Biomedical subjects

David J Clark

Publications and source records attributed to David J Clark.

At least 19 recordsLinked to original sources

PubMed2007

Cooperative binding of the yeast Spt10p activator to the histone upstream activating sequences is mediated through an N-terminal dimerization domain.

The yeast Spt10p activator is a putative histone acetyltransferase (HAT) possessing a sequence-specific DNA-binding domain (DBD) which binds to the upstream activation sequences (UAS elements) in the histone gene promoters. Spt10p binds to a pair of histone UAS elements with extreme positive cooperativity. The molecular basis of this cooperativity was addressed. Spt10p (640 residues) is an elongated dimer, but the isolated DBD (residues 283-396) is a monomer and binds non-cooperatively to DNA. A Spt10p fragment comprising the N-terminal domain (NTD), HAT domain and DBD (residues 1-396) binds cooperatively and is a dimer, whereas an overlapping Spt10p fragment comprising the DBD and C-terminal domains (residues 283-640) binds non-cooperatively and is a monomer. These observations imply that cooperative binding requires dimerization. The isolated NTD (residues 1-98) is a dimer and is responsible for dimerization. We propose that cooperativity involves a conformational change in the Spt10p dimer which facilitates the simultaneous recognition of two UAS elements. In vivo, deletion of the NTD results in poor growth, but does not prevent the binding at the HTA1 promoter, suggesting that dimerization is biologically important. Residues 1-396 are sufficient for normal growth, indicating that the critical functions of Spt10p reside in the N-terminal domains.

Binding Sites↗

PubMed2006

Use of drug-eluting stents in Victorian public hospitals.

OBJECTIVE: We aimed to assess the pattern of use of drug-eluting stents (DESs) in patients undergoing percutaneous coronary interventions (PCIs) in Victorian public hospitals. DESIGN, SETTING AND PATIENTS: Prospective study comparing the use of one or more DESs versus bare-metal stents (BMSs) only, in consecutive patients undergoing 2428 PCIs with stent implantation from 1 April 2004 to 31 December 2005 at seven Victorian public hospitals. MAIN OUTCOME MEASURES: Adherence to current Victorian Department of Human Services guidelines which recommend DES use in patients with high-risk features for restenosis (diabetes, small vessels, long lesions, in-stent restenotic lesions, chronic total occlusions and bifurcation lesions). RESULTS: Of the 2428 PCIs performed, at least one DES was implanted in 1101 (45.3%) and BMSs only were implanted in 1327 (54.7%). In 87.7% (966/1101) of PCI with DESs, there was at least one criterion for high risk of restenosis. DESs were more likely to be used in patients with diabetes (risk ratio [RR], 2.45; 95% CI, 2.02-2.97), small vessels (RR, 3.35; 95%CI, 2.35-4.76), long lesions (RR, 3.87; 95% CI, 3.23-4.65), in-stent restenotic lesions (RR, 3.98; 95%CI, 2.67-6.06), chronic total occlusions (RR, 1.30; 95% CI, 0.51-2.88) and bifurcation lesions (RR, 2.23; 95%CI, 1.57-3.17). However, 66.2% (1608/2428) of all PCIs were in patients eligible for DESs according to Victorian guidelines, and in 39.9% (642/1608) of these PCIs, a BMS was used. CONCLUSION: In Victorian public hospitals, DESs have been largely reserved for patients at high risk of restenosis in accordance with Department of Human Services guidelines. However, many patients with high-risk criteria for restenosis did not receive DESs. Greater use of DESs in these patients may improve outcomes by reducing the need for repeat revascularisation.

Angioplasty, Balloon, Coronary↗

PubMed2006

Activation of Saccharomyces cerevisiae HIS3 results in Gcn4p-dependent, SWI/SNF-dependent mobilization of nucleosomes over the entire gene.

The effects of transcriptional activation on the chromatin structure of the Saccharomyces cerevisiae HIS3 gene were addressed by mapping the precise positions of nucleosomes in uninduced and induced chromatin. In the absence of the Gcn4p activator, the HIS3 gene is organized into a predominant nucleosomal array. In wild-type chromatin, this array is disrupted, and several alternative overlapping nucleosomal arrays are formed. The disruption of the predominant array also requires the SWI/SNF remodeling machine, indicating that the SWI/SNF complex plays an important role in nucleosome mobilization over the entire HIS3 gene. The Isw1 remodeling complex plays a more subtle role in determining nucleosome positions on HIS3, favoring positions different from those preferred by the SWI/SNF complex. Both the SWI/SNF and Isw1 complexes are constitutively present in HIS3 chromatin, although Isw1 tends to be excluded from the HIS3 promoter. Despite the apparent disorder of HIS3 chromatin generated by the formation of multiple nucleosomal arrays, nucleosome density profiles indicate that some long-range order is always present. We propose that Gcn4p stimulates nucleosome mobilization over the entire HIS3 gene by the SWI/SNF complex. We suggest that the net effect of interplay among remodeling machines at HIS3 is to create a highly dynamic chromatin structure.

Adenosine Triphosphatases↗

PubMed2006

Activation impairment alters muscle torque-velocity in the knee extensors of persons with post-stroke hemiparesis.

OBJECTIVE: To elucidate mechanisms of impaired force production in post-stroke hemiparesis. METHODS: Knee extensor torque-velocity and activation-velocity relationships were examined in seventeen persons with post-stroke hemiparesis (age 57.5, +/-6.9) and thirteen non-disabled (age 63.0 +/-10.4) persons. RESULTS: Velocity-dependent concentric torque impairment was exaggerated in subjects with hemiparesis relative to control subjects (p<.001). Muscle power was also less in the group with hemiparesis (p<.001), and plateaued at velocities > or =90deg/s (p>.05). In the control group agonist EMG during concentric actions exhibited a positive linear relationship as velocity increased (R(2)=.93, p<.05). The group with hemiparesis produced 34-60% less agonist EMG than controls (p<.02) and modulation was absent (p>.05). Antagonist EMG was either greater in the control (biceps femoris, p<.006) or similar between groups (semimembranosus, p=.95). Under eccentric testing conditions, torque normalized to peak isometric torque (p=.44) and rectus femoris activation (p=.33) were similar between groups, indicating a relative preservation of eccentric torque producing capacity post-stroke. CONCLUSIONS: Certain clinical perspectives assert that weakness following central nervous system injury stems from spastic antagonist restraint. Instead, absence of an antagonist restraint strongly suggests that impaired agonist activation is the principal determinant of hemiparetic weakness. SIGNIFICANCE: These findings have important implications for promoting optimal recovery of motor function in neuro-rehabilitation.

Electromyography↗

PubMed2006

Topological analysis of plasmid chromatin from yeast and mammalian cells.

Yeast has proven to be a powerful system for investigation of chromatin structure. However, the extent to which yeast chromatin can serve as a model for mammalian chromatin is limited by the significant number of differences that have been reported. To further investigate the structural relationship between the two chromatins, we have performed a DNA topological analysis of pRSSVO, a 5889 base-pair plasmid that can replicate in either yeast or mammalian cells. When grown in mammalian cells, pRSSVO contains an average of 33 negative supercoils, consistent with one nucleosome per 181 bp. This is close to the measured nucleosome repeat length of 190 bp. However, when grown in yeast cells, pRSSVO contains an average of only 23 negative supercoils, which is indicative of only one nucleosome per 256 bp. This is dramatically different from the measured nucleosome repeat length of 165 bp. To account for these observations, we suggest that yeast chromatin is composed of relatively short ordered arrays of nucleosomes with a repeat of 165 bp, separated by substantial gaps, possibly corresponding to regulatory regions.

Animals↗

PubMed2006

Mechanisms and predictors of carotid artery stent restenosis: a serial intravascular ultrasound study.

OBJECTIVES: The aim of this study was to determine the mechanisms and predictors of carotid artery restenosis after carotid artery stenting (CAS) using serial intravascular ultrasound (IVUS) imaging. BACKGROUND: Carotid artery stenting is increasingly used to treat high-grade obstructive carotid disease, but our knowledge of carotid in-stent restenosis and remodeling remains limited. METHODS: Post-procedural and 6-month (median 6 months) follow-up quantitative carotid angiography and IVUS were performed after self-expanding stent deployment in 50 internal carotid arteries (ICA). The IVUS measurements at multiple designated sites included minimal luminal diameter, lumen area, stent area (SA), and neointimal hyperplasia area (NIH). RESULTS: Late stent enlargement at follow-up was found at all segments, and the percentage increase was greatest at the ICA lesion site (mean +/- SD, 48.9 +/- 35.3%). The NIH, expressed as a percentage of SA, was seen within all segments of the stent and was greatest at the ICA lesion site (37.3 +/- 23.3%). There was a strong positive correlation between the amount of NIH and late stent enlargement (r = 0.64; p < 0.001). Immediate post-procedural minimum ICA SA (r = -0.37; p < 0.01) and stent expansion (r = -0.44; p = 0.001) correlated negatively with the percentage restenotic area at follow-up. CONCLUSIONS: Although self-expanding carotid stents generate considerable neointimal hyperplasia, the process is balanced by marked late stent enlargement. Small stent dimensions immediately post-procedure were associated with a higher risk of restenosis.

Aged↗

PubMed2006

Chronic pain and genetic background interact and influence opioid analgesia, tolerance, and physical dependence.

Opioids are commonly used in the treatment of moderate to severe pain. However, their chronic use is limited by analgesic tolerance and physical dependence. Few studies have examined how chronic pain affects the development of tolerance or dependence, and essentially no studies have looked at the role of both genetics and pain together. For these studies we used 12 strains of inbred mice. Groups of mice from each strain were tested at baseline for morphine analgesic sensitivity, mechanical nociceptive threshold, and thermal nociceptive threshold. Mice were then given morphine in a 4-day escalating morphine administration paradigm followed by reassessment of the morphine dose-response relationship. Finally, physical dependence was measured by administering naloxone. Parallel groups of mice underwent hind paw injection of complete Freund's adjuvant (CFA) to induce chronic hind paw inflammation 7 days prior to the beginning of testing. The data showed that CFA treatment tended to lower baseline ED(50) values for morphine and enhanced the degree of analgesic tolerance observed after 4 days of morphine treatment. In addition, the degree of jumping behavior indicative of physical dependence was often altered if mice had been treated with CFA. The influence of background strain was substantial for all traits measured. In silico haplotypic mapping of the tolerance and physical dependence data demonstrated that CFA pretreatment altered the pattern of the predicted associations and greatly reduced their statistical significance. We conclude that chronic inflammatory pain and genetics interact to modulate the analgesic potency of morphine, tolerance, and physical dependence.

Analgesics, Opioid↗

PubMed2006

The DNA-binding domain of the yeast Spt10p activator includes a zinc finger that is homologous to foamy virus integrase.

The yeast SPT10 gene encodes a putative histone acetyltransferase that binds specifically to pairs of upstream activating sequence (UAS) elements found only in the histone gene promoters. Here, we demonstrate that the DNA-binding domain of Spt10p is located between residues 283 and 396 and includes a His(2)-Cys(2) zinc finger. The binding of Spt10p to the histone UAS is zinc-dependent and is disabled by a zinc finger mutation (C388S). The isolated DNA-binding domain binds to single histone UAS elements with high affinity. In contrast, full-length Spt10p binds with high affinity only to pairs of UAS elements with very strong positive cooperativity and is unable to bind to a single UAS element. This implies the presence of a "blocking" domain in full-length Spt10p, which forces it to search for a pair of UAS elements. Chromatin immunoprecipitation experiments indicate that, unlike wild-type Spt10p, the C388S protein does not bind to the promoter of the gene encoding histone H2A (HTA1) in vivo. The C388S mutant has a phenotype similar to that of the spt10Delta mutant: poor growth and global aberrations in gene expression. Thus, the C388S mutation disables the DNA-binding function of Spt10p in vitro and in vivo. The zinc finger of Spt10p is homologous to that of foamy virus integrase, perhaps suggesting that this integrase is also a sequence-specific DNA-binding protein.

Amino Acid Sequence↗

PubMed2006

Reliability of concentric and eccentric torque during isokinetic knee extension in post-stroke hemiparesis.

BACKGROUND: Emerging evidence on the velocity-dependent nature of force impairment in post-stroke hemiparesis has emphasized the complexity of strength and motor performance assessments in this clinical population. The need to establish reliability and responsiveness of muscle performance measures across a broad range of concentric and eccentric movement speeds is therefore clear, as these metrics will provide benchmarks both for making clinical inference and evaluating meaningful clinical change following interventions. METHODS: Isokinetic knee extensor strength was tested at 14 angular velocities in 17 adults with chronic post-stroke hemiparesis (>18 months), and 13 non-disabled controls. Identical tests were conducted on two occasions separated by two days. Test-retest reliability of maximal isokinetic torque was evaluated using intraclass correlation. Absolute reliability was assessed using standard error of measurement from which smallest real differences were derived. FINDINGS: Overall, intraclass correlation coefficients were excellent for both hemiparetic (0.891) and control (0.937) groups. Intraclass correlation coefficients for each criterion speed were also high for both groups (>0.86). Measurement error relative to the mean torque varied between 14.1% and 26.3% for hemiparetic subjects and 6.0-18.1% for controls. The smallest real difference relative to mean torque was 39.0-72.7% and 16.6-50.2% for hemiparetic and control subjects, respectively. INTERPRETATION: Isokinetic knee extension torque can be measured reliably in persons with chronic post-stroke hemiparesis and in non-disabled controls across a full functional range of concentric and eccentric speeds. Established measurement error and smallest real differences will aid interpretation of longitudinal observations of muscle performance in this clinical population.

Adult↗

PubMed2006

Proteomic profiling of cell envelope-associated proteins from Staphylococcus aureus.

The emergence of highly virulent community acquired Staphylococcus aureus and continued progression of resistance to multiple antimicrobials, including methicillin and vancomycin, marks the reemergence of S. aureus as a serious health care threat. Investigation of proteins localized to the cell surface could help to elucidate mechanisms of virulence and antibiotic resistance in S. aureus. In this study, proteomic profiling methods were developed to solubilize, display, and evaluate abundance levels of proteins present in the supernatants of the lysostaphin-digested cell envelope from cultured vancomycin-intermediate S. aureus (VISA) cells. Combining approaches of 2-DE or chromatographic separation of proteins with MS analyses resulted in the identification of 144 proteins of particular interest. Of these proteins, 48 contained predicted cell wall localization or export signal motifs, including 14 with distinct covalent peptidoglycan-anchor sites, four of which are uncharacterized to date. One of the two most abundant cell envelope proteins, which showed remarkably high variations in MW and pI in the 2-DE gel display, was the S. aureus surface protein G. The display of numerous secreted proteins that are not covalently cell wall-anchored, suggests that, in the exponential growth phase, secreted proteins can be retained physiologically in the cell envelope and may interact with cell wall-anchored proteins and carbohydrate structures in a manner yet to be determined. The remaining 96 proteins, devoid of recognizable motifs, were repeatedly profiled in the VISA cell envelope fractions. We describe a novel semiquantitative method to determine abundance factors of such proteins in 2-DE gels of cell envelope fractions relative to whole cell lysates and discuss these data in the context of true cell envelope localization versus experimentally caused cell lysis.

Amino Acid Sequence↗

PubMed2006

Comparative proteomic analysis of Staphylococcus aureus strains with differences in resistance to the cell wall-targeting antibiotic vancomycin.

Three isogenic strains derived from a clinical vancomycin-intermediate Staphylococcus aureus isolate were examined by comparative protein abundance analysis. Subcellular fractionation was followed by protein separation in 2-DE gels and spot identification by MALDI-TOFTOF-MS and LC-MS/MS. Sixty-five significant protein abundance changes were determined. Numerous enzymes participating in the purine biosynthesis pathway were dramatically increased in abundance in strain VP32, which featured the highest minimal inhibitory concentration for vancomycin, compared to strains P100 and HIP5827. Peptidoglycan hydrolase LytM (LytM) and the SceD protein, a putative transglycosylase, were increased in abundance in the cell envelope fraction of strain VP32, whereas the enzyme D-Ala-D-Ala ligase was decreased in its cytosol fraction. Furthermore, penicillin-binding protein 2 (PBP2) had substantially higher activity in strain VP32 compared to that in strain HIP5827. LytM, PBP2 and D-Ala-D-Ala ligase catalyze reactions in the biosynthesis or the metabolism of cell wall peptidoglycan. It is plausible that expression and activity changes of these enzymes in strain VP32 are responsible for an altered cell wall turnover rate, which has been observed, and an altered peptidoglycan structure, which has yet to be elucidated for this highly vancomycin-resistant strain.

Amino Acid Sequence↗

PubMed2006

Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: a preliminary prospective study.

UNLABELLED: There is accumulating evidence that opioid therapy might not only be associated with the development of tolerance but also with an increased sensitivity to pain, a condition referred to as opioid-induced hyperalgesia (OIH). However, there are no prospective studies documenting the development of opioid tolerance or OIH in patients with chronic pain. This preliminary study in 6 patients with chronic low back pain prospectively evaluated the development of tolerance and OIH. Patients were assessed before and 1 month after initiating oral morphine therapy. The cold pressor test and experimental heat pain were used to measure pain sensitivity before and during a target-controlled infusion with the short-acting mu opioid agonist remifentanil. In the cold pressor test, all patients became hyperalgesic as well as tolerant after 1 month of oral morphine therapy. In a model of heat pain, patients exhibited no hyperalgesia, although tolerance could not be evaluated. These results provide the first prospective evidence for the development of analgesic tolerance and OIH by using experimental pain in patients with chronic back pain. This study also validated methodology for prospectively studying these phenomena in larger populations of pain patients. PERSPECTIVE: Experimental evidence suggests that opioid tolerance and opioid-induced hyperalgesia might limit the clinical utility of opioids in controlling chronic pain. This study validates a pharmacologic approach to study these phenomena prospectively in chronic pain patients and suggests that both conditions do occur within 1 month of initiating opioid therapy.

Administration, Oral↗

PubMed2006

Mapping histone modifications by nucleosome immunoprecipitation.

Studies of histone modification patterns and their role in gene regulation have led to the proposal that there is a "histone code." We have developed a method for nucleosome immunoprecipitation that can precisely identify the specific nucleosomes that carry a posttranslational modification of interest. The process involves the isolation and micrococcal nuclease digestion of minichromosomes to generate nucleosome core particles. These are then used in immunoprecipitation reactions with an antibody directed against the histone modification of interest. Subsequently, nucleosome core particle DNA is purified and end labeled. The original locations of the nucleosomes in the immunoprecipitate can be determined at low resolution (using a modified Southern blot hybridization procedure) or at maximal resolution (using the monomer extension method). Using the latter method, the positions of specific nucleosomes that carry the posttranslational modification of interest can be identified precisely. This method is sensitive, provides maximal resolution, and is inexpensive. The approach described here may serve as a paradigm for the study of histone-modifying patterns.

Animals↗

PubMed2006

Genetic variants of the P-glycoprotein gene Abcb1b modulate opioid-induced hyperalgesia, tolerance and dependence.

OBJECTIVE: Opioid-induced hyperalgesia (OIH) is a state of paradoxically increased nociceptive sensitivity seen in both humans and rodents following the resolution of the acute opioid antinociceptive effects or during periods of chronic opioid administration. Using the power of genetic analysis, we hoped to discover novel mechanisms modulating this trait. BASIC METHODS: The degree of opioid-induced hyperalgesia displayed in response to a thermal stimulus applied to the hind paw was measured in 16 strains of inbred mice after 4 days of morphine administration. The degree of thermal sensitization was then used in a recently developed in silico haplotypic mapping algorithm along with a haplotypic map constructed from a database containing 209,000 single nucleotide polymorphisms. MAIN RESULTS: Analysis of the data resulted in the identification of several haplotype blocks strongly associated with the thermal opioid-induced hyperalgesia trait. The most strongly associated block was located within the Abcb1b P-glycoprotein drug transporter gene. Experiments using the P-glycoprotein inhibitor cyclosporine A and P-glycoprotein null mutant mice supported the hypothesis that a functional association exists between P-glycoprotein transporters and opioid-induced hyperalgesia. The observation of a correlation between morphine brain concentrations and the development of opioid-induced hyperalgesia was consistent with this hypothesis as well. In addition, P-glycoprotein gene deletion and pharmacological inhibition altered morphine ED50, tolerance and physical dependence. CONCLUSIONS: We conclude that the use of haplotypic mapping to identify novel mechanisms controlling complex traits is a viable approach. Variants of the Abcb1b gene may explain some portion of the interstrain differences in OIH and perhaps other consequences of chronic opioid administration.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Characteristics and treatment of headache after traumatic brain injury: a focused review.

Headache is one of the most common complaints in patients with traumatic brain injury. By definition, headache that develops within 1 wk after head trauma (or within 1 wk after regaining consciousness) is referred to as posttraumatic headache (PTH). Although most PTH resolves within 6-12 mos after injury, approximately 18-33% of PTH persists beyond 1 yr. We performed a systematic literature review on this topic and found that many patients with PTH had clinical presentations very similar to tension-type headache (37% of all PTH) and migraine (29% of all PTH). Although there is no universally accepted protocol for treating PTH, many clinicians treat PTH as if they were managing primary headache. As a result of the heterogeneity in the terminology and paucity in prospective, well-controlled studies in this field, there is a definite need for conducting double-blind, placebo-controlled treatment trials in patients with PTH.

Analgesics↗

PubMed2006

Single-dose pharmacokinetics of varenicline, a selective nicotinic receptor partial agonist, in healthy smokers and nonsmokers.

Varenicline is a novel and selective alpha4beta2 nicotinic receptor partial agonist that is under development for smoking cessation. The primary objectives of this double-blind, placebo-controlled, single-dose, dose-escalation study were to determine the clinical pharmacology of single doses of varenicline in healthy smokers and nonsmokers under fed and fasted conditions and to determine the clinical pharmacology of varenicline administered in the morning and in the evening to smokers. Within each subject group, 4 subjects were randomized to varenicline and 2 subjects to placebo. Subjects received one single oral administration of varenicline or placebo: 6 doses (0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg) were investigated in nonsmokers and 7 doses in smokers (0.01, 0.03, 0.1, 0.3, 1.0, 3.0, and 10.0 mg). Varenicline was well tolerated after single doses up to 3.0 mg in smokers and 1.0 mg in nonsmokers. Nausea and vomiting at doses above 3.0 mg in smokers and 1.0 mg in nonsmokers were dose limiting. Systemic exposure to varenicline and pharmacokinetic variability were similar between smokers and nonsmokers. Coadministration with food, smoking restriction, and time-of-day dosing did not affect the pharmacokinetics of varenicline.

Administration, Oral↗

PubMed2006

Pharmacokinetics, safety, and tolerability after single and multiple oral doses of varenicline in elderly smokers.

Varenicline is a novel selective alpha4beta2 nicotinic acetylcholine partial agonist developed for smoking cessation. This study investigated the single- and multiple-dose pharmacokinetics, safety, and tolerability of varenicline in elderly (> or = 65 years) smokers. Twenty-four elderly smokers with normal renal function for their age (estimated creatinine clearance > or = 70 mL/min) received varenicline 1 mg once daily (n = 8) or placebo (n = 4) for 7 days, or 1 mg twice daily (n = 8) or placebo (n = 4) for 6 days with a single dose on day 7 in a double-blind, parallel group and placebo-controlled design. There was no evidence of concentration- or time-dependent changes in varenicline pharmacokinetics upon repeat dosing. Once- and twice-daily dosing was associated with an approximate 2-fold and 3-fold increase, respectively, in systemic exposure to varenicline. Varenicline was well tolerated; all adverse events reported were mild to moderate in intensity. Thus, no dose adjustment is necessary based on age alone.

Administration, Oral↗

PubMed2006

Multiple-dose pharmacokinetics of the selective nicotinic receptor partial agonist, varenicline, in healthy smokers.

Varenicline is a novel and selective alpha4beta2 nicotinic acetylcholine receptor partial agonist developed for smoking cessation. The primary objectives of this double-blind, placebo-controlled, dose-escalation study were to determine the pharmacokinetics, safety, and tolerability of multiple oral doses of varenicline given as tablets once (1 mg, 2 mg, and 3 mg) or twice (1 mg) daily to healthy adult smokers. Within each dose level, 8 subjects were randomized to varenicline and 4 subjects to placebo. Varenicline was well tolerated at doses up to and including 2 mg daily. Dose-proportional increases in maximum observed plasma concentrations and area under the plasma concentration-time curve from time zero to the end of the dosing interval values were observed between the 1-mg and 2-mg daily doses of varenicline. Once- and twice-daily dosing resulted, on average, in an approximate 2- and 3-fold increase in varenicline systemic exposure, respectively, compared with single dose. There was no evidence of concentration- or time-dependent changes in the pharmacokinetics of varenicline upon repeat dosing.

Administration, Oral↗