Biomedical subjects
Stephanie F Gardner
Publications and source records attributed to Stephanie F Gardner.
AGI-1067: a novel vascular protectant for prevention of restenosis.
OBJECTIVE: To review the synthesis, pharmacology, clinical trials, and adverse effects of AGI-1067, a novel agent for preventing restenosis. DATA SOURCES: Literature searches were conducted using MEDLINE (1966-July 2005) and International Pharmaceutical Abstracts (1970-July 2005) for English-language articles containing the search terms AGI-1067, AGI 1067, and probucol. In addition, bibliographies from relevant articles were reviewed for additional references. STUDY SELECTION AND DATA EXTRACTION: All articles identified from data sources were reviewed for relevant information. Applicable information was included in this review. DATA SYNTHESIS: AGI-1067, a derivative of the lipid-lowering agent probucol, is the first of a new class of drugs termed vascular protectants. It has antioxidant and lipid-lowering effects. In addition, it inhibits inflammatory processes without resultant immunosuppression through its selective inhibition of vascular cell adhesion molecule-1 expression. AGI-1067 also exhibited anti-atherosclerotic effects in preclinical studies. Relatively short-term treatment with AGI-1067 showed positive results compared with probucol in preventing restenosis in patients undergoing percutaneous coronary intervention. AGI-1067 appears to be well tolerated and holds important advantages over probucol in that it has fewer adverse effects on high-density lipoprotein cholesterol and the QT interval. CONCLUSIONS: The favorable safety profile of AGI-1067 offers potential advantages over its precursor, probucol. Preclinical and clinical studies indicate that it possesses antioxidant, antiinflammatory, and lipid-lowering properties. Ongoing Phase II and III studies will determine AGI-1067's place in therapy for the prevention of restenosis and reduction in cardiovascular events in patients undergoing percutaneous intervention for coronary atherosclerosis.
In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes.
OBJECTIVES: 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 goldenseal ( Hydrastis canadensis ), black cohosh ( Cimicifuga racemosa ), kava kava ( Piper methysticum ), or valerian ( Valeriana officinalis ) extracts affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4/5 activity. METHODS: Twelve healthy volunteers (6 women) were randomly assigned to receive goldenseal, black cohosh, kava kava, or valerian for 28 days. For each subject, a 30-day washout period was interposed between each supplementation phase. Probe drug cocktails of midazolam and caffeine, followed 24 hours later by chlorzoxazone and debrisoquin (INN, debrisoquine), were administered before (baseline) and at the end of supplementation. Presupplementation and postsupplementation phenotypic trait measurements were determined for CYP3A4/5, CYP1A2, CYP2E1, and CYP2D6 by use of 1-hydroxymidazolam/midazolam serum ratios (1-hour sample), paraxanthine/caffeine serum ratios (6-hour sample), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour sample), and debrisoquin urinary recovery ratios (8-hour collection), respectively. The content of purported "active" phytochemicals was determined for each supplement. RESULTS: Comparisons of presupplementation and postsupplementation phenotypic ratio means revealed significant inhibition (approximately 40%) of CYP2D6 (difference, -0.228; 95% confidence interval [CI], -0.268 to -0.188) and CYP3A4/5 (difference, -1.501; 95% CI, -1.840 to -1.163) activity for goldenseal. Kava produced significant reductions (approximately 40%) in CYP2E1 only (difference, -0.192; 95% CI, -0.325 to -0.060). Black cohosh also exhibited statistically significant inhibition of CYP2D6 (difference, -0.046; 95% CI, -0.085 to -0.007), but the magnitude of the effect (approximately 7%) did not appear to be clinically relevant. No significant changes in phenotypic ratios were observed for valerian. CONCLUSIONS: Botanical supplements containing goldenseal strongly inhibited CYP2D6 and CYP3A4/5 activity in vivo, whereas kava inhibited CYP2E1 and black cohosh weakly inhibited CYP2D6. Accordingly, serious adverse interactions may result from the concomitant ingestion of goldenseal supplements and drugs that are CYP2D6 and CYP3A4/5 substrates. Kava kava and black cohosh may interact with CYP2E1 and CYP2D6 substrates, respectively. Valerian appears to be less likely to produce CYP-mediated herb-drug interactions.
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.
OBJECTIVES: Elderly 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. METHODS: Twelve 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. RESULTS: Comparisons of pre- and post-St John's wort phenotypic ratios revealed significant induction of CYP3A4 (approximately 140%) and CYP2E1 activity (approximately 28%). Garlic oil inhibited CYP2E1 activity by approximately 22%. P. ginseng inhibition of CYP2D6 was statistically significant, but the magnitude of the effect (approximately 7%) did not appear to be clinically relevant. None of the supplements tested in this study appeared to affect CYP1A2 activity. CONCLUSIONS: Elderly 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.
The renal protective effects of angiotensin II receptor blockers in type 2 diabetes mellitus.
OBJECTIVE: To review the renal protective effects of angiotensin II receptor blockers (ARBs) in patients with type 2 diabetes mellitus. DATA SOURCES: A MEDLINE search (1966-March 2004) was completed using irbesartan, candesartan, losartan, valsartan, eprosartan, olmesartan, telmisartan, renal protection, nephropathy, albuminuria, and type 2 diabetes mellitus as key words. STUDY SELECTION AND DATA EXTRACTION: All identified English-language articles were reviewed. References of the identified sources were used to identify additional articles. Articles representative of the subject matter of our review were included. DATA SYNTHESIS: ARBs have extensive data showing their renal protective benefits in hypertensive type 2 diabetic patients with microalbuminuria or proteinuria. The benefits are over and above that of blood pressure reduction alone and extend to normotensive diabetic patients as well. Maximizing the ARB dose before adding additional therapies or another renal-protecting agent (angiotensin-converting enzyme [ACE] inhibitor or non-dihydropyridine calcium-channel blocker) may be superior to adding another class of antihypertensive, even if similar blood pressures can be achieved. CONCLUSIONS: ARBs are an important therapy for hypertensive type 2 diabetic patients and can benefit normotensive diabetic patients as well. ARB dosage optimization or the addition of a second renoprotective agent (ACE inhibitor or non-dihydropyridine calcium-channel blocker) may be important for optimal renoprotection, although further research is clearly needed in this area.
In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto.
OBJECTIVES: 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. METHODS: Twelve healthy volunteers (6 women, 6 men) were randomly assigned to receive C aurantium , E purpurea , milk thistle, or saw palmetto for 28 days. For each subject, a 30-day washout period was interposed between each supplementation phase. Probe drug cocktails of midazolam and caffeine, followed 24 hours later by chlorzoxazone and debrisoquin (INN, debrisoquine), were administered before (baseline) and at the end of supplementation. Presupplementation and postsupplementation phenotypic trait measurements were determined for CYP3A4, CYP1A2, CYP2E1, and CYP2D6 by use of 1-hydroxymidazolam/midazolam serum ratios (1-hour sample), paraxanthine/caffeine serum ratios (6-hour sample), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour sample), and debrisoquin urinary recovery ratios (8-hour collection), respectively. The content of purported "active" phytochemicals was determined for each supplement. RESULTS: Comparisons of presupplementation and postsupplementation phenotypic ratios suggested that these particular supplements had no significant effect on CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity. Phytochemical profiles indicated that C aurantium was devoid of the CYP3A4 inhibitor 6',7'-dihydroxybergamottin. Quantities of fatty acids, flavonolignans, and cichoric acid were consistent with label claims for saw palmetto, milk thistle, and E purpurea , respectively. CONCLUSIONS: Botanical supplements containing C aurantium , milk thistle, or saw palmetto extracts appear to pose a minimal risk for CYP-mediated herb-drug interactions in humans. Although the effects of E purpurea on CYP activity were minor, further study into the interaction potential of this botanical is merited.
Effect of a multicomponent, ephedra-containing dietary supplement (Metabolife 356) on Holter monitoring and hemostatic parameters in healthy volunteers.
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Olmesartan medoxomil: the seventh angiotensin receptor antagonist.
OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and adverse effects of olmesartan medoxomil, an angiotensin II receptor antagonist for the treatment of hypertension. DATA SOURCES: Information was obtained from MEDLINE searches (1996-April 2002) of English-language medical literature. Search terms included CS-866, olmesartan, olmesartan medoxomil, RNH-6270 (active metabolite of olmesartan), Benicar, angiotensin receptors, and antihypertensive agents. In addition, references from relevant articles were reviewed for additional citations. The authors independently reviewed literature identified in the searches. Studies evaluating olmesartan (i.e., abstracts, clinical trials, data on file with manufacturer) were considered for inclusion. STUDY SELECTION: All articles identified from data sources with pertinent information regarding olmesartan medoxomil were evaluated, and all information deemed relevant was included in this review. DATA SYNTHESIS: Olmesartan medoxomil is a competitively priced addition to the class of angiotensin II receptor antagonists. Monotherapy with olmesartan medoxomil in once-daily doses of 20-40 mg has produced significant reductions in systolic and diastolic blood pressure in hypertensive patients. Adverse effects have been minimal with olmesartan medoxomil, with dizziness being the only adverse effect occurring more often than with placebo in clinical trials. Additionally, animal studies indicate that olmesartan medoxomil may prove to be useful treatment for diabetic nephropathy, as well as atherosclerosis. CONCLUSIONS: Olmesartan medoxomil has a favorable safety and efficacy profile, with blood pressure-lowering effects comparable to those of other angiotensin receptor blockers (i.e., losartan, valsartan, irbesartan). At this time, formulary decisions will be driven primarily by economic issues. Theoretical benefits of olmesartan medoxomil in reducing atherogenesis and lowering angiotensin II concentrations better than the alternative agents will be determined only with more extensive research.
Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans.
OBJECTIVES: 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 John's wort, garlic oil, Panax ginseng, and Ginkgo biloba affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity. METHODS: Twelve healthy volunteers (6 females) were randomly assigned to receive either St John's wort, garlic oil, P ginseng, or G biloba for 28 days. For each subject, a 30-day washout period was interposed between each supplementation phase. Probe-drug cocktails of midazolam, caffeine, chlorzoxazone, and debrisoquin (INN, debrisoquine) were administered before supplementation (baseline) and at the end of supplementation. Presupplementation and postsupplementation phenotypic trait measurements were determined for CYP3A4, CYP1A2, CYP2E1, and CYP2D6 with the use of 1-hydroxymidazolam/midazolam serum ratios (1-hour sample), paraxanthine/caffeine serum ratios (6-hour sample), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour sample), and debrisoquin urinary recovery ratios (8-hour collection), respectively. RESULTS: Comparisons of presupplementation and postsupplementation ratios indicated that St John's wort significantly induced the activity of CYP2E1 and CYP3A4 (P <.0001). Among female subjects, St John's wort produced significantly greater increases in CYP3A4 phenotypic ratios that appeared to be unrelated to body mass index. This finding is suggestive of a sexual dimorphism in CYP3A4 inducibility. Garlic oil reduced CYP2E1 activity by 39% (P =.030), whereas no significant effect on CYP activity was observed for P ginseng and G biloba. CONCLUSIONS: Single-time point phenotypic metabolic ratios may provide a practical means of predicting CYP-mediated herb-drug interactions in humans.
24-hour ambulatory blood pressure monitoring in male children receiving stimulant therapy.
OBJECTIVE: To determine whether cardiac indices are altered as assessed by 24-hour ambulatory blood pressure monitoring (ABPM) in male children receiving either chronic methylphenidate or dextroamphetamine/levoamphetamine (Adderall) therapy. METHODS: Boys 7-11 years old who were receiving methylphenidate or Adderall for a minimum of 2 months were asked to participate. Subjects wore ambulatory blood pressure monitors for 24-hour periods both off and on stimulant therapy. RESULTS: Subjects (n = 17; 8 methylphenidate, 9 Adderall) were well matched. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate differed between off and on stimulant therapy (p < 0.05). DBP load calculated from ABPM reference data was increased significantly (9.0% +/- 5.6% on and 4.8% +/- 4.5% off therapy; p < 0.05) while subjects were taking Adderall. There was a trend toward a greater elevation in blood pressure load during awake hours and a more pronounced decrease during the asleep hours for periods on compared with off-stimulant therapy. This trend resulted in significant (p < 0.05) nocturnal dipping on-stimulant phases compared with off-stimulant therapy for both SBP and DBP (Adderall) and SBP (methylphenidate). Two subjects (1 Adderall, 1 methylphenidate) met the criteria to be considered hypertensive based both on mean awake and 24-hour blood pressure load assessments during their on-treatment period. One additional subject receiving Adderall therapy met the criteria to be considered hypertensive based on blood pressure load criteria while off therapy only. Positive correlation coefficients (p < 0.05) were found when comparing stimulant dose (mg/kg) with the percent change of mean SBP, DBP, and heart rate between off and on therapy (r = 0.56, 0.61, and 0.58, respectively). CONCLUSIONS: These preliminary data suggest that blood pressure and heart rate appear to be altered in male patients while receiving stimulant therapy for attention-deficit hyperactivity disorder. Blood pressure and heart rate screening and monitoring during stimulant therapy to determine whether alterations become clinically significant is encouraged.