43 MV patients in medical and surgical ICU (38 Caucasian and 2 Black).
To determine the effect of CYP2A6 polymorphisms on DEX Cls.
(i) All patients received DEX. (ii) Patients grouped into normal (), intermediate (), or slow () metabolizers. (iii) Cls determined via median of five plasma DEX concentrations.
No significant difference in DEX amongst normal (48.5 L/h; 39.8–58.7 L/hr), intermediate (56.9 L/hr; 31.6–94.4 L/hr) or slow (86.2 L/hr; 26.9–218.7 L/hr) metabolizers. Presented as (median; 95% credible interval)
To develop a new population PK model to more accurately accommodate outliers.
(i) All patients received DEX titrated by the bedside nurse from 0.15 mcg/kg/h to a maximum of 1.5 mcg/kg/h to achieve targeted sedation. (ii) Serum levels were collected at three specific, predefined times (05:00 ± 2 h, 10:00 ± 2 hrs, 16:00 ± 2 h).
Incorporation of CYP2A6 genotype as a covariate did not alter the population pharmacokinetics.
To evaluate the clinical effect of the ADRA-2A C-1291G polymorphism on DEX response via HD effects and sedation.
(i) All patients received DEX after surgery once in the ICU to a targeted infusion rate of 1.4 mcg/kg/hr. (ii) HD effects (SAP, DAP, HR) monitored via routine invasive monitoring. (iii) Sedation effects monitored via BIS and RSS. (iv) Patients were grouped into G allele carriers and noncarriers.
(i) No significant difference in HD (SAP, DAP, HR) effects. (ii) Patients with C-1291-G polymorphisms had higher BIS () after 30 min and RSS () after 55–60 min starting infusion, showing a longer period to fall asleep or a decrease in DEX effect.
To evaluate the clinical effect of ADRA-2A polymorphisms on CV effects of DEX by changes in SBP and plasma NE concentrations.
(i) Patients received 3 placebo infusions then 3 DEX infusions (0.1, 0.15, 0.15 mcg/kg for total of 0.4 mcg/kg). (ii) SBP and plasma NE concentrations were measured 10 min after infusion. (iii) Patients were grouped into 9 different polymorphisms.
(i) After a sensitivity analysis, individuals who were homozygous or carriers of HT3 had a 39% (0.61 fold) smaller decrease (ΔSBP= mmHG and mmHG, respectively; ) in SBP after DEX. Individuals who were homozygous for HT4 had an 82% (1.8 fold) larger decrease (ΔSBP= mmHG compared to mmHG for non-carriers; ). (ii) There was no difference in plasma NE levels.
To evaluate the presence of the ethnic differences in the response to DEX through the clinical effect of ADRA-2C del322-325 polymorphism and G-protein GNB3 C825T polymorphism on CV effects by changes in BP and HR and plasma NE concentrations.
(i) Patients received 3 placebo infusions then 3 DEX infusions (0.1, 0.15, 0.15 mcg/kg for total of 0.4 mcg/kg). (ii) BP, HR, and plasma NE concentrations were measured at the end of the infusion then 10 min and 20 min after. (iii) Patients were grouped into ADRA-2C del322-325 or no deletion and GNB3 C825T or no polymorphism.
No significant differences in BP, HR, and plasma NE concentrations for both ADRA-2C del322-325 and GNB3 C825T polymorphism were detected.
To evaluate the clinical effect of several ADRA-2C polymorphisms on pain perception and cognitive responses.
(i) Pain rating via VAS from a cold pressor test before infusions and 30 min after the final DEX infusion. (ii) Cognitive responses were measured before the infusions, 10 min after the placebo and DEX infusions. (iii) Patients received 3 placebo infusions then 3 DEX infusions (0.1, 0.15, 0.15 mcg/kg for total of 0.4 mcg/kg). (iv) Patients were grouped into five different polymorphisms, including ADRA-2C del322-325.
(i) VAS scores from patients with del322-325 were significantly higher than any other polymorphism (). (ii) DEX lowered mean pain scores significantly (from cm to , ). (iii) The change in pain score after DEX administration was not significantly associated with any genotype. (iv) No genotype, especially del322-325, was significantly associated with differences in sedation scores or memory response.
To examine the clinical effect of ADRA-2B del 301-303 polymorphism on vascular response.
(i) Patients were grouped into wt/wt (), wt/del (), del/del (). (ii) Patients received DEX at increasing doses ranging from 0.01–1000 ng/min. (iii) Venoconstriction was measured via LVDT and the ED50 (dose that produced 50% of maximum venoconstriction or ) was calculated. (iv) Maximum venoconstriction was the percentage of reduction in vein diameter from maximal dilation.
(i) There was no difference in ED50 and among the three groups. (ii) The ED50 for wt/wt was 1.39 ng/min (95% CI 0.03–63 ng/min), for wt/del 1.63 ng/min (95% CI 0.01–177.8 ng/min), and for del/del 2.37 ng/min (95% CI 0.17–33.7 ng/min). (iii) The for wt/wt was , for wt/del , for del/del .
To determine if adrenergic vasoconstriction sensitivity through 1 and 2 receptors are determined through mechanisms downstream from the receptor and thus linked.
(i) Patients received either DEX at increasing doses ranging from 0.01–100 ng/min or phenylephrine at increasing doses ranging from 12–12000 ng/min. (ii) Venoconstriction was measured via LVDT and the ED50 (dose that produced 50% of maximum venoconstriction or ) was calculated. (iii) Maximum venoconstriction was the percentage of reduction in vein diameter from maximal dilation.
(i) Median ED50 for DEX was 1.32 ng/min (IQR 0.45–5.37 ng/min) and for phenylephrine was 177.8 ng/min (IQR 40.7–436.5 ng/min). (ii) There was no correlation between ED50 (individual sensitivity) for DEX and phenylephrine before and after covariates. (iii) The for DEX was 80.0% (64.7–95.2%) and for phenylephrine was 90.8% (82.2–99.6%).
