D. Keith Williams

Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans.

Phytochemical‐mediated modulation of cytochrome P450 (CYP) activity may underlie many herb‐drug interactions. Single‐time point phenotypic metabolic ratios were used to determine whether long‐term supplementation of St Johns wort, garlic oil, Panax ginseng, and Ginkgo biloba affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity.

Clinical assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly: St John's wort, garlic oil, Panax ginseng and Ginkgo biloba.

ObjectivesElderly patients are more likely to ingest prescription medications concurrently with botanical supplements, and may therefore be vulnerable to herb-drug interactions. Phytochemical-mediated modulation of cytochrome P450 (CYP) activity may underlie many herb-drug interactions. Some evidence suggests that CYP activity may decrease in the elderly. If so, herb-mediated changes in CYP activity may take on greater clinical relevance in this population. In this study, single timepoint, phenotypic metabolic ratios were used to determine whether long-term supplementation of St John’s wort, garlic oil, Panax ginseng, and Ginkgo biloba affected CYP1A2, CYP2D6, CYP2E1 or CYP3A4 activity in elderly subjects.MethodsTwelve healthy volunteers between the ages of 60 and 76 years (mean age 67 years) were randomly assigned to receive each botanical supplement for 28 days followed by a 30-day washout period. Probe drug cocktails of midazolam, caffeine, chlorzoxazone and debrisoquine were administered before and at the end of supplementation. Pre- and post-supplementation phenotypic ratios were determined for CYP3A4, CYP1A2, CYP2E1 and CYP2D6 using 1-hydroxymidazolam/midazolam serum ratios (1-hour), paraxanthine/caffeine serum ratios (6-hour), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour) and debrisoquine urinary recovery ratios (8-hour), respectively. The content of purported ‘active’ phytochemicals was determined for each supplement.ResultsComparisons of pre- and post-St John’s wort phenotypic ratios revealed significant induction of CYP3A4 (≈140%) and CYP2E1 activity (≈28%). Garlic oil inhibited CYP2E1 activity by approximately 22%. P. ginseng inhibition of CYP2D6 was statistically significant, but the magnitude of the effect (≈7%) did not appear to be clinically relevant. None of the supplements tested in this study appeared to affect CYP1A2 activity.ConclusionsElderly subjects, like their younger counterparts, are susceptible to herb-mediated changes in CYP activity, especially those involving St John’s wort. Pharmacokinetic herb-drug interactions stemming from alterations in CYP activity may adversely affect drug efficacy and/or toxicity. When compared with earlier studies that employed young subjects, the data suggest that some age-related changes in CYP responsivity to botanical supplementation may exist. Concomitant ingestion of botanical supplements with prescription medications, therefore, should be strongly discouraged in the elderly.

In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto

Phytochemical‐mediated modulation of cytochrome P450 (CYP) activity may underlie many herb‐drug interactions. Single‐time point phenotypic metabolic ratios were used to determine whether long‐term supplementation of Citrus aurantium, Echinacea purpurea, milk thistle (Silybum marianum), or saw palmetto (Serenoa repens) extracts affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity.

The effects of hypercapnia on cerebral autoregulation in ventilated very low birth weight infants.

Permissive hypercapnia, a strategy allowing high Paco2, is widely used by neonatologists to minimize lung damage in ventilated very low birth weight (VLBW) infants. While hypercapnia increases cerebral blood flow (CBF), its effects on cerebral autoregulation of VLBW infants are unknown. Monitoring of mean CBF velocity (mCBFv), Paco2, and mean arterial blood pressure (MABP) from 43 ventilated VLBW infants during the first week of life was performed during and after 117 tracheal suctioning procedures. Autoregulation status was determined during tracheal suctioning because it perturbs cerebral and systemic hemodynamics. The slope of the relationship between mCBFv and MABP was estimated when Paco2 was fixed at 30, 35, 40, 45, 50, 55, and 60 mm Hg. A slope near or equal to 0 suggests intact autoregulation, i.e. CBF is not influenced by MABP. Increasing values >0 indicate progressively impaired autoregulation. Infants weighed 905 ± 259 g and were 26.9 ± 2.3 wk gestation. The autoregulatory slope increased as Paco2 increased from 30 to 60 mm Hg. While the slopes for Paco2 values of 30 to 40 mm Hg were not statistically different from 0, slopes for Paco2 ≥45 mm Hg indicated a progressive loss of cerebral autoregulation. The autoregulatory slope increases with increasing Paco2, suggesting the cerebral circulation becomes progressively pressure passive with hypercapnia. These data raise concerns regarding the use of permissive hypercapnia in ventilated VLBW infants during the first week of life, as impaired autoregulation during this period may be associated with increased vulnerability to brain injury.

Clinical assessment of CYP2D6-mediated herb–drug interactions in humans: Effects of milk thistle, black cohosh, goldenseal, kava kava, St. John's wort, and Echinacea

Cytochrome P450 2D6 (CYP2D6), an important CYP isoform with regard to drug-drug interactions, accounts for the metabolism of approximately 30% of all medications. To date, few studies have assessed the effects of botanical supplementation on human CYP2D6 activity in vivo. Six botanical extracts were evaluated in three separate studies (two extracts per study), each incorporating 16 healthy volunteers (eight females). Subjects were randomized to receive a standardized botanical extract for 14 days on separate occasions. A 30-day washout period was interposed between each supplementation phase. In study 1, subjects received milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa). In study 2, kava kava (Piper methysticum) and goldenseal (Hydrastis canadensis) extracts were administered, and in study 3 subjects received St. Johns wort (Hypericum perforatum) and Echinacea (Echinacea purpurea). The CYP2D6 substrate, debrisoquine (5 mg), was administered before and at the end of supplementation. Pre- and post-supplementation phenotypic trait measurements were determined for CYP2D6 using 8-h debrisoquine urinary recovery ratios (DURR). Comparisons of pre- and post-supplementation DURR revealed significant inhibition (approximately 50%) of CYP2D6 activity for goldenseal, but not for the other extracts. Accordingly, adverse herb-drug interactions may result with concomitant ingestion of goldenseal supplements and drugs that are CYP2D6 substrates.

Effect of milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa) supplementation on digoxin pharmacokinetics in humans

Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may underlie many herb-drug interactions. Serial serum concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with milk thistle or black cohosh modified P-gp activity in vivo. Sixteen healthy volunteers were randomly assigned to receive a standardized milk thistle (900 mg daily) or black cohosh (40 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxicaps, 0.4 mg) was administered orally before and at the end of each supplementation and control period. Serial digoxin serum concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the serum concentration time curves from 0 to 3 h (AUC(0–3)), AUC(0–24), Cmax, apparent oral clearance of digoxin (CL/F), and elimination half-life were used to assess the effects of milk thistle, black cohosh, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC(0–3), AUC(0–24), and Cmax, whereas clarithromycin increased these parameters significantly (p < 0.01). Significant changes in digoxin half-life and CL/F were also observed with clarithromycin. No statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either milk thistle or black cohosh, although digoxin AUC(0–3) and AUC(0–24) approached significance (p = 0.06) following milk thistle administration. When compared with rifampin and clarithromycin, supplementation with these specific formulations of milk thistle or black cohosh did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.

Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: Comparative effects of St. John's wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics

Concomitant administration of botanical supplements with drugs that are P-glycoprotein (P-gp) substrates may produce clinically significant herb-drug interactions. This study evaluated the effects of St. Johns wort and Echinacea on the pharmacokinetics of digoxin, a recognized P-gp substrate. Eighteen healthy volunteers were randomly assigned to receive a standardized St. Johns wort (300 mg three times daily) or Echinacea (267 mg three times daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (300 mg twice daily, 7 days) and clarithromycin (500 mg twice daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin 0.25 mg) was administered orally before and after each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC)((0-3)), AUC((0-24)), elimination half-life, and maximum serum concentration were used to assess the effects of St. Johns wort, Echinacea, rifampin, and clarithromycin on digoxin disposition. St. Johns wort and rifampin both produced significant reductions (p < 0.05) in AUC((0-3)), AUC((0-24)), and C(max), while clarithromycin increased these parameters significantly (p < 0.05). Echinacea supplementation did not affect digoxin pharmacokinetics. Clinically significant P-gp-mediated herb-drug interactions are more likely to occur with St. Johns wort than with Echinacea.

Assessing the clinical significance of botanical supplementation on human cytochrome P450 3A activity: Comparison of a milk thistle and black cohosh product to rifampin and clarithromycin

Phytochemical‐mediated modulation of cytochrome P450 enzymes (CYPs) may underlie many herb‐drug interactions. This studys purpose was to assess the effects of milk thistle and black cohosh supplementation on CYP3A activity and compare them to a clinically recognized inducer, rifampin, and inhibitor, clarithromycin. Healthy volunteers were randomly assigned to receive a standardized milk thistle (900 mg) or black cohosh (80 mg) supplement for 14 days. Subjects also received rifampin (600 mg) and clarithromycin (1000 mg) for 7 days as positive controls for CYP3A induction and inhibition, respectively. Midazolam was administered orally before and after each supplementation and control period. The effects of milk thistle, black cohosh, rifampin, and clarithromycin on midazolam pharmacokinetics were determined using noncompartmental techniques. Unlike those observed for rifampin and clarithromycin, midazolam pharmacokinetics was unaffected by milk thistle or black cohosh. Milk thistle and black cohosh appear to have no clinically relevant effect on CYP3A activity in vivo.

Cost-effectiveness of a Primary Care Depression Intervention

AbstractOBJECTIVE: To determine the incremental cost-effectiveness of a quality improvement depression intervention (enhanced care) in primary care settings relative to usual care. DESIGN: Following stratification, we randomized 12 primary care practices to enhanced or usual care conditions and followed patients for 12 months. SETTING: Primary care practices located in 10 states across the United States. PATIENTS/PARTICIPANTS: Two hundred eleven patients beginning a new treatment episode for major depression. INTERVENTIONS: Training the primary care team to assess, educate, and monitor depressed patients during the acute and continuation stages of their depression treatment episode over 1 year. MEASUREMENTS AND MAIN RESULTS: Cost-effectiveness was measured by calculating incremental (enhanced minus usual care) costs and quality-adjusted life years (QALYs) derived from SF-36 data. The mean incremental cost-effectiveness ratio in the main analysis was

Cost-effectiveness analysis of a rural telemedicine collaborative care intervention for depression

15,463 per QALY. The mean incremental cost-effectiveness ratios for the sensitivity analyses ranged from