Published online before print December 10, 2007, doi: 10.1161/HYPERTENSIONAHA.107.098939
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(Hypertension. 2008;51:406.)
© 2008 American Heart Association, Inc.
Original Articles |
Ethnic and Genetic Determinants of Cardiovascular Response to the Selective 
2-Adrenoceptor Agonist Dexmedetomidine
From the Departments of Medicine and Pharmacology, Division of Clinical Pharmacology (D.K., E.A.F., M.M., G.G.S., A.J.J.W., C.M.S.), and the Department of Biomedical Statistics (W.D.D.), Vanderbilt University School of Medicine, Nashville, Tenn; the Department of Pharmacology, Drug Development and Therapeutics (M.S.), University of Turku, and Clinical Pharmacology, TYKSLAB, Hospital District of Southwest Finland, Turku, Finland.
Correspondence to C. Michael Stein, MD, Division of Clinical Pharmacology, 542 RRB, Vanderbilt University School of Medicine, Nashville, TN 37232. E-mail michael.stein{at}vanderbilt.edu
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Abstract |
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The
2-adrenoceptor agonist clonidine reduces blood pressure more effectively in White than Black Americans despite similar degrees of sympatholysis. Functional genetic variation in receptor signaling mechanisms, for example in the β3 G-protein subunit (GNB3 C825T) and in the 2C-adrenoceptor subtype (ADRA2C del322–325), may affect drug responses. We examined the hypothesis that there are ethnic differences in the responses to the highly selective 2-agonist, dexmedetomidine, and that these genetic variants contribute to interindividual variability in drug responses. In a placebo-controlled, single-masked study, 73 healthy subjects (37 whites and 36 blacks) received 3 placebo infusions and then 3 incremental doses of dexmedetomidine (cumulative dose, 0.4 µg/kg), each separated by 30 minutes. Blood pressure, heart rate, and plasma catecholamine concentrations were determined after each infusion. We measured dexmedetomidine concentrations after the last infusion and determined ADRA2C del322–325 and GNB3 C825T genotypes. Dexmedetomidine lowered blood pressure and plasma catecholamine concentrations significantly (all P<0.001). There was substantial interindividual variability in the reduction of systolic blood pressure (range, 1 to 34 mm Hg) and plasma norepinephrine concentrations (range, 24 to 424 pg/mL). However, there were no differences between black and white subjects in dexmedetomidine responses (P>0.16 for all outcomes) before or after adjustment for covariates. Neither ADRA2C del322–325 nor GNB3 C825T genotypes affected the responses to dexmedetomidine (all P>0.66). There is large interindividual variability in response to the selective 2-AR agonist dexmedetomidine, and neither ethnicity nor ADRA2C and GNB3 genotypes contribute to it. Further studies to identify determinants of 2-AR–mediated responses will be of interest.
Key Words: cardiovascular physiology • receptors, adrenergic, -2 • G-protein beta3 subunit • dexmedetomidine • pharmacogenetics • ethnic groups
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Introduction |
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2-Adrenoceptors (2-ARs) in the central nervous system and on presynaptic sympathetic nerve terminals play a key role in the regulation of the sympathetic response and thus cardiovascular control. The systemic administration of an 2-AR agonist causes a reduction in sympathetic tone resulting in a decrease in blood pressure and heart rate, and the 2-AR agonist clonidine is widely used as antihypertensive medication. There is, however, substantial interindividual variability in response to 2-AR agonists, and black hypertensive patients achieved blood pressure control with clonidine monotherapy less often than whites.1,2 Concordant with that observation, we found that clonidine reduced blood pressure less in healthy black subjects than white subjects, despite similar decreases in norepinephrine spillover.3 The reasons for these ethnic differences remain unclear.
Functionally significant genetic variants of 2-ARs and other proteins in their signaling pathways have been identified. The prevalence of these allelic variants differs substantially among different ethnic groups, and they could therefore contribute to ethnic differences in response to 2-AR agonists. For example, a single nucleotide polymorphism in the gene for the β3 subunit of the G-protein coupled to 2-ARs (GNB3 C825T) is twice as common in blacks as whites. In healthy White subjects, carriers of the T allele had greater reductions in blood pressure and total peripheral resistance after clonidine than noncarriers.4 Another genetic variant that may influence responses to 2-AR agonists is a deletion of 4 amino acids in the 2C-AR (ADRA2C del322 -325), which results in 85% loss of receptor function in vitro. This deletion variant is 10 times more frequent in blacks than whites, and subjects homozygous for the deletion variant (del/del) had greater increases in norepinephrine spillover and heart rate after the administration of the 2-AR antagonist yohimbine.5
Most previous pharmacological studies of 2-AR–mediated responses have used clonidine to activate the receptor. However, clonidine also has 1-AR agonist activity and may induce vasoconstriction through this mechanism, potentially confounding its 2-AR–mediated hypotensive response.6 We therefore investigated the genetic and ethnic contributors to variability in 2-AR responses using the highly selective 2-AR agonist dexmedetomidine. We tested the hypotheses (1) that Black subjects have attenuated blood pressure reduction after dexmedetomidine, similar to the previous findings with clonidine, and (2) that the GNB3 C825T and ADRA2C del322–325 genetic variants affect dexmedetomidine responses and contribute to ethnic differences.
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Methods |
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Subjects
The Institutional Review Board of Vanderbilt University Medical Center approved the study protocol, and subjects gave written informed consent. African-American and European-American subjects were eligible to participate if they were unrelated residents of Middle Tennessee, between 18 to 45 years of age, nonsmokers, and had no clinically significant abnormality based on medical history, physical examination, and routine laboratory testing. Six black subjects with known ADRA2C homozygous genotype (3 each homozygous for either the insertion allele [ins/ins] or the deletion allele [del/del]) were recruited to enrich these genotypes. Subjects reported their ethnicity and that of their parents and grandparents using check-boxes; a subject was assigned to an ethnic group when at least 3 of 4 grandparents were of the same ethnicity. Family history of hypertension was determined by self-report. Subjects adhered to an alcohol- and caffeine-free diet (providing daily 150 mmol of sodium, 70 mmol of potassium, and 600 mmol of calcium) for 5 days before the study and were free of medications and dietary supplements for at least 2 weeks.
Study Procedure
The study was designed as a placebo-controlled, single-masked study. After an overnight fast, subjects were admitted on the morning (around 8:00 AM) of the 6th study day to the Vanderbilt University Clinical Research Center. Two intravenous cannulae (21 to 23 G), one for blood collection and one for drug infusion, were inserted into antecubital veins, one in each arm. After a 30-minute supine resting period, blood pressure and heart rate were measured at the left brachial artery by a semi-automated device (Dinamap MPS; GE Medical Systems), with a cuff size appropriate for the arm circumference.7 For all heart rate and blood pressure determinations during the study, 2 recordings were obtained 1 minute apart and averaged. Then, 6 infusion cycles followed. Subjects received a 10-minute infusion (placebo [normal saline] during cycles 1 to 3, and dexmedetomidine [Precedex, Abbott Laboratories] at doses of 0.1, 0.15, and 0.15 µg/kg body weight, respectively, during cycles 4 to 6), each followed by a 20 minute observation period. The total dose administered (0.4 µg/kg) targeted relatively low plasma dexmedetomidine concentrations (approximately 0.2 ng/mL), that are in the linear part of the dose-response curve for reduction in blood pressure and plasma norepinephrine concentrations.8,9 We measured heart rate and blood pressure at the completion of each infusion and 10 and 20 minutes afterward. Blood samples (10 mL) for the determination of plasma catecholamine concentrations were drawn at baseline (after the 30 minute rest period) and 10 minutes after the completion of each infusion, and an additional blood sample for the determination of plasma dexmedetomidine concentrations and for DNA extraction was drawn 10 minutes after completion of the last dexmedetomidine infusion.
Genotyping
The ADRA2C del322–325 variant was genotyped by DNA fragment analysis as described previously,10 and the GNB3 C825T polymorphism (rs5443) was performed by allelic discrimination with TaqMan 5'-nuclease assays.11 Further details are available in the online supplement (please see http://hyper.ahajournals.org).
Plasma Catecholamine Determination
Blood was collected into cooled heparinized tubes which were immediately placed on ice until centrifuged at 4°C for 10 minutes at 3000 rpm. Plasma was harvested and stored in tubes containing 40 µL of reduced glutathione (6%) at –20°C until assayed. Norepinephrine and epinephrine concentrations were measured by high-performance liquid chromatography (HPLC) using electrochemical detection with dihydroxybenzylamine as internal standard.12
Plasma Dexmedetomidine Determination
Dexmedetomidine plasma concentrations were determined by reversed-phase HPLC with tandem mass spectrometric detection (PE Sciex API365, PE Sciex), with slight modifications from a published protocol.13 The lower limit of quantitation (LLOQ) of the assay was 0.020 ng/mL. Within- and between-run precision, expressed as coefficient of variation, ranged between 2.0% and 5.2%.
Data and Statistical Analysis
Data are expressed as mean±SD or 95% confidence interval (CI) in tables and text, and as mean±SEM or median and interquartile range (IQR) in the figure. Comparisons of demographic data and outcomes in the 2 ethnic groups and among genotypes were performed by Chi-square test, independent t test, and 1-way analysis of variance. Within-subject comparisons between responses during the placebo and dexmedetomidine study phase were performed by paired t test. Allele distribution was tested for deviations from Hardy-Weinberg equilibrium with the use of a chi-square test with 1 degree of freedom. Because 6 black subjects preselected to enrich homozygous ADRA2C genotypes had been included in the cohort, we performed analyses both with and without these subjects, to satisfy the assumption of a randomly selected sample. Maximal blood pressure and heart rate responses to dexmedetomidine were recorded 10 minutes after completion of the infusion, coinciding with the time of the plasma sample. Therefore, measurements from this time point were analyzed. For each subject, systolic and diastolic blood pressure, heart rate, and plasma catecholamine concentrations were plotted against time. For each outcome, we calculated a summary variable representing the overall response, the area under the curve (AUC), by the trapezoidal rule for the 1.5-hour periods of placebo and of dexmedetomidine infusions, respectively. At low doses, dexmedetomidine primarily reduces blood pressure and plasma norepinephrine concentrations,8,9 and we therefore specified these as the main outcomes. Dexmedetomidine responses were assessed (1) as the decrease in the outcome measure from the last placebo infusion to the last dexmedetomidine infusion, representing the response at the highest dexmedetomidine concentration; and (2) as the difference in AUC of the response variable during the placebo and dexmedetomidine infusions. Heart rate and plasma epinephrine concentrations were analyzed similarly as secondary outcomes. We performed multiple linear regression analyses to examine the contribution of non-genetic covariates (sex, race, age, plasma dexmedetomidine concentration) and genetic variants (ADRA2C and GNB3 genotype) on the outcome measures. Based on previous studies,5,14 we assumed a recessive mode of inheritance for the functional effects of the ADRA2C del322–325 variant and compared carriers of the insertion allele (Ins/Ins and Ins/Del combined) with subjects homozygous for the deletion (del/del); for the functional effects of the GNB3 C825T variant, we assumed a dominant mode of inheritance4,15 and compared subjects homozygous for the C allele (CC) with carriers of the T allele (CT and TT combined). All tests were 2-tailed, and a probability value of <0.05 was considered statistically significant. Analyses were performed with the statistical software SPSS (SPSS v.14.0, SPSS Inc) and STATA 9.1 (StataCorp).
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Results |
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Subject Characteristics
We studied a total of 73 subjects (37 whites and 36 blacks); demographic characteristics are shown in Table 1. Blacks had a significantly higher body mass index than whites.
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Genetic Analysis
Allele frequencies for the ADRA2C deletion were within the expected range and differed significantly between the ethnic groups (4.1% for white and 50.0% for black subjects; P<0.001). The ADRA2C genotype distribution (ins/ins: 91.9% and 33.3%; ins/del: 8.1% and 33.3%; and del/del: 0.0% and 33.3% for whites and blacks, respectively) was consistent with Hardy-Weinberg equilibrium in whites (P=0.82), but not in blacks (
2=4.0; P=0.046), reflecting the 6 subjects preselected for the homozygous genotypes; after their exclusion, the genotype distribution in blacks conformed with Hardy-Weinberg equilibrium (2=1.2; P=0.27). For GNB3, frequencies of the T allele (41.7% and 86.1% for white and black subjects, respectively) and the genotype distributions (CC: 36.1% and 0.0%; CT: 44.4% and 27.8%; TT: 19.4% and 72.2% for whites and blacks, respectively) were in the expected range, conformed to Hardy-Weinberg equilibrium (P=0.61 and P=0.33 for whites and blacks, respectively), and differed significantly between the 2 ethnic groups (P<0.001). Excluding the 6 preselected black subjects did not appreciably affect GNB3 genotype distribution or allele frequencies.
Baseline Measures and Placebo Phase
At baseline, black subjects had higher systolic blood pressure and a similar trend for diastolic blood pressure (Table 1). After adjustment for sex, age, and body mass index, the ethnic difference in systolic and diastolic blood pressure was attenuated (mean ethnic difference, 4.6 mm Hg; 95% CI, 1.1 to 8.1 mm Hg; P=0.01, and 2.6 mm Hg; 95% CI, -0.6 to 5.9 mm Hg; P=0.11). During the 3 placebo infusions, blacks tended to have higher systolic blood pressure (mean adjusted ethnic difference of SBP-AUC during placebo phase, 5.5 mm Hg*hr; 95% CI, 0.0 to 10.9 mm Hg*hr; P=0.05), but there were no ethnic differences for the AUC for diastolic blood pressure, heart rate, and plasma catecholamine concentrations (all P>0.13). ADRA2C and GNB3 genotypes were not significantly associated with the baseline measures or the AUC during the placebo phase (all P>0.15).
Response to Dexmedetomidine: Ethnic Effects
Dexmedetomidine significantly decreased blood pressure, plasma catecholamine concentrations, and heart rate (all probability values <0.001; Table 2 and Figure 1). There were no ethnic differences in the responses to dexmedetomidine (all probability values >0.19; Table 2 and Figure 2). After adjustment for nongenetic covariates (sex, race, age, body mass index, dexmedetomidine plasma concentration, and placebo response [ie, value after placebo infusions] and ADRA2C and GNB3 genotypes), estimates of ethnic differences were essentially unchanged and not statistically significant (Figure 2). Analyses after the exclusion of the 6 preselected Black subjects yielded similar results. Similarly, comparing unadjusted and adjusted AUC for systolic and diastolic blood pressure and plasma norepinephrine between the placebo and dexmedetomidine study phases did not reveal any ethnic differences.
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Responses to Dexmedetomidine: Genetic Effects
Unadjusted analysis of responses of blood pressure and plasma norepinephrine concentrations to dexmedetomidine showed no association with the ADRA2C and GNB3 genotypes (Figure S1 in the online supplement; please see http://hyper.ahajournals.org). Similarly, after adjustment for all covariates, there was no evidence for a genotype effect on the outcomes (all probability values >0.66). Analyses of the reduction of AUC for blood pressure and plasma norepinephrine between the placebo and dexmedetomidine phases showed no significant genotype effects (all probability values >0.13). An analysis restricted to the subgroup of black subjects yielded similar results.
Dexmedetomidine Concentrations
Mean (±SD) plasma dexmedetomidine concentrations after the third infusion were 0.17±0.05 ng/mL (range, 0.05 to 0.36 ng/mL). Black subjects had higher plasma dexmedetomidine concentrations (mean ethnic difference, 0.05 ng/mL; 95% CI, 0.03 to 0.07 ng/mL; P<0.001) than white subjects.
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Discussion |
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This is the first study to examine ethnic differences in the systemic cardiovascular effects of the highly selective
2-AR agonist, dexmedetomidine, in a large biethnic study population comprised of African-American (black) and European-American (white) subjects. Our objective was to examine, under controlled experimental conditions, whether race or functional genetic polymorphisms in the 2C-AR or in a G protein subunit associated with 2-ARs, all previously reported to affect responses to clonidine or the 2-antagonist yohimbine, would affect the responses to a more selective 2-AR agonist than clonidine, dexmedetomidine. Our main findings were that white and black subjects had similar sympatholytic and cardiovascular responses, and that neither ADRA2C del322–325 nor GNB3 C825T genotypes were associated with the responses to dexmedetomidine.
The substantial differences between American blacks and whites in the prevalence and complications of hypertension16 have given rise to the hypothesis that ethnic differences exist in the mechanisms of blood pressure regulation, and that variability in genes associated with blood pressure regulation could contribute to such ethnic differences.17 2-ARs play a central role in the control of sympathetic tone and blood pressure. Hypertensive black patients were less responsive to the 2-AR agonist clonidine than whites, suggesting ethnic differences in 2-AR mediated blood pressure regulation.1,2 In a previous study, we found that clonidine lowered sympathetic tone similarly in healthy black and white subjects, but resulted in a greater blood pressure reductions in whites.3 A possible explanation for this observation was that regulation of resting blood pressure depends less on sympathetic tone in blacks than in whites. An alternative explanation is that blacks are more sensitive to 1-AR mediated vasoconstriction than whites,18 because clonidine, although relatively selective for 2-ARs, retains 1-AR agonist properties.6
We now addressed this question using dexmedetomidine, an 2-agonist that has an 8-fold higher 2-/1-AR selectivity (1620:1) than clonidine.19 Dexmedetomidine resulted in similar decreases in sympathetic tone (as reflected by plasma norepinephrine concentrations) in whites and blacks, but in contrast to clonidine, there was no ethnic difference in blood pressure reduction. Moreover, we have previously shown that peripheral venoconstriction in response to dexmedetomidine is similar in black and white Americans.20 Thus, our current and previous findings combined suggest that the blood pressure response to decreased sympathetic activity is similar in blacks and whites, and therefore that the differential effects of clonidine on blood pressure and plasma norepinephrine in blacks and whites may be related to its direct 1-AR -mediated effects. Indeed, there is evidence that 1-AR–mediated vascular sensitivity is increased in black subjects.18
There were marked interindividual differences in the responses to dexmedetomidine that remain unexplained. A genetic variant encoding the deletion of 4 amino acids in the third intracellular loop (ADRA2C del322–325) markedly reduces agonist-promoted receptor G protein coupling in vitro.21 This loss of function would be expected to result in reduced inhibition of norepinephrine release at sympathetic synapses, resulting in increased sympathetic tone. Indeed, in a small study in healthy African-American subjects, homozygous carriers of the deletion variant had enhanced heart rate and norepinephrine spillover responses to the 2-antagonist yohimbine.5 However, larger studies found no associations between the ADRA2C deletion and markers of elevated resting sympathetic tone, blood pressure, or heart rate.10,22 Variable results regarding the association between the ADRA2C deletion variant and cardiac function14,23 suggest that the functional effects of the deletion variant may be most apparent in circumstances of substantially elevated sympathetic tone (eg, after yohimbine administration or in advanced congestive heart failure), and only in subjects who are homozygous for the deletion.10,24
Another approach to examine the functional consequences of the ADRA2C deletion is to administer an 2-AR agonist. A small study in healthy white Europeans found no effects of the deletion variant on blood pressure, heart rate, and plasma norepinephrine responses to clonidine, but among the 9 subjects carrying the deletion allele, only 3 were homozygous.25 Our study provided a much larger and biethnic group of heterozygous and homozygous deletion carriers, and used a more selective 2-agonist, dexmedetomidine, to reduce confounding by 1-AR–mediated vasoconstriction. The ADRA2C deletion did not affect the blood pressure, plasma catecholamine, or heart rate responses to dexmedetomidine. These findings would be consistent with the notion that the deletion variant may have little or no functional significance in states of reduced sympathetic tone. Another possibility is that central and vascular effects of other 2-AR subtypes act to obscure functional differences resulting from the variant 2C-AR subtype.
The G protein β3-subunit couples with 2-ARs to mediate intracellular signal transduction.15 The common C825T variant is associated with alternative mRNA splicing, and the splice variant Gβ3-s (characterized by deletion of 41 amino acids) exhibits enhanced intracellular signal transduction in vitro.26 In population studies, the C825T variant has been variably associated with increased risk of hypertension, atherosclerosis, myocardial infarction, and stroke.15 Although GNB3 genotype did not affect the vasoconstricting effect of peripherally acting 2-agonists, mediated by vascular 2-receptors,27 the sympathoinhibitory response to the centrally acting 2-agonist clonidine differed by GNB3 genotype: In keeping with the in vitro findings, a study in 30 White Europeans found that clonidine reduced blood pressure, total peripheral resistance, and plasma norepinephrine concentrations significantly more in carriers of the T825 allele than in noncarriers.4 Our study included a similar number of C allele homozygotes and 4 times as many carriers of the T allele, and found no genotype effect on the centrally mediated dexmedetomidine responses. Differences in agonist selectivity and study populations may account for these findings.
A strength of our study was that we measured plasma dexmedetomidine concentrations. Interestingly, blacks had higher plasma dexmedetomidine concentrations than whites. This ethnic difference does not compromise the validity of our findings because we adjusted for plasma dexmedetomidine concentrations in all our analyses. Studies of ethnic differences in dexmedetomidine pharmacokinetics, possibly related to genetic variants in the enzymes responsible for its metabolism, will be of interest.
Other strengths of our study were that it included a large biethnic study population to examine the interaction of race and candidate genetic variants in responses, and the use of a highly selective 2-AR agonist to avoid confounding by direct 1-AR–mediated vasoconstriction. The study had >99% and 90% power to detect ethnic and GNB3 genotype differences, respectively, of a magnitude previously reported for clonidine,3,4 and the sample size allowed for adjustment for multiple potential confounders. Studying healthy young subjects under controlled experimental conditions allows the examination of genetic and nongenetic determinants of blood pressure regulation without the confounding effects of disease, concomitant medications, and age-related changes. However, our findings cannot be extrapolated to other populations, for example patients with congestive heart failure, in whom the response to clonidine is altered.28 We used forearm venous plasma catecholamine concentrations to assess sympathetic tone. Venous plasma norepinephrine concentrations correlate well with other measures of sympathetic activity, but they are an imprecise marker of sympathetic tone, especially during dynamic changes in blood pressure, because the plasma concentrations reflect both synaptic norepinephrine release (spillover) into the systemic circulation and clearance from it, as well as local secretion and clearance in the forearm. Norepinephrine spillover studies require administration of radioactive tracers and arterial catheterization and are not suited for larger studies.
Perspectives
In view of the central role of 2-ARs in the regulation of sympathetic tone, interindividual differences in 2-AR–mediated responses may contribute to variability in blood pressure regulation. In subjects studied under carefully controlled conditions, we found substantial interindividual differences in the responses to the highly selective 2-agonist dexmedetomidine. In contrast to previous findings with the less selective agonist, clonidine, ethnicity and ADRA2C del322–325 and GNB3 C825T genotypes were not significantly associated with the responses to the selective 2-agonist dexmedetomidine. Future studies to identify genetic and nongenetic determinants of the variability in response to 2-AR agonists will be of interest.
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Acknowledgments |
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The Vanderbilt DNA Resource Core and Vanderbilt University Center for Human Genetics Research provided technical assistance for this work. Kristo Hakala is acknowledged for skillful performance of the dexmedetomidine assay.
Sources of Funding
This study was supported by U.S. Public Health Service grants HL04012, M01 RR-00095 from the National Center for Research Resources, P01 HL56693, GM31304, and the NIH/National Institute of General Medical Sciences Pharmacogenetics Research Network and Database (U01GM61374, http://pharmgkb.org under grant HL65962). Drs Kurnik and Muszkat were recipients of a Merck Sharp & Dohme International Fellowship in Clinical Pharmacology and an Israeli Medical Association Fellowship Award.
Disclosures
Dr Scheinin is engaged in consultation and contract research for Orion Pharma, the manufacturer of dexmedetomidine.
Received July 27, 2007; first decision August 13, 2007; accepted November 13, 2007.
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