Topic
Cmin
About: Cmin is a research topic. Over the lifetime, 932 publications have been published within this topic receiving 18846 citations.
Papers published on a yearly basis
Papers
TL;DR: Oral L-citrulline supplementation raises plasma L-arginine concentration and augments NO-dependent signalling in a dose-dependent manner, and a correlation between the increase of arginine/ADMA ratio and improvement of FMD is revealed.
Abstract: WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
• L-Arginine is a semiessential amino acid that is converted to nitric oxide (NO) by NO synthase (NOS).
• NO improves endothelial function by elevating cyclic guanosine monophosphate.
• However, oral L-arginine treatment in humans is hampered by extensive metabolism.
WHAT THIS STUDY ADDS
• Oral L-citrulline supplementation raises plasma L-arginine concentration and augments NO-dependent signalling in a dose-dependent manner.
• L-Citrulline may thus be an alternative to L-arginine in patients with impaired NOS activity.
AIMS
Oral L-arginine supplementation has been used in several studies to improve endothelium-dependent, nitric oxide (NO)-mediated vasodilation. L-Arginine treatment is hampered by extensive presystemic elimination due to intestinal arginase activity. In contrast, L-citrulline is readily absorbed and at least in part converted to L-arginine. The aim of our study was to assess this metabolic conversion and its subsequent pharmacodynamic effects.
METHODS
In a double-blind, randomized, placebo-controlled cross-over study, 20 healthy volunteers received six different dosing regimes of placebo, citrulline, and arginine. Pharmacokinetic parameters (Cmax, Tmax, Cmin, AUC) were calculated after 1 week of oral supplementation. The ratio of plasma L-arginine over asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase (arginine/ADMA ratio), urinary cyclic guanosine monophosphate (cGMP) and nitrate excretion rates, and flow-mediated vasodilation (FMD) was measured to assess pharmacodynamic effects.
RESULTS
L-Citrulline dose-dependently increased AUC and Cmax of plasma L-arginine concentration more effectively than L-arginine (P < 0.01). The highest dose of citrulline (3 g bid) increased the Cmin of plasma L-arginine and improved the L-arginine/ADMA ratio from 186 ± 8 (baseline) to 278 ± 14 [P < 0.01, 95% confidence interval (CI) 66, 121]. Moreover, urinary nitrate and cGMP were increased from 92 ± 10 to 125 ± 15 µmol mmol−1 creatinine (P = 0.01, 95% CI 8, 58) and from 38 ± 3.3 to 50 ± 6.7 nmol mmol−1 creatinine (P = 0.04, 95% CI 0.4, 24), respectively. No treatment improved FMD over baseline. However, pooled analysis of all FMD data revealed a correlation between the increase of arginine/ADMA ratio and improvement of FMD.
CONCLUSION
Our data show for the first time that oral L-citrulline supplementation raises plasma L-arginine concentration and augments NO-dependent signalling in a dose-dependent manner.
478 citations
TL;DR: In patients with advanced GIST, IM trough levels at SS were associated with clinical benefit, and patients with IM C(min) below 1,100 ng/mL showed a shorter TTP and lower rate of clinical benefit (OOBR).
Abstract: Purpose To study the pharmacokinetics (PK) of imatinib (IM) in patients with advanced GI stromal tumors (GISTs) treated in a randomized phase II study and to explore the potential relationship between IM plasma levels and long-term clinical outcomes. Patients and Methods Patients were randomly assigned to receive IM at 400 mg versus 600 mg daily. IM plasma levels were analyzed in a subset of patients (n = 73) for whom PK data on day 1 and at steady-state (SS, day 29) were available. IM PK was evaluated using a population PK approach. The relationship between IM plasma exposure and clinical outcome was explored by grouping patients into quartiles according to IM trough concentration (Cmin). The clinical outcome parameters evaluated include overall objective benefit rate (OOBR; complete response plus partial response plus stable disease) time to progression (TTP), and KIT genotyping. Results IM PK exposure showed a high inter-patient variability, and clinical outcomes were correlated with IM trough levels a...
413 citations
TL;DR: This analysis demonstrated that a daptomycin C(min) 24.3 mg/L was associated with an increased probability of a CPK elevation, and Stratified Kaplan-Meier analysis and Cox proportional hazards regression demonstrated C(Min) to be a significant predictor of time to aCPK elevation.
Abstract: Background. The objective of this analysis was to evaluate the relationship between daptomycin exposure and the probability of an elevation in the creatine phosphokinase (CPK) level (hereafter, “CPK elevation”) in patients with Staphylococcus aureus bacteremia with or without infective endocarditis. Methods. Phase 3 data for patients with S. aureus bacteremia, with or without infective endocarditis, who received intravenous daptomycin (6 mg/kg daily) and in whom pharmacokinetic data were collected were evaluated. On the basis of univariate logistic regression, the relationship between Bayesian post hoc exposure estimates and the probability of a CPK elevation was evaluated. Time to CPK elevation was examined with Kaplan-Meier analysis and Cox proportional hazards regression. Results. Significant relationships between the minimum concentration of drug (Cmin) and area under the plasma concentration time curve and probability of CPK elevation were observed in 108 evaluable patients. Of the 108 patients evaluated, 6 (5.56%) demonstrated a defined CPK elevation, regardless of treatment relationship. Cmin (breakpoint of 24.3 mg/L) was most significantly associated with CPK elevation (P p .002). The probabilities of a CPK elevation with a Cmin 24.3 mg/L and !24.3 mg/L were 0.5 and 0.029, respectively. Increases in Cmin, evaluated as a continuous variable, were also significantly associated with CPK elevation (P p .01). Stratified Kaplan-Meier analysis and Cox proportional hazards regression demonstrated Cmin to be a significant predictor of time to a CPK elevation (P .003). The probability of a CPK elevation was 0 and 0.01 after 7 days of treatment in patients with a Cmin 24.3 mg/L or !24.3 mg/L, respectively. After 14 days, the probabilities were 0.5 and 0.025, respectively. Conclusions. This analysis demonstrated that a daptomycin Cmin 24.3 mg/L was associated with an increased probability of a CPK elevation. Clinical trials registration. Clinical trials.gov NCT00093067.
262 citations
TL;DR: These studies in renal transplant patients suggest that tacrolimus in combination with MMF may result in a greater degree of immunosuppression than may be anticipated.
236 citations
TL;DR: Maintenance over time of C(min) between 2 and 7mg/L and/or of AUC₂₄ between 160 and 300 mg/L · h may be helpful in improving safety outcomes while retaining appropriate efficacy in adult patients receiving prolonged linezolid treatment.
Abstract: Methods: We performed a retrospective study of patients who had trough (Cmin) and peak (Cmax) plasma levels measured during prolonged linezolid treatment. Dosage adjustments were performed when Cmin ≥10 mg/L and/or AUC24 ≥400 mg/L.h. Patients were divided into two subgroups according to the absence or presence of co-treatment with rifampicin (the linezolid group and the linezolid +rifampicin group, respectively). Data on demographic characteristics, disease, microbiology and haematochemical parameters were collected and outcomes in relation to drug exposure were compared between groups. Results: A total of 45 patients were included. Dosage adjustments were needed in 40% versus 0% of patients in the linezolid group (n¼35) versus the linezolid+rifampicin group (n¼10), respectively. Patients in the linezolid group had either significantly higher Cmin [3.71 mg/L (1.43‐6.38) versus 1.37 mg/L (0.67‐2.55), P,0.001] or AUC24 [212.77 mg/L.h (166.67‐278.42) versus 123.33 mg/L.h (97.36‐187.94), P,0.001]. Thrombocytopenia appeared in 51.4% versus 0% of cases in the linezolid group versus the linezolid+rifampicin group, respectively. In 33.3% of those patients who were experiencing thrombocytopenia, therapeutic drug monitoring (TDM)guided dosage reductions allowed recovery from toxicity and prosecution of therapy with good outcome. A logistic regression model for thrombocytopenia estimated a probability of 50% in the presence of Cmin of 6.53 mg/L and/or of AUC24 of 280.74 mg/L.h. Conclusions: MaintenanceovertimeofCminbetween2and7 mg/Land/orofAUC24between160and300 mg/L.h may be helpful in improving safety outcomes while retaining appropriate efficacy in adult patients receiving prolonged linezolid treatment.
233 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2025 | 7 |
| 2024 | 22 |
| 2023 | 56 |
| 2022 | 101 |
| 2021 | 68 |
| 2020 | 63 |