scholarly journals Pharmacokinetics of Lidocaine, Bupivacaine, and Levobupivacaine in Plasma and Brain in Awake Rats

2010 ◽  
Vol 112 (6) ◽  
pp. 1396-1403 ◽  
Author(s):  
Yuko Ikeda ◽  
Yutaka Oda ◽  
Taketo Nakamura ◽  
Ryota Takahashi ◽  
Wakako Miyake ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Extracellular Fluid ◽  
Calibration Method ◽  
Pharmacokinetic Parameters ◽  
Total Plasma ◽  
Unbound Fraction ◽  
Brain Concentration ◽  
Total Brain ◽  
Fluid Concentration ◽  
Total Plasma Concentration

Background We have compared the pharmacokinetics and brain distribution of lidocaine, racemic bupivacaine (bupivacaine), and levobupivacaine in awake, spontaneously breathing rats. Methods Lidocaine (0.5 mg x kg x min), bupivacaine (0.1 mg x kg x min), or levobupivacaine (0.1 mg x kg x min) was continuously administered to rats for 2 h (n = 12, each anesthetic). Blood samples and cerebral dialysate were collected during infusion and for 2 h after termination of infusion. Concentrations of anesthetics in the cerebral extracellular fluid were measured by microdialysis using the retrodialysis calibration method. Tissue-to-plasma partition coefficients calculated from the total (protein-bound and unbound) and unbound concentrations in plasma and brain as well as pharmacokinetic parameters in plasma and cerebral extracellular fluid were compared among the three anesthetics. Results There were no differences in plasma total or unbound concentrations between bupivacaine and levobupivacaine. Concentrations of bupivacaine in the cerebral extracellular fluid were significantly higher than levobupivacaine (P < 0.001). Despite no differences in the ratio of total brain concentration to total plasma concentration among the three anesthetics, the ratio of cerebral extracellular fluid concentration to plasma unbound fraction of bupivacaine was significantly higher than lidocaine and levobupivacaine (0.58 +/- 0.09, 0.47 +/- 0.18, and 0.40 +/- 0.09, respectively; P = 0.03 and 0.003, respectively). Conclusions Although the ratio of total brain concentration to total plasma concentrations of lidocaine, bupivacaine, and levobupivacaine was similar, concentration ratio of bupivacaine in the cerebral extracellular fluid to plasma unbound fraction was significantly higher than lidocaine and levobupivacaine.

Pharmacokinetics and Analgesic Effect of Ropivacaine during Continuous Epidural Infusion for Postoperative Pain Relief

1996 ◽  
Vol 84 (4) ◽  
pp. 834-842. ◽  
Author(s):  
Carl-Johan Erichsen ◽  
Jan Sjovall ◽  
Henrik Kehlet ◽  
Cecilia Hedlund ◽  
Torbjorn Arvidsson
Keyword(s):  
Postoperative Pain ◽  
Pain Relief ◽  
Visual Analog Scale ◽  
Plasma Concentrations ◽  
Epidural Infusion ◽  
Postoperative Pain Relief ◽  
Total Plasma ◽  
Analog Scale ◽  
Continuous Epidural Infusion ◽  
Unbound Fraction

Background The pharmacokinetics and clinical efficacy of ropivacaine (2.5 mg/ml) during a 24-h continuous epidural infusion for postoperative pain relief in 20 patients scheduled for abdominal hysterectomy were characterized using an open-label, increasing-dose design. Methods Through an epidural catheter inserted at T10-T12, a test dose of 7.5 mg ropivacaine was given 3 min before a bolus dose of 42.5 mg and immediately followed by a 24-h continuous epidural infusion with either 10 or 20 mg/h. Peripheral venous plasma samples were collected up to 48 h after infusion, and urinary excretion was followed up to the end of infusion. Postoperative pain at rest, on coughing, and at mobilization was assessed by means of a visual analog scale 2,4,6,8,12, and 24 h after the end of surgery. Sensory (pinprick) and motor block (modified Bromage scale) were assessed at the same intervals. Results The total plasma concentrations of ropivacaine increased markedly and consistently during the 24-h epidural infusion, in contrast to stable unbound concentrations. Both total and unbound plasma concentrations at the end of infusion were proportional to the total dose, although only the latter was proportional to the infusion rate. The total and unbound plasma clearance was independent of dose. Total mean clearance decreased on average by 21% (P < 0.001) during the last 12 h of epidural infusion, i.e., from 539 +/- 191 ml/min to 418 +/- 138 ml/min, indicating time-dependent kinetics. The unbound clearance also varied between estimates after 8 h of infusion and the end of treatment, i.e., a 5.3% decrease from 10.4 +/- 5.3 l/min to 9.5 +/- 3.9 l/min (P < 0.05). The unbound fraction of ropivacaine in plasma decreased during treatment, and this was related to the increase in alpha1-acid glycoprotein concentration. Pain was generally well controlled, and median visual analog scale scores during mobilization were less than 30 mm in patients receiving ropivacaine at 20 mg/h. Conclusions The pharmacokinetics of ropivacaine were independent of dose, but total clearance decreased with time over 24 h. The consistent increase in total plasma concentration during the postoperative epidural infusion contrasted to much less variation in the unbound plasma concentrations of ropivacaine.

Repeated determination of moxifloxacin concentrations in interstitial space fluid of muscle and subcutis in septic patients

2019 ◽  
Vol 74 (9) ◽  
pp. 2681-2689 ◽  
Author(s):  
Hartmuth Nowak ◽  
Caroline Weidemann ◽  
Stefan Martini ◽  
Zoe Anne Oesterreicher ◽  
Christoph Dorn ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Antimicrobial Treatment ◽  
Interstitial Space ◽  
Pharmacokinetic Parameters ◽  
Tissue Concentrations ◽  
Unbound Fraction ◽  
Daily Dose ◽  
Lower Protein ◽  
Exposure Levels

Abstract Background For an effective antimicrobial treatment, it is crucial that antibiotics reach sufficient concentrations in plasma and tissue. Currently no data exist regarding moxifloxacin plasma concentrations and exposure levels in tissue under septic conditions. Objectives To determine the pharmacokinetics of moxifloxacin in plasma and interstitial space fluid over a prolonged period. Patients and methods Ten septic patients were treated with 400 mg of moxifloxacin once a day; on days 1, 3 and 5 of treatment plasma sampling and microdialysis in the subcutis and muscle of the upper thigh were performed to determine concentrations of moxifloxacin in different compartments. This trial was registered in the German Clinical Trials Register (DRKS, register number DRKS00012985). Results Mean unbound fraction of moxifloxacin in plasma was 85.5±3.4%. On day 1, Cmax in subcutis and muscle was 2.8±1.8 and 2.5±1.3 mg/L, respectively, AUC was 24.8±15.1 and 21.3±10.5 mg·h/L, respectively, and fAUC0–24/MIC was 100.9±62.9 and 86.5±38.3 h, respectively. Cmax for unbound moxifloxacin in plasma was 3.5±0.9 mg/L, AUC was 23.5±7.5 mg·h/L and fAUC0–24/MIC was 91.6±24.8 h. Key pharmacokinetic parameters on days 3 and 5 showed no significant differences. Clearance was higher than in healthy adults, but tissue concentrations were comparable, most likely due to a lower protein binding. Conclusions Surprisingly, the first dose already achieved exposure comparable to steady-state conditions. The approved daily dose of 400 mg was adequate in our patient population. Thus, it seems that in septic patients a loading dose on the first day of treatment with moxifloxacin is not required.

scholarly journals Plasma and Intrapulmonary Concentrations of Cefepime and Zidebactam following Intravenous Administration of WCK 5222 to Healthy Adult Subjects

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Keith A. Rodvold ◽  
Mark H. Gotfried ◽  
Rakesh Chugh ◽  
Mugdha Gupta ◽  
Anasuya Patel ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Healthy Adult ◽  
Plasma Concentrations ◽  
Sampling Time ◽  
Pharmacokinetic Parameters ◽  
The Novel ◽  
Total Plasma ◽  
Dosing Regimen ◽  
Time Curve ◽  
Epithelial Lining Fluid

ABSTRACTWCK 5222 is a combination of cefepime and the novel β-lactam enhancer zidebactam being developed for the treatment of serious Gram-negative bacterial infections. The objective of this study was to compare plasma (total), epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of cefepime and zidebactam in healthy adult subjects. The WCK 5222 dosing regimen was 2 g cefepime/1 g zidebactam administered as a 1-h intravenous infusion every 8 h for a total of 7 doses. Subjects were assigned to one bronchoalveolar lavage (BAL) sampling time at 0.5, 1.25, 3, 6, 8, or 10 h after the seventh dose. Noncompartmental pharmacokinetic parameters were determined from serial plasma concentrations collected over 8-hour and 10-hour intervals following the first and seventh doses, respectively. Penetration ratios were calculated from the area under the plasma concentration-time curve from 0 to 8 h (AUC0–8) for plasma, ELF, and AM using mean and median concentrations at each BAL sampling time. The plasma maximum concentration of drug (Cmax) and AUC values of cefepime and zidebactam increased by 8% to 9% after the seventh versus the first dose of WCK 5222. The respective AUC0–8values based on mean concentrations of cefepime and zidebactam in ELF were 127.9 and 52.0 mg · h/liter, and 87.9 and 13.2 mg · h/liter in AM. The ELF to total plasma penetration ratios of cefepime and zidebactam based on mean AUC0–8values were 0.39 and 0.38, respectively. The AM to total plasma ratios were 0.27 and 0.10, respectively. The observed plasma, ELF, and AM concentrations of cefepime and zidebactam support studies of WCK 5222 for treatment of pneumonia caused by susceptible pathogens.

Quantitative Changes in Plasma Amino Acids Induced by Oral Contraceptives

1971 ◽  
Vol 41 (4) ◽  
pp. 301-307 ◽  
Author(s):  
I. L. Craft ◽  
T. J. Peters
Keyword(s):  
Amino Acids ◽  
Oral Contraceptives ◽  
Plasma Concentrations ◽  
Plasma Amino Acids ◽  
Total Plasma ◽  
Hormone Production ◽  
Contraceptive Pills ◽  
High Concentrations ◽  
Normal Women ◽  
Quantitative Changes

1. Plasma amino acids have been determined in healthy untreated women and in those receiving synthetic steroids to suppress ovulation. Both groups were studied early in the cycle when endogenous sex hormone production is low, and again later in the same cycle, when endogenous or exogenous hormones are at high concentrations respectively. 2. In normal women there is a significant decrease in plasma concentrations of serine, glutamate and ornithine, and of total amino acids in the second half of the cycle. 3. At this time those taking oral contraceptives have significant decreases in plasma concentrations of proline, glycine, alanine, valine, leucine and tyrosine, and of total plasma amino acids. In addition plasma glutamate, glycine, isoleucine and tyrosine concentrations are significantly lower than in normal women. 4. In the interval between completing one course of contraceptive pills and commencing the next, total plasma amino acid concentration reverts to normal, but a significant decrease in plasma glycine concentration persists. 5. It is suggested that these changes are due to the influence of endogenous and exogenous sex hormones respectively.

scholarly journals Pharmacokinetics and Tissue Penetration of Ceftolozane-Tazobactam in Diabetic Patients with Lower Limb Infections and Healthy Adult Volunteers

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Marguerite L. Monogue ◽  
Sean M. Stainton ◽  
Arlinda Baummer-Carr ◽  
Ashley K. Shepard ◽  
James F. Nugent ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Subcutaneous Tissue ◽  
Free Drug ◽  
Free Time ◽  
Pharmacokinetic Parameters ◽  
Diabetic Patients ◽  
Total Plasma ◽  
Tissue Penetration ◽  
Gram Negative ◽  
Time Zero

ABSTRACT Ceftolozane-tazobactam displays potent activity against Gram-negative bacteria that can cause diabetic foot infections (DFI), making it an attractive treatment option when few alternatives exist. The pharmacokinetics and tissue penetration of ceftolozane-tazobactam at 1.5 g every 8 h (q8h) in patients (n = 10) with DFI were compared with those in healthy volunteers (n = 6) using in vivo microdialysis. In the patient participants, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: maximum concentration (C max), 55.2 μg/ml (range, 40.9 to 169.3 μg/ml); half-life (t 1/2), 3.5 h (range, 2.3 to 4.7 h); and area under the concentration-time curve (AUC) from time zero to 8 h (AUC0–8), 191.6 μg · h/ml (range, 147.1 to 286.6 μg · h/ml). The median AUC for tissue (AUCtissue; where AUCtissue was the AUC0–8 for tissue for ceftolozane)/AUC for plasma for each antibiotic corrected by the fraction of free drug (fAUCplasma) was 0.75 (range, 0.35 to 1.00), resulting in a mean free time above 4 μg/ml (the Pseudomonas aeruginosa susceptibility breakpoint) in tissue of 99.8% (range, 87.5 to 100%). In the patient participants, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows: C max, 14.2 μg/ml (range, 7.6 to 64.2 μg/ml); t 1/2, 2.0 h (range, 0.7 to 2.4 h); and AUC0–8, 27.1 μg · h/ml (range, 15.0 to 70.0 μg · h/ml). The AUCtissue (where AUCtissue was the AUC from time zero to the time of the last measureable concentration in tissue for tazobactam)/fAUCplasma for tazobactam was 1.18 (range, 0.54 to 1.44). In the healthy volunteers, the median values of the pharmacokinetic parameters for ceftolozane in total plasma were as follows: C max, 91.5 μg/ml (range, 65.7 to 110.7 μg/ml); t 1/2, 1.9 h (range, 1.6 to 2.1 h); and AUC0–8, 191.3 μg · h/ml (range, 118.1 to 274.3 μg · h/ml). The median AUCtissue/fAUCplasma was 0.87 (range, 0.54 to 2.20), resulting in a mean free time above 4 μg/ml in tissue of 93.8% (range, 87.5 to 100%). In the healthy volunteers, the median values of the pharmacokinetic parameters for tazobactam in total plasma were as follows: C max, 17.5 μg/ml (range, 15.4 to 27.3 μg/ml); t 1/2, 0.7 h (range, 0.6 to 0.8 h); and AUC0–8, 22.2 μg · h/ml (range, 19.2 to 36.4 μg · h/ml). The AUCtissue/fAUCplasma for tazobactam was 0.85 (range, 0.63 to 2.10). Both ceftolozane and tazobactam penetrated into subcutaneous tissue with exposures similar to those of free drug in plasma in both patients with DFI and healthy volunteers. These data suggest that ceftolozane-tazobactam at 1.5 g q8h can achieve the optimal exposure with activity against susceptible Gram-negative pathogens in the tissue of patients with DFI. (This study has been registered at ClinicalTrials.gov under identifier NCT02620774.)

scholarly journals A Pilot Study of Immune Activation and Rifampin Absorption in HIV-Infected Patients without Tuberculosis Infection: A Short Report

2017 ◽  
Vol 2017 ◽  
pp. 1-7
Author(s):  
Christopher Vinnard ◽  
Isabel Manley ◽  
Brittney Scott ◽  
Mariana Bernui ◽  
Joella Adams ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Pilot Study ◽  
Bacterial Translocation ◽  
Immune Activation ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Short Report ◽  
Hiv Viral Load ◽  
Time Curve ◽  
Immunodeficiency Virus

Background. Rifampin malabsorption is frequently observed in tuberculosis patients coinfected with human immunodeficiency virus (HIV) but cannot be predicted by patient factors such as CD4+ T cell count or HIV viral load. Methods. We sought to describe the relationship between HIV-associated immune activation, measures of gut absorptive capacity and permeability, and rifampin pharmacokinetic parameters in a pilot study of 6 HIV-infected, tuberculosis-uninfected patients who were naïve to antiretroviral therapy. Results. The median rifampin area under the concentration-versus-time curve during the 8-hour observation period was 42.8 mg·hr/L (range: 21.2 to 57.6), with a median peak concentration of 10.1 mg/L (range: 5.3 to 12.5). We observed delayed rifampin absorption, with a time to maximum concentration greater than 2 hours, in 2 of 6 participants. There was a trend towards increased plasma concentrations of sCD14, a marker of monocyte activation in response to bacterial translocation, among participants with delayed rifampin absorption compared to participants with rapid absorption (p=0.06). Conclusions. Delayed rifampin absorption may be associated with elevated markers of bacterial translocation among HIV-infected individuals naïve to antiretroviral therapy. This trial is registered with NCT01845298.

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 Ceramide Levels and Covid-19 Respiratory Distress, a Causal Relationship

2021 ◽  
Author(s):  
Mehran Khodadoust
Keyword(s):  
Respiratory Distress ◽  
Causal Relationship ◽  
Fold Increase ◽  
Plasma Samples ◽  
Total Plasma ◽  
Lipidomic Analysis ◽  
Distress Symptoms ◽  
Concentration Dependency ◽  
Ceramide Synthesis ◽  
Total Plasma Concentration

Abstract A causal relationship between plasma ceramide concentration and Covid-19 patients with respiratory distress symptoms is presented. In this study, plasma samples of 52 individuals infected with Covid-19 were utilized in a lipidomic analysis. Lipids belonging to ceramide class exhibited a 400-fold increase in total plasma concentration in infected patients. Further analysis lead to demonstration of concentration dependency, for severe Covid-19 respiratory symptoms, in a subclass of ceramides. The subclasses Cer(d18:0/24:1), Cer(d18:1/24:1), and Cer(d18:1/22:0) are shown to be increased by 48, 40, and 33–folds respectively in infected plasma samples, and to 116, 91 and 50-folds in plasma samples with respiratory distress. Hence, monitoring of plasma ceramide concentration, targeting ceramide synthesis, its salvage and its regulatory mechanisms, are validated approach towards enhancing survival from Covid-19 respiratory distress.

Concentration–Effect Relation of Succinylcholine Chloride during Propofol Anesthesia

2002 ◽  
Vol 97 (5) ◽  
pp. 1082-1092 ◽  
Author(s):  
Julie J. Roy ◽  
François Donati ◽  
Daniel Boismenu ◽  
France Varin
Keyword(s):  
Rate Constant ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Quantitative Model ◽  
Concentration Effect ◽  
Pharmacokinetic Parameters ◽  
Effect Compartment ◽  
Duration Of Action ◽  
Arterial Blood ◽  
Effect Relation

Background The pharmacokinetics and pharmacodynamics of succinylcholine were studied simultaneously in anesthetized patients to understand why the drug has a rapid onset and short duration of action. A quantitative model describing the concentration-effect relation of succinylcholine was proposed. The correlation between hydrolysis in plasma and elimination was also examined. Methods Before induction of anesthesia, blood was drawn for analysis in seven adults. Anesthesia was induced with propofol and remifentanil. Single twitch stimulation was applied at the ulnar nerve every 10 s, and the force of contraction of the adductor pollicis was measured. Arterial blood was drawn frequently after succinylcholine injection to characterize the front-end kinetics. Plasma concentrations were measured by mass spectrometry, and pharmacokinetic parameters were derived using compartmental and noncompartmental approaches. Pharmacokinetic-pharmacodynamic relations were estimated. Results The mean degradation rate constant in plasma (1.07 +/- 0.49 min(-1)) was not different from the elimination rate constant (0.97 +/- 0.30 min(-1)), and an excellent correlation (r2 = 0.94) was observed. Total body clearance derived using noncompartmental (37 +/- 7 ml x min(-1) x kg(-1)) and compartmental (37 +/- 9 ml x min(-1) x kg(-1)) approaches were similar. The plasma-effect compartment equilibration rate constant (k(eo)) was 0.058 +/- 0.026 min(-1), and the effect compartment concentration at 50% block was 734 +/- 211 ng/ml. Conclusion Succinylcholine is a low-potency drug with a very fast clearance that equilibrates relatively slowly with the effect compartment. Its disappearance is greatly accountable by a rapid hydrolysis in plasma.

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