scholarly journals Dose-Dependent Increase in Unconjugated Cinnamic Acid Concentration in Plasma Following Acute Consumption of Polyphenol Rich Curry in the Polyspice Study

Nutrients ◽  
2018 ◽  
Vol 10 (7) ◽  
pp. 934 ◽  
Author(s):  
Sumanto Haldar ◽  
Sze Lee ◽  
Jun Tan ◽  
Siok Chia ◽  
Christiani Henry ◽  
...  
Keyword(s):  
Cinnamic Acid ◽  
Plasma Concentrations ◽  
High Dose ◽  
Aromatic Acids ◽  
Time Curve ◽  
Concentration Time ◽  
Liquid Chromatography Tandem Mass ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Randomized Crossover Study

Spices that are rich in polyphenols are metabolized to a convergent group of phenolic/aromatic acids. We conducted a dose-exposure nutrikinetic study to investigate associations between mixed spices intake and plasma concentrations of selected, unconjugated phenolic/aromatic acids. In a randomized crossover study, 17 Chinese males consumed a curry meal containing 0 g, 6 g, and 12 g of mixed spices. Postprandial blood was drawn up to 7 h at regular intervals and plasma phenolic/aromatic acids were quantified via liquid chromatography tandem mass spectrometry (LC-MS/MS). Cinnamic acid (CNA, p < 0.0001) and phenylacetic acid (PAA, p < 0.0005) concentrations were significantly increased with mixed spices consumption, although none of the other measured phenolic/aromatic acids differ significantly between treatments. CNA displayed a high dose-exposure association (R2 > 0.8, p < 0.0001). The adjusted mean area under the plasma concentration-time curve until 7 h (AUC0–7 h) for CNA during the 3 increasing doses were 8.4 ± 3.4, 376.1 ± 104.7 and 875.7 ± 291.9 nM.h respectively. Plasma CNA concentration may be used as a biomarker of spice intake.

scholarly journals Dose-Dependent Increase in Unconjugated Cinnamic Acid Concentration in Plasma Following Consumption of Polyphenol Rich Curry in the Polyspice Study

2018 ◽  
Author(s):  
Sumanto Haldar ◽  
Sze Han Lee ◽  
Jun Jie Tan ◽  
Siok Ching Chia ◽  
Christiani Jeyakumar Henry ◽  
...  
Keyword(s):  
Crossover Study ◽  
Phenolic Acids ◽  
Cinnamic Acid ◽  
Phenylacetic Acid ◽  
Plasma Concentrations ◽  
The Other ◽  
High Dose ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Randomized Crossover Study

Spices rich in polyphenols are metabolized to a convergent group of phenolic acids. We conducted a dose-exposure nutrikinetic study to investigate associations between mixed spices intake and plasma concentrations of selected, unconjugated phenolic acids. In a randomized crossover study, 20 Chinese males consumed a curry meal containing 0 g, 6 g, and 12 g of mixed spices. Postprandial blood was drawn up to 7 h at regular intervals and plasma phenolic acids were quantified via LC-MS/MS. Cinnamic acid (CNA, p &lt; 0.0001) and phenylacetic acid (PAA, p &lt; 0.0005) concentrations were significantly increased with mixed spices consumption, although none of the other measured phenolic acids differ significantly between treatments. CNA displayed a high dose-exposure association (R2 &gt; 0.8, p &lt; 0.0001). The adjusted mean AUC0-7 h for CNA during the 3 increasing doses were 8.4 &plusmn; 3.4, 376.1 &plusmn; 104.7 and 875.7 &plusmn; 291.9 nM&middot;h respectively. Plasma CNA concentration may be used as a biomarker of spice intake.

scholarly journals Repeated Administration of High-Dose Intermittent Rifapentine Reduces Rifapentine and Moxifloxacin Plasma Concentrations

2008 ◽  
Vol 52 (11) ◽  
pp. 4037-4042 ◽  
Author(s):  
Kelly Dooley ◽  
Charles Flexner ◽  
Judith Hackman ◽  
Charles A. Peloquin ◽  
Eric Nuermberger ◽  
...  
Keyword(s):  
Phase I ◽  
Adverse Reactions ◽  
Plasma Concentrations ◽  
Repeated Administration ◽  
Hypersensitivity Syndrome ◽  
Sequential Design ◽  
High Dose ◽  
Time Curve ◽  
Concentration Time ◽  
The Mean

ABSTRACT Moxifloxacin- and rifapentine-based regimens are under investigation for the treatment of tuberculosis. However, rifapentine may induce enzymes that metabolize moxifloxacin, resulting in decreased moxifloxacin concentrations. In this phase I, two-period, sequential-design study, 13 subjects received 400 mg moxifloxacin daily for 4 days followed by daily moxifloxacin coadministered with 900 mg rifapentine thrice weekly. Pharmacokinetic analyses were performed after the 4th and 19th doses of moxifloxacin and after the 1st and 7th doses of rifapentine. For moxifloxacin, the mean area under the concentration-time curve from 0 to 24 h (AUC0-24) decreased by 17.2% (P = 0.0006) when the drug was coadministered with rifapentine, and the mean half-life (t 1/2) decreased from 11.1 to 8.9 h (P = 0.0033). For rifapentine, the mean AUC0-48 after seven thrice-weekly doses decreased by 20.3% (P = 0.0035) compared to the AUC0-48 after the first dose, and the mean t 1/2 decreased from 18.5 to 14.8 h (P = 0.0004). The AUC0-48 for the 25-desacetyl-rifapentine metabolite diminished 21%. Two days after completing the study drugs, one subject developed a fever and hepatitis, and another developed a flu-like illness with a rash. In conclusion, rifapentine modestly reduced moxifloxacin concentrations. Changes consistent with rifapentine autoinduction of metabolism were seen. Adverse reactions in two subjects may have represented rifamycin hypersensitivity syndrome, although some features were atypical.

scholarly journals Improved Oral Bioavailability of Lopinavir in Melt-Extruded Tablet Formulation Reduces Impact of Third Trimester on Lopinavir Plasma Concentrations

2011 ◽  
Vol 56 (2) ◽  
pp. 816-824 ◽  
Author(s):  
L. J. Else ◽  
M. Douglas ◽  
L. Dickinson ◽  
D. J. Back ◽  
S. H. Khoo ◽  
...  
Keyword(s):  
Oral Bioavailability ◽  
Plasma Concentrations ◽  
Undetectable Viral Load ◽  
Pharmacokinetic Data ◽  
Third Trimester ◽  
Time Curve ◽  
The Third ◽  
Concentration Time ◽  
Liquid Chromatography Tandem Mass ◽  
In Pregnancy

ABSTRACTLopinavir exposure was reduced during the third trimester in pregnant women receiving standard dosing of the soft-gel capsule (SGC; 400/100 mg twice daily [b.i.d.]). Pharmacokinetic data on the lopinavir tablet in pregnancy are limited. On the basis of the tablet's improved bioavailability, standard dosing (400/100 mg b.i.d.) may provide adequate lopinavir exposure in pregnancy without a need for dose adjustment. Here we compared the total and unbound lopinavir pharmacokinetics throughout pregnancy in the second and third trimesters in HIV-infected women receiving standard dosing of the lopinavir SGC or tablet. Postpartum sampling was also performed in patients continuing therapy postdelivery. Blood samples were collected at 0 to 12 h postdosing, and lopinavir concentrations were determined by high-pressure liquid chromatography-tandem mass spectrometry. Nineteen patients were included: 8 received the SGC (cohort 1) and 11 received the tablet (cohort 2). Total lopinavir exposures in the third trimester were lower than those in the second trimester (35 and 28% for cohorts 1 and 2, respectively) and postpartum (35% for cohort 2). In the third trimester, the area under the concentration-time curve (AUC) from 0 to 12 h (AUC0–12) and maximum concentration were ∼15% and 25% higher, respectively, for the lopinavir tablet than the SGC. One SGC patient had lopinavir concentrations of <1,000 ng/ml; all patients on the tablet had concentrations of >1,000 ng/ml. In cohort 2, the percentage of the AUC that was unbound was higher (nonsignificantly) in the second (1.28%) and third (1.18%) trimesters than postpartum (1.01%). Seventeen of 19 patients had an undetectable viral load at delivery. There were no HIV transmissions. Although lopinavir (tablet) exposures were reduced during the third trimester, the higher total and unbound concentrations achieved in women receiving the tablet than in women receiving the SGC suggest that the tablet's improved oral bioavailability may partly compensate for the reduction in lopinavir exposure during the later stages of pregnancy.

scholarly journals Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 386
Author(s):  
Tung-Hu Tsai ◽  
Yu-Jen Chen ◽  
Li-Ying Wang ◽  
Chen-Hsi Hsieh
Keyword(s):  
Stereotactic Body Radiation Therapy ◽  
In Vivo Studies ◽  
Control Group ◽  
High Dose ◽  
Dependent Manner ◽  
Hep G2 ◽  
Time Curve ◽  
Dose Dependent

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).

Lack of Effect of Ginkgo biloba on Voriconazole Pharmacokinetics in Chinese Volunteers Identified as CYP2C19 Poor and Extensive Metabolizers

2009 ◽  
Vol 43 (4) ◽  
pp. 726-731 ◽  
Author(s):  
He-Ping Lei ◽  
Guo Wang ◽  
Lian-Sheng Wang ◽  
Dong-sheng Ou-yang ◽  
Hao Chen ◽  
...  
Keyword(s):  
Single Dose ◽  
Ginkgo Biloba ◽  
Poor Metabolizers ◽  
Pharmacokinetic Parameters ◽  
Extensive Metabolizers ◽  
Herbal Supplements ◽  
Time Curve ◽  
Concentration Time ◽  
Apparent Clearance ◽  
Randomized Crossover Study

Background: Ginkgo biloba is one of the most popular herbal supplements in the world. The supplement has been shown to induce the enzymatic activity of CYP2C19, the main cytochrome P450 isozyme involved in voriconazole metabolism. Because this enzyme exhibits genetic polymorphism, the inductive effect was expected to be modulated by the CYP2C19 metabolizer status. Objective: To examine the possible effects of Ginkgo biloba as an inducer of CYP2C19 on single-dose pharmacokinetics of voriconazole in Chinese volunteers genotyped as either CVP2C19 extensive or poor metabolizers. Methods: Fourteen healthy, nonsmoking volunteers–7 CYP2C19 extensive metabolizers (2C19*1/2C19*1) and 7 poor metabolizers (2C19*2/2C19*2)–were selected to participate in this study. Pharmacokinetics of oral voriconazole 200 mg after administration of Ginkgo biloba 120 mg twice daily for 12 days were determined for up to 24 hours by liquid chromatography–electrospray tandem mass spectrometry in a 2-phase randomized crossover study with 4-week washout between phases. Results: For extensive metabolizers, the median value for voriconazole area under the plasma concentration–time curve from zero to infinity (AUC0-00) was 5.17 μg•h/mL after administration of voriconazole alone and 4.28 μg•/mL after voriconazole with Ginkgo biloba (p > 0.05). The other pharmacokinetic parameters of voriconazole such as AUC0-24, time to reach maximum concentration, half-life, and apparent clearance also did not change significantly for extensive metabolizers in the presence of Ginkgo biloba. Pharmacokinetic parameters followed a similar pattern for poor metabolizers. Conclusions: The results suggest that 12 days of treatment with Ginkgo biloba did not significantly alter the single-dose pharmacokinetics of voriconazole in either CYP2C19 extensive or poor metabolizers. Therefore, the pharmacokinetic interactions between voriconazole and Ginkgo biloba may have limited clinical significance.

Exposure to Retinoic Acids in Non-Pregnant Women Following High Vitamin A Intake with a Liver Meal

2005 ◽  
Vol 75 (3) ◽  
pp. 187-194 ◽  
Author(s):  
Hartmann ◽  
Brørs ◽  
Bock ◽  
Blomhoff ◽  
Bausch ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Vitamin A ◽  
Safety Concern ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Pregnant Female ◽  
Time Curve ◽  
High Vitamin ◽  
Concentration Time ◽  
Plasma Concentration Time Curve

Animal liver is a rich source of vitamin A. Due to retinoic acid (RA) metabolites, vitamin A has a teratogenic potential and women are generally advised to avoid or to limit the consumption of liver during pregnancy. In a recent study in non-pregnant female volunteers following single and repeated doses of up to 30,000 IU/day of vitamin A as a supplement, the plasma concentration time curve of all-trans RA acid showed a diurnal-like profile. But, the overall exposure (AUC24h) remained essentially unaltered whereas AUC24h increased linearly with dose for 13-cis and 13-cis-4-oxo RA. The current study in non-pregnant female volunteers showed that a single high vitamin A intake with a liver meal (up to 120,000 IU) exhibited a similar diurnal-like plasma concentration time curve for all-trans RA and its overall exposure remained also unaltered, despite a temporary two-fold increase in peak plasma concentration. Concentrations of 13-cis and 13-cis-4-oxo RA increased several-fold after a liver meal, and exposure (AUC24h) increased three- to five-fold. Pooling our results with data in the literature revealed a linear relation between the mean AUC24h of 13-cis and 13-cis-4-oxo RA and vitamin A intake with liver. Metabolism to all-trans RA of vitamin A with liver seems not to be of safety concern. However, the observed increase of plasma concentrations and the dose-dependent increase in exposure to 13-cis and 13-cis-4-oxo RA support the current safety recommendations on vitamin A intake and suggest that women should be cautious regarding their consumption of liver-containing meals during pregnancy.

scholarly journals In VivoPharmacodynamic Evaluation of an FtsZ Inhibitor, TXA-709, and Its Active Metabolite, TXA-707, in a Murine Neutropenic Thigh Infection Model

2015 ◽  
Vol 59 (10) ◽  
pp. 6568-6574 ◽  
Author(s):  
Alexander J. Lepak ◽  
Ajit Parhi ◽  
Michaela Madison ◽  
Karen Marchillo ◽  
Jamie VanHecker ◽  
...  
Keyword(s):  
Active Metabolite ◽  
Methicillin Resistance ◽  
Dose Fractionation ◽  
Infection Model ◽  
Time Curve ◽  
Cellular Division ◽  
Content Type ◽  
Concentration Time ◽  
Dependent Activity ◽  
Dose Dependent

ABSTRACTAntibiotics with novel mechanisms of action are urgently needed. Processes of cellular division are attractive targets for new drug development. FtsZ, an integral protein involved in cell cytokinesis, is a representative example. In the present study, the pharmacodynamic (PD) activity of an FtsZ inhibitor, TXA-709, and its active metabolite, TXA-707, was evaluated in the neutropenic murine thigh infection model against 5Staphylococcus aureusisolates, including both methicillin-susceptible and methicillin-resistant isolates. The pharmacokinetics (PK) of the TXA-707 active metabolite were examined after oral administration of the TXA-709 prodrug at 10, 40, and 160 mg/kg of body weight. The half-life ranged from 3.2 to 4.4 h, and the area under the concentration-time curve (AUC) and maximum concentration of drug in serum (Cmax) were relatively linear over the doses studied. All organisms exhibited an MIC of 1 mg/liter. Dose fractionation demonstrated the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) to be the PD index most closely linked to efficacy (R2= 0.72). Dose-dependent activity was demonstrated against all 5 isolates, and the methicillin-resistance phenotype did not alter the pharmacokinetic/pharmacodynamic (PK/PD) targets. Net stasis was achieved against all isolates and a 1-log10kill level against 4 isolates. PD targets included total drug 24-h AUC/MIC values of 122 for net stasis and 243 for 1-log10killing. TXA-709 and TXA-707 are a promising novel antibacterial class and compound forS. aureusinfections. These results should prove useful for design of clinical dosing regimen trials.

scholarly journals Pharmacokinetics of Daptomycin in Critically Ill Pediatric Patients

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Charalampos Antachopoulos ◽  
Stavroula Ilia ◽  
Paschalis Kadiltzoglou ◽  
Eirini Baira ◽  
Aristides Dokoumetzidis ◽  
...  
Keyword(s):  
Critically Ill ◽  
Drug Exposure ◽  
Pediatric Patients ◽  
Plasma Concentrations ◽  
Therapeutic Drug ◽  
Burn Patients ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time ◽  
Optimal Drug

ABSTRACT The pharmacokinetics of daptomycin (10 mg/kg once daily) was studied in 4 critically ill pediatric patients aged 8 to 14 yrs. The area under the concentration-time curve from time zero to infinity (AUC 0–∞ ) of plasma concentrations on day 1 ranged between 123.8 to 663.9 μg · h/ml, with lower values observed in septic and burn patients; clearance ranged from 15.1 to 80.7 ml/h/kg. Higher-than-recommended doses of daptomycin may be needed in septic children to ensure optimal drug exposure. Interpatient variability may suggest a role for therapeutic drug monitoring.

Methotrexate pharmacokinetics following administration of recombinant carboxypeptidase-G2 in rhesus monkeys.

1992 ◽  
Vol 10 (8) ◽  
pp. 1359-1364 ◽  
Author(s):  
P C Adamson ◽  
F M Balis ◽  
C L McCully ◽  
K S Godwin ◽  
D G Poplack
Keyword(s):  
Plasma Concentration ◽  
Rhesus Monkeys ◽  
Alternative Form ◽  
High Dose ◽  
Time Curve ◽  
Carboxypeptidase G2 ◽  
Concentration Time ◽  
Bacterial Enzyme ◽  
Plasma Pharmacokinetics ◽  
Plasma Concentration Time Curve

PURPOSE Carboxypeptidase-G2 (CPDG2) is a bacterial enzyme that rapidly hydrolyzes methotrexate (MTX) into inactive metabolites. As an alternative form of rescue after high-dose MTX (HDMTX), CPDG2 has more potential advantages than standard leucovorin (LV) rescue. In this study, the plasma pharmacokinetics of MTX with and without CPDG2 were evaluated in adult rhesus monkeys. MATERIALS AND METHODS The plasma pharmacokinetics of MTX were determined in groups of animals that had received a 300-mg/m2 loading dose of MTX followed by a 60-mg/m2/h infusion during an 18-hour period. One group received CPDG2 at the end of the infusion, and the other group served as a control. Two additional animals with high titers of anti-CPDG2 antibody also were studied. RESULTS During infusion, the steady-state MTX plasma concentration was 11.3 +/- 4.8 mumol/L. Without CPDG2, the postinfusion plasma MTX concentration remained above 0.1 mumol/L for more than 6 hours. After the administration of 50 U/kg of CPDG2, plasma MTX concentrations decreased to nontoxic levels (less than 0.05 mumol/L) within 30 minutes. The initial half-life (t1/2 alpha) of MTX decreased from 5.8 +/- 2.1 minutes to 0.7 +/- 0.02 minutes after enzyme administration. The postinfusion area under the plasma concentration time curve of MTX was 301 +/- 171 mumol/L/min without CPDG2 compared with 19.6 +/- 6.1 mumol/L/min with CPDG2. The immunogenicity studies performed indicated that although animals developed anti-CPDG2 antibodies, none of them manifested allergic symptoms. The effectiveness of CPDG2 was diminished but not eliminated in animals with high titers of anti-CPDG2 antibody. CONCLUSIONS CPDG2 is capable of rapidly decreasing plasma MTX concentrations to nontoxic levels. The administration of CPDG2 seems safe, well tolerated, and it may be useful as an alternative to LV rescue.

scholarly journals High‐Dose Glucagon Has Hemodynamic Effects Regardless of Cardiac Beta‐Adrenoceptor Blockade: A Randomized Clinical Trial

2020 ◽  
Vol 9 (21) ◽  
Author(s):  
Kasper M. Petersen ◽  
Søren Bøgevig ◽  
Troels Riis ◽  
Niklas W. Andersson ◽  
Kim P. Dalhoff ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Plasma Concentrations ◽  
Random Order ◽  
Beta Blockade ◽  
High Dose ◽  
Clinical Effects ◽  
Hemodynamic Effects ◽  
Unique Identifier ◽  
Beta Adrenoceptor ◽  
Randomized Crossover Study

Background Intravenous high‐dose glucagon is a recommended antidote against beta‐blocker poisonings, but clinical effects are unclear. We therefore investigated hemodynamic effects and safety of high‐dose glucagon with and without concomitant beta‐blockade. Methods and Results In a randomized crossover study, 10 healthy men received combinations of esmolol (1.25 mg/kg bolus+0.75 mg/kg/min infusion), glucagon (50 µg/kg), and identical volumes of saline placebo on 5 separate days in random order (saline+saline; esmolol+saline; esmolol+glucagon bolus; saline+glucagon infusion; saline+glucagon bolus). On individual days, esmolol/saline was infused from −15 to 30 minutes. Glucagon/saline was administered from 0 minutes as a 2‐minute intravenous bolus or as a 30‐minute infusion (same total glucagon dose). End points were hemodynamic and adverse effects of glucagon compared with saline. Compared with saline, glucagon bolus increased mean heart rate by 13.0 beats per minute (95% CI, 8.0–18.0; P <0.001), systolic blood pressure by 15.6 mm Hg (95% CI, 8.0–23.2; P =0.002), diastolic blood pressure by 9.4 mm Hg (95% CI, 6.3–12.6; P <0.001), and cardiac output by 18.0 % (95% CI, 9.7–26.9; P =0.003) at the 5‐minute time point on days without beta‐blockade. Similar effects of glucagon bolus occurred on days with beta‐blockade and between 15 and 30 minutes during infusion. Hemodynamic effects of glucagon thus reflected pharmacologic glucagon plasma concentrations. Glucagon‐induced nausea occurred in 80% of participants despite ondansetron pretreatment. Conclusions High‐dose glucagon boluses had significant hemodynamic effects regardless of beta‐blockade. A glucagon infusion had comparable and apparently longer‐lasting effects compared with bolus, indicating that infusion may be preferable to bolus injections. Registration Information URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03533179.

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