Because disease genes also mark functional pathways, they may serve as reference molecules for other related molecules in the affected network, which may represent, more suitable drug targets with regard

to their molecular properties and genetic variability pattern. With respect to the second issue, one major consequence to be drawn is to establish as an essential requirement of the systematic Inhibitors,research,lifescience,medical and comprehensive analysis of the entire individual gene sequences encoding the drug targets in appropriately chosen samples. It will be mandatory to determine the entire polymorphic spectra of the genes, as well as the haplotype structures underlying them. A second critical analytical task in this context, will be to evaluate to what extent potentially given complexity can be reduced to functionally distinct, haplotype classes and/or Inhibitors,research,lifescience,medical GABA Receptor inhibitor distinct protein isoforms. In-depth knowledge on the genetic variability of a drug

target under consideration, especially the spectrum and frequencies of underlying haplotype structures in populations,84 will have to become an indispensable prerequisite for drug target evaluation, characterization, Inhibitors,research,lifescience,medical and prioritization. Needless to say these requirements refer to both the specific drug targets under consideration and the genes involved in drug metabolism and transport. There is currently no a priori way of predicting the specific genetic variability in a drug target, or any other gene of pharmaceutical relevance, Inhibitors,research,lifescience,medical given its stochastic nature; each gene must, be rigorously subjected to systematic comparative sequence and haplotype

analysis in populations. Extrapolating from the body of data described above, about two to seven different, haplotypes that occur most, frequently Inhibitors,research,lifescience,medical (at frequencies of the minor allele >5%) may be expected on average. This implies that the most, frequent, haplotypes amount to fractions of 16% to >50% of all haplotypes, constituting altogether about 51 % to 96% of the total of ha.pl otypes.29,33,46,70 Moreover, the numbers of rare haplotypes (frequencies of the minor allele <1%) may potentially be substantial, as outlined above. However, diversity at the sequence and haplotype level does not necessarily imply Urease diversity at the protein level. Thus, the assignment of individual sequence haplotypes to protein isoforms will be one first, critical step towards the evaluation of the implications of given candidate gene variability. Hardly any data have been presented regarding the relationships between sequence haplotypes and protein isoforms, with the exception of the work on APOE sequence haplotypes by Fullerton et al.25 These authors demonstrated convergence of 31 different sequence haplotypes onto three different protein isoforms.

Patients assigned a score of “0” are unable to perform the task. Each item is rated using a scale from 1 to 7, with a score of “1” corresponding to total assistance and “7” corresponding to complete independence.26, 30 The FIM scores “6” (modified

independence) and “7” (complete independence) were not considered for the Perme ICU Mobility Score because we determined that patients in the ICU are not likely to have such a high level of independence. The scoring system adopted in the Perme ICU Mobility Score is similar to the FIM and FSS-ICU but instead ranges from 0 to 3. Of the 15 items on the Perme ICU Mobility Score, Inhibitors,research,lifescience,medical 6 had kappa values of < .60, which is considered moderate to nonagreement.31 To improve agreement, we developed instructions to standardize the use of the tool. Future testing of

reliability Inhibitors,research,lifescience,medical is planned using the new instructions sheet. Item 2 in the Perme ICU Mobility Score had a kappa value of “0,” which means non-agreement between two raters. The authors decided to retain the item, as the real and expected agreement for Inhibitors,research,lifescience,medical this item was 97.17%. This represented just one patient with non-agreement, leading to the decision to keep the item in the tool. In our study, the “real agreement” between raters for all items had a median IQR percentage of 94.29% (68.57-100%), and items in the categories of “bed mobility” and “transfers” showed moderate agreement. For the “bed mobility” category, the “supine to sit” item showed an agreement of 77.14% and Inhibitors,research,lifescience,medical “sitting balance on the side of bed” showed an agreement of 71.43%. For the “transfers” category, the “sit to stand” item showed an agreement of 77.14%, “standing balance”

showed an agreement of 68.57%, and “transfer to chair” showed an agreement of 74.29%. One reason for the moderate agreement between raters in these items could be a different perception of patient’s effort, since one physical therapist assisted the patient while the Inhibitors,research,lifescience,medical other only observed without physically touching the patient. In the future, we plan to test the same patient repeatedly and randomize the two raters’ sequence of assisting versus observing. The Perme ICU Mobility Score is a well-defined quantitative tool that provides a reliable assessment of an ICU patient’s mobility status. It is also practical in that it can be completed first in just a few minutes at the end of mobility interventions. This is clinically relevant for clinicians, as it provides an objective evaluation of the mobility status in the ICU setting. The tool is intended for use in any ICU population and in both clinical and research applications. However, in the present study the tool was only selleck inhibitor applied in a CVICU, which can be considered a limitation. Further studies are needed to test its validity, reliability, and applicability across different ICU populations.

The major glycans of glycoproteins can be classified into two groups according to their glycan-peptide linkage regions. Those that are linked to asparagine (Asn) residues of polypeptides are termed N-glycans, while those that are linked to serine (Ser) or threonine (Thr) residues are called O-glycans. In N-glycans, the reducing terminal N-acetylglucosamine (GlcNAc) is linked to the amide group of Asn, via an aspartylglycosylamine linkage. In O-glycans, the reducing terminal N-acetylgalactosamine (GalNAc) is attached to the hydroxyl groups of Ser and Thr residues of polypeptides.

However, in addition to the Rapamycin abundant O-GalNAc forms, several unique types of protein O-glycosylation have been reported, such Inhibitors,research,lifescience,medical as O-fucose, O-glucose,

O-GlcNAc, O-xylose, O-galactose Inhibitors,research,lifescience,medical on hydroxylysine, and O-mannose which will be reviewed here. Recently O-mannosylation of the mammalian glycoprotein dystroglycan has been shown to be important in muscle and brain development. Dystroglycan α-Dystroglycan is an extracellular peripheral membrane glycoprotein anchored by binding to a transmembrane glycoprotein, β-dystroglycan. These two dystroglycan subunits were originally identified as members of the sarcolemmal dystrophin-glycoprotein complex. Dystroglycan Inhibitors,research,lifescience,medical is thought to act as a transmembrane linker between the extracellular matrix and intracellular cytoskeleton (2). α-Dystroglycan strongly binds to extracellular matrix proteins containing Inhibitors,research,lifescience,medical laminin G (LamG) domains, such as laminin, neurexin, and agrin in a calcium-dependent manner. α-Dystroglycan is heavily glycosylated, and its glycans have a role in the binding to these molecules. Previously we reported that the glycans of α-dystroglycan include O-mannosylglycan: Siaα2–3Galβ1–4GlcNAcβ1–2Man Inhibitors,research,lifescience,medical (3). α-Dystroglycan has a mucin-type O-glycosylation site in the central region of the molecule. Thr, Ser and proline (Pro) are densely distributed into the predicted mucin domain (amino acid residues 316-489), which is thought to have the form of a rigid

rod, since complex secondary and tertiary structures are hindered by heavy glycosylation. Dystroglycan is encoded by a single gene (DAG1) (2). The function of dystroglycan in the body has been examined by targeting the DAG1 gene in mice. However, disruption of this gene in mice results in embryonic lethality. To allow the embryo Dipeptidyl peptidase to develop, chimeric mice generated from targeted embryonic stem cells have been produced. Dystroglycan-null chimeric mice showed muscular dystrophy, although muscle basement membrane formation was normal (4). The function of dystroglycan in specific tissues was examined with the Cre/LoxP system. Targeting the dystroglycan gene specifically in differentiated skeletal muscle did not affect muscle basement membrane formation but resulted in a mild dystrophic phenotype (5).

1998). They are involved in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins, and products of oxidative stress, by conjugation with glutathione. It has been reported that individuals with GSTM1 null genotype and high exposure to solvents are at increased risk of developing solvent-induced chronic toxic encephalopathy (Söderkvist et al. 1996) and Parkinson’s SB202190 disease (Dick et al. 2007). The GSTT1

gene is situated on chromosome 22. For both GSTT1 and GSTM1, the null genotype has been associated with an increased risk of optic neuropathies (Abu-Amero et al. 2009) and adverse events to drugs, including cognitive impairment after therapy Inhibitors,research,lifescience,medical in patients with medulloblastoma (Barahmani et al. 2009), but not to Leber’s Hereditary Optic Neuropathy (Ishikawa et al. 2005) or neuropathy in patients receiving oxaliplatin-based chemotherapy (Lecomte et al. 2006). Since activity of these xenobiotic-metabolizing enzymes generally Inhibitors,research,lifescience,medical is necessary to promote efficient detoxification,

thereby protecting the body from injury caused by exposures, we analyzed whether polymorphisms for the null alleles of GSTM1 and GSTT1 and a genetic variation of mEPHX (low activity) Inhibitors,research,lifescience,medical affect the risk of developing polyneuropathy. Materials and Methods In a previous study of patients with cryptogenic neuropathy, 168 consecutive outpatients from departments of neurology at three hospitals in two neighboring counties in Sweden (Östergötland County, University Hospital, Linköping and Motala Hospital and Jönköping County, Ryhov County Hospital, Jönköping) between 40 and 79 years of age at the time of diagnosis Inhibitors,research,lifescience,medical were studied (Lindh et al. 2005). Ethics committee approval was obtained to re-review records and contact

these subjects. Medical records were reexamined with a predetermined study protocol including symptoms, signs, and laboratory tests, in order to confirm the correct diagnosis in each case. Patients with a dominantly demyelinating neuropathy, hereditary Inhibitors,research,lifescience,medical neuropathy, or any other identified cause of neuropathy were excluded (Lindh et al. 2005). Of the initial cohort of 168 patients, 158 were still alive, and they were asked to participate in the study. Blood samples were collected from the 79 patients L-NAME HCl (response rate 50%) who agreed to participate. There were 54 men and 25 women with polyneuropathy (mean age 71.0 and 68.5, respectively). The 89 patients who did not participate were slightly older (72.5 vs. 70.2 years old), had higher clinical (1.6 vs. 1.4) and neurophysiological severity (2.0 vs. 1.8), but the differences did not reach statistical significance, and there was no difference in sex distribution. The control group was 398 persons from a population-based control group from the Swedish part of a Parkinson’s disease study of the same genetic polymorphisms living in the same geographic area (Dick et al. 2007).

11-14) Of note, TDI velocity is almost the exclusive modality adopted for measurement, because of the discernable and consistent signal of early diastole (Table 1). Dyssynchrony and CRT The compelling evidence from multicenter clinical trials has established CRT as the most promising therapeutic modality in heart failure management over the past decade.15) Inhibitors,research,lifescience,medical CRT not only improves symptoms and cardiac function, but also reduces heart failure hospitalization and all-cause/cardiovascular mortality in patients with advanced CHF. However, it remains a major problem that non-responders of therapy are constantly observed in about one-third

of patients receiving CRT, based on the current guidelines for patient selection in which the QRS duration ≥ 120 ms is regarded as the only marker of ventricular Vadimezan mouse electromechanical Inhibitors,research,lifescience,medical delay.16),17) The presence of a prolonged QRS duration

in CHF is associated with more advanced myocardial disease, more severe LV dysfunction, worse prognosis and higher all-cause mortality.18) However, a prolonged QRS duration may not necessarily be equivalent to significant mechanical dyssynchrony, even in the form of left bundle branch block (LBBB). Inhibitors,research,lifescience,medical Fung et al.19) observed that regional electrical conduction delay could be absent in CHF patients with LBBB. Using the 3D non-contact mapping electrograms, homogenous delay in LV the propagation

of endocardial activation similar to that of normal subjects was found in some patients with typical LBBB, while typical delay Inhibitors,research,lifescience,medical in depolarization over the LV lateral or posterior wall was observed in others. In fact, the QRS duration on surface ECG is a rather inaccurate estimation of myocardial electrical activation which correlates poorly with the occurrence of systolic mechanical dyssynchrony.20-22) The correction of cardiac electromechanical delay is suggested to be one of Inhibitors,research,lifescience,medical the major mechanisms for CRT benefits. Therefore, direct measurement of mechanical dyssynchrony by echocardiography has become clinically relevant in estimating the likelihood of response when ECG as a surrogate marker may fail. Over the last decade, a number of single-center studies have demonstrated that the lack of mechanical dyssynchrony Oxygenase assessed by noninvasive echocardiographic techniques is closely related to the lack of response in patients who received CRT. Nevertheless, those results were challenged by the Predictors of Response to CRT (PROSPECT) trial, the first multicenter trial in which no single echocardiographic measure of mechanical dyssynchrony could predict CRT responses with a good sensitivity and specificity.

CFTR inhibitor treatment of OCD patients refractory to serotonergic antidepressants Despite the proven efficacy of SSRIs and clomipramine in OCD, as shown above, about 40% to 60% of patients show no or just partial symptom improvement to a treatment with a first-line drug.28 Therefore, the search for effective second-line treatment strategies in drugrefractory OCD patients is of great clinical importance. However, most of the following options still stand Inhibitors,research,lifescience,medical on considerably weaker empirical grounds than the wellestablished first-line recommendations described above. Modification

of serotonergic drug therapy with firstline agents Intravenous clomipramine was shown to be more effective than oral clomipramine in two double-blind placebo-controlled trials,29-30 and thus was considered a recommendation grade 3 strategy for treatment-resistant OCD patients Inhibitors,research,lifescience,medical (limited evidence from controlled studies).24 Regarding citalopram, an open trial

showed a beneficial and relatively rapid response in OCD patients resistant to previous oral therapy.31 However, more sophisticated studies are still needed. High-dose treatment with Inhibitors,research,lifescience,medical serotonergic drugs is another strategy worth considering. Greater improvement with higher vs lower doses of SSRI was reported using 250 to400 mg/d vs 200 mg/d of sertraline32 and with escitalopram after an increase of dose from 20 up to 50 mg/d.33

However, two recent studies with escitalopram contradict the notion Inhibitors,research,lifescience,medical that a positive response requires higher doses of treatment. A similar response after 24 weeks of 10 mg/d vs 20 mg/d was shown in a double-blind placebo-controlled study.26 In an open study, a superior reduction in OCD symptoms was found with 30 mg/d vs 20 mg/d of escitalopram, which, however, disappeared when initial comorbid depression and anxiety were considered as analysis covariates.34 Whether switching from one first-line Inhibitors,research,lifescience,medical drug to another may be advisable, is still an unresolved issue. In one open study, switching else from one SSRI to another resulted in a lower response rate (0% to 20%) than switching from one SSRI to clomipramine (33% to 40%).35 Although meta-analyses have reported a larger treatment effect of oral clomipramine than for SSRIs, head-to-head comparator studies do not support this evidence.36 Some open-label studies suggest that combined treatment of clomipramine and an SSRI is effective and well tolerated. Positive results have been reported with longterm augmentation with citalopram (up to 60 mg/d) in 20 treatment-resistent OCD patients on clomipramine.37 In smaller samples, encouraging data have also been reported with the combination of clomipramine with fluoxetine38 or with sertraline.

281,282 Unlike putaminal MSNs, these large interhttp://www.selleckchem.com/products/AZD1480.html neurons are spontaneously active and they do not discharge in relation to specific parameters of movement preparation or execution, such as direction or force, although they do show selectivity for the mode of movement guidance (eg, self-initiated versus visually guided versus memory-guided).283 Rather, they discharge briefly and synchronously following the presentation of a conditioned sensory stimulus that signifies the imminent, delivery of a reward.284,285 In this Inhibitors,research,lifescience,medical respect, their

behavior is similar to that of nigrostriatal DA neurons. And yet, there is a crucial difference: cholinergic interneurons signal the subject’s prediction that a reward is imminent, while DA neurons signal reward prediction errors.286,287 The cholinergic large aspiny neurons are the only striatal cells that express significant levels of the m2 receptor,224 which – like the m4 receptor – is coupled to a G-protein that decreases intracellular Inhibitors,research,lifescience,medical cAMP. The m2 receptors are concentrated on cholinergic axons of aspiny interneurons that form symmetric synapses

Inhibitors,research,lifescience,medical on the proximal dendrites and cell bodies of MSNs.224 Pathophysiology of nigrostriatal DA depletion in the motor circuit The data recounted above are consistent with the relatively simple functional Inhibitors,research,lifescience,medical models of basal ganglia circuitry developed throughout, the 1990s to provide a framework for approaching the pathophysiology of motor dysfunction in PD.188,204,288 These models typically emphasized the opposing actions of the direct, and indirect pathways in determining

the level of thalamic inhibition exerted by the basal ganglia, output nuclei. Studies of MPTP-induced parkinsonism had revealed increased tonic discharge rates in GPi and SNr neurons as well as in STN, and decreased rates of discharge in GPe.186,187,190 This suggested that excessive inhibition of the thalamic targets Inhibitors,research,lifescience,medical to which GPi. and SNr projected might be the basis for the hypokinesia and rigidity of parkinsonism.188 Reduced dopaminergic activation of d1-like below receptors on striatal-GPi/SNr spiny neurons would reduce the effectiveness of their glutamatergic inputs from cortex and CM/Pf, leading to disinhibition of GPi/SNr. Reduced dopaminergic activation of d2-like receptors on striatal-GPe neurons would increase the effectiveness of their glutamatergic inputs, leading to increase inhibition of GPe, which would in turn disinhibit STN. The resulting increase in glutamatergic drive from STN would further increase the activity of GPi/SNr neurons, further depressing thalamocortical activity. Perhaps the opposite effect, excessively low levels of tonic basal ganglia outflow, was the basis for certain hyperkinetic disorders, including levodopainduced dyskinesia.

Figure 1. Euphoric responses to µ opiate receptor agonist administration. A) Visual analogue scale (VAS) scores as mean values before and up to 60 min after administration of 0.2 mg fentanyl/kg; 0 mm = very unpleasant feelings; 1 00 mm = extremely positive … Evidence for abundant DNA sequence variability in the gene selleck inhibitor encoding the human µ opiate receptor Major advances in human molecular genetics in the

late 1980s led to the cloning of numerous genes encoding pharmacologically characterized receptors. This allowed in principle to address the role of receptors in disease and individually different drug response for the first time at the most Inhibitors,research,lifescience,medical basic level, that is, DNA sequence information. If DNA sequence differences in the receptor gene were identified that were correlated

with the individual phenotype in question, this could provide important clues on underlying receptor dysfunction and its nature. Since it is the entire gene and its encoded protein that act as the units of function which potentially affect Inhibitors,research,lifescience,medical a phenotype (and ultimately allow the first conclusions on disease mechanisms), it appeared Inhibitors,research,lifescience,medical mandatory to analyze the entire sequences of the individual genes, including their regulatory and critical intronic sequences. This required DNA sequence analyses at a previously unprecedented scale, in the Megabase range. Thus, we developed a powerful technique to perform comparative candidate gene sequencing in large numbers of patients and controls, “Multiplex Polymerase Chain Reaction (PCR) Sequencing.” In principle, this technology allowed processing multiple (up to 55) sequencing reactions simultaneously in one reaction Inhibitors,research,lifescience,medical tube, increasing throughput accordingly. Inhibitors,research,lifescience,medical As a second prerequisite, we generated significant information on the genomic organization of the human µ opiate receptor gene, extending the previously cloned complimentary DNA (cDNA) sequence information7 significantly. We determined several kb of 5′ regulatory region, identified a number of potential binding sites for transcriptional regulatory factors, and cloned critical intronic sequences.8

These lines of research and technology development were combined to conduct the first systematic and to date most comprehensive analysis of DNA sequence variation in the human µ opiate receptor gene (OPRMf ).9 In a total of 250 individuals with a phenotype of severe substance Megestrol Acetate (heroine/cocaine dependence and controls from two major populations, AfricanAmericans and European-Americans, abundant DNA sequence diversity was revealed (Figure 2). Regarding the nature and distribution of sequence variation in OPRM1, a total of 43 biallelic variants were identified. Clearly, the density of variants was higher in the 5′ regulatory and untranslated regions than in the coding regions, where six variants, five of which affect the encoded protein, were found.

Rosenzweig et al.4) reported on a case of a 69-year-old man with a history of mitral valve repair 4 years previously and a recent cerebrovascular event; the transesophageal echocardiography revealed an incompletely ligated LAA and thrombus within it. As no other cause of stroke was found, the authors thought that the LAA thrombus was associated with the patient’s cerebrovascular event. Inhibitors,research,lifescience,medical There were 2 reported cases of incompletely ligated

LAA, in which thrombus formation occurred during the postoperative period.5) In a study analyzing 50 Selleckchem MDV3100 patients who underwent mitral valve surgery and ligation of the LAA, they reported that the patients with incomplete ligation had increased incidence of thromboembolic events.6) They found that 18 of 50 patients had incompletely ligated

LAA, and 4 of 18 patients (22%) had thromboembolic events. Inhibitors,research,lifescience,medical In the study that focused on 137 patients with a previous history of LAA closure, only 55 of 137 (40%) closure were successful, and transesophageal echocardiography revealed LAA thrombus in 28 of 68 patients (41%) Inhibitors,research,lifescience,medical with unsuccessful closure.7) They found that 12 patient with unsuccessful closure (15%) had evidence of stroke or transient ischemic attack. There is still debate about the safety and usefulness of LAA exclusion surgery, yet there is agreement among authors that patients with a remnant LAA have a higher risk of thromboembolism. As Inhibitors,research,lifescience,medical observed in the cases with an incompletely ligated LAA, the patients with idiopathic LAA ostial stenosis could be considered to have a higher

risk of thromboembolic events than the patients with a normal LAA structure. Neither intracardiac thrombus formation nor significant cerebrovascular events were demonstrated in our cases, yet marked spontaneous echo contrast in the left atrium and LAA was observed in 1 case. The patient with spontaneous echo contrast was on aspirin, whereas the Inhibitors,research,lifescience,medical other patient was on anticoagulation treatment. In a study that analyzed patients with nonrheumatic atrial fibrillation, the incidence of spontaneous echo contrast Tryptophan synthase and ischemic stroke was significantly lower in the subgroup with a high LAA flow profile (higher than 20 cm/sec).8) The finding that the spontaneous echo contrast exists despite the high LAA flow velocity and taking antiplatelet agent implies that anticoagulation therapy could be safer way to prevent thromboembolic events in a patient with idiopathic LAA ostial stenosis, and especially when LAA dysfunction occurs. More experience, further investigation and long term follow up data are all needed to clarify the clinical meaning of LAA ostial stenosis.
A 77-year-old female was admitted with effort-related chest tightness and shortness of breath for several weeks. The chest tightness occasionally radiated to the left scapular area and lasted more than half an hour. The patient had history of hypertension for 10 years.

20 The spray is administered to each nostril every 1 to 2 hours with a range of 8 to 40 doses per day.21 The usual recommended

dose is 1 mg per administration over 8 weeks. Gradual taper is recommended between weeks 9 and 14.21 Side effects of the nasal spray may include nasal and throat irritation, sneezing, coughing, and watery eyes.22-24 The nicotine AUY 922 inhaler administers nicotine via cartridges placed in cigarette4ike plastic rods which produce a nicotine vapor (0.013 mg/puff) when inhaled.25,26 The nicotine is absorbed through the buccal mucosa and following inhalation. Inhibitors,research,lifescience,medical The recommended dose is 6 to 16 cartridges daily, with use for approximately 12 weeks.6 Each cartridge contains 10 mg of nicotine and delivers a maximum of 4 mg of nicotine, and provides approximately 20 minutes of active puffing. Peak Inhibitors,research,lifescience,medical plasma nicotine concentrations are typically achieved within 15 minutes.20 Throat irritation or coughing can occur in up to 50% of inhaler users.26,27 Because of the rapid delivery of the spray and inhaler, there is some potential for abuse liability after quitting Inhibitors,research,lifescience,medical smoking, leading to continued use >6 months.28-31 Patients who utilize nicotine replacement therapy improve their likelihood of quitting by 1.5 to 2 times.6,32 Long-term efficacy of NRT

on smoking cessation may actually be modest, however (5% to 10% above placebo).33 Most trials assess the effect of smoking reduction at 1 year or less, and the effect is attenuated by about Inhibitors,research,lifescience,medical 12%

after 12 months due to relapse occurring after the first year.33 Antidepressants The observed relationship between nicotine dependence and mood disorders such as depression supports the use of antidepressant medications as effective pharmacotherapies for cigarette smoking cessation.34 Sustainedrelease bupropion, an atypical antidepressant agent, has been the most commonly used medication for the pharmacotherapy Inhibitors,research,lifescience,medical of smoking cessation, improving quit rates in short- and long-term follow-up. Bupropion blockade of norepinephrine and dopamine uptake may attenuate nicotine withdrawal symptoms. In addition, bupropion also blocks the nicotinic acetylcholine receptor, thus offering a potential reduction in the reinforcing effects of nicotine.35,36 Patients start treatment at the recommended 150 mg/day Rolziracetam 7 days prior to their target quit date, since steady-state plasma levels are achieved within 1 week of initiation. Dosing is then increased to 300 mg/day after 3 to 4 days.6 Bupropion can also be used in combination with NRT. Two large, multicenter clinical trials demonstrated the efficacy of bupropion for the treatment of nicotine dependence, and it is recommended as a first-line treatment for smoking cessation.