scholarly journals Effect of High Dose Folic Acid Therapy on Hyperhomocysteinemia in Hemodialysis Patients

2000 ◽  
Vol 11 (6) ◽  
pp. 1106-1116 ◽  
Author(s):  
GERE SUNDER-PLASSMANN ◽  
MANUELA FÖDINGER ◽  
HEIDI BUCHMAYER ◽  
MENELAOS PAPAGIANNOPOULOS ◽  
JADWIGA WOJCIK ◽  
...  
Keyword(s):  
Folic Acid ◽  
Treatment Period ◽  
Plasma Levels ◽  
Methylenetetrahydrofolate Reductase ◽  
Plasma Concentrations ◽  
Hemodialysis Patients ◽  
High Dose ◽  
Acid Therapy ◽  
Total Homocysteine

Abstract. Homocysteine is associated with atherosclerosis and enhanced cardiovascular risk. In previous studies, treatment with folic acid up to 15 mg/d failed to correct hyperhomocysteinemia in the majority of end-stage renal disease patients. A dose of 30 or 60 mg of folic acid per day was compared with 15 mg/d in an attempt to normalize hyperhomocysteinemia in 150 hemodialysis patients. In a randomized, double-blind, multicenter study, 144 patients completed the 4-wk treatment period and 121 patients completed the 6-mo follow-up. Total homocysteine plasma levels were reduced by 32.1% (15 mg/d), 29.9% (30 mg/d), or 37.8% (60 mg/d) with no significant differences found between the three treatment groups. Baseline total homocysteine plasma concentration was an independent predictor of the response to folic acid therapy (P= 0.0001), whereas the 5,10-methylenetetrahydrofolate reductase polymorphisms (MTHFR677C → T and 1298A → C) had no influence. Nevertheless, patients with theMTHFR677TT genotype more frequently attained normal total homocysteine plasma levels than patients with the CC or CT genotype (P= 0.025). In response to 60 mg of folic acid per day, TT genotype patients had lower folate plasma levels compared to CC or CT genotype patients (P= 0.016). After completion of the 4-wk treatment period with 30 or 60 mg of folic acid per day, there was a marked rebound of total homocysteine plasma levels at the end of the follow-up in patients with theMTHFR677TT genotype, which even exceeded baseline values in several patients (P= 0.0001). This study clearly demonstrates that doses of 30 or 60 mg of folic acid per day are not more effective than 15 mg/d in reducing hyperhomocysteinemia in regular hemodialysis patients. Patients with theMTHFR677TT genotype are more likely to realize normal total homocysteine plasma levels. Folic acid at 30 or 60 mg/d but not 15 mg/d results in a rebound of total homocysteine plasma concentrations when treatment is stopped.

scholarly journals Effect of MTHFR 1298A→C and MTHFR 677C→T Genotypes on Total Homocysteine, Folate, and Vitamin B12 Plasma Concentrations in Kdiney Graft Recipients

2000 ◽  
Vol 11 (10) ◽  
pp. 1918-1925
Author(s):  
MANUELA FÖDINGER ◽  
HEIDI BUCHMAYER ◽  
GOTFRIED HEINZ ◽  
MENELAOS PAPAGIANNOPOULOS ◽  
JOSEF KLETZMAYR ◽  
...  
Keyword(s):  
Creatinine Clearance ◽  
Plasma Levels ◽  
Methylenetetrahydrofolate Reductase ◽  
Plasma Concentrations ◽  
Vitamin B ◽  
Compound Heterozygous ◽  
Kidney Graft ◽  
Linear Regression Models ◽  
Total Homocysteine ◽  
Folate And Vitamin B12

Abstract. The effect of 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T and 1298A→C on total homocysteine (tHcy), folate and vitamin B12 levels was investigated in 733 kidney graft recipients. The six major genotype combinations were used as grouping variables, and age, gender, BMI, serum creatinine, and creatinine clearance and ln-folate, ln-vitamin B12, or logarithmus naturalis tHcy (ln-tHcy) were used as covariates in three ANCOVA and multiple stepwise linear regression models. Hyperhomocysteinemia was present in 49.7% of the patients. The allele frequency of MTHFR 677T and 1298C was 0.319 and 0.326. MTHFR genotype and all other variables were significant predictors of ln-tHcy (higher tHcy plasma levels for MTHFR 677TT/1298AA versus all other five genotype groups: P < 0.05). BMI, creatinine clearance, ln-tHcy, and MTHFR genotype influenced ln-folate (lower folate levels for MTHFR 677TT/1298AA versus all other genotype groups: P < 0.05). Creatinine clearance and ln-tHcy were the only predictors of ln-vitamin B12 levels. In a prespecified subgroup analysis (n = 496), the MTHFR genotype also influenced tHcy levels and compound heterozygous patients had significantly lower folate levels as compared with MTHFR 677CC/1298AA and 677CC/1298CC. This study shows that the MTHFR 677TT/1298AA and 677CT/1298AC genotypes are significant predictors of tHcy and folate plasma levels.

Promising Efficacy with the New Anti-CD20 Antibody GA101 In Heavily Pre-Treated NHL Patients – First Results From a Phase II Study In Patients with Relapsed/Refractory DLBCL and MCL

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2878-2878 ◽  
Author(s):  
Guillaume Cartron ◽  
Catherine Thieblemont ◽  
Philippe Solal-Celigny ◽  
Franck Morschhhauser ◽  
Corinne Haioun ◽  
...  
Keyword(s):  
Treatment Period ◽  
Phase Ii ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Progression Free Survival ◽  
Respiratory Arrest ◽  
High Dose ◽  
Cd20 Antibody ◽  
Anti Cd20

Abstract Abstract 2878 Background: GA101 is the first type II, glycoengineered and humanized monoclonal anti-CD20 antibody with Phase I (Salles, ASH 2008, 2009; Cartron, EHA 2009; Morschhauser, ASH 2009; Sehn, ASH 2009) and indolent NHL phase II results (Salles, EHA, 2010) previously reported. Methods: Forty eligible patients [25 DLBCL/15 MCL] were randomized to receive GA101 in a low-dose (LD, n=21 [10 DLBCL/11 MCL]) or a high dose (HD, n=19 [15 DLBCL/4 MCL]) cohort. GA101 was given on d1, d8, d22 and q21 days for total of 9 infusions. In the LD cohort, GA101 was given 400mg all infusions; in the HD cohort, d1 and d8 at 1600mg and 800mg thereafter. Primary endpoint was end of treatment response (EOR), assessed 4 weeks after last infusion (44 weeks after treatment start). Secondary objectives were safety, pharmacokinetics and progression free survival (PFS). Results: Patients (Table 1) were heavily pre-treated (median 3 prior therapies), with 63% of patients not responding to or relapsing within six months after a previous rituximab-containing regimen (rituximab refractory) and 45% of patients completed all 9 infusions. For the LD cohort, EOR was 24% 5/21 (DLBCL – 2 PR, 1 CRu; MCL – 2 CR) and 32% (6/19) in the HD cohort (DLBCL – 4 PR; MCL – 2 PR). For DLBCL patients EOR was:28% (7/15) (1 CRu, 6 PR). For MCL patients EOR was: 27% (4/15) (2 CR, 2 PR). Of 13 refractory patients in LD, 1 patient achieved PR (8%) and of 12 refractory patients in HD, 3 patients achieved PR (25%), with two converting to CR during additional follow-up. Median PFS was 78 days [8-356+] and 83 days [7-428+] for the LD and HD cohorts respectively (Hazard ratio 0.88 [95% CI 0.43;1.79]).The most common AEs were G1-2 infusion related reactions (LD 81%, HD 68% of patients). Fourteen patients experienced at least one SAE during treatment period (LD=9, HD=5), with 7 related to GA101 (LD n=5, HD n=2), and 5 of these events associated with the first infusion (IRR=3; TLS=2), one after day 8 infusion (pyrexia), and one after cycle 6 infusion (bradycardia). During treatment, related G3-4 hematological AEs were transient neutropenia (n = 1 in HD), anemia (n = 2 in LD) and thrombocytopenia (n = 3 in LD). Ten patients had at least one G1-2 infection (5 in each cohort) with no G3-4 infections reported. GA101 plasma profiles were explored reflecting that mantle cell lymphoma patients in the HD (n=4) and LD (n=10) appeared to show lower plasma concentrations compared to DLBCL patients. There were 17 patient deaths reported (LD=11, HD=6), with 14 due to PD and 3 due to AE (1 during treatment period; cardio-respiratory arrest; not GA101-related) and two SAEs (LD) in follow-up (gastric haemorrhage, lung infection – both not GA101-related). Conclusion: In this group of heavily pre-treated DLBCL and MCL patients, single-agent GA101 was well tolerated with promising evidence of efficacy. Disclosure: Cartron: Roche: Consultancy, Honoraria; GSK: Honoraria. Morschhhauser:Roche: Honoraria. Birkett:Roche: Employment. Wenger:Roche: Employment. Asikanius:Roche: Employment. Salles:Roche: Honoraria.

Variations in the Lipid Profile of Patients with Chronic Renal Failure, Treated with Folic Acid

2003 ◽  
Vol 73 (3) ◽  
pp. 215-220 ◽  
Author(s):  
de Gómez Dumm ◽  
Giammona ◽  
Touceda
Keyword(s):  
Renal Failure ◽  
Folic Acid ◽  
Chronic Renal Failure ◽  
Density Lipoprotein ◽  
Plasma Homocysteine ◽  
Lipid Profiles ◽  
Erythrocyte Membranes ◽  
Favorable Effect ◽  
High Dose ◽  
Acid Therapy

Dyslipidemia and increases in plasma homocysteine usually occur at end-stage renal disease; both are recognized as risk factors for atherosclerosis. Folate administration reduces homocysteine concentration. In this study we determined the effect of a high dose of folic acid (40 mg intravenous injection three times a week) on plasma and red blood cell lipid profiles in twelve chronic renal failure patients on regular hemodialysis. Fasting blood samples were taken at the beginning of the study (baseline) and after 21, 42, and 64 days of treatment. Folic acid supplementation decreased plasma homocysteine. Plasma triglyceride levels decreased whereas polyunsaturated fatty acid values increased after 21 days; then they returned to baseline levels at the end of treatment. Total cholesterol and low-density lipoprotein (LDL) cholesterol were higher than those of the baseline during all the study, whereas high-density lipoprotein (HDL) cholesterol was reduced. In erythrocyte membranes, folic acid therapy enhanced cholesterol/phospholipid ratios and the fluorescence anisotropy of diphenyl-hexatriene. We conclude that large doses of folic acid produce a favorable effect, reducing plasma homocysteine levels and protecting patients from atherosclerosis. However, as this therapy induces significant alterations in both plasma and erythrocyte membrane lipid profiles, plasma lipid values should be controlled throughout the treatment of patients with renal failure.

scholarly journals Long-term Effect of Folic Acid and Vitamin B12 Supplementation on Fracture Risk and Cardiovascular Disease: Follow-up Study of B-PROOF Trial (P24-031-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Sadaf Oliai Araghi ◽  
Jessica C Kiefte-de Jong ◽  
Suzanne van Dijk ◽  
Natasja van Schoor ◽  
Lisette CPGM de Groot ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Folic Acid ◽  
Fracture Risk ◽  
Vitamin B12 ◽  
Homocysteine Level ◽  
Fracture Incidence ◽  
Total Homocysteine ◽  
The Hague ◽  
Vitamin B12 Supplementation

Abstract Objectives To investigate the possible effects of the intervention with folic acid and vitamin B12 supplementation on fracture and cardiovascular disease risk: 5–7 years after the end of the intervention period of 2–3 years. Methods Extended follow-up of B-PROOF trial, a multi-center, double-blind randomized placebo-controlled trial designed to assess the effect of 2–3 years daily supplementation with folic acid (400 µg) and vitamin-B12 (500 µg) versus placebo on fracture incidence. Fracture and cardiovascular outcomes were assessed by follow-up questionnaire. Fracture incidence (and a part of cardiovascular disease incidence) was verified by general practitioners (GPs). Results A total of 1298 individuals participated in the second follow-up round. Median age at baseline was 71.0 years [68.0–76.0] for both groups (n = 662 in the treatment group and n = 636 in the placebo group). No effect of the intervention on first osteoporotic fracture and other fracture risk after a follow up of 5–7 years was observed (HR: 0.99, 95% CI: 0.62; 1.59 and HR: 0.77; 95% CI: 0.50; 1.19, respectively) and also not for cardiovascular- or cerebrovascular disease (OR: 1.14; 95%CI: 0.74–1.74 and OR: 1.01; 95%CI: 0.76–1.33, respectively). Significant interaction for total homocysteine level was observed for osteoporotic- and any fracture (P = 0.10 and 0.06 resp.), which indicated a significantly lower risk of fracture in the intervention group with higher total homocysteine level. Conclusions This study does not support a prolonged effect of supplementation of folic acid and vitamin B12 on fracture risk, or on cardiovascular disease in older individuals with elevated homocysteine concentration. However, B-vitamin supplementation may be beneficial in reducing fractures in individuals with higher total homocysteine levels. Funding Sources The initial B-PROOF study has received funding so far by The Netherlands Organization for Health Research and Development (ZonMw), the Hague; unrestricted grant from NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; NCHA (Netherlands Consortium Healthy Ageing) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovationn, the Hague; Wageningen University, Wageningen; VUmc, Amsterdam; Erasmus Medical Center, Rotterdam. Supporting Tables, Images and/or Graphs

scholarly journals Stroke in hemodialysis patients randomized to different intravenous iron strategies: a prespecified analysis from the PIVOTAL trial

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0004272021
Author(s):  
Patrick B. Mark ◽  
Pardeep S. Jhund ◽  
Matthew R. Walters ◽  
Mark C. Petrie ◽  
Albert Power ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stroke Risk ◽  
Controlled Trial ◽  
Intravenous Iron ◽  
Hemodialysis Patients ◽  
High Dose ◽  
Pivotal Trial ◽  
Increased Risk ◽  
Iv Iron

Background: People with kidney failure treated with hemodialysis (HD) are at increased risk of stroke compared to similarly aged people with normal kidney function. One concern is that treatment of renal anemia might increase stroke risk. We studied risk factors for stroke in a prespecified secondary analysis of a randomized controlled trial of intravenous iron treatment strategies in HD. Methods: We analyzed data from the Proactive IV IrOn Therapy in HaemodiALysis Patients (PIVOTAL) trial focusing on variables associated with risk of stroke. The trial randomized 2,141 adults, who had started hemodialysis <12 months earlier and who were receiving an erythropoiesis-stimulating agent (ESA), to high-dose IV iron administered proactively or low-dose IV iron administered reactively in a 1:1 ratio. Possible stroke events were independently adjudicated. We performed analyses to identify variables associated with stroke during follow-up and assessed survival following stroke. Results: During a median 2.1 years follow-up, 69 (3.2%) patients experienced a first post randomization stroke. 57 (82.6%) were ischemic strokes and 12 (17.4%) hemorrhagic strokes. There were 34 post randomization strokes in the proactive arm and 35 in the reactive arm (hazard ratio (95% confidence interval): 0.90 (0.56, 1.44), p=0.66). In multivariable models, female gender, diabetes, history of prior stroke at baseline, higher baseline systolic blood pressure, lower serum albumin and higher C-reactive protein were independently associated with stroke events during follow up. Hemoglobin, total iron or ESA dose were not associated with risk of stroke. 58% of patients with a stroke event died during follow-up, compared to 23% without a stroke. Conclusions: In hemodialysis patients, stroke risk is broadly associated with risk factors previously described to increase cardiovascular risk in this population. Proactive intravenous iron does not increase stroke risk.

Retrospective Study of Trough Imatinib Plasma Levels Conducted as Part of the Follow-up of Patients with Chronic Myeloid Leukemia in a Canadian Cohort

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4258-4258
Author(s):  
Rahima Jamal ◽  
Danielle Desmarais ◽  
John Chapdelaine ◽  
Yvan Côté ◽  
Lambert Busque
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Plasma Levels ◽  
Myeloid Leukemia ◽  
Plasma Concentrations ◽  
The Body ◽  
Inadequate Response ◽  
Molecular Responses ◽  
The Impact ◽  
Trough Levels

Abstract While imatinib biodisponibility is excellent, trough imatinib plasma levels associated with standard dose imatinib are variable and cannot be predicted by the age, the body surface area or the weight of the patient. Imatinib trough levels have recently been associated with both cytogenetic and molecular responses, making imatinib pharmacokinetics a possible target in optimisation of the treatment of patients with chronic myeloid leukemia. We retrospectively analysed trough imatinib plasma levels prescribed as part of the longitudinal follow-up of a cohort of patients with chronic myeloid leukemia in Canada. Indications for testing were inadequate response, important side effects or suspicion of non compliance. The objectives of the study were to evaluate the variability of trough imatinib plasma levels in our cohort and determine the impact a first result had on the subsequent plasma level in patients with more than one imatinib plasma determination. Analyses of trough plasma levels in 278 patients were conducted in a central canadian laboratory from April 2007 to April 2008. Trough imatinib plasma levels were measured using liquid chromatography and tandem mass spectrometry (LC/MS/MS) with deuterated imatinib as the internal standard. Distribution of trough imatinib plasma levels according to the established IRIS quartiles (Q1–Q4; BLOOD. 2008, vol 11, p4022)) showed an important variability, with plasma levels distributed between less than 100 ng/ml and more than 4500 ng/ml. Sixty-two (22.3%) patients in our cohort had plasma levels below 647 ng/ml (Q1), 101(36.3%) patients had levels between 647–1170 ng/ml (Q2–Q3) and 115 (41.3%) patients had trough levels above 1170 ng/ml (Q4). There were 31 patients (11.2%) with levels above 2000 ng/ml, all of whom were included in the Q4. Thirty seven patients in our cohort had more than one analysis of trough imatinib plasma levels done during the one year follow-up for a total of 82 analyses. Sub-group analysis of trough imatinib plasma levels was conducted in the 13 patients in the Q1 and the six patients in the Q4 who had 2 analyses done. Mean trough imatinib plasma levels went from 401ng/ml to 665 ng/ml in the Q1 patients and from 2845 ng/ml to 1065 ng/ml in the Q4 patients. These results confirm the feasibility of imatinib plasma levels testing in the community and the important variability of trough imatinib plasma concentrations in individual patients, as described by other groups. A significant portion of patients in our cohort had trough levels below 647 ng/ml, which has been associated with less favourable cytogenetic and molecular responses in studies. These results also suggest that physicians act on the information procured by the determination of imatinib plasma levels as second level determination was improved for patients initially in Q1 or Q4. Further follow up analyses are needed to document if optimisation of dosing leads to better response or improvement in tolerability of the drug.

Imatinib Plasma Levels and Its Correlation with Response in Chronic-Phase Chronic Myeloid Leukemia: Experience of One Centre.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4284-4284
Author(s):  
J. Valentin Garcia. Gutierrez ◽  
Jesús Odriozola ◽  
Pilar Herrera ◽  
Javier Lopez ◽  
Maria Calbacho ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Plasma Levels ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Plasma Concentrations ◽  
Chronic Phase ◽  
Control Group ◽  
Treatment Optimisation ◽  
Number Of Patients

Abstract Abstract 4284 Introduction Imatinib (IM), 400 mg/d. induces durable responses in chronic myeloid leukaemia (CML) in chronic phase (CP). However, although IM-biodisponibility is fairly good, its plasma levels are variable and can not be predicted. Recently, these plasma concentrations have been related both to the dose being administrated and to the cytogenetic and molecular responses. Thus, Imatinib pharmacokinetics could be an issue towards treatment optimisation in CML patients. Recent studies suggest that therapeutic IM plasma levels should be above 1040 ng/dl. Aims To evaluate the association between IM dose and throughout plasma levels with different clinical outcomes. Results In this study, we looked for an association between plasma concentrations and clinical outcomes in 16/86 CML chronic phase patients who did not achieve optimal responses following the European Leukemia Net guidelines (ELN) (table 1). Patients with optimal responses and treated with the same standard doses were also analysed as a control group. Patients receiving doses above 400 mg showed throughout plasma levels considered as appropriate. In 7 of 16 patients (47.5%) not achieving optimal responses (ELN criteria), plasma levels were below the supposed therapeutic ranges. We have found no evidence for a correlation between clinical risk factors at diagnosis and the measurement of optimal plasma levels. Conclusions IM plasma levels are well correlated with IM dose administrated in the patients studied. In almost 50% of patients who did not achieve optimal responses, IM plasma levels were under the ranges considered therapeutic. Probably these are the patients who may benefit of a dose increase. Obviously, to learn more about the practical value of these measurements a longer follow up with a larger number of patients is needed. Disclosures: No relevant conflicts of interest to declare.

scholarly journals High-dose micafungin in neonates and young infants with invasive candidiasis: results of a phase 2 study

2021 ◽  
Author(s):  
Cinzia Auriti ◽  
Bianca M. Goffredo ◽  
Maria P. Ronchetti ◽  
Fiammetta Piersigilli ◽  
Sara Cairoli ◽  
...  
Keyword(s):  
Invasive Candidiasis ◽  
Plasma Levels ◽  
Plasma Concentrations ◽  
High Dose ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Limited Data ◽  
Young Infants ◽  
Phase 2 Study

Limited data are available on the most appropriate dosing, efficacy and safety of micafungin in neonates with invasive candidiasis (IC). This study evaluated plasma levels, efficacy and safety of micafungin at a dose of 8 mg/kg/day for a mean of 13·3 (± 5·2) days in 35 neonates and young infants with IC. Micafungin plasma concentrations were 5·70 mg/L pre-administration and 17·23, 15·59 and 10·27 mg/L after 1, 2, and 8 hours, respectively. The resolution of the infection was achieved in 86·7% of patients treated 14 or more days. In 20·0% of patients we observed a transient hyper-transaminasemia. Micafungin at a dose of 8 mg/kg/day is effective and well tolerated in neonates and young infants with IC.

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