Aaron H. Burstein

St John's Wort: Effect on CYP3A4 activity

St Johns Wort is a widely used herbal product. Information regarding its potential for drug interactions is required for responsible treatment of patients using St Johns Wort. CYP3A4 is a metabolic enzyme implicated in most clinically significant drug‐drug interactions.

Cytochrome P450 3A4 activity after surgical stress

ObjectiveTo evaluate the relationship between the acute inflammatory response after surgical trauma and changes in hepatic cytochrome P450 3A4 activity, compare changes in cytochrome P450 3A4 activity after procedures with varying degrees of surgical stress, and to explore the time course of any potential drug-cytokine interaction after surgery. DesignProspective, open-label study with each patient serving as his or her own control. SettingUniversity-affiliated, acute care, general hospital. PatientsA total of 16 patients scheduled for elective repair of an abdominal aortic aneurysm (n = 5), complete or partial colectomy (n = 6), or peripheral vascular surgery with graft (n = 5). InterventionsCytochrome P450 3A4 activity was estimated using the carbon-14 [14C]erythromycin breath test (ERMBT) before surgery and 24, 48, and 72 hrs after surgery. Abdominal aortic aneurysm and colectomy patients also had an ERMBT performed at discharge. Blood samples were obtained before surgery, immediately after surgery, and 6, 24, 32, 48, and 72 hrs after surgery for determination of plasma concentrations of interleukin-6, interleukin-1&bgr;, and tumor necrosis factor-&agr;. Clinical markers of surgical stress that were collected included duration of surgery, estimated blood loss, and volume of fluids administered in the operating room. Measurements and Main ResultsERMBT results significantly declined in all three surgical groups, with the lowest value at the time of the 72-hr study in all three groups. There was a trend toward differences in ERMBT results among groups that did not reach statistical significance (p = .06). The nadir ERMBT result was significantly and negatively correlated with both peak interleukin-6 concentration (rs = −.541, p = .03) and log interleukin-6 area under the curve from 0 to 72 hrs (rs = −.597, p = .014). Subjects with a peak interleukin-6 of >100 pg/mL had a significantly lower nadir ERMBT compared with subjects with a peak interleukin-6 of <100 pg/mL (35.5% ± 5.2% vs. 74.7% ± 5.1%, p < .001). ConclusionsAcute inflammation after elective surgery was associated with a significant decline in cytochrome P450 3A4 activity, which is predictive of clinically important changes in the metabolism of commonly used drugs that are substrates for this enzyme.

Cytochrome P450 3A4 activity in premenopausal and postmenopausal women, based on 6-β-hydroxycortisol:cortisol ratios

Study Objective. To characterize cytochrome P450 (CYP) 3A4 activity in premenopausal and postmenopausal women by evaluating the urinary 6‐β‐hydroxycortisokcortisol ratio.

Displacement of Serotonin and Dopamine Transporters by Venlafaxine Extended Release Capsule at Steady State: A [123I]2??-Carbomethoxy-3??-(4-Iodophenyl)-Tropane Single Photon Emission Computed Tomography Imaging Study

Both positron emission tomography and single photon emission computed tomography (SPECT) studies suggest that saturation of serotonin transporters (SERT) is present during treatment with therapeutic doses of selective serotonin reuptake inhibitors (SSRIs). Selective serotonin reuptake inhibitors also appear to increase the availability of dopamine transporters (DAT). The current study measured SERT occupancy and modulation of DAT by the serotonin/norepinephrine reuptake inhibitor (SNRI) venlafaxine using [123I]2β-carbomethoxy-3β-(4-iodophenyl)-tropane SPECT. Eight healthy subjects were administered open-label venlafaxine extended release capsules (75 mg/d for 4 days followed by 150 mg/d for 5 days). Venlafaxine significantly inhibited [123I]β-CIT binding to SERT in the brainstem (55.4%) and the diencephalon (54.1%). In contrast, venlafaxine increased [123I]β-CIT binding to DAT in the striatum (10.1%) after 5 days of administration of 150 mg/d. The displacement of [123I]β-CIT from brain SERT and the increase in striatal [123I]β-CIT binding to DAT appear similar to previous work with the SSRI citalopram (40 mg/d). A literature review of SERT occupancy by marketed SSRIs and the SNRI venlafaxine using SPECT ([123I]β-CIT) or positron emission tomography ([11C](N, N-Dimethyl-2-(2-amino-4-cyanophenylthio)-benzylamine) imaging suggests that therapeutic doses of SNRI are associated with virtual saturation of the serotonin transporter.

Efficacy of the Cation Exchange Resin, Sodium Polystyrene Sulfonate, to Decrease Iron Absorption

Background: Iron is not bound by charcoal; therefore, a method of binding iron in the gastrointestinal tract to prevent absorption in iron overdose is needed. This study investigated the efficacy and safety of sodium polystyrene sulfonate to prevent absorption of iron in human volunteers. Methods: Six adult volunteers completed this prospective crossover trial. Following an oral dose of elemental iron 10 mg/kg, each subject received sodium polystyrene sulfonate 30 g or water as control. Baseline and serial serum iron samples were drawn to determine pharmacokinetic parameters. Results: A trend toward increased time to peak following sodium polystyrene sulfonate compared to the control arm (5.7 vs 3.6 hours) was observed but was not statistically significant (p = 0.517). A trend toward smaller area-under-the-curve for the sodium polystyrene sulfonate was evident but was not statistically significant (p = 0.77). Iron concentration increased on average 298 mcg/dL and 370 mcg/dL above baseline in the treatment and control arms (p = 0.44). Sodium polystyrene sulfonate is not an effective method of decontamination for iron overdose.

Absorption of phenytoin from rectal suppositories formulated with a polyethylene glycol base

Study Objective. To compare phenytoin pharmacokinetics following administration of an oral suspension and a rectal suppository formulated with a polyethylene glycol base.

Evaluation of a sparse sampling strategy for determining vancomycin pharmacokinetics in preterm neonates: Application of optimal sampling theory

Objective To use optimal sampling theory to determine the fewest vancomycin concentrations required and the appropriate sampling times to calculate vancomycin pharmacokinetic parameters in neonates. Design Unblinded evaluation in neonates with presumed sepsis. Setting Level 3 community-based neonatal intensive care unit. Patients Eleven neonates with presumed sepsis. Interventions Twelve courses of intravenous vancomycin 20 mg/kg were administered. Blood samples were collected 3 and 9 hours after initiation of a 1-hour infusion of the first dose. Measurements and Main Results A two-compartment model was fit to vancomycin concentrations using iterative two-stage analysis. Pharmacokinetic parameter estimates were used for determination of optimal sampling times for two-, three-, and four-sample strategies with subsequent generation of two-, three-, and four-sample concentration data for 100 cases. Relative performance of strategies was compared through calculation and comparison of D efficiency for the determined strategies. Bias (median percent error) and precision (median percent absolute error) of pharmacokinetic parameter estimates for each strategy in the 100 simulated cases were determined. Conclusions For estimation of total clearance and volume in the central and peripheral compartments, all strategies performed similarly with no difference in efficiency or bias and precision of estimates. Our results suggest that for clinical evaluations two appropriately timed samples (0.5 h after a 1-h infusion, trough concentration) are adequate for estimation of vancomycin clearance in neonates.

Oculogyric Crisis Possibly Related to Pentazocine

OBJECTIVE: To report and describe the apparent first case of acute oculogyric crisis following administration of pentazocine, and to discuss the possible mechanism for this reaction. DATA SOURCES/CASE SUMMARY: Patient case and relevant review of literature. The patient, a 39-year-old woman, developed acute oculogyric crisis following administration of Talacen (pentazocine and acetaminophen) for pain relief. The crisis resolved after discontinuation of the medication and administration of intravenous diphenhydramine 50 mg. CONCLUSIONS: Based on the temporal relationship of drug administration to occurrence of the event, pentazocine is implicated as the cause of this acute oculogyric crisis. A plausible mechanism for precipitation of this crisis is the agonism of pentazocine on sigma opiate receptors, with postulated subsequent modulation of dopamine receptors.