scholarly journals Clinical Validation of a Volumetric Absorptive Micro-Sampling Device for Pharmacokinetic Studies With Tranexamic Acid

2021 ◽  
Vol 12 ◽  
Author(s):  
Stanislas Grassin-Delyle ◽  
Elodie Lamy ◽  
Michaela Semeraro ◽  
Iléana Runge ◽  
Jean-Marc Treluyer ◽  
...  
Keyword(s):  
Tranexamic Acid ◽  
Whole Blood ◽  
Plasma Concentrations ◽  
High Sensitivity ◽  
Pharmacokinetic Studies ◽  
Limits Of Agreement ◽  
Sampling Device ◽  
Average Bias ◽  
Alternative Routes ◽  
Matched Samples

We assessed the accuracy of tranexamic acid (TXA) concentrations measured in capillary whole blood using volumetric absorptive micro-sampling (VAMS) devices. Paired venous and VAMS capillary blood samples were collected from 15 healthy volunteers participating in a pharmacokinetic study of alternative routes (oral, IM and IV) of administering TXA. To assess accuracy across a range of concentrations, blood was drawn at different times after TXA administration. We measured TXA concentrations in plasma, whole blood from samples collected by venepuncture and whole blood from venous and capillary samples collected using VAMS devices. TXA was measured using a validated high sensitivity liquid chromatography - mass spectrometry method. We used Bland-Altman plots to describe the agreement between the TXA concentrations obtained with the different methods. In the 42 matched samples, the mean plasma TXA concentration was 14.0 mg/L (range 2.6–36.5 mg/L) whereas the corresponding whole blood TXA concentration was 7.7 mg/L (range 1.6–17.5 mg/L). When comparing TXA concentrations in VAMS samples of venous and capillary whole blood, the average bias was 0.07 mg/L (lower and upper 95% limits of agreement: −2.1 and 2.2 mg/L respectively). When comparing TXA concentrations in venous whole blood and VAMS capillary whole blood, the average bias was 0.7 mg/L (limits of agreement: −2.7 and 4.0 mg/L). Volumetric absorptive micro-sampling devices are sufficiently accurate for use in pharmacokinetic studies of tranexamic acid treatment in the range of plasma concentrations relevant for the assessment of fibrinolysis inhibition.

Improvement and assessment of enzyme-linked immunosorbent assay to detect low FK506 concentrations in plasma or whole blood within 6 hours

1993 ◽  
Vol 39 (6) ◽  
pp. 1045-1049 ◽  
Author(s):  
P E Wallemacq ◽  
I Firdaous ◽  
A Hassoun
Keyword(s):  
Detection Limit ◽  
Whole Blood ◽  
Clinical Investigation ◽  
Plasma Concentrations ◽  
Original Method ◽  
Enzyme Linked Immunosorbent Assay ◽  
Pharmacokinetic Studies ◽  
Blood Concentrations ◽  
Blood Temperature ◽  
Biological Variables

Abstract FK506, a promising new immunosuppressant, is currently under clinical investigation. Because dose-dependent toxicity is possible, blood concentrations of FK506 should be monitored. We improved the original ELISA of FK506 by shortening the incubation time. With some modification of materials, results are obtained within 6 h instead of 2 days, with similar or even better precision. Internal and external quality-control programs showed that our results correlated satisfactorily both with values determined by the original method and the theoretical expected values. Either plasma (detection limit 0.1 microgram/L) or whole-blood (detection limit 1 microgram/L) samples can be used. The sensitivity of the method makes it particularly useful for accurate pharmacokinetic studies or measurement of low blood concentrations. Twenty-four drugs and nine biological variables showed no significant interference on the assay. Study of the concentration- and temperature-dependent distribution of FK506 shows that the drug is largely bound to erythrocytes (ratio of blood to plasma concentrations is 10-40); as the erythrocytes become saturated, more of the drug is found in the plasma. Plasma concentrations may vary according to the blood temperature. We conclude that whole blood should be used for FK506 monitoring, as it is for monitoring cyclosporine.

TGR-1202: A Novel, Targeted PI3Kδ Inhibitor in Multiple Myeloma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5018-5018
Author(s):  
Swaroop Vakkalanka ◽  
Srikant Viswanadha ◽  
Lawrence H. Boise ◽  
Peter Sportelli ◽  
Hari Miskin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Whole Blood ◽  
Therapeutic Potential ◽  
Plasma Concentrations ◽  
Intervention Strategy ◽  
Xenograft Model ◽  
Pharmacokinetic Studies ◽  
Employment Equity ◽  
Pharmacokinetic Properties ◽  
Equity Ownership

Abstract Abstract 5018 Background: The bone marrow microenvironment contributes to the pathogenesis of Multiple Myeloma (MM) by promoting the oncogenic process including drug resistance. High expression levels of the PI3Kδ isoform in patient MM cells implicate this target as a novel and attractive intervention strategy aimed at attenuating the progression of the disease. Herein, we describe the biological and pharmacokinetic properties of TGR-1202, a novel and small molecule PI3Kδ inhibitor with scope to be developed as a clinical candidate for patients with relapsed and/or refractory MM. Material & Methods: Activity of TGR-1202 on individual PI3K isoforms was determined in enzyme, cell, and whole blood based assays. Potency of the compound was confirmed viaMM cell viability and apoptosis assays besides testing for inhibition of pAkt, a downstream kinase regulating cell survival and growth. Additionally, the compound was tested for potency in viability, apoptosis, and Akt phosphorylation assays using immortalized and MM patient derived primary cells. ADME and pharmacokinetic properties of the molecule were also determined. Results: TGR-1202 demonstrated significant potency against PI3Kδ (22. 2 nM) with several fold selectivity over the α (>10000), β (>50), and γ (>48) isoforms. Additionally, the compound inhibited B-cell proliferation (24. 3 nM) and FcεR1 induced CD63 expression in human whole blood basophils (68. 2 nM) indicating specificity towards the delta isoform. The addition of 5 μM TGR-1202 to dexamethasone (0. 55 μM) caused a dramatic shift in GI50 of MM-1S cells compared to that of either TGR-1202 (9. 7 μM) or dexamethasone (18. 3 μM) alone. Further viability testing demonstrated that the compound caused a dose-dependent inhibition (>50% @ 1–3 μM) in growth of immortalized (U266B1 and MM-1R) as well as patient-derived MM cells. Reduction in viability was accompanied by a reduction in pAKT (>80% @ 3 μM) along with induction of apoptosis in both cell lines and patient samples. Pharmacokinetic studies across species indicated good oral absorption (>40% bioavailability for mice, rat, and dog) with favorable plasma concentrations (3–10 μM @ 20 mg/kg for mice, rat, and dog) relevant for efficacy. Conclusions: Data demonstrate the therapeutic potential of TGR-1202 in MM viainhibition of the PI3Kδ pathway. Data from immortalized as well as primary patient-derived cells justify further evaluation of this molecule in MM. Combination therapy of TGR-1202 and dexamethasone in a mouse MM-1S xenograft model is currently ongoing. Disclosures: Vakkalanka: Rhizen Pharmaceuticals S A: Employment, Equity Ownership. Viswanadha:Incozen Therapeutics: Employment. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership.

Pharmacokinetics of culture-directed antibiotics for the treatment of peritonitis in automated peritoneal dialysis: A systematic narrative review

2021 ◽  
Vol 41 (3) ◽  
pp. 261-272
Author(s):  
Chau Wei Ling ◽  
Kamal Sud ◽  
Connie Van ◽  
Syed Tabish Razi Zaidi ◽  
Rahul P. Patel ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Case Reports ◽  
Plasma Concentrations ◽  
Case Series ◽  
Therapeutic Drug ◽  
Pharmacokinetic Studies ◽  
Pharmacokinetic Data ◽  
Automated Peritoneal Dialysis ◽  
Final Study ◽  
Drug Plasma

The objectives of this study were to provide a summary of the pharmacokinetic data of some intraperitoneal (IP) antibiotics that could be used for both empirical and culture-directed therapy, as per the ISPD recommendations, and examine factors to consider when using IP antibiotics for the management of automated peritoneal dialysis (APD)-associated peritonitis. A literature search of PubMed, EMBASE, Scopus, MEDLINE and Google Scholar for articles published between 1998 and 2020 was conducted. To be eligible, articles had to describe the use of antibiotics via the IP route in adult patients ≥18 years old on APD in the context of pharmacokinetic studies or case reports/series. Articles describing the use of IP antibiotics that had been recently reviewed (cefazolin, vancomycin, gentamicin and ceftazidime) or administered for non-APD-associated peritonitis were excluded. A total of 1119 articles were identified, of which 983 abstracts were screened. Seventy-three full-text articles were assessed for eligibility. Eight records were included in the final study. Three reports had pharmacokinetic data in patients on APD without peritonitis. Each of cefepime 15 mg/kg IP, meropenem 0.5 g IP and fosfomycin 4 g IP given in single doses achieved drug plasma concentrations above the minimum inhibitory concentration for treating the susceptible organisms. The remaining five records were case series or reports in patients on APD with peritonitis. While pharmacokinetic data support intermittent cefepime 15 mg/kg IP daily, only meropenem 0.5 g IP and fosfomycin 4 g IP are likely to be effective if given in APD exchanges with dwell times of 15 h. Higher doses may be required in APD with shorter dwell times. Information on therapeutic efficacy was derived from case reports/series in individual patients and without therapeutic drug monitoring. Until more pharmacokinetic data are available on these antibiotics, it would be prudent to shift patients who develop peritonitis on APD to continuous ambulatory peritoneal dialysis, where pharmacokinetic information is more readily available.

Development of a point-of-care assay system for high-sensitivity C-reactive protein in whole blood

2003 ◽  
Vol 332 (1-2) ◽  
pp. 51-59 ◽  
Author(s):  
Jae Soon Ahn ◽  
Sunga Choi ◽  
Sang Ho Jang ◽  
Hyuk Jae Chang ◽  
Jae Hoon Kim ◽  
...  
Keyword(s):  
Whole Blood ◽  
Point Of Care ◽  
High Sensitivity ◽  
Assay System ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Point Of Care Assay

Oral consumption of electrokinetically modified water attenuates muscle damage and improves postexercise recovery

2013 ◽  
Vol 114 (12) ◽  
pp. 1736-1742 ◽  
Author(s):  
Paul A. Borsa ◽  
Kelly L. Kaiser ◽  
Jeffrey S. Martin
Keyword(s):  
Muscle Damage ◽  
Functional Recovery ◽  
Biceps Brachii ◽  
Plasma Concentrations ◽  
High Sensitivity ◽  
Self Report ◽  
Placebo Control ◽  
Elbow Extension ◽  
Blood Draw ◽  
Oral Consumption

The purpose of this study was to assess the effects of consuming electrokinetically modified water (EMW) on attenuating muscle damage and improving functional recovery following a single bout of isokinetic resistance exercise. Subjects were randomly assigned to an EMW ( n = 20) or a placebo control ( n = 20) group. Subjects consumed EMW or placebo water daily for 23 days. On day 19 subjects completed an exercise protocol for the biceps brachii to induce muscle damage. The protocol consisted of three sets of 20 repetitions using concentric and eccentric contractions of the elbow flexors. Blood draw and clinical measurements were performed preexercise as well as 24, 48, and 96 h postexercise. Clinical measures included maximal isometric strength, muscle soreness, pain with elbow extension, relaxed elbow angle (RANG), and self-report arm disability. Plasma samples were analyzed to determine concentrations of creatine kinase (CK) and high-sensitivity C-reactive protein (hsCRP). Pain with elbow extension and self-report arm disability were significantly higher in the placebo group compared with the EMW group at 48 h ( P < 0.01) and 96 h ( P < 0.01) after exercise, while RANG was significantly higher in the EMW group compared with placebo at 48 h ( P < 0.01) and 96 h ( P < 0.01) after exercise. Similarly, plasma concentrations for hsCRP and CK were significantly lower in the EMW group compared with placebo at 48 h ( P < 0.05) and 96 h ( P < 0.01) after exercise. Oral consumption of EMW significantly reduced exercise-induced muscle damage and inflammation and improved functional recovery.

Comparison of tranexamic acid plasma concentrations when administered via intraosseous and intravenous routes

2017 ◽  
Vol 35 (2) ◽  
pp. 227-233 ◽  
Author(s):  
Søren R. Boysen ◽  
Jessica M. Pang ◽  
John R. Mikler ◽  
Cameron G. Knight ◽  
Hugh A. Semple ◽  
...  
Keyword(s):  
Tranexamic Acid ◽  
Plasma Concentrations

scholarly journals Toxicity and Pharmacokinetic Studies of Lidocaine and Its Active Metabolite, Monoethylglycinexylidide, in Goat Kids

Animals ◽  
2018 ◽  
Vol 8 (8) ◽  
pp. 142
Author(s):  
Dinakaran Venkatachalam ◽  
Paul Chambers ◽  
Kavitha Kongara ◽  
Preet Singh
Keyword(s):  
Total Dose ◽  
Plasma Concentrations ◽  
Subcutaneous Administration ◽  
Lidocaine Hydrochloride ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Liquid Chromatography Mass Spectrometry ◽  
Elimination Half ◽  
The Mean ◽  
Safe Dose

This study determined the convulsant plasma concentrations and pharmacokinetic parameters following cornual nerve block and compared the results to recommend a safe dose of lidocaine hydrochloride for goat kids. The plasma concentrations of lidocaine and monoethylglycinexylidide (MGX) were quantified using liquid chromatography-mass spectrometry. A total dose of 7 mg/kg body weight (BW) was tolerated and should therefore be safe for local and regional anesthesia in goat kids. The mean plasma concentration and mean total dose that produced convulsions in goat kids were 13.59 ± 2.34 µg/mL and 12.31 ± 1.42 mg/kg BW (mean ± S.D.), respectively. The absorption of lidocaine following subcutaneous administration was rapid with Cmax and Tmax of 2.12 ± 0.81 µg/mL and 0.33 ± 0.11 h, respectively. The elimination half-lives (t½λz) of lidocaine hydrochloride and MGX were 1.71 ± 0.51 h and 3.19 ± 1.21 h, respectively. Injection of 1% lidocaine hydrochloride (0.5 mL/site) was safe and effective in blocking the nerves supplying horn buds in goat kids.

scholarly journals Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study

2009 ◽  
Vol 161 (1) ◽  
pp. 119-130 ◽  
Author(s):  
Gudmundur Johannsson ◽  
Ragnhildur Bergthorsdottir ◽  
Anna G Nilsson ◽  
Hans Lennernas ◽  
Thomas Hedner ◽  
...  
Keyword(s):  
Single Dose ◽  
Replacement Therapy ◽  
Plasma Cortisol ◽  
Plasma Concentrations ◽  
Pharmacokinetic Studies ◽  
Double Blind ◽  
Once Daily ◽  
Physiological Serum ◽  
Cortisol Levels ◽  
Dual Release

BackgroundEndogenous plasma cortisol levels have a well-defined circadian rhythm. The aim of this project is to develop a once daily oral dual-release formulation for cortisol replacement therapy that mimics the diurnal variation in the plasma cortisol profile.ObjectiveTo determine single-dose plasma pharmacokinetics and dose-proportionality of oral 5 and 20 mg dual-release hydrocortisone tablets in healthy volunteers. In addition, the effect of food intake was investigated for the 20 mg dose.DesignA randomised, controlled, two-way cross-over, double-blind, phase I study of oral hydrocortisone (modified (dual) release; 5 and 20 mg) with an open food-interaction arm.MethodsThe single dose pharmacokinetic studies were performed with betamethasone suppression. The two first study days were blinded and randomised between morning administration of 5 and 20 mg tablet in a fasting state. The third day was open with a 20 mg tablet taken 30 min after a high-calorie, high-fat meal. The plasma samples were assayed using both a validated LC–MS/MS and an immunoassay. The plasma pharmacokinetic variables were calculated using non-compartmental data analysis.ResultsThe time to reach a clinically significant plasma concentration of cortisol (>200 nmol/l) was within 20 min and a mean peak of 431 (s.d. 126) nmol/l was obtained within 50 min after administration of the 20 mg tablet. Plasma cortisol levels remained above 200 nmol/l for around 6 h thereafter and all plasma concentrations 18–24 h after intake were below 50 nmol/l. In the fed state the time to reach 200 nmol/l was delayed by 28 and 9 min based on LC–MS/MS and immunoassay, respectively. The 5 and 20 mg tablets produced an increase in plasma exposure of cortisol that was not fully dose proportional.ConclusionThe dual release hydrocortisone tablet with once-daily administration produced a diurnal plasma cortisol profile mimicking the physiological serum cortisol profile.

scholarly journals Soluble Ecto-5′-nucleotidase (5′-NT), Alkaline Phosphatase, and Adenosine Deaminase (ADA1) Activities in Neonatal Blood Favor Elevated Extracellular Adenosine

2013 ◽  
Vol 288 (38) ◽  
pp. 27315-27326 ◽  
Author(s):  
Matthew Pettengill ◽  
Simon Robson ◽  
Megan Tresenriter ◽  
José Luis Millán ◽  
Anny Usheva ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Adenosine Deaminase ◽  
Whole Blood ◽  
Cell Function ◽  
Immune Cell ◽  
Expression Patterns ◽  
Plasma Concentrations ◽  
Metabolizing Enzymes ◽  
Extracellular Adenosine ◽  
Neonatal Blood

Extracellular adenosine, a key regulator of physiology and immune cell function that is found at elevated levels in neonatal blood, is generated by phosphohydrolysis of adenine nucleotides released from cells and catabolized by deamination to inosine. Generation of adenosine monophosphate (AMP) in blood is driven by cell-associated enzymes, whereas conversion of AMP to adenosine is largely mediated by soluble enzymes. The identities of the enzymes responsible for these activities in whole blood of neonates have been defined in this study and contrasted to adult blood. We demonstrate that soluble 5′-nucleotidase (5′-NT) and alkaline phosphatase (AP) mediate conversion of AMP to adenosine, whereas soluble adenosine deaminase (ADA) catabolizes adenosine to inosine. Newborn blood plasma demonstrates substantially higher adenosine-generating 5′-NT and AP activity and lower adenosine-metabolizing ADA activity than adult plasma. In addition to a role in soluble purine metabolism, abundant AP expressed on the surface of circulating neonatal neutrophils is the dominant AMPase on these cells. Plasma samples from infant observational cohorts reveal a relative plasma ADA deficiency at birth, followed by a gradual maturation of plasma ADA through infancy. The robust adenosine-generating capacity of neonates appears functionally relevant because supplementation with AMP inhibited whereas selective pharmacologic inhibition of 5′-NT enhanced Toll-like receptor-mediated TNF-α production in neonatal whole blood. Overall, we have characterized previously unrecognized age-dependent expression patterns of plasma purine-metabolizing enzymes that result in elevated plasma concentrations of anti-inflammatory adenosine in newborns. Targeted manipulation of purine-metabolizing enzymes may benefit this vulnerable population.

scholarly journals Monitoring DOACs with a Novel Dielectric Microsensor: A Clinical Study

2020 ◽  
Author(s):  
Debnath Maji ◽  
Aman Opneja ◽  
Michael A. Suster ◽  
Kara L. Bane ◽  
Brigid M. Wilson ◽  
...  
Keyword(s):  
Whole Blood ◽  
Point Of Care ◽  
Oral Anticoagulants ◽  
Characteristic Curve ◽  
Direct Oral Anticoagulants ◽  
Unmet Need ◽  
Area Under The Curve ◽  
High Sensitivity ◽  
Diagnostic Study ◽  
Coagulation Tests

Abstract Background There are acute settings where assessing the anticoagulant effect of direct oral anticoagulants (DOACs) can be useful. Due to variability among routine coagulation tests, there is an unmet need for an assay that detects DOAC effects within minutes in the laboratory or at the point of care. Methods We developed a novel dielectric microsensor, termed ClotChip, and previously showed that the time to reach peak permittivity (T peak) is a sensitive parameter of coagulation function. We conducted a prospective, single-center, pilot study to determine its clinical utility at detecting DOAC anticoagulant effects in whole blood. Results We accrued 154 individuals: 50 healthy volunteers, 49 rivaroxaban patients, 47 apixaban, and 8 dabigatran patients. Blood samples underwent ClotChip measurements and plasma coagulation tests. Control mean T peak was 428 seconds (95% confidence interval [CI]: 401–455 seconds). For rivaroxaban, mean T peak was 592 seconds (95% CI: 550–634 seconds). A receiver operating characteristic curve showed that the area under the curve (AUC) predicting rivaroxaban using T peak was 0.83 (95% CI: 0.75–0.91, p < 0.01). For apixaban, mean T peak was 594 seconds (95% CI: 548–639 seconds); AUC was 0.82 (95% CI: 0.73–0.91, p < 0.01). For dabigatran, mean T peak was 894 seconds (95% CI: 701–1,086 seconds); AUC was 1 (p < 0.01). Specificity for all DOACs was 88%; sensitivity ranged from 72 to 100%. Conclusion This diagnostic study using samples from “real-world” DOAC patients supports that ClotChip exhibits high sensitivity at detecting DOAC anticoagulant effects in a disposable portable platform, using a miniscule amount of whole blood (<10 µL).

Sign in / Sign up

Export Citation Format

Share Document