scholarly journals Relationship Between the Free and Total Methotrexate Plasma Concentration in Children and Application to Predict the Toxicity of HD-MTX

2021 ◽  
Vol 12 ◽  
Author(s):  
Wei-Chong Dong ◽  
Jia-Liang Guo ◽  
Xi-Kun Wu ◽  
Meng-Qiang Zhao ◽  
Hao-Ran Li ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
High Plasma ◽  
Therapeutic Drug ◽  
High Dose ◽  
Plasma Samples ◽  
Simple Method ◽  
Drug Molecules ◽  
Validation Parameters ◽  
Toxic Reactions

High-dose methotrexate (HD-MTX) can be highly effective as well as extremely toxic. Many drug molecules can bind to plasma proteins to different extents in vivo, whereas only the free drug can reach the site of action to exert a pharmacological effect and cause toxicity. However, free MTX concentrations in plasma have not been reported. Traditional analyses of free drugs are both cumbersome and inaccurate. We collected 92 plasma samples from 52 children diagnosed with ALL or NHL or other lymphomas that were treated with HD-MTX. The hollow fiber centrifugal ultrafiltration (HFCF-UF) was used to prepare plasma samples for analysis of the free MTX concentration. Protein precipitation was employed to measure the total MTX concentration. The HFCF-UF is a simple method involving a step of ordinary centrifugation; the validation parameters for the methodological results were satisfactory and fell within the acceptance criteria. A linearity coefficient r2 of 0.910 was obtained for the correlation between the free and total MTX plasma concentrations in 92 plasma samples. However, the free and total MTX concentrations was only weakly correlated in 16 clinical plasma specimens with total MTX concentrations >2 μmol L−1 (r2 = 0.760). Both the free and total MTX concentrations at 42 h were negatively correlated with the creatinine clearance (CCr) level (P = 0.023, r = −0.236 for total MTX and P = 0.020, r = −0.241for free MTX, respectively). The free MTX concentration could not be accurately estimated from the total MTX concentration for patients with high MTX levels which are conditions under which toxic reactions are more likely to occur. High plasma MTX levels could become a predictor of the occurrence of MTX nephrotoxicity to draw people's attention. The proposed HFCF-UF method is a simple and accurate way to evaluate efficacy and toxicity in clinical therapeutic drug monitoring.

Renal handling of phenol red. IV. Tubular localization in rabbit and rat kidney in vivo

1980 ◽  
Vol 238 (3) ◽  
pp. F159-F165
Author(s):  
M. I. Sheikh ◽  
J. V. Moller
Keyword(s):  
Rat Kidney ◽  
Plasma Concentrations ◽  
High Plasma ◽  
Tubular Secretion ◽  
Rabbit Kidney ◽  
High Dose ◽  
Phenol Red ◽  
Renal Handling ◽  
Pars Recta

In the rabbit kidney accumulation of phenol red in cortex tissue is directly related to phenol red excretion. In histological preparations of rabbit cortex the major part of phenol red is localized to the pars recta of proximal tubules at low plasma concentrations of dye. The extra uptake of dye by the pars recta is abolished by administration of a high dose of probenecid and also by high plasma dye concentrations, when dye secretion is low relative to tubular reabsorption. Tissue accumulation of phenol red in the rat exhibits features similar to those in the rabbit. However, extra dye uptake in the pars recta is maintained after administration of probenecid, and disappears after intravenous injection of phenol red during ureteral occlusion to impede access of dye from tubule fluid to the luminal membrane. It is concluded that in the rabbit phenol red uptake by the pars recta probably is due to tubular secretion across the peritubular membrane, whereas in the rat extra uptake of dye by this segment is consistent with uptake at the luminal cell membrane.

scholarly journals Hyaluronic Acid-Coated MTX-PEI Nanoparticles for Targeted Rheumatoid Arthritis Therapy

Crystals ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 321
Author(s):  
Shenghui Zhong ◽  
Peng Liu ◽  
Jinsong Ding ◽  
Wenhu Zhou
Keyword(s):  
Rheumatoid Arthritis ◽  
Hyaluronic Acid ◽  
Targeted Delivery ◽  
High Dose ◽  
One Pot ◽  
Inflammatory Site ◽  
Pei Nanoparticles ◽  
Toxic Reactions

Methotrexate (MTX) is an anchor drug for the treatment of rheumatoid arthritis (RA); however, long-term and high-dose usage of MTX for patients can cause many side effects and toxic reactions. To address these difficulties, selectively delivering MTX to the inflammatory site of a joint is promising in the treatment of RA. In this study, we prepared MTX-PEI@HA nanoparticles (NPs), composed of hyaluronic acid (HA) as the hydrophilic negative electrical shell, and MTX-linked branched polyethyleneimine (MTX-PEI) NPs as the core. MTX-PEI@HA NPs were prepared in the water phase by a one-pot method. The polymeric NPs were selectively internalized via CD44 receptor-mediated endocytosis in the activated macrophages. In the in vivo mice mode study, treatment with MTX-PEI@HA NPs mitigated inflammatory arthritis with notable safety at a high dose of MTX. We highlight the distinct advantages of aqueous-synthesized NPs coated with HA for arthritis-selective targeted delivery, thus verifying MTX-PEI@HA NPs as a promising MTX-based nanoplatform for treatment of RA.

scholarly journals Validation of an HPLC–MS/MS Method for the Determination of Plasma Ticagrelor and Its Active Metabolite Useful for Research and Clinical Practice

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 278
Author(s):  
Jennifer Lagoutte-Renosi ◽  
Bernard Royer ◽  
Vahideh Rabani ◽  
Siamak Davani
Keyword(s):  
Active Metabolite ◽  
Plasma Concentrations ◽  
Antiplatelet Agent ◽  
High Plasma ◽  
Therapeutic Drug ◽  
Routine Practice ◽  
Daily Routine ◽  
Limit Of Quantification ◽  
Wide Range

Ticagrelor is an antiplatelet agent which is extensively metabolized in an active metabolite: AR-C124910XX. Ticagrelor antagonizes P2Y12 receptors, but recently, this effect on the central nervous system has been linked to the development of dyspnea. Ticagrelor-related dyspnea has been linked to persistently high plasma concentrations of ticagrelor. Therefore, there is a need to develop a simple, rapid, and sensitive method for simultaneous determination of ticagrelor and its active metabolite in human plasma to further investigate the link between concentrations of ticagrelor, its active metabolite, and side effects in routine practice. We present here a new method of quantifying both molecules, suitable for routine practice, validated according to the latest Food and Drug Administration (FDA) guidelines, with a good accuracy and precision (<15% respectively), except for the lower limit of quantification (<20%). We further describe its successful application to plasma samples for a population pharmacokinetics study. The simplicity and rapidity, the wide range of the calibration curve (2–5000 µg/L for ticagrelor and its metabolite), and high throughput make a broad spectrum of applications possible for our method, which can easily be implemented for research, or in daily routine practice such as therapeutic drug monitoring to prevent overdosage and occurrence of adverse events in patients.

Isavuconazole: Case Report and Pharmacokinetic Considerations

Chemotherapy ◽  
2018 ◽  
Vol 63 (5) ◽  
pp. 253-256 ◽  
Author(s):  
Francesco Marchesi ◽  
Corrado Girmenia ◽  
Bianca Maria Goffredo ◽  
Emanuela Salvatorelli ◽  
Atelda Romano ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Plasma Concentrations ◽  
Real Life ◽  
Concomitant Administration ◽  
Invasive Fungal Disease ◽  
High Plasma ◽  
Adult Patients ◽  
Therapeutic Drug ◽  
Hepatic Toxicity ◽  
Maintenance Chemotherapy

Invasive fungal disease (IFD) is one of the major causes of morbidity and mortality in immunocompromised patients. Voriconazole (VCZ) and posaconazole (PCZ) remain the most widely used antifungals for the prophylaxis and treatment of IFD. However, VCZ and PCZ are liable for drug-drug interactions and show a pharmacokinetic variability that requires therapeutic drug monitoring (TDM). Isavuconazole (IVZ) is a newest generation triazole antifungal approved for the treatment of invasive aspergillosis (IA) in adult patients and for the treatment of invasive mucormycosis in adult patients for whom treatment with amphotericin B is inappropriate. In clinical trials, IVZ showed linear pharmacokinetics and little or no evidence for interactions with other drugs. There is only modest evidence on IVZ pharmacokinetics and TDM in real-life settings. Here, we report on IVZ pharmacokinetics in a young adult with Ph chromosome-negative acute lymphoblastic leukemia (ALL) who developed a “probable” IA during induction chemotherapy. The patient was initially treated with VCZ, but she developed a severe hepatic toxicity that was associated to the high plasma levels of VCZ. Therefore, VCZ was discontinued and the patient was switched to IVZ. After a loading dose of IVZ, the patient remained on IVZ for 5 months while also receiving standard maintenance chemotherapy for ALL. At day 65 after the start of IVZ, the patient experienced a significant hepatic toxicity; however, no change in IVZ plasma concentrations was observed in the face of a concomitant administration of many other drugs (cancer drugs, antiemetics, other anti-infectives). Hepatic toxicity resolved after discontinuing maintenance chemotherapy but not IVZ. These results show that (i) IVZ plasma concentrations remained stable throughout and were not affected by concomitant ALL therapy, and (ii) there was no relation between IVZ plasma concentration and hepatic toxicity. Thus, in clinical practice IVZ may not require TDM.

scholarly journals Renin dynamics in adipose tissue: adipose tissue control of local renin concentrations

2009 ◽  
Vol 296 (2) ◽  
pp. E343-E350 ◽  
Author(s):  
Jason D. Fowler ◽  
Stacy B. Krueth ◽  
David A. Bernlohr ◽  
Stephen A. Katz
Keyword(s):  
Adipose Tissue ◽  
Cardiac Tissue ◽  
Plasma Concentrations ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Treated Group ◽  
Rat Plasma ◽  
High Plasma ◽  
Tissue Growth

The renin-angiotensin system (RAS) has been implicated in a variety of adipose tissue functions, including tissue growth, differentiation, metabolism, and inflammation. Although expression of all components necessary for a locally derived adipose tissue RAS has been demonstrated within adipose tissue, independence of local adipose RAS component concentrations from corresponding plasma RAS fluctuations has not been addressed. To analyze this, we varied in vivo rat plasma concentrations of two RAS components, renin and angiotensinogen (AGT), to determine the influence of their plasma concentrations on adipose and cardiac tissue levels in both perfused (plasma removed) and nonperfused samples. Variation of plasma RAS components was accomplished by four treatment groups: normal, DOCA salt, bilateral nephrectomy, and losartan. Adipose and cardiac tissue AGT concentrations correlated positively with plasma values. Perfusion of adipose tissue decreased AGT concentrations by 11.1%, indicating that adipose tissue AGT was in equilibrium with plasma. Cardiac tissue renin levels positively correlated with plasma renin concentration for all treatments. In contrast, adipose tissue renin levels did not correlate with plasma renin, with the exception of extremely high plasma renin concentrations achieved in the losartan-treated group. These results suggest that adipose tissue may control its own local renin concentration independently of plasma renin as a potential mechanism for maintaining a functional local adipose RAS.

scholarly journals Correlation of hair risperidone concentration and serum level among patients with schizophrenia

2019 ◽  
Vol 32 (1) ◽  
pp. e100042 ◽  
Author(s):  
Xiujia Sun ◽  
Lihua Wang ◽  
Fuzhong Yang ◽  
Juanjuan Ren ◽  
Ping Jiang ◽  
...  
Keyword(s):  
Correlation Analysis ◽  
Serum Concentration ◽  
Total Concentration ◽  
Rapid Onset ◽  
High Plasma ◽  
Statistical Correlation ◽  
Therapeutic Drug ◽  
Experimental Basis ◽  
Drug Concentrations

BackgroundRisperidone (RSP) has a rapid onset in vivo, low dosage and high plasma protein binding rate, therefore therapeutic drug monitoring (TDM) is needed to ensure safety in clinical treatment. However, compared with blood, hair is non-invasive, safe, non-infectious and easy to transport and store.AimsThis study aims to investigate the correlations among the drug concentrations of RSP in hair and serum, which provides an experimental basis to explore hair as a novel biomaterial to meet the needs of clinical detection.Methods34 patients with schizophrenia treated with RSP for more than 3 months were enrolled in this study. About 1 cm section of hair near the scalp was taken from the subjects, pretreated and detected by liquid chromatography-mass spectrometry. A correlation analysis was conducted among the drug concentrations in hair, the serum concentrations and the daily dosage. The data were analysed using SPSS 20.0 software.Results There was significant correlation between the hair concentration of RSP (two-tailed test, r=0.440,p=0.009) with the serum concentration of RSP, and the hair concentration of 9-hydroxyrisperidone (9-HR) with the serum concentration of 9-HR had no significant correlation (two-tailed test, r=−0.217,p=0.217); the total concentration of the RSP and 9-HR had no significant correlation between hair and serum (r=0.227,p=0.196). The dosage had no statistically significant correlation with the concentration of RSP in hair (r=0.207,p=0.241), 9-HR in hair (r=−0.194,p=0.271) and the total concentration of RSP and 9-HR in hair (r=0.188,p=0.288). There was no statistical correlation between the dosage and the concentration of RSP in serum (r=−0.059,p=0.741), but significant correlation between the dosage and 9-HR in serum (r=0.581p<0.001) was found, and the correlation between the dosage and the total concentration of the two drugs RSP and 9-HR in serum was also significant (r=0.437,p=0.01).ConclusionThe correlation analysis showed that the concentration of RSP in hair was statistically significant with the serum RSP concentration. In this study, we provided some experimental basis for hair as a new biomaterial to monitor the therapeutic drug concentration.

Absence of negative feedback by oxytocin on release from magnocellular neurones in conscious rats

1992 ◽  
Vol 70 (1) ◽  
pp. 100-105 ◽  
Author(s):  
Savio W. T. Cheng ◽  
William G. North
Keyword(s):  
Negative Feedback ◽  
Plasma Concentrations ◽  
Plasma Osmolality ◽  
High Plasma ◽  
High Dose ◽  
Salt Loading ◽  
Significant Difference ◽  
And Control ◽  
The Relationship ◽  
Oxytocin Neurones

Peripheral administration of vasopressin (VP) was previously shown to exert a negative feedback influence on its own release and on the release of oxytocin (OT). In this study we examined the possible influence that OT has on the function of hypothalamic magnocellular neurones. Oxytocin was administered intraperitoneally and its effects on release from VP neurones and from OT neurones were determined as indexed by plasma concentrations of vasopressin-associated neurophysin ([VP-RNP]) and oxytocin-associated neurophysin ([OT-RNP]) under basal conditions and conditions of high plasma osmolality (Posm) induced by acute salt loading. Studies were performed on conscious, chronically instrumented Long-Evans rats. Oxytocin (1 nmol or 10 nmol) dissolved in 1 mL of 0.9% saline was administered intraperitoneally to animals 1 h before they received an intravenous infusion of hypertonic saline over 60 min at a rate designed to raise Posm by approximately 0.75 mosmol∙min−1. Intraperitoneal injection of vehicle or 1 nmol of OT did not significantly alter [VP-RNP], [OT-RNP], or basal Posm. Administration of 10 nmol OT also had no effect on [VP-RNP] or [OT-RNP], but this dose of peptide significantly lowered basal Posm (299 ± 2 to 290 ± 2 mosmol/kg H2O, p < 0.001). Both doses of OT did not significantly alter the responsiveness of VP neurones to hyperosmotic stimulation. The slopes of the relationship between the rise in [VP-RNP] (A[VP-RNP]) and the rise in Posm (ΔPosm) for the groups receiving pretreatment of 1 nmol OT (n = 5), 10 nmol OT (n = 7), and vehicle (n = 7) were similar (6.1 ± 1.4, r = 0.86; 5.1 ± 0.9, r = 0.91; and 6.6 ± 0.9 fmol∙mL−1∙mosmol−1∙kg−1, r = 0.93, respectively). For the 1-nmol dose of OT that generated plasma OT levels in the physiological range, the slopes of the relationship between the rise in [OT-RNP] (Δ[OT-RNP]) and ΔPosm over the period of salt loading for peptide-treated animals and control animals (39.5 ± 8.9, r = 0.89 vs. 23.4 ± 5.9, fmol∙mL−1∙mosmol−1∙kg−1, r = 0.93) indicated an increased responsiveness of OT neurones, but this difference was not significant (p < 0.1426). Higher plasma levels of OT were generated by administering the 10 nmol dose of OT, and the slopes of the relationship between Δ[OT-RNP] and ΔPosm for peptide-treated animals and control animals (13.9 ± 1.6, r = 0.96 vs. 23.4 ± 8.9 fmol∙mL−1∙mosmol−1∙kg−1, r = 0.93) suggested a decreased responsiveness of OT neurones, but again this difference was not significant (p < 0.1637). However, there was a significant difference in the rise in OT-RNP with plasma osmolality for rats receiving high versus low dose of peptide (p < 0.0475). Our data indicate that peripherally administered OT, unlike VP, does not exert a negative feedback influence on osmotically stimulated release from VP neurones and most probably OT neurones. However, it cannot be ruled out that the lack of modulation of magnocellular neurones by the high dose of OT could be due to the summation of a positive OT effect (since the 1-nmol group appeared to exhibit an enhancing effect) and of a negative VP effect as indicated by blood pressure increases and plasma dilution. OT also does not appear to have an influence on basal release from magnocellular neurones.Key words: neurophysins, oxytocin neurones, vasopressin neurones.

Factors affecting 48-hour methotrexate levels following high-dose methotrexate (HDMTX) in lymphoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e20033-e20033
Author(s):  
Darragh O'Donoghue ◽  
Huong Truong ◽  
Heidi Diann Finnes ◽  
Jennifer McDonald ◽  
Stephen M. Ansell ◽  
...  
Keyword(s):  
Prolonged Exposure ◽  
Plasma Concentrations ◽  
High Plasma ◽  
High Dose ◽  
Factors Affecting ◽  
Significant Toxicity ◽  
Increased Risk ◽  
Central Nervous System Penetration ◽  
Male Patients ◽  
Lymphoma Therapy

e20033 Background: HDMTX is an important component of lymphoma therapy due to its central nervous system penetration. Although HDMTX can be safely administered to most patients, it can cause significant toxicity with those who have prolonged exposure to high plasma concentrations of MTX due to delayed elimination. Therefore, serum MTX concentration monitoring is still a standard approach for identifying patients at high risk of developing MTX toxicity. A majority of MTX is excreted within the first 48 hours of infusion. Higher MTX plasma concentrations at 48 hrs increase the likelihood of delayed MTX elimination. This study will assess baseline characteristics associated with high 48-hour MTX levels (≥ 1µM) which has been associated with increased risk of complications. Methods: A retrospective review of the electronic medical record was conducted to identify lymphoma patients who received HDMTX from 1/1/2002 to 12/31/18. Baseline demographics including age, gender, comorbidities, body surface area, BMI, weight and baseline chronic kidney disease (CKD) were recorded. Demographics, HDMTX dosing per protocol (3.5g/m2 vs 8g/m2), HDMTX adjusted by renal function (CrCl < 100), and ratio of MTX dose to BSA (MTX/BSA) were compared to 48 hour MTX levels. Analysis was performed in JMP 15. Results: 2553 cycles were of HDMTX were identified. There was a significant association of increasing age, (p = 0.039), male patients (p < 0.001), 8g/m2 dosing (p < 0.001), higher MTX dose (p < 0.001), MTX/BSA (p < 0.001), GFR by CKD-EPI (p < 0.001) and lower number of comorbidities (p < 0.001) with 48-hour MTX levels ≥1. There was no significant association of 48-hour MTX levels ≥1 and GFR by Cockcroft-Gault (p = 0.73), baseline CKD (p = 0.78), and renal adjusted HDMTX (p = 0.52). Multivariate analysis revealed significance for MTX/BSA, gender, BSA, GFR by CKDEPI (p < 0.001), and age (P = 0.0002). Conclusions: Hematologists should be aware that age, gender, GFR by CKD-EPI, and ratio of MTX dose to BSA are associated with elevated 48-hour MTX levels ≥1.

Busulfan

1994 ◽  
Vol 28 (9) ◽  
pp. 1055-1062 ◽  
Author(s):  
Isabella Buggia ◽  
Franco Locatelli ◽  
Mario B. Regazzi ◽  
Marco Zecca
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Autologous Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Plasma Concentrations ◽  
Myelogenous Leukemia ◽  
Therapeutic Drug ◽  
High Dose ◽  
Allogeneic Bone

OBJECTIVE: To review the current published studies evaluating the pharmacokinetics, clinical efficacy, safety, and toxicity of busulfan in pediatric and adult patients. DATA SOURCES: English-language literature published between 1953 and 1993 was analyzed; pertinent literature was reviewed. STUDY SELECTION: Emphasis was placed on pharmacologic studies and clinical trials involving busulfan therapy both in myeloproliferative disorders and in conditioning regimens for autologous or allogeneic bone marrow transplantation. DATA EXTRACTION: Data from both pediatric and adult studies were evaluated; emphasis was placed on the relationship between plasma concentrations of busulfan and its efficacy and toxicity. DATA SYNTHESIS: Busulfan has been used widely at conventional dosages (1–12 mg/d) for the treatment of patients with chronic myelogenous leukemia (CML). Busulfan at high doses (usually 16 mg/kg) given with other cytotoxic drugs (especially cyclophosphamide) is a common preparative regimen in patients undergoing allogeneic or autologous bone marrow transplantation (BMT) for acute or chronic leukemia and other nonmalignant disorders (e.g., hemoglobinopathies, inborn error of immune system, congenital metabolic disorders). Pharmacokinetics of high-dose busulfan are age-dependent. Busulfan systemic exposure and, thus, tissue and tumor exposure are lower in children than with adults. Relationships between toxicity (principally neutropenia, hepatic veno-occlusive disease, incidence of seizures) and drug exposure were found for busulfan. CONCLUSIONS: Busulfan is a useful, sufficiently safe drug in the treatment of patients with CML. At higher dosages, busulfan is a fundamental part of myeloablative therapies for patients undergoing BMT. As the pharmacokinetics and metabolism of busulfan is further understood, there is great potential for improving treatment outcome. An assessment of maximal tolerated exposure determined by therapeutic drug monitoring may decrease the incidence and lethality of regimen-related toxicities.

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