Pharmacokinetic Interactions of a Licorice Dietary Supplement with Cytochrome P450 Enzymes in Female Participants.

Licorice, the roots and rhizomes of Glycyrrhiza glabra L., has been used as a medicinal herb, herbal adjuvant, and flavoring agent since ancient times. Recently, licorice extracts have become popular as dietary supplements used by females to alleviate menopausal symptoms. Exposure to licorice products containing high levels of glycyrrhizic acid can cause hypokalemia, but independent from this effect, preclinical data indicate that licorice can inhibit certain cytochrome P450 (P450) enzymes. To evaluate whether clinically relevant pharmacokinetic interactions of licorice with P450 enzymes exist, a phase 1 clinical investigation was carried out using a licorice extract depleted in glycyrrhizic acid (content <1%) and a cocktail containing caffeine, tolbutamide, alprazolam, and dextromethorphan, which are probe substrates for the enzymes CYP1A2, CYP2C9, CYP3A4/5, and CYP2D6, respectively. The botanically authenticated and chemically standardized extract of roots from G. glabra was consumed by 14 healthy menopausal and postmenopausal female participants twice daily for 2 weeks. The pharmacokinetics of each probe drug were evaluated immediately before and after supplementation with the licorice extract. Comparison of the average areas under the time-concentration curves (AUCs) for each probe substrate in serum showed no significant changes from licorice consumption, whereas time to reach peak concentration for caffeine and elimination half-life for tolbutamide showed small changes. According to the US Food and Drug Administration guidance, which is based on changes in the AUC of each probe substrate drug, the investigated licorice extract should not cause any clinically relevant pharmacokinetic interactions with respect to CYP3A4/5, CYP2C9, CYP2D6, or CYP1A2. SIGNIFICANCE STATEMENT: Despite generally-recognized-as-safe status, the licorice species Glycyrrhiza glabra has been associated with some toxicity. Preclinical studies suggest that G. glabra might cause pharmacokinetic drug interactions by inhibiting several cytochrome P450 enzymes. This phase 1 clinical study addressed these concerns by evaluating clinically relevant effects with respect to CYP3A4/5, CYP2C9, CYP2D6, and CYP1A2. These results showed that a standardized G. glabra extract did not cause any clinically relevant pharmacokinetic drug interactions with four major cytochrome P450 enzymes.

Abutment Material Effect on Peri-implant Soft Tissue Color and Perceived Esthetics.

PURPOSE: The purpose of this study was to evaluate the effect of implant abutment material on peri-implant soft tissue color using intraoral spectrophotometric analysis and to compare the clinical outcomes with patient and clinician perception and satisfaction. MATERIALS AND METHODS: Thirty patients and four prosthodontic faculty members participated. Abutments were zirconia, gold-hued titanium, and titanium. Peri-implant mucosa color of a single anterior implant restoration was compared to the patient's control tooth. Spectrophotometric analysis using SpectroShadeTM Micro data determined the color difference (ΔE, ΔL*, Δa*, Δb*) between the midfacial peri-implant soft tissue for each abutment material and the marginal gingiva of the control tooth. Color difference values of the abutment groups were compared using ANOVA (α = 0.05). Patient and clinician satisfaction surveys were also conducted using a color-correcting light source. The results of each patient and clinician survey question were compared using chi-square analysis (α = 0.05). Pearson correlation analyses identified the relationship between the total color difference (ΔE) and the patient/clinician perception and satisfaction, as well as between ΔE and tissue thickness. RESULTS: Zirconia abutments displayed significantly smaller spectrophotometric gingival color difference (ΔE) compared to titanium and gold-hued titanium abutments (respectively, 3.98 ± 0.99; 7.22 ± 3.31; 5.65 ± 2.11; p < 0.05). Among ΔL*, Δa*, and Δb*, only Δa* (red-green spectrum) showed significant difference between groups. There was no significant correlation between measured soft tissue thickness and ΔE, but thick gingival phenotype, determined by a probe test, demonstrated a smaller ΔE than thin phenotype (4.82 ± 1.49; 6.41 ± 3.27; p = 0.097). There was no statistical difference in patient or clinician satisfaction among abutment materials, and no correlation between ΔE and the patient and clinician satisfaction. Patient satisfaction was significantly higher than clinician, and patient-perceived differences were lower than clinicians' (p < 0.01). Clinicians' satisfaction was higher for gingival (pink) esthetics than crown (white) esthetics (p < 0.05). CONCLUSIONS: Peri-implant mucosa with zirconia abutments demonstrated significantly lower mean color difference compared to titanium or gold-hued titanium abutments as measured spectrophotometrically; however, no statistical difference in patient or clinician perception/satisfaction among abutment materials was demonstrated. Patients were significantly more satisfied than clinicians.

Association of the GGCX (CAA)16/17 repeat polymorphism with higher warfarin dose requirements in African Americans.

OBJECTIVE: Little is known about genetic contributors to higher than usual warfarin dose requirements, particularly for African Americans. This study tested the hypothesis that the γ-glutamyl carboxylase (GGCX) genotype contributes to warfarin dose requirements greater than 7.5 mg/day in an African American population. METHODS: A total of 338 African Americans on a stable dose of warfarin were enrolled. The GGCX rs10654848 (CAA)n, rs12714145 (G>A), and rs699664 (p.R325Q); VKORC1 c.-1639G>A and rs61162043; and CYP2C9*2, *3, *5, *8, *11, and rs7089580 genotypes were tested for their association with dose requirements greater than 7.5 mg/day alone and in the context of other variables known to influence dose variability. RESULTS: The GGCX rs10654848 (CAA)16 or 17 repeat occurred at a frequency of 2.6% in African Americans and was overrepresented among patients requiring greater than 7.5 mg/day versus those who required lower doses (12 vs. 3%, P=0.003; odds ratio 4.0, 95% confidence interval, 1.5-10.5). The GGCX rs10654848 genotype remained associated with high dose requirements on regression analysis including age, body size, and VKORC1 genotype. On linear regression, the GGCX rs10654848 genotype explained 2% of the overall variability in warfarin dose in African Americans. An examination of the GGCX rs10654848 genotype in warfarin-treated Caucasians revealed a (CAA)16 repeat frequency of only 0.27% (P=0.008 compared with African Americans). CONCLUSION: These data support the GGCX rs10654848 genotype as a predictor of higher than usual warfarin doses in African Americans, who have a 10-fold higher frequency of the (CAA)16/17 repeat compared with Caucasians.

Pharmacogenomics of warfarin dose requirements in Hispanics.

While Hispanics are the largest and most rapidly growing minority population in the United States, they are underrepresented in pharmacogenomic studies with warfarin. We sought to determine the combination of clinical and genetic influences of warfarin dose requirements in Hispanics. In addition, we tested the performance of published warfarin dosing algorithms derived from largely non-Hispanic cohorts in an inner-city U.S. Hispanic population. Genetic samples and clinical data were obtained from 50 Hispanics on a stable dose of warfarin. The contribution of cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex-1 (VKORC1) genotypes and clinical factors to warfarin dose requirements was determined. The correlation between the predicted dose using published algorithms and therapeutic dose was also assessed. Compared to the VKORC1-1639 GG genotype, warfarin dose requirements were 30% and 62% lower with the GA and AA genotypes, respectively (p=0.001). The combination of the VKORC1-1639G>A and CYP2C9 genotypes and clinical factors explained 56% of the inter-patient variability in warfarin dose. Warfarin dose predicted using algorithms derived from mostly non-Hispanic cohorts was significantly correlated with the therapeutic dose in our Hispanic cohort (r(2)=0.43 to 0.49; p<0.001); the predicted dose was within 1.0 mg/day of the therapeutic dose for 40% to 50% of patients. Our data suggest that factors influencing warfarin dose requirements in Hispanic Caucasians are similar to those previously described in European Caucasians and that dosing algorithms derived from non-Hispanic Caucasian cohorts are applicable to Hispanics living in the U.S.

Effect of repeated screw joint closing and opening cycles on implant prosthetic screw reverse torque and implant and screw thread morphology.

STATEMENT OF PROBLEM: Clinicians must know if a new screw can predictably increase reverse torque after multiple screw insertion cycles. PURPOSE: The purpose of this study was (1) to compare the effect of multiple implant prosthetic screw insertion and removal cycles on reverse torque, (2) to determine whether a new screw, after multiple screw insertion cycles, affects reverse torque, and (3) to assess implant and prosthetic screw thread surface morphology with scanning electron microscopy (SEM). MATERIAL AND METHODS: One primary screw was paired with an implant (MT Osseospeed) and inserted to 25 Ncm torque 9, 19, 29, or 39 times (n=10). Primary screw reverse torque values were recorded after each insertion. A second, reference screw was then paired with each implant for a final screw insertion, and reverse torque was measured. Maximum, minimum, median, and mean values (P(max), P(min), P(median), and P(mean)) were identified for primary screws. A 1-way ANOVA and Tukey HSD post hoc analysis assessed the influence of multiple screw insertion cycles on P(max), P(min), P(median), and P(mean) values (α=.05). Confidence intervals were used to test differences between reference (REF) screw data and corresponding DMAX and DMIN (DMAX=P(max)-REF; DMIN=P(min)-REF). The surface topography of an unused implant and screw and of 1 implant and screw from each group was evaluated with SEM. RESULTS: Pairwise comparisons showed that 9 or fewer insertion cycles resulted in significantly greater mean reverse torque (20.9 ± 0.5 Ncm; P<.01). After 19, 29, or 39 cycles, the second, reference screw achieved significantly greater reverse torque than the minimum recorded values (P<.05). Implant thread surface morphology changes occurred primarily during the first 10 insertions. CONCLUSIONS: After 10 screw insertion cycles, a new prosthetic screw should be used with the implant system tested to maximize screw reverse torque and maintain preload when an abutment is definitively placed.

No Clinically Relevant Pharmacokinetic Interactions of a Red Clover Dietary Supplement with Cytochrome P450 Enzymes in Women.

Extracts of red clover (Trifolium pratense L.), containing estrogenic isoflavones like genistein and daidzein and the proestrogenic isoflavones formononetin and biochanin A, are used by women as dietary supplements for the management of menopausal symptoms. Although marketed as a safer alternative to hormone therapy, red clover isoflavones have been reported to inhibit some cytochrome P450 (CYP) enzymes involved in drug metabolism. To evaluate the potential for clinically relevant drug-red clover interactions, we tested a standardized red clover dietary supplement (120 mg isoflavones per day) for interactions with the pharmacokinetics of four FDA-approved drugs (caffeine, tolbutamide, dextromethorphan, and alprazolam) as probe substrates for the enzymes CYP1A2, CYP2C9, CYP2D6, and CYP3A4/5, respectively. Fifteen peri- and postmenopausal women completed pharmacokinetic studies at baseline and 2 weeks after consuming red clover. The averaged pharmacokinetic profiles of probe substrates in serum showed no significant alterations and no changes in the areas under the curve (AUC) over 96 h. Subgroup analysis based on the demographic characteristics (BMI, menopausal status, race, and age) also showed no differences in AUC for each probe substrate. Analysis of red clover isoflavones in serum showed primarily conjugated metabolites that explain, at least in part, the red clover pharmacokinetic safety profile.

Pharmacokinetic Interactions of a Hop Dietary Supplement with Drug Metabolism in Perimenopausal and Postmenopausal Women.

Botanical dietary supplements produced from hops (Humulus lupulus) containing the chemopreventive compound xanthohumol and phytoestrogen 8-prenylnaringenin are used by women to manage menopausal symptoms. Because of the long half-lives of prenylated hop phenols and reports that they inhibit certain cytochrome P450 enzymes, a botanically authenticated and chemically standardized hop extract was tested for Phase I pharmacokinetic drug interactions. Sixteen peri- and postmenopausal women consumed the hop extract twice daily for 2 weeks, and the pharmacokinetics of tolbutamide, caffeine, dextromethorphan, and alprazolam were evaluated before and after supplementation as probe substrates for the enzymes CYP2C9, CYP1A2, CYP2D6, and CYP3A4/5, respectively. The observed area under the time-concentration curves were unaffected, except for alprazolam which decreased 7.6% (564.6 ± 46.1 h·µg/L pre-hop and 521.9 ± 36.1 h·µg/L post-hop; p-value 0.047), suggesting minor induction of CYP3A4/5. No enzyme inhibition was detected. According to FDA guidelines, this hop dietary supplement caused no clinically relevant pharmacokinetic interactions with respect to CYP2C9, CYP1A2, CYP2D6, or CYP3A4/5. The serum obtained after consumption of the hop extract was analyzed using ultra-high performance liquid chromatography-tandem mass spectrometry to confirm compliance. Abundant Phase II conjugates of the hop prenylated phenols were observed including monoglucuronides and monosulfates as well as previously unreported diglucuronides and sulfate-glucuronic acid diconjugates.

Influence of cyclooxygenase-1 genotype on ex vivo aspirin response in patients at risk for stroke.

BACKGROUND: We sought to determine whether cyclooxygenase-1 (PTGS1) genotype is associated with the ability of aspirin to inhibit platelet aggregation in patients at risk for stroke. METHODS: Blood and urine samples were collected from 60 subjects, including 28 African Americans, who were taking aspirin for primary or secondary stroke prevention. Samples were analyzed for the PTGS1 A-707G, PTGS1 P17L, and glycoprotein IIIa (ITGB3)P1(A1/A2) genotypes, ex-vivo platelet aggregation, serum cholesterol, plasma salicylate levels, and urinary 11-dehydrothromboxane B(2) (11-dhTxB(2)) concentrations. The association between PTGS1 A-707G and P17L genotypes and aspirin response, as assessed by ex vivo studies and 11-dhTxB(2) concentrations, was evaluated by statistical testing and nonlinear mapping. RESULTS: Salicylate concentrations, ITGB3 genotype distribution and 11-dhTxB(2) concentrations were similar among PTGS1 genotype groups. More subjects with the PTGS1 17PP versus PL genotype had incomplete ex-vivo inhibition of platelet aggregation by aspirin (57 vs. 20%; p = 0.04). Fifty-nine percent of subjects homozygous for both the PTGS -707A and 17P alleles, but none with both the PTGS1 -707G and 17L alleles had incomplete inhibition with aspirin; p = 0.04. Similarly, nonlinear mapping showed a direct relationship between the PTGS1 17P allele and decreased aspirin response. When analyzed separately by ethnicity, the association with the P17L genotype and aspirin response persisted in African Americans, but not Caucasians. CONCLUSIONS: Our data suggest that the PTGS1 P17L genotype contributes to response to aspirin as assessed by ex-vivo platelet aggregation. Our data further suggest that the association between PTGS1 genotype and aspirin response might vary by ethnicity.

Objective measurement of periocular pigmentation.

PURPOSE: To evaluate the Minolta CR-400 chromameter in objectively measuring periocular/facial pigmentation in subjects of different ethnicities. METHODS: The CR-400 was used to obtain skin color measurements from 75 African-American, Caucasian and Hispanic subjects in 16 facial and periocular locations. Comparisons between ethnic and Fitzpatrick groups and instrument reliability were analyzed. RESULTS: Significant differences in L* were observed among all three ethnic groups, while values a* and b* were less sensitive to differences in pigmentation. Comparison between Fitzpatrick groups again identified value L* as being the most sensitive, demonstrating significant differences between the more heavily pigmented groups. The 16 facial locations measured were found to be statistically similar to each other, and the chromameter demonstrated excellent inter- and intra-instrument reliability. CONCLUSIONS: The Minolta CR-400 chromameter reliably measures facial pigmentation and can be useful for studies evaluating changes in skin pigmentation. Value L* is the parameter that is most sensitive to differences between ethnic and Fitzpatrick groups. Overlap between groups was observed, demonstrating that in future studies, each individual must serve as their own control when monitoring changes in pigmentation. The similarity between all the locations tested demonstrates uniformity of facial pigmentation within an individual.

Association of beta-blocker dose with serum procollagen concentrations and cardiac response to spironolactone in patients with heart failure.

STUDY OBJECTIVE: To determine whether beta-blocker dose influences cardiac collagen turnover and the effects of spironolactone on cardiac collagen turnover in patients with heart failure. DESIGN: Prospective clinical study. SETTING: Two heart failure centers. PATIENTS: Eighty-eight spironolactone-naïve patients with heart failure who were taking beta-blockers. INTERVENTION: In a subset of 29 patients, spironolactone was started at 12.5 mg/day, with the dosage titrated to 25 mg/day if tolerated. MEASUREMENTS AND MAIN RESULTS: Venous blood samples were collected from each patient. Serum procollagen type I and type III aminoterminal peptides (PINP and PIIINP) were determined by radioimmunoassay and compared between the 25 patients receiving low doses (< 50% of recommended target dose) and the 63 patients receiving high doses (> or = 50% of recommended target dose) of beta-blockers. Patients receiving low-dose beta-blockers had higher mean +/- SD PIIINP concentrations (6.6 +/- 3.5 vs 4.9 +/- 2.6 microg/L, p=0.03) and tended to have higher PINP concentrations (74.0 +/- 44.1 vs 57.1 +/- 28.6 microg/L, p=0.10) compared with those receiving high doses. A repeat blood sample was collected from the 29 patients who received spironolactone after 6 months of therapy. Changes in procollagen peptides also were compared in this subset between low-dose (9 patients) and high-dose (20 patients) beta-blocker groups. Low beta-blocker doses were associated with greater reductions in concentrations of PINP (median [intraquartile range] -14.3 microg/L [-9.8 to -19.3 microg/L] vs -2.5 microg/L [5.9 to -9.8 microg/L], p=0.02) and PIIINP (-1.4 microg/L [-0.9 to -2.4 microg/L] vs 0.1 microg/L [0.9 to -1.3 microg/L], p=0.045) with spironolactone therapy than high beta-blocker doses. In addition, 100% of the patients in this subset taking low-dose beta-blockers versus only 35% taking higher doses had reductions in both markers of cardiac fibrosis. CONCLUSION: Spironolactone may benefit patients with heart failure who cannot tolerate upward titration of beta-blocker dosages, at least in terms of its effects on cardiac remodeling.

A method of determining the dose of digoxin for heart failure in the modern era.

BACKGROUND: The therapeutic range for digoxin in heart failure has recently changed to become lower and narrower, and the new range is associated with improved mortality. However, dosing methods have not been modified to reflect this change. In this study, we sought to develop a new method to determine the initial dose of digoxin in patients with heart failure. METHODS: Over a 6-month period, medical records were screened and reviewed for hospitalized adult patients who had a steady state digoxin concentration. A multiple linear regression was estimated relating digoxin concentration, digoxin dose, creatinine clearance, and ideal body weight to generate an equation relating the dose of digoxin with these variables and a specific target digoxin concentration of 0.7 ng/mL (0.9 nmol/L). This new method was then compared with 2 existing methods. RESULTS: Included in the study were 54 patients (mean [SD] age, 68 [15] years, with a mean (SD) creatinine clearance of 50 (25) mL/min (0.8 [0.4] mL/s) and mean (SD) ideal body weight of 62 (11) kg. Our proposed method and the Jusko and Koup method were more accurate than the Jelliffe method in predicting digoxin concentration. Root mean square errors were as follows: for the Jelliffe method (using ideal body weight), 0.810; for the Koup and Jusko method (with heart failure), 0.401; our proposed method, 0.375. The proposed method was then used to create a dosing nomogram. CONCLUSIONS: Because the new therapeutic window of digoxin is associated with improved outcomes, more intensive dosage refinement should be considered. To this end, we offer new dosing recommendations and a nomogram for determining the initial dose of digoxin in patients with heart failure.

Embolization of intracranial aneurysms with hydrogel-coated coils versus inert platinum coils: effects on packing density, coil length and quantity, procedure performance, cost, length of hospital stay, and durability of therapy.

BACKGROUND AND PURPOSE: The durability of aneurysm coil embolization is thought to depend on packing density. The expansile property of hydrogel coating on coils increases volumetric packing per coil length. We describe our experience using hydrogel-coated coils (HydroCoils) compared with inert platinum coils in intracranial aneurysm embolization. METHODS: Fifty aneurysms embolized primarily using HydroCoils from 2003 to 2004 were compared with 57 volume- and shape-matched aneurysms treated with standard platinum coils from 2000 to 2003. Outcome measures included volumetric percentage occlusion (VPO), length and number of coils used, procedure time, fluoroscopy time, contrast volume, coil cost, length of hospital stay, and durability of therapy. RESULTS: Seventeen/26/5 small/medium/large aneurysms treated with HydroCoils were matched with 29/24/4 small/medium/large aneurysms treated with inert platinum. HydroCoil embolization yielded significantly greater VPO (84.8% versus 29.8%; P<0.001), decreased average total coil length used per aneurysm (33.2 versus 44.3 cm), reduced fluoroscopy time (53.2 versus 65.2 minutes; P=0.016), but increased contrast volume used (174.8 versus 112.9 cc; P<0.001). There were no differences in length of hospital stay. Procedure-related morbidity and mortality rates in the HydroCoil cohort were 4% and 0%, respectively. Follow-up angiography at mean 12.3 months revealed lower aneurysm recurrence rates (17% versus 24%; number-needed-to-treat [NNT] 14.3). Initial costs associated with HydroCoil embolization were higher ($5835 versus $4017; P=0.004) but countered by lower retreatment rates (10% versus 17%; NNT 14.3). CONCLUSIONS: HydroCoil embolization achieves greater aneurysm packing density with decreased coil length. Initial durability data favor HydroCoils, with lower recurrence and retreatment rates.

Racial differences in potassium response to spironolactone in heart failure.

Evidence of racial differences in aldosterone concentrations and K+ disposition suggests that response to aldosterone antagonism might vary by race. The authors sought to determine whether K+ response to spironolactone differs between African Americans and Caucasians with heart failure. Heart failure patients of African-American (n = 34) or Caucasian (n = 17) race were started on spironolactone 12.5 mg/d, with up-titration as tolerated. Laboratory values and drug therapy were similar between racial groups at baseline. Spironolactone was titrated to a median dose of 25 mg/d in both groups. Neither concomitant medications nor serum creatinine changed significantly in either group during spironolactone dose titration. Median serum K+ concentrations increased by 0.5 mEq/L (range, -0.7 to 1.6 mEq/L) in Caucasians, but only 0.1 mEq/L (range, -0.8 to 0.9 mEq/L) in African Americans; p < 0.01. These data suggest that African Americans with heart failure may be less responsive to the renal effects of spironolactone.

Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression: preliminary results of a randomized trial.

BACKGROUND: Many severely depressed patients do not benefit from or tolerate existing treatments. Repetitive transcranial magnetic stimulation (rTMS) has been reported to benefit depression. We compared rTMS to electroconvulsive therapy (ECT) in severely ill, depressed patients. METHODS: Twenty-five patients with a major depression (unipolar or bipolar) deemed clinically appropriate for ECT were randomly assigned to rTMS (10-20 treatments, 10 Hz, 110% motor threshold applied to the left dorsolateral prefrontal cortex for a total of 10,000-20,000 stimulations) or a course of bitemporal ECT (4-12 treatments). The primary outcome measure was the 24-item Hamilton Depression Rating Scale (HDRS). The Brief Psychiatric Rating Scale (BPRS), Young Mania Rating Scale (YMS), and Clinical Global Impression scale (CGI) were secondary measures. Minimal rescue medications were utilized. RESULTS: Mean percent improvement on the baseline HDRS score did not significantly differ between the two treatments (i.e., 55% for the rTMS group vs. 64% for the ECT group [p = ns]). With response defined as a 50% reduction from baseline and a final score < or = 8 on the HDRS, there was also no significant difference between the two groups. We did not observe any differences between groups on the secondary measures. CONCLUSIONS: A 2-4 week randomized, prospective trial comparing rTMS to ECT produced comparable therapeutic effects in severely depressed patients.

Single-dose pharmacokinetic study of lycopene delivered in a well-defined food-based lycopene delivery system (tomato paste-oil mixture) in healthy adult male subjects.

This report details the findings of a single-dose Phase I pharmacokinetic and toxicity study of a food-based formulation of lycopene in healthy adult male subjects. Five dosing groups (n = 5 per group) were sequentially treated with increasing doses of lycopene ranging from 10 to 120 mg. Blood samples were collected for a total of 28 days (672 h) after administration of single doses of lycopene. The mean time (t(max)) to reach maximum total lycopene concentration (C(max)) ranged from 15.6 to 32.6 h. The C(max) for total lycopene ranged between 4.03 and 11.27 microg/dl (0.075-0.210 microm). Mean AUC(0-96) and elimination half-life for total lycopene ranged from 214 to 655 microg h/dl (3.986-12.201 micromol h/l) and 28.1 and 61.6 h, respectively. The changes observed in lycopene exposure parameters (e.g., C(max) and AUC(0-96)) were not proportional to increments in dose, with larger increases observed at the lowest end of the dosing range (10-30 mg). Chylomicron lycopene was measured during the first 12 h with the differences observed among the dosing groups not reaching statistical significance. These findings may reflect a process of absorption that is saturable at very low dosing levels or may be explained by the large interindividual variability in attained lycopene concentrations that were observed within each dosing group. Pharmacokinetic parameters for trans- and cis-lycopene isomers were calculated and are reported here. The formulation was well tolerated with minimal side effects, which were mainly of gastrointestinal nature and of very low grade.

Racial differences in patients' potassium concentrations during spironolactone therapy for heart failure.

STUDY OBJECTIVE: To determine whether the effects of spironolactone on potassium homeostasis vary by race by comparing serum potassium concentrations and potassium supplement use in African-American and Caucasian patients receiving spironolactone for heart failure. DESIGN: Retrospective medical record review. SETTING: Two heart failure centers. PATIENTS: Fifty African-American and 67 Caucasian patients with heart failure who were receiving a stable dosage of spironolactone in addition to standard heart failure therapy with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker. MEASUREMENTS AND MAIN RESULTS: Medical records of eligible patients were reviewed by pharmacists and physicians who specialize in heart failure management. No significant differences were observed in diuretic therapy or renal function between racial groups; however, African-Americans were receiving higher doses of ACE inhibitors. African-Americans had lower serum potassium concentrations (4.2 +/- 0.4 vs 4.5 +/- 0.5 mEq/L, p<0.01) and a higher prevalence of potassium supplementation (48% vs 15%, p<0.01). In a subset of patients, spironolactone therapy was associated with a 2-fold greater increase in serum potassium concentration and a 3-fold greater reduction in potassium supplement use among Caucasians than African-Americans. CONCLUSION: Our findings suggest that a large percentage of patients with heart failure, particularly African-Americans, still require potassium supplementation despite treatment with spironolactone and standard vasodilator therapy.

Liquid chromatography-mass spectrometry of cis- and all-trans-lycopene in human serum and prostate tissue after dietary supplementation with tomato sauce.

Several epidemiological studies suggest a lower incidence of prostate cancer in men who routinely consume tomato products. Tomatoes are the primary dietary source of lycopene, which is among the most potent antioxidants of the carotenoids. Men with clinical stage T1 or T2 prostate adenocarcinoma were recruited (n = 32) and consumed tomato sauce based pasta dishes for 3 weeks (equivalent to 30 mg of lycopene per day) before radical prostectomy. Prostate tissue from needle biopsy just before intervention and prostectomy after supplementation from a subset of 11 subjects was evaluated for both total lycopene and lycopene geometrical isomer ratios. A gradient HPLC system using a C(18) column with UV-vis absorbance detection was used to measure total lycopene. Because the absorbance detector was insufficiently sensitive, HPLC with a C(30) column and positive ion atmospheric pressure chemical ionization mass spectrometric (LC-MS) detection was developed as a new assay to measure the ratio of lycopene cis/trans isomers in these samples. The limit of detection of the LC-MS method was determined to be 0.93 pmol of lycopene on-column, and a linear response was obtained over 3 orders of magnitude. Total lycopene in serum increased 2.0-fold from 35.6 to 69.9 microg/dL (from 0.664 to 1.30 microM) as a result of dietary supplementation with tomato sauce, whereas total lycopene in prostate tissue increased 3.0-fold from 0.196 to 0.582 ng/mg of tissue (from 0.365 to 1.09 pmol/mg). all-trans-Lycopene and at least 14 cis-isomer peaks were detected in prostate tissue and serum. The mean proportion of all-trans-lycopene in prostate tissue was approximately 12.4% of total lycopene before supplementation but increased to 22.7% after dietary intervention with tomato sauce. In serum there was only a 2.8% but statistically significant increase in the proportion of all-trans-lycopene after intervention. These results indicate that short-term supplementation with tomato sauce containing primarily all-trans-lycopene (83% of total lycopene) results in substantial increases in total lycopene in serum and prostate and a substantial increase in all-trans-lycopene in prostate but relatively less in serum.

Pharmacokinetics of prenylated hop phenols in women following oral administration of a standardized extract of hops.

SCOPE: Women seeking alternatives to hormone-replacement therapy for menopausal symptoms often try botanical dietary supplements containing extracts of hops (Humulus lupulus L.). Hops contain 8-prenylnaringenin (8-PN), a potent phytoestrogen, the related flavanones 6-prenylnaringenin and isoxanthohumol (IX), and the prenylated chalcone xanthohumol (XN). METHODS AND RESULTS: After chemically and biologically standardizing an extract of spent hops to these marker compounds, an escalating dose study was carried out in menopausal women to evaluate safety and pharmacokinetics. 8-PN, 6-prenylnaringenin, IX, and XN, sex hormones, and prothrombin time were determined in blood samples and/or 24 h urine samples. There was no effect on sex hormones or blood clotting. The maximum serum concentrations of the prenylated phenols were dose-dependent and were reached from 2 to 7 h, indicating slow absorption. The marker compounds formed glucuronides that were found in serum and urine. Secondary peaks at 5 h in the serum concentration-time curves indicated enterohepatic recirculation. The serum concentration-time curves indicated demethylation of IX to form 8-PN and cyclization of XN to IX. Slow absorption and enterohepatic recirculation contributed to half-lives exceeding 20 h. CONCLUSION: This human study indicated long half-lives of the estrogenic and proestrogenic prenylated phenols in hops but no acute toxicity.

Metástase gástrica de melanoma maligno / Gastric metastasis of malignant melanoma

O melanoma maligno corresponde a 5% de todas as neoplasias da pele. Apresenta elevada agressividade local e tendência à disseminação através de metástases. O aparelho digestivo não é sítio secundário comum de melanoma, e o estômago é raramente comprometido. Relatamos caso de paciente do sexo masculino, 64 anos, com quadro de astenia progressiva, anemia, episódio de síncope e história de exérese de melanoma maligno nível IV de Clark em asa nasal há 6 anos, com esvaziamento de cadeia linfonodal cervical ipsilateral. Durante a investigação, foi encontrada massa gástrica, sendo submetido à gastrectomia total com reconstrução em Y de Roux, com melhora substancial dos sintomas. O exame anatomopatológico da massa gástrica confirma o resultado de metástase de melanoma maligno pela biópsia endoscópica pré-operatória. O paciente segue em acompanhamento ambulatorial sem manifestações de novas metástases até o momento. (AU)

Malignant melanoma accounts for 5% of all skin cancers. It has high local aggressiveness and tendency to spread through metastases. The digestive tract is not common secondary site of melanoma, and the stomach is rarely compromised. We report the case of a male patient, 64, with progressive asthenia, anemia, syncope and previously excision of malignant melanoma Clark level IV in nasal wing for 6 years with ipsilateral cervical lymph node emptying. During the investigation we found gastric mass and underwent total gastrectomy and Roux-en-Y with substantial improvement in symptoms. The anatomopathological examination of the gastric mass confirms the result of malignant melanoma metastasis by the preoperative endoscopic biopsy. The patient is in outpatient treatment without signs of new metastases so far. (AU)

Association of apolipoprotein E genotype with duration of time to achieve a stable warfarin dose in African-American patients.

STUDY OBJECTIVE: To test the hypothesis that genotypes for proteins affecting vitamin K availability influence the duration of time required to achieve a stable warfarin dose in African-American patients. DESIGN: Retrospective cohort study. SETTING: Pharmacist-managed antithrombosis clinic. PATIENTS: Ninety-two African-American adults whose warfarin therapy was initiated between September 2, 1999, and July 8, 2009. MEASUREMENTS AND MAIN RESULTS: During a routine anticoagulation clinic visit, a sample was collected from each patient for genetic analysis. genotyping was performed for the following variants: apolipoprotein E ε2, ε3, and ε4; NAD(P)H:quinone oxidoreductase (NQO1)*2; cytochrome P450 (CYP) 4F2 V433M; CYP2C9*2, *3, *5, *8, and *11; and vitamin K epoxide reductase complex 1 (VKORC1) -1639G>A. Patients' medical records were then reviewed, and data were collected retrospectively for each anticoagulation clinic visit during the first 6 months of warfarin therapy or until dose stabilization. The median time required to reach a stable warfarin dose, defined as the dose that produced therapeutic anticoagulation for three consecutive clinic visits, was 83 days. Compared with the 46 patients who achieved a stable warfarin dose within 83 days, the 46 patients who required longer durations for dose stabilization had a higher frequency of the apolipoprotein E ε3/ε3 genotype (37% vs 59%, p=0.037). Sixty-one percent of patients with the ε3/ε3 genotype versus 40% of those with an ε2 or ε4 allele had a delay in achieving a stable dose (p=0.037). Neither the CYP4F2 nor NQO1 genotype was associated with warfarin dose stabilization. CONCLUSION: Our data support the hypothesis that the apolipoprotein E genotype is associated with duration of time to reach a stable warfarin dose in African-American patients. Further insight into the genetic effects on warfarin dose stabilization could reveal novel methods to improve anticoagulation control during the warfarin initiation period.