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Alimentary Pharmacology & Therapeutics Review article: the prevalence and clinical relevance ofcytochrome P450 polymorphisms P . A . H . M . W I J N E N * , R . A . M . O P D E N B U I J S C H * , M . D R E N T   , P . M . J . C . K U I P E R S à , C . N E E F § , A . B A S T – , O . B E K E R S * & G . H . K O E K * * Most drugs currently used in clinical practice are effective in only 25% to 60% of patients, while adverse drug reactions (ADRs) as a conse- quence of treatment are estimated to cost billions of US dollars and tens enterology ⁄ Hepatology, Departmentof Internal Medicine, University To review the prevalence and clinical significance of cytochrome P450 The cytochrome P450 enzyme families 1–3 are responsible for 70 to 80% of all phase I dependent drug metabolisms. In 90% metabolic activity dependents on six enzymes: CYP1A2, CYP3A, CYP2C9, CYP2C19, CYP2D6 and CYP2E1. Polymorphisms in the CYP450 gene can influence metabolic activity of the subsequent enzymes. A poormetabolizer (PM) has no or very poor enzyme activity. A consequence of PM is drug toxicity if no other metabolic route is available, or when multiple drugs are metabolized by the same cytochrome. In that casedose reduction is an option to prevent toxic effects.
ConclusionsIn the future genotyping should be considered to identify patients who might be at risk of severe toxic responses, in order to guide appropriate individual dosage. Medical therapy should be a close cooperationbetween clinicians, pharmacologists and laboratory specialists, leadingto reduced therapeutic errors, ADRs and health care costs.
Aliment Pharmacol Ther 26 (Suppl 2), 211–219 Journal compilation ª 2007 Blackwell Publishing Ltddoi:10.1111/j.1365-2036.2007.03490.x 212 P . A . H . M . W I J N E N et al.
(absorption, distribution, metabolism and excretion) of a certain drug (Table 1). The existence of large popula- The success of modern medicine is partly the result of tion differences with small intra-patient variability is effective medical treatment. Although the overall consistent with inheritance as determinant of drug advantage of many drugs outweighs the side effects, response; it is estimated that genetics can account for substantial costs are still made due to the complica- 20–95% of variability in drug disposition and effects.6 tions of drug therapy. Adverse drug reactions (ADRs) Two metabolization routes (phase I and phase II reac- account for 8.2% hospital admissions in the Nether- tions) in the liver are responsible for the transforma- lands, four times more often in elderly persons. An tion of the majority of the clinically used medication.
estimated calculation showed that about 430 million Phase I reactions, performed mainly by cytochrome euros could be saved each year when side effects are P450 enzymes, involve hydroxylation, reduction and reduced.1 More recently an observational study was oxidation while in phase II reactions glucuronidation, performed in 21 different Dutch hospitals which sulfation, acetylation or methylation take place (Fig- showed that 2.4% of hospitalizations were the result of ure 1). These processes enhance the polarity or water ADRs. Calculations showed that 85 million Euros solubility of the resulting metabolites, thus facilitating could be saved when these ADRs were prevented their removal through urine or bile. With the wide- (http://www.nvza.nl; Hospital Admissions Related to spread possibility of determining the genetic profile of the cytochrome P450 enzymes, the metabolic capacity In the United States, as many as 3% of the hospital- can be determined. Patients can be divided into ultra izations per year are for reasons of drug–drug interac- extensive (UEM), extensive (EM), intermediate (IM) or tions.2 ADRs are the fourth to sixth leading cause of poor metabolizers (PM).7 Important cytochrome P450 death and direct hospital costs are between 1.56 and 4 enzymes for drug metabolism are 1A2, 2C9, 2C19 and billion dollars.3 Pirmohamed et al.4 analysed 18 820 2D6. This review will focus on the clinical relevance hospitalizations in the United Kingdom (UK) in 2004 and prevalence of cytochrome P450 polymorphisms and found a correlation in 1225 cases between ADRs that are important in metabolism of many clinically and the use of drugs like acetylic acid, diuretics, war- farin and non-steroidal anti-inflammatory drugs. Byextrapolating these numbers Hitchen5 reported that C Y T O C H R O M E P 4 5 0 E N Z Y M E S ADRs are the cause of 250 000 hospitalizations peryear in the UK. Thus, drug interactions have become The completion of the sequence of the human genome an important preventable iatrogenic complication and revealed the presence of 115 human CYP genes: 57 therefore knowledge of drug metabolisms is a prere- active and 58 pseudo-genes8 which are summarized at quisite to prevent ADRs. The variability in drug response among patients is multi-factorial, including P450.html. An overview regarding some relevant extrinsic factors like environmental aspects and also Internet sites about cytochrome P450 enzymes is genetic and intrinsic factors that affect the disposition shown in Table 2. The cytochrome P450 enzymes are Prescribed drugsOver-the-counter drugsHerbal supplements Disturbed kidney excretion functionDiminished liver blood perfusionChanged metabolic function Polymorphisms in genes encoding metabolic enzymes ª 2007 The Authors, Aliment Pharmacol Ther 26 (Suppl 2), 211–219Journal compilation ª 2007 Blackwell Publishing Ltd R E V I E W : C Y T O C H R O M E P 4 5 0 P O L Y M O R P H I S M S Lipid-soluble drugs
Adding polar group
Product of
oxidation
reduction
hydrolysis
Conjugation
Glucuronyltransferase
Sulfonyltransferase
Water-soluble product
Figure 1. Most metabolic biotransformations occur at some point between absorption of the drug into the gen- eral circulation and its renal elimination. A few transfor- mations occur in the intestinal lumen or intestinal wall.
In general, all these reactions can be assigned to one of two major categories called phase I and phase II reac- a superfamily of haemoproteins that are the terminaloxidases of the mixed function oxidase system foundon the membrane of the smooth endoplasmic reticu-lum preferentially expressed in the centrilobular areaof the liver.9 Explanation of the term cytochrome P450 is: cyto stands for microsomal vesicles, chrome for coloured, Pfor pigmented and 450 for the 450 nanometer spectro- phometric absorption peak.10 Cytochrome P450 pro- teins are conveniently arranged into families andsubfamilies on the basis of percentage amino acidsequence identity;11–16 ‡40% identity on amino acid level is required for being in the same family, a letterindicating the subfamily ‡55% amino acid sequence identity and a number for the gene. Figure 2 illustratesan example of the cytochrome P450 enzyme nomen- http://drnelson.utmem.edu/cytochromeP450.html http://www.genotest.com/human_p450_database/index.h clature. The cytochrome P450 isoenzymes in families1–3 are responsible for 70–80% of all phase I-depen-dent metabolism of clinically used drugs17–19 and par-ticipate also in the metabolism of a large number of Substances (medicines or other compounds) that are metabolized by cytochrome P450 enzymes are called substrates. Some substances can inhibit the action of a cytochrome (so-called inhibitors), for CYP3A4, while other substances (so-called inducers) can enhance the metabolism of a specific cytochrome P450 enzyme, for example smoking induces the ª 2007 The Authors, Aliment Pharmacol Ther 26 (Suppl 2), 211–219Journal compilation ª 2007 Blackwell Publishing Ltd 214 P . A . H . M . W I J N E N et al.
CYP 2 D 6 *4 Cytochrome 1A2 (CYP1A2) is found exclusively in the liver and the metabolic activity is primarily hydroxyl- ation and demethylation of compounds through oxida- tive metabolism. Substrates for CYP1A2 metabolism are, for example, caffeine,22 theophylline and nap-roxen.23 When any of these medicines is used with a Figure 2. An example of the nomenclature of the cyto- CYP1A2 inhibitor, serum levels of the former may chrome P450 enzymes. The number of the cytochrome increase, and toxicity may result. Compounds with P450 2D6 alleles can vary from *1 to *63. The wild typeallele is indicated with *1 and has a normal functioning inhibiting capacity for CYP1A2 are, for example, cytochrome P450 2D6 enzyme whereas the variant alleles grapefruit juice and drugs like fluvoxamine24 and the of CYP2D6 indicated with the higher allele numbers have fluoroquinolone antibiotic ciprofloxacin.25 Induction an aberrant functioning cytochrome P450 2D6 enzyme.
of the CYP1A2 metabolism can be achieved by Brus-sels sprouts, broccoli, cabbage and other cruciferousvegetables, and charbroiled foods (burned meats). An The metabolic capacity of the different cytochrome important toxin that induces the working of CYP1A2 P450 enzymes is also defined as low affinity ⁄ high is tobacco smoke, probably through stimulation of capacity or high affinity ⁄ low capacity. The CYP2D6 enzyme is, like CYP2C9 and CYP2C19, defined as a high affinity ⁄ low capacity, which implies that these CYP2E1, CYP1A1 and CYP1B1) often metabolizes cytochrome P450 enzymes prefer to metabolize spe- cific substrates at a low concentration. As the concen- Cytochrome 1A2 is a low affinity ⁄ high capacity tration of a medicine increases, the metabolism can enzyme in contrast to CYP2D6, CYP2C9 and CYP2C19 spill over to CYP3A4 and CYP1A2, which are low in the metabolism of many drugs.29 Gender differences have been found in the Chinese population, with men A difference is found between the CYP expression summarized in Table 3. In some cases probe drugsare used to investigate the metabolic activity of CYP Cytochrome 2C9 (CYP2C9) is found in various tissues Extra-hepatic cytochrome P450 enzymes have been like the kidney, testes, glands, prostate, ovary and duo- identified in a wide range of tissues, which include the denum.31 Most of the CYP2C9 activity in terms of drug small intestine, pancreas, brain, lung, adrenal gland, metabolism takes place in the liver.32 To date, 30 vari- kidney, bone marrow, mast cells, skin, ovary and tes- ant alleles of the CYP2C9 enzymes have been identified tis.21 Specific for drug metabolism, important cyto- and Lee et al.33 determined that two of these CYP2C9 chromes, such as 1A2, 2D6, 2C6 and 2C19, are variant alleles, *2 and *3, are found in 35% of the Cau- casians. These CYP2C9 variant alleles are present muchless frequently in African Americans and Asians. Thegenetic Table 3. Difference between CYP P450 distribution and defined as EM, PM and IM (summarized in Table 4).
Some drugs such as tolbutamide34 and phenytoin35 have been used as probe drugs for CYP2C9 activity.
Patients with the CYP2C9*2 variant allele and the CYP2C9*3 variant allele require lower maintenance doses of warfarin because of the reduced activity of these common variants. The most effective CYP2C9 although the more commonly prescribed azole anti-fungal ª 2007 The Authors, Aliment Pharmacol Ther 26 (Suppl 2), 211–219Journal compilation ª 2007 Blackwell Publishing Ltd R E V I E W : C Y T O C H R O M E P 4 5 0 P O L Y M O R P H I S M S are also involved. Aoyama et al.49 discovered that Table 4. Prevalence (%) of CYP genotype in the Cauca- patients with Helicobacter pylori (HP) gastritis who were PMs for CYP2C19 responded better to both ame- lioration of symptoms and eradication HP. This out-come is thought to be due to the higher exposure to serum omeprazole in PMs. In subsequent studies, some investigators have confirmed the findings50 while oth- ers did not support these results.51 Determining the metabolizer phenotype may also help in the case oftreatment with other drugs that rely on CYP2C19, reuptake inhibitor fluvoxamine38, 39 may also be cate- including phenytoin, cyclophosphamide and ifosfa- gorized as strong CYP2C9 inhibitors. The only clearly mide. CYP2C19 inhibitors are fluvoxamine and ticlopi- recognized inducer of CYP2C9 is rifampicin. Rifampi- cin has been shown to reduce, by induction, serum Simultaneous use of S-omeprazole and diazepam leads levels of warfarin,40 tolbutamide41 and phenytoin.42 to an 81% increase in the AUC of diazepam’s elimina- An overview of cytochrome P450 enzyme substrates, tion half-life.55 Oral contraceptives are moderate inhibitors and inducers is given on a website men- inhibitors of CYP2C19 and may cause phenytoin tox- icity as phenytoin induces the metabolism of oral con-traceptives. Rifampicin has been identified as aninducer of both CYP2C19 and CYP2C9.56 Other drugs (anti-convulsants and steroids) that typically induce Cytochrome 2C19 (CYP2C19) is found in many tissues, other cytochrome P450 enzymes may also induce but predominantly in the liver where it accounts CYP2C19 but to a lesser extent than they induce together with CYP2C9, for approximately 20% of the total cytochrome P450 activity. Until recently 19 dif-ferent variant alleles for CYP2C9 were identified (see Table 1 for websites with information about cyto-chrome P450 isoenzyme variant alleles).
Although cytochrome 2D6 (CYP2D6) represents only The prevalence of CYP2C19 enzyme polymorphisms 1–2% of the liver cytochrome P450 isoenzymes32, 58 differs between ethnic groups. For example, the PM by weight, it is believed to be of high affinity ⁄ low phenotype occurs in 2–6% of Caucasians, as confirmed capacity.44 Although CYP2D6 plays its role in the drug in our locally performed study population, and in 15– metabolism mainly in the liver, CYP2D6 is also found 30% Asians.43 Alam and Sharma44 described seven in many other tissues, including the brain,59 the pros- different variant alleles in addition to the normal wild tate60 and the heart.61 CYP2D6 activity does not type. Six of the seven variant alleles are from single change with age;62 however, CYP2D6 activity may nucleotide changes, and the other is from an inversion appear to be altered because of age-associated changes of a base pair. All these variant alleles of CYP2C19 in hepatic blood flow or a decrease in renal elimina- lead to reduced or no enzyme function. In general, tion of metabolites. For many drugs, especially psy- (Table 4), 15–20% of Japanese and 10–20% of Afri- affinity ⁄ low capacity enzyme, which implies that cans are PMs.45 S-mephenytoin has been used in the CYP2D6 will preferentially metabolize drugs at lower laboratory as a substrate probe for CYP2C19 activity concentrations.32 There are ethnic differences in the and measuring the clearance of S-mephenytoin can distribution of EMs, PMs and UEMs. PMs are present help to establish whether a patient is a PM for in approximately 5–14% of Caucasians (Table 4).63, 64 CYP2C19.46, 47 Jiang et al.48 demonstrated that the Bradford65 indicated in a review that Asians, Pacific area under the curve (AUC) of amitriptyline was sig- Islanders, Africans and African Americans have a nificantly higher in PMs than in EMs, suggesting that higher percentage of reduced-function or non-func- CYP2C19 plays a role in the metabolism of amitripty- tional CYP2D6 (between 40% and 50%) than do Cau- line, despite the fact that other cytochrome P450 casians (26%) while previous reports indicated a lower isoenzymes (such as CYP1A2, CYP3A4 and CYP2C9) incidence of PMs in these groups.66 UEMs carry a ª 2007 The Authors, Aliment Pharmacol Ther 26 (Suppl 2), 211–219Journal compilation ª 2007 Blackwell Publishing Ltd 216 P . A . H . M . W I J N E N et al.
duplication of a fully functional CYP2D6 allele which metabolizing enzymes and transporters), therefore results in higher CYP2D6 enzyme levels. Due to these polygenic determinants of drug effects have become higher CYP2D6 enzyme levels, UEMs require a higher increasingly important in pharmacogenetics.
daily dose to obtain a therapeutic drug blood level.
The disadvantage of drug development is the fact that UEMs are generally rare representing 1–3% of the drugs are tested in a standardized population which Caucasian population.67 Chou et al.68 studied 100 psy- rules out severe toxicity but will not always predict drug chiatric patients in relation to their CYP2D6 genotypes interaction(s). The pathways of phase I and II reactions and clinical outcomes. They found that PMs (12% of can be clear but in many cases genetic metabolic differ- the study group) had more adverse medication effects ences, like the presence of one or multiple polymor- and longer, more expensive hospital stays. Andreassen phisms in cytochrome P450 enzymes, sometimes make et al.69 found that PMs were more likely to develop it difficult to predict therapeutic drug reactions.
tardive dyskinesia over 11 years when exposed to Although in most cases the clinical consequences anti-psychotics. Similarly, Ellingrod et al.70 showed may be minor, the impact can be enormous for that heterozygotes for CYP2D6 were at higher risk of patients receiving medicines with a narrow therapeutic developing movement disorders when exposed to anti- index because of subtherapeutic or severe (toxic) side psychotics compared with homozygotes for CYP2D6.
effects. With the population growing older, the amount Finally, Schillevoort et al.71 demonstrated that PMs of diseases or age-related afflictions is increasing and when treated with CYP2D6-dependent antipsychotic more and different medication is needed to treat drugs were four times more likely to use anti-parkin- patients. The elderly patient, on the other hand, is sonian medications than were EMs and this was not more prone to develop severe side effects, partly the case among patients using non-CYP2D6-dependent because of the fact that the excretory function of the anti-psychotics. An alternative method to genetic test- kidney is lower, the liver blood perfusion is diminished ing is to administer first a probe drug mainly metabo- and the overall metabolic function is changed.
lized by CYP2D6 and then look for specific CYP2D6 Different patient categories could be tested for CYP metabolites. Dextromethorphan, debrisoquin and spar- polymorphisms: elderly patients with many drugs for teine are drugs that can be used to assess CYP2D6 different diseases, patients using drugs with small activity.72 Fluoxetine, its metabolite norfluoxetine and therapeutic range and patients with unexplained side paroxetine are effective CYP2D6 inhibitors.73–75 Other effects. Although the genotype profile does not always drugs with the potential for effective inhibition of predict the phenotypic expression, the interaction pro- file between different drugs can be estimated by a dine,59, 78 ritonavir,54 terbinafine79 and ticlopidine.80 computer model available at http://www.genelex.com.
Until now it is not elucidated whether CYP2D6 is Starting with a lower dose or using a medicine that is metabolized by another enzyme or route is often away to prevent side effects and reduce interactions.
Additionally, the best way to check the effect is to measure serum levels of the drug and its metabolites.
In the treatment of patients, doctors prescribe drugs on However, a disadvantage is the fact that the therapeu- the basis of standardized protocols. Before registration, tic serum levels of many drugs are not available or animal and human studies were performed to predict expensive. In organ transplantation medicine, on the consistent and reproducible clinical effects of a drug.
other hand, drug therapy monitoring together with However, many clinically used drugs are effective in cytochrome P450 genotyping is already daily practice only 25–60% of the patients;81 therefore it is important because of the high costs and the small therapeutic to determine different co-factors in the metabolism of range of the immunosuppressive medication.82, 83 In drugs given to a specific patient as depicted in Table 1.
this way therapeutic drug monitoring is cost effective.
With the possibility of investigating genetic CYP On the other hand, genetic polymorphisms of phase II polymorphisms more insight becomes available about enzymes should be developed to complete the genetic the interplay of several gene products that influences the pharmacokinetics and pharmacodynamics of medi- Nevertheless, genotyping should be considered to cations. These include the inherited differences in drug identify patients who might be at risk of severe toxic targets (e.g. receptors) and drug disposition (e.g.
responses to environmental, pharmacological, herbal ª 2007 The Authors, Aliment Pharmacol Ther 26 (Suppl 2), 211–219Journal compilation ª 2007 Blackwell Publishing Ltd R E V I E W : C Y T O C H R O M E P 4 5 0 P O L Y M O R P H I S M S remedies and ⁄ or nutritional stimuli, in order to guide standard clinical practice. In this way the number of appropriate individual dosage(s). Both clinical and side effects and related medical consumption will genetic risk stratification (pharmacogenomics) may decrease, which in the end will lead to a better phar- lead to more accurate prevention of drug-induced macotherapy for the patients and reduced healthcare damage in future. Further research in a large cohort is costs. To achieve this, a close cooperation between needed to explore the clinical relevance.
medical specialists, a hospital pharmacist, a pharma- An ideal situation would be the introduction of a cologist and laboratory specialists will be necessary to genetic medical passport for each patient to achieve a individualize pharmacotherapy on the basis of the system in which therapeutic drug monitoring will be 1 Beijer HJ, De Blaey CJ. Hospitalisations 22 Miners JO, Birkett DJ. The use of caf- a meta-analysis of observational studies.
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JM, et al. Protease inhibitors as inhibi- patic distribution of the human CYP2Cs.
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in patients with cirrhosis or cholestasis alleles. Pharmacogenetics 1996; 6: 193– et al. Influence of rifampicin and isonia- ª 2007 The Authors, Aliment Pharmacol Ther 26 (Suppl 2), 211–219Journal compilation ª 2007 Blackwell Publishing Ltd R E V I E W : C Y T O C H R O M E P 4 5 0 P O L Y M O R P H I S M S 74 Stevens JC, Wrighton SA. Interaction of 68 Chou WH, Yan FX, de Leon J, et al.
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