1-5 When taking place at the genomic level, epigenetic modifications do not consist of mutations, but of chemical modifications of the DNA or of DNA-associated proteins, with important consequences on chromatin structure and gene expression. In both cases epigenetic changes can be implemented for very long periods of time – in many cases throughout the whole lifetime. This does not mean that, in species where adaptation relies primarily on epigenetic changes (eg, in Homo sapiens),

genetics is out of the game. It means that, in the course of evolution, developmental strategies have been genetically Inhibitors,research,lifescience,medical selected to allow an extreme use of adaptation processes taking place in individuals through the process of epigenetic individualization. Not all Inhibitors,research,lifescience,medical animal species are equal when it comes to individualization. Since the nervous system (the brain in particular) is the most important – although not the only – interactive organ, its evolution is a key factor in the complexity and wealth of our interactions with the surrounding world. In short, if humans are individuals to

an extreme, it is because they are social-extreme individuals. Small causes with dramatic Inhibitors,research,lifescience,medical consequences In the context of the general process of evolution, this short review is intended to summarize our present understanding of the enormous leap that we could call “humanization,” permitted by the dramatic differences between Homo sapiens and his closest cousins, Pan paniscus and Pan troglodytes, from which he separated approximately 7 million years ago. These

Inhibitors,research,lifescience,medical differences are obvious from a morphological, cognitive, and cultural point of view. In terms of morphology, the first variable to consider is size. Among primates, the size of the brain is grossly proportional to that of the body. This rule is easily understandable if one realizes that the brain is primarily, and at its origin, an organ with sensory-motor functions; this is why plants do not need a nervous system. Applied to Homo sapiens, this rule Inhibitors,research,lifescience,medical many would mean a brain Selleck FK228 weighing approximately 500 g for a body weighing 75 kg, meaning that we have an excess of 900 g of brain matter. In addition to this size difference, say between chimpanzees and humans, there are also structural differences, since this increase is not proportional between all structures. A good example is the relative decrease in the size of areas devoted to vision or smell in humans and, conversely, the increase in the size of areas devoted to language (barely present in the chimpanzee) and, above all, to associative and cognitive tasks. This forces us to consider mechanisms that not only have allowed a size increase, but also have modified the positioning of boundaries between territories, ie, cortical areas.

Because of the relatively high rate of nonresponders, prediction of response to different therapeutic approaches in OCD and a further understanding of the neurobiological underpinnings of successful treatment of OCD is another important area of further research. Table I Algorithm for drug treatment of patients with obsessive-compulsive disorder Currently, psychopathological or clinical parameters are not very

helpful in predicting response to pharmacotherapy, not to mention in providing us with differential therapeutic support regarding which drug or therapy to choose. For treatment with SSRIs, selleck chemicals llc severity and duration of OCD, psychosocial disability, earlier age at onset, older age, comorbidity with Inhibitors,research,lifescience,medical depression and personality disorder, absence of a positive family history for OCD, and poor insight, as well as neurological soft signs, were identified to predict poorer outcome.122-129 Studies on the impact of different symptom dimensions of OCD on response to SSRIs have been Inhibitors,research,lifescience,medical equivocal, eg, while compulsive hoarding was associated with poorer response to different SSRIs in some studies,130,131 hoarding symptoms were reported to improve as much as other symptoms of OCD after paroxetine.132 Inhibitors,research,lifescience,medical Concerning neurobiological markers of response and nonresponse to medication in OCD, preliminary results using endophenotyping or brain imaging have been reported. Functional polymorphisms

in the serotonin system and their impact on the response to serotonergic Inhibitors,research,lifescience,medical antidepressants have yielded inconsistent results. No differences on the total OCD score in fluvoxamine response were detected in the genotype groups of

the promoter region of the serotonin transporter gene (5-HTTLPR),133 as well as on treatment with different SRIs. 134 In contrast, it was reported that a significant majority of responders to paroxetine and venlafaxine carried the s/l genotype of the 5-HTTLPR polymorphism; in OCD patients successfully treated with paroxetine response was associated with the G/G genotype of Inhibitors,research,lifescience,medical the 5-HT2A receptor polymorphism. 135 Using single photon emission computed tomography (SPECT), higher pretreatment thalamushypothalamus serotonin transporter availability in OCD patients was found to significantly predicted better treatment response to clomipramine.136 In a positron emission tomography (PET) study in OCD patients, local cerebral metabolic rate for glucose GPX6 was significantly decreased in the head of the right caudate nucleus compared with pretreatment values in responders to fluoxetine; percentage change in OCD symptoms correlated significantly with the percent of right caudate/ipsilateral hemisphere change.137 In another PET study, higher pretreatment regional glucose metabolism in the right caudate nucleus was shown to significantly correlate with antiobsessional response to paroxtine.

6 It is underscored that the symptom pattern, rather than specific symptoms or the number of symptoms, defines the disorder. For a PMS/PMDD diagnosis, it is essential to confirm the symptom pattern for two to three menstrual cycles with prospective daily symptom ratings maintained by the patient, especially if the symptoms are mild. Less than half the women who report PM.S provide daily symptom reports that corroborate their retrospective reports,22 which are less reliable when Inhibitors,research,lifescience,medical symptoms are not consistent and severe.23 The major consideration after identifying the symptom pattern is whether the condition is purely PMS/PMDD or a premenstrual exacerbation

of other psychiatric problems or medical conditions. Premenstrual exacerbation of symptoms may occur in other conditions such as asthma,24,25 migraine,26 seizure disorders,27 alcohol intake,28,29 depression,14 and schizophrenia.30 There is no laboratory test that identifies PMS/PMDD, and such tests are useful only Inhibitors,research,lifescience,medical if there are other questions that might, be answered. PMS and PMDD

are based on regular menstrual cycles within the normal range of 22 to 35 days, and patients with irregular cycling should be examined for other conditions. Standard hematology and blood chemistry profiles are conducted to confirm general good health. A thorough examination Inhibitors,research,lifescience,medical includes a review of current and past psychiatric status, particularly mood and anxiety disorders that are commonly Inhibitors,research,lifescience,medical associated with PMS/PMDD. A gynecologic examination is important to rule out problems such as

endometriosis, which might account for the symptoms. Serotonergic antidepressants The serotonergic antidepressants, particularly the SSRIs, appear to be the treatment of choice for severe PMS and PMDD at this time. Modulating serotonergic function is consistent with the dominant theoretical view that the normal gonadal steroid fluctuations of the menstrual cycle trigger an abnormal serotonergic response in vulnerable women. Indications of abnormalities in markers of serotonergic transmission in women with severe PMS include evidence of a lowered platelet imipramine binding (a peripheral marker Inhibitors,research,lifescience,medical of serotonin [5-hydroxytryptamine, 5-HT] function) in the luteal phase,31 decreased platelet 5-HT content and 5-HT uptake during the luteal phase,32,33 and significantly decreased Mephenoxalone whole blood 5-HT levels premenstrually.34 PMS patients showed a lower 5-HT response to tryptophan (a 5-HT precursor) during the luteal phase compared with the selleck chemical follicular or midluteal phases.35 Challenge tests depleting tryptophan provoked PMS symptoms,36 while tryptophan supplementation relieved PMS symptoms in open-label treatment.37. Following administration of the serotonin -releasing fenfluramine, the women with PMDD had a significantly blunted prolactin response compared with the normal controls.38 Fenfluramine administered to PMS subjects improved depressed mood and food cravings.

The authors of this review consider that there is no indication left for tricyclic antidepressants or MAOIs as first-line therapy for any depressive or anxiety disorder. The reason for this is, aside from the known side effects of tricyclic antidepressants, the long list of physical disorders that are a contraindication to tricyclic antidepressants: heart failure, cardiac conduction disorder, hepatic insufficiency, renal insufficiency, epilepsy, Parkinson’s disease,

cerebrovascular disease, etc. Are two antidepressants better than one? The clinician can rightly ask whether there is an advantage in combining two antidepressants to multiply the targets of pharmacological actions and achieve a higher rate of efficacy. Inhibitors,research,lifescience,medical In clinical practice, the combination of two recent antidepressants is common. One Inhibitors,research,lifescience,medical such combination has been known for years, ie, to add a sedative to compensate for the stimulation

due to an antidepressant; trazodone, nefazodone, mianserin, and mirtazapine can be used as sedatives, acting on sleep difficulties and anxiety in patients receiving a stimulating antidepressant. The combination of two antidepressants in other situations should be limited. In treatment-resistant patients, it is logical to combine antidepressants with different pharmacological modes of action Inhibitors,research,lifescience,medical and different clinical configurations (for example, a stimulating SSRI such as sertraline with a low or moderate dose of a sedating compound such as mirtazapine or nefazodone). There are no controlled clinical trials to confirm the benefit of combining two antidepressants. Is there a better response at higher doses of antidepressants? Drug-monitoring studies have indicated a linear or curvilinear relationship Inhibitors,research,lifescience,medical between efficacy and concentration of tricyclic antidepressants such as imipramine, desipramine, and nortriptyline. Inhibitors,research,lifescience,medical Proteasome inhibitor However, recent results from the Danish University Antidepressant. Group (DUAG) have shown little difference between clomipramine doses of 25, 50, 75, 1 25, and 200 mg/day in severely depressed patients.25 With fluoxetine, 5 mg/day seems to be

clinically equivalent to 20 or 40 mg/day, in terms of antidepressant effect.26 There are hints that venlafaxine, nefazodone, and reboxetine are more efficacious Isotretinoin at higher doses. The explanation put forward is that the pharmacological mode of action differs as a function of the dose, a point that is difficult to prove in humans; for example, it has been said that at low doses venlafaxine acts as an SSRI, and only at higher doses docs it influence the reuptake of noradrenaline.27 While the existence of a better response at higher doses of antidepressant is a subject, of debate, there is consensus about the increased risk of side effects at higher doses.4 For example, dosages of 225 or 375 mg/day venlafaxine lead to 24% and 30% dropouts, respectively, in comparison to 17% for 75 mg/day and 5% for placebo.

Especially in adolescence, persistent

loss of sleep can have a depressing effect and lead to the problems at home and at school to which reference has also been made. Disturbed sleep can affect a child’s emotional state and behavior in various other ways. Bedtime can become a source of distress if associated with frightening thoughts or experiences that are associated with various sleep disorders, including night-time fears. Intellectual function and education There is convincing evidence that insufficient sleep can cause impaired concentration, memory, decision-making, and general ability to learn. Performance on tasks calling for sustained attention is particularly Inhibitors,research,lifescience,medical affected, and also those requiring abstract thinking or creativity. Similarly, motor skills and reaction time can be impaired. Studies in the USA have suggested Inhibitors,research,lifescience,medical that 80% of adolescents obtain less than adequate sleep (ie, 9 hours), 25% less than 6 hours, and over 25% fall asleep in class. Students with insufficient sleep generally achieve lower school grades.17 Findings in other countries

might well be similar. Physical effects As the production of growth hormone is closely linked to deep NREM sleep, if sleep is seriously disrupted from an early age, physical growth may be affected. Inhibitors,research,lifescience,medical As mentioned earlier, OSA can disrupt sleep from about the age of 2, causing the child to “fail to thrive” and be smaller for his or her age than ideal. In addition to this effect of

OSA on growth, persistent sleep loss in particular Inhibitors,research,lifescience,medical is being increasingly associated in adults with physical ill-health such as impaired immunity, obesity, hypertension, and diabetes.18 There is no particular reason to expect that children are free of at least some of these Inhibitors,research,lifescience,medical risks. Family and other social effects There have been reports that relationships between parent and a child with a serious and persistent sleep problem can be severely tested to the point of increased use of physical punishment in extreme cases.19 Parents may disagree with each other about ways of dealing with the child’s refusal to go to sleep at the required time, or his or her insistence ADP ribosylation factor on joining them in their own bed after waking during the night. In these circumstances, marital relationships may become seriously strained. Because of the changes of behavior that can result from sleep disturbance, the affected child’s interpersonal problems may extend beyond his family. Irritable, difficult, or otherwise disturbed behavior is likely to affect friendships. Relationships with teachers can also easily suffer, especially if they are unaware that behavioral problems can be the result of inadequate or otherwise disturbed sleep. In view of these various potential complications to the child’s life, it is essential that ail concerned realize they can be at least partly the result of sleep disturbance for which effective treatment can be Paclitaxel mw provided in most instances.

The most common behaviors consist of arm flailing and punching, kicking, and vocalizations; these behaviors occur in bed or result in falling out of bed. About 32% of patients report self-injury ranging from falling out of bed to striking or bumping into the furniture or walls. Olson reported one patient attempted to fire an unloaded gun, while another attempted to set fire to his bed.147 Sixty-four percent of spouses report being assaulted during sleep.147 Dream content in RBD has aggressive themes in about 89% of patients, with the most common one being defense of the sleeper against attack. Although RBD is usually idiopathic, it Inhibitors,research,lifescience,medical can occur secondarily on a transient or chronic basis. Acute RBD can

result from drug withdrawal (meprobamate, pentazocine, nitrazepam, and butalbital)152 or intoxication (bipcriden, tricyclic antidepressants, monoamine oxidase [MAO] inhibitors, Inhibitors,research,lifescience,medical or caffeine).149,153 Chronic RBD can be produced by drugs (tricyclic antidepressants, fluoxetine, venlafaxine, mirtazapine, selegeline, and anticholinergic Inhibitors,research,lifescience,medical medications), vascular problems (subarachnoid hemorrhage, vasculitis), tumors (pontine neoplasms, acoustic tumors), infectious/postinfectious diseases (Guillain-Barre), degenerative or demyelinating conditions (amyotrophic lateral sclerosis, fatal familial insomnia, dementia, Parkinson’s disease, multiple

sclerosis, olivopontocerebellar degeneration, Shy-Drager Inhibitors,research,lifescience,medical syndrome, multiple system atrophy), and developmental, congenital, or familial diseases (narcolepsy, Tourctte’s syndrome, Group A xeroderma pigmentosum, mitochondrial encephalomyopathy).147,149,153-155 Because

of the overwhelming male preponderance (90%), questions of relationships between sexual hormones, aggression, and violence have been raised.148,149 selleck screening library Diffuse lesions of the hemispheres, bilateral thalamic abnormalities, or primary brain stem lesions may result in RBD.150 The PSG shows at Inhibitors,research,lifescience,medical least one of the following: excessive augmentation of chin-EMG tone or excessive chin/limb phasic EM’G twitching associated with one or more of the following: excessive limb or body jerking, complex vigorous/violent behaviors, and absence of epileptic activity in association with the disorder. Shirakawa and colleagues performed M’RI and SPECT imaging on 20 patients with RBD and reported decreased blood flow in the upper portions of the frontal crotamiton lobe and pons.156 Albin and colleagues found decreased striatal dopaminergic innervation in RBD patients.157 Treatment of RBD has been effective in 90% of patients using clonazepam starting at 0.5 mg at bedtime and gradually incrementing the dose until control is effected. Other drugs, such as gabapentin, clonidine, carbamazepine, donezepil, levodopa, and melatonin have been anecdotally reported to be useful.149,158-162 Environmental safety measures are very important.

First, a breakdown of the sensory

filter could lead to an increased stimulation of primary sensory cortical areas. Such a defective filter would implicate abnormalities in the thalamic relay nuclei. Second, dysfunction of the MD nucleus could lead to impairments of cortical association areas, especially the DLPFC. Direct evidence for an involvement of the thalamus in the pathophysiology of schizophrenia is still limited. The most convincing evidence comes from morphometric studies, pointing to a volume reduction of the thalamus, especially the MD nucleus,50,133 which Inhibitors,research,lifescience,medical has been attributed to cell loss.133 A postmortem study reported a decrease in parvalbumin-positive neurons in the anteroventral nucleus, which would result in a loss of thalamocortical projections to the prefrontal cortex.134 Recently, some135,136 but not all,137,138 neuroimaging studies have revealed smaller thalamic volume. In addition, thalamic metabolism and blood flow were found to be impaired at rest and Inhibitors,research,lifescience,medical during the performance of cognitive tasks.136,138,139 Of interest, the decrease in metabolism during the performance of a serial verbal learning test involved primarily the region of the mediodorsal thalamic nucleus.138 Basal ganglia The basal ganglia include the ventral striatum, the dorsal ZD1839 clinical trial striatum (caudate and putamcn),

and the globus pallidus. The dorsal striatum (caudate, Inhibitors,research,lifescience,medical putamen) receives input from motor cortex and projects to the globus pallidus. The globus pallidus relays the neostriatal input to the thalamus. The thalamus, in turn, projects back to the cortical areas that gave rise to the corticostriatal projections, thereby closing the cortico-striato-pallido-thalamo-cortical loop. This loop is involved in the generation and control Inhibitors,research,lifescience,medical of motor behavior. In contrast, Inhibitors,research,lifescience,medical the ventral striatum (the nucleus accumbens) is connected with the amygdala, hippocampus, and hypothalamus, and is therefore considered part of limbic system. Reward and expectancy behavior, and their

derailment during drug addiction, involve the recruitment of the nucleus accumbens. All basal ganglia structures are modulated by neurotransmitter-specific projection systems, in particular by dopaminergic neurons. Dopaminergic neurons of the SN project to the neostriatum (nigrostriatal fibers) and dopaminergic neurons of the VTA project to the nucleus accumbens (mesolimbic fibers) and cortex (mesocortical fibers). The two major DA receptors in the dorsal striatum are the D1 and D2 receptors. The nucleus accumbens expresses PAK6 primarily the D3 receptor. The basal ganglia have been a focus of interest in psychosis research for three reasons: as potential sites of neuroleptic drug action at D2 receptors, as a potential site for the generation of abnormal motor behavior during psychosis (eg, catatonia), and as a site for pathology in the limbic system.140-143 Dopaminergic afférents The most extensive search has been at the level of dopamine receptors.

Ethanol did not alter the conversion of [3H]3α,5α-THP to [3H]5α-DHP in rat olfactory bulb and tubercle or adrenal gland. An increase in the reductive activity of the 3α-HSD with no change in the oxidative direction would cause a greater conversion of 5α-DHP to 3α,5α-THP. This effect could contribute to ethanol-induced increases in brain 3α,5αTHP levels. Indeed, the increased reductive activity of 3α-HSD would be predicted

to increase brain levels of both 3α,5α-THP and other 3α,5α-reduced neuroactive steroids such as 3α,5α-THDOC. Suppression of neuroactive steroid responses following chrowing chronic ethanol exposure in rats It is well known that chronic stress results in Inhibitors,research,lifescience,medical adaptation of the HPA axis, leading

to decreased levels of corticosterone in rats.89 Repeated exposure to alcohol also blunts the response of the HPA axis to a second ethanol challenge.90 This blunting of the HPA axis is associated Inhibitors,research,lifescience,medical with reduction in CRF and ACTH elevations following ethanol challenge.91 In line with these observations, chronic ethanol consumption in Inhibitors,research,lifescience,medical rats results in blunted elevation of cerebral cortical 3α,5α-THP4 and plasma and brain DOC levels following acute ethanol challenge,79 compared with pair-fed control rats. These findings suggest that there is tolerance to ethanol-induced increases in neuroactive steroid levels. Since decreases in brain neurosteroid levels were concomitant with decreases in plasma neurosteroid levels, it is likely that the observed decreases in 3α,5α-THP and DOC levels were dependent on blunted HPA axis activity. Thus, adaptations of the HPA axis may contribute to tolerance to Inhibitors,research,lifescience,medical effects of ethanol that are mediated by the GABAergic neuroactive steroids. Chronic ethanol administration to rodents and humans produces tolerance to ethanol and cross-tolerance Inhibitors,research,lifescience,medical to benzodiazepines and barbiturates. In contrast, ethanoldependent rats are sensitized to the anticonvulsant effects of both 3α,5α-THP and 3α,5α-THDOC.92,94

These studies also show that GABAA receptor sensitivity to 3α,5α-THP and 3α,5α-THDOC is enhanced in ethanoldependent rats, likely due to the reduction of ethanolinduced levels in these Z-VAD-FMK mw animals described above. Since ethanol-dependent rats are sensitized to anticonvulsant actions of neuroactive steroids, this class of compounds much may be therapeutic during ethanol withdrawal Indeed, neurosteroid therapy may have advantages over benzodiazepine therapy since benzodiazepines exhibit crosstolerance with ethanol. Further studies are needed to explore this possibility. Effects of ethanol on neuroactive steroids in humans The potential role of neuroactive steroids in alcohol action in humans is relatively unexplored and inconsistent. Recent human studies show that male and female adolescents seen in the emergency room for alcohol intoxication had elevated plasma levels of the neuroactive steroid 3α,5α-THP.

2005). However, some PD0332991 research buy divergent observations were reported (Pouydebat et al. 2010), concluding to the difficulty to establish a stable handedness among Gorillas, based on different behavioral tasks. In Old World monkeys, handedness seems to be less consistent among the family (Westergaard et al. 1997, 2001a,b), as it appears to depend on the species, especially in Macaques. Although some macaques, such as Macaca mulatta,

exhibited population-level left-handedness when they performed a specific task (also Macaca fuscata, see Murata et al. 2008), other species like M. fascicularis did not exhibit any manual bias at the population-level for the same tasks (tube task, reaching to food morsel; Westergaard et Inhibitors,research,lifescience,medical al. 1997, 2001a,b; see also Lehman 1980b). The above data for M. mulatta are not consistent with previous observations derived from food reaching tests (Lehman 1978a), which showed roughly equal numbers of right- and left-handed individuals. Furthermore, the latter author and others reported that handedness

Inhibitors,research,lifescience,medical was accentuated Inhibitors,research,lifescience,medical with monkeys’ age, as well as with task repetition (e.g., Lehman 1978a,b, 1980a,b; Westergaard and Suomi 1996; Westergaard and Lussier 1999; Zhao et al. 2012). Similarly, Hopkins (2004) found a less prominent handedness among Old and New World monkeys in comparison to the great apes. It is, however, interesting to highlight that, for some investigators (e.g.,

Lehman 1980a, 1989; Hopkins et al. 1989; Fagot and Vauclair 1991; Uomini 2009), these disparate results may depend on the task used to determine handedness (see also Spinozzi et al. 1998, 2007). Indeed, these authors showed that the complexity of the task plays an important role. A high-level Inhibitors,research,lifescience,medical manual activity involves, most of the time, a manual bias at the population-level, whereas a simple and low-level task does not. A typical example of high-level manual performance is the precision grip (opposition of thumb and usually index finger Inhibitors,research,lifescience,medical to grasp an object), requiring the cooperation of several muscles of hand and arm, tendons, ligaments, and the stabilization of the upper limb to ensure a better effectiveness (e.g., Lemon 1993, 2008; Porter and Lemon 1993). Bimanual tasks are considered as high-level ones, involving a coordination of different (-)-p-Bromotetramisole Oxalate limbs and movements. As demonstrated in squirrel monkeys, hand preference is correlated to an asymmetry in functional topography of motor cortex between the two hemispheres, with a greater distal forelimb representation in the dominant hemisphere, opposite the preferred hand (Nudo et al. 1992). Asymmetries in the primary motor cortex related to handedness was reported in great apes (Hopkins and Pilcher 2001; Hopkins et al. 2002, 2010; Hopkins and Cantalupo 2004; Dadda et al. 2006; Sherwood et al. 2007) and in humans (e.g., Dassonville et al. 1997).

People for whom certain genetic variations hinder the metabolism of a certain drug, thus making that drug either ineffective or toxic, should simply not be prescribed that specific drug. However, the real picture

is slightly more complicated. There are four criteria for judging the clinical usefulness of pharmacogenomics. Firstly, the strength of association with the clinical problem is essential. Clearly, if the strength of association is low, so is the use of pharmacogenomics. Secondly, we need to evaluate the clinical importance of the specific clinical problem to justify the use of pharmacogenomics. Trivial medical Inhibitors,research,lifescience,medical problems do not warrant the use of pharmacogenomics. Thirdly, we need to factor in the predictiveness of pharmacogenomics for the individual patient, and lastly, other available treatment options must be considered. Inhibitors,research,lifescience,medical These four factors must be taken into account when bringing pharmacogenomics into the practice of medicine. CARDIOVASCULAR DISEASE, LATE STENT THROMBOSIS, AND PHARMACOGENOMICS Heart disease fits the criterion of clinical importance.

Inhibitors,research,lifescience,medical More than 2,200 Americans die of cardiovascular disease (CVD) each day,2 and there are many pharmacogenomic implications for CVD.3–5 If a life-saving drug was shown to be less effective for people who carry a certain genetic marker, and, even more pertinent, if as a result of this genetic predisposition they were at risk if given a certain drug, it is clearly medically relevant. One common procedure performed on patients with acute CVD is stenting. Over 1 Inhibitors,research,lifescience,medical million stent procedures are annually performed in the United States.6 Although drug-eluting stents have been very successful in preventing re-narrowing, or restenosis Inhibitors,research,lifescience,medical of the coronary arteries, these stents carry a slight increase in risk for late stent selleck chemical thrombosis (Figure 1). The occurrence of late stent thrombosis

is the result of several factors such as incomplete stent apposition. The frequency of late stent thrombosis occurrence is low, but the risk continues over time. Despite the low frequency, the clinical implication of stent thrombosis is dire since the chance of death or myocardial infarction from stent thrombosis Cediranib (AZD2171) is 40%–60%. Therefore, patients with drug-eluting stents are treated with dual antiplatelet therapy (aspirin plus clopidogrel, ticagrelor, or prasugrel) for the recommended duration. Figure 1 Stent thrombosis. ANTIPLATELET THERAPY AND CLOPIDOGREL The antiplatelet therapy drug, clopidogrel (Plavix®) is a prodrug which is activated in the liver in a two-step process by cytochrome P450 enzymes (Figure 2). The bioavailability of clopidogrel is determined by the genetic make-up of these enzymes and other enzymes in addition to intestinal absorption. Clopidogrel acts upon an ADP receptor that is found on platelet cell membranes.