informa- tion in patient management to enable therapy decisions.
