Identifying risk factors for adverse events of pyridoxal phosphate in infantile epileptic spasms syndrome.

INTRODUCTION: Infantile epileptic spasms syndrome (IESS) is characterized by epileptic spasms, regardless of hypsarrhythmia on electroencephalogram or neurodevelopmental delay. In Japan, pyridoxal 5'-phosphate (PLP) is often used as the first-line treatment for IESS because it is effective in a certain number of patients. Although several studies have reported serious adverse events following PLP treatment, no study has investigated the risk factors for such occurrences. OBJECTIVE: To investigate adverse events associated with PLP therapy for the treatment of IESS and to identify the associated risk factors. MATERIALS AND METHODS: We retrospectively evaluated adverse events in 59 patients with IESS at Tottori University Hospital between January 1995 and September 2022. We subsequently collected and analyzed their clinical data and analyzed the risk factors associated with each adverse event. The cutoff values and relative risk (RR) were analyzed for items with significant associations with adverse events. RESULTS: Twenty-seven (51.9%) participants experienced adverse events, including vomiting in 16 participants (59.3%), elevated liver enzyme levels in 15 participants (55.6%), and rhabdomyolysis in two participants (3.4%). No significant differences were observed between the non-adverse events group and the overall adverse events group, as well as between the non-adverse events group and the vomiting group, in terms of the factors examined. However, when comparing the non-adverse events group with the group with elevated liver enzyme levels, age at PLP treatment showed a negative correlation, whereas PLP dose showed a positive correlation with elevated liver enzyme levels. The cutoff dose was 40 mg/kg/day (73.3% sensitivity and 60.7% specificity), and the cutoff age was 9 months (100% sensitivity and 40.0% specificity). RRs of doses ≥40 mg/kg/day and age <9 months were 2.6 and 3.6, respectively. CONCLUSIONS: Adverse events of PLP therapy, including vomiting, elevated liver enzymes, and rhabdomyolysis, were observed in approximately half of the participants. Age under 9 months and a dose ≥40 mg/kg/day were identified as risk factors for elevation of liver enzymes on PLP treatment in infants with IESS, with rhabdomyolysis can occur in the younger or higher dose cases.

Novel strategies for the treatment of acetaminophen hepatotoxicity.

INTRODUCTION: Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the western world. Despite extensive investigations into the mechanisms of cell death, only a single antidote, N-acetylcysteine, is in clinical use. However, there have recently been more efforts made to translate mechanistic insight into identification of therapeutic targets and potential new drugs for this indication. AREAS COVERED: After a short review of the key events in the pathophysiology of APAP-induced liver injury and recovery, the pros and cons of targeting individual steps in the pathophysiology as therapeutic targets are discussed. While the re-purposed drug fomepizole (4-methylpyrazole) and the new entity calmangafodipir are most advanced based on the understanding of their mechanism of action, several herbal medicine extracts and their individual components are also considered. EXPERT OPINION: Fomepizole (4-methylpyrazole) is safe and has shown efficacy in preclinical models, human hepatocytes and in volunteers against APAP overdose. The safety of calmangafodipir in APAP overdose patients was shown but it lacks solid preclinical efficacy studies. Both drugs require a controlled phase III trial to achieve regulatory approval. All studies of herbal medicine extracts and components suffer from poor experimental design, which questions their clinical utility at this point.

Randomised open label exploratory, safety and tolerability study with calmangafodipir in patients treated with the 12-h regimen of N-acetylcysteine for paracetamol overdose-the PP100-01 for Overdose of Paracetamol (POP) trial: study protocol for a randomised controlled trial.

BACKGROUND: Paracetamol (acetaminophen) overdose (POD) is the commonest cause of acute liver failure in Europe and North America. Current treatment involves the use of the antidote N-acetylcysteine (NAC) in patients deemed at risk of liver damage. This regimen was introduced in the 1970s and has remained largely unchanged even though the initial NAC infusion is frequently associated with adverse reactions, in particular nausea, vomiting, and anaphylactoid reactions. NAC has reduced efficacy for preventing liver injury in those patients who present later after overdose. We designed a randomised study investigating the safety and tolerability of a superoxide dismutase (SOD) mimetic, calmangafodipir (PP100-01), co-treatment with a 12-h NAC regimen compared with NAC treatment alone in patients with POD. METHODS/DESIGN: We have designed an open-label, randomised, exploratory, rising dose design, NAC-controlled, phase 1 safety and tolerability study in patients treated with NAC for POD. A total of 24 patients will be assigned into one of three dosing cohorts of eight patients (n = 6 for PP100-01 and NAC; n = 2 for NAC alone). The doses of PP100-01 are 2, 5, and 10 µmol/kg. The primary outcome is the safety and tolerability of PP100-01 when co-administered with a 12-h NAC regimen compared with NAC treatment alone. Furthermore, the study will explore if PP100-01 has potential efficacy for the treatment of paracetamol-induced liver injury by measurement of conventional clinical and exploratory biomarkers. DISCUSSION: The aim of the study is to test the safety and tolerability of a SOD mimetic, PP100-01, in combination with a 12-h NAC regimen in patients presenting within 24 h of POD. This study will provide valuable data regarding the incidence of adverse events caused by the 12-h NAC plus PP100-01 regimen and may provide evidence of PP100-01 efficacy in the treatment of paracetamol-induced liver injury. TRIAL REGISTRATION: EudraCT, 2017-000246-21; ClinicalTrials.gov, NCT03177395 . Registered on 6 June 2017.

Pyridoxal Phosphate Supplementation in Neuropediatric Disorders.

Pyridoxal phosphate (PLP) is the active form of vitamin B6 and a cofactor in many enzyme reactions including neurotransmitter metabolism. PLP metabolism disturbances may mostly lead to refractory seizures. In this report, we review the main pathophysiological factors related with PLP deficiency and our experience in PLP treatment in pediatric patients with low-normal cerebrospinal fluid PLP values who presented epilepsy. Only one case had a definite diagnosis (Phelan-McDermid syndrome). The results of extensive metabolic workups and targeted genetic studies were normal for all patients. In 5 cases, the response to PLP supplementation (10-30mg/kg/d) was initially positive. PLP adverse reactions were noticed in 4 patients and PLP was discontinued; however, one of the most noticeable symptoms was an asymptomatic increase in liver enzymes. These negative results with PLP supplementation are worth reporting, to improve the information we use to treat our patients.

Pyridoxal 5 phosphate for neuroleptic-induced tardive dyskinesia.

BACKGROUND: Tardive dyskinesia is a chronic and disabling abnormal movement disorder affecting the muscles of the face, neck, tongue and the limbs. It is a common side effect of long-term antipsychotic medication use in individuals with schizophrenia and other related psychotic disorders. While there are no known effective treatments for tardive dyskinesia to date, some reports suggest that pyridoxal 5 phosphate may be effective in reducing the severity of tardive dyskinesia symptoms. OBJECTIVES: To determine the effectiveness of pyridoxal 5 phosphate (vitamin B6 or Pyridoxine or Pyridoxal phosphate) in the treatment of neuroleptic-induced tardive dyskinesia among people with schizophrenia and other related psychotic disorders. SEARCH METHODS: The Cochrane schizophrenia group's register of clinical trials was searched (January 2013) using the phrase: [*Pyridoxal* OR *Pyridoxine* OR *P5P* OR *PLP* OR *tardoxal* OR *Vitamin B6* O *Vitamin B 6* R in title, abstract or index terms of REFERENCE, or interventions of STUDY. References of relevant identified studies were handsearched and where necessary, the first authors of relevant studies were contacted. SELECTION CRITERIA: Studies described as randomised controlled trials comparing the effectiveness pyridoxal 5 phosphate with placebo in the treatment of neuroleptic-induced tardive dyskinesia among patients with schizophrenia. DATA COLLECTION AND ANALYSIS: The review authors independently extracted data from each selected study. For dichotomous data, we calculated risk ratios (RR) and their 95% confidence intervals (CIs) on an intention-to-treat basis based on a fixed-effect model. For continuous data, we calculated mean differences (MD) with 95% CIs, again based on a fixed-effect model. We assessed risk of bias for each included study and used GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to rate quality of evidence. MAIN RESULTS: Of the 12 records retrieved by the search, three trials published in 2001, 2003 and 2007, involving 80 inpatients with schizophrenia, aged 18 to 71 years, admitted in a psychiatric facility and followed up for a period nine weeks to 26 weeks, were included. Overall, pyridoxal 5 phosphate produced a significant improvement in tardive dyskinesia symptoms when compared with placebo, assessed by a change in Extrapyramidal Symptoms Rating Scale (ESRS) scores from baseline to the end of the first phase of the included studies (2 RCTs n = 65, RR 19.97, CI 2.87 to 139.19, low quality evidence). The endpoint tardive dyskinesia score (a measure of its severity) assessed with the ESRS, was significantly lower among participants on pyridoxal 5 phosphate compared to those on placebo (2 RCTs n = 60, MD -4.07, CI -6.36 to -1.79, low quality evidence).It was unclear whether pyridoxal 5 phosphate led to more side effects (n = 65, 2 RCTs, RR 3.97, CI 0.20 to 78.59, low quality evidence) or caused deterioration in tardive dyskinesia symptoms when compared to placebo (n = 65, 2 RCTs, RR 0.16, CI 0.01 to 3.14, low quality evidence). Five participants taking pyridoxal 5 phosphate withdrew from the study because they were not willing to take more medications while none of the participants taking placebo discontinued their medications (n = 65, 2 RCTs, RR 8.72, CI 0.51 to 149.75, low quality evidence).There was no significant difference in the endpoint positive and negative psychiatric symptoms scores, measured using the Positive and Negative symptoms Scale (PANSS) between participants taking pyridoxal 5 phosphate and those taking placebo. For the positive symptoms: (n = 15, 1 RCT, MD -1.50, CI -4.80 to 1.80, low quality evidence). For negative the symptoms: (n = 15, 1 RCT, MD -1.10, CI -5.92 to 3.72, low quality evidence). AUTHORS' CONCLUSIONS: Pyridoxal 5 phosphate may have some benefits in reducing the severity of tardive dyskinesia symptoms among individuals with schizophrenia. However, the quality of evidence supporting the effectiveness of pyridoxal 5 phosphate in treating tardive dyskinesia is low, based on few studies, short follow-up periods, small sample sizes and inadequate adherence to standardised reporting guidelines for randomised controlled trials among the included studies.

A randomized, double-blind, placebo-controlled, multicenter study to evaluate the cardioprotective effects of MC-1 in patients undergoing high-risk coronary artery bypass graft surgery: MC-1 to Eliminate Necrosis and Damage in Coronary Artery Bypass Graft Surgery Trial (MEND-CABG) II--study design and rationale.

BACKGROUND: Coronary artery bypass graft (CABG) surgery is effective in relieving angina and improving survival and quality of life in patients with obstructive coronary artery disease; however, recurrent angina, myocardial infarction, neurological injury, and death can occur in the perioperative and postoperative period. MC-1 (pyridoxal 5'-phosphate) is a novel agent that has shown promise in reducing myocardial necrosis by reducing cellular calcium overload after percutaneous coronary intervention and CABG surgery in high-risk patients undergoing these procedures. METHODS: MEND-CABG II is a phase III study evaluating the efficacy and safety of MC-1 in reducing cardiovascular morbidity and mortality after CABG. High-risk patients undergoing CABG surgery will be randomly assigned to receive either MC-1 (250 mg/d) or matching placebo immediately before and continuing for 30 days after the procedure. The primary end point is the occurrence of cardiovascular death or nonfatal myocardial infarction through postoperative day 30. A total of 3023 patients were enrolled at 130 sites in Canada, the United States, and Germany between October 2006 and September 2007, with results anticipated shortly after completion of 90-day follow-up in March 2008. CONCLUSIONS: The data from the MEND-CABG II trial will establish whether peri- and postoperative treatment with MC-1 can decrease the short- and intermediate-term morbidity and mortality of high-risk patients undergoing CABG surgery.

MC-1 (pyridoxal 5'-phosphate): novel therapeutic applications to reduce ischaemic injury.

Despite the overall efficacy of mechanical reperfusion therapies, such as percutaneous coronary intervention and coronary artery bypass graft surgery, in reducing the morbidity and mortality that is associated with acute ischaemic syndromes, many of the treated patients develop ischaemia-reperfusion injury due to impaired microvascular integrity, embolisation of atherothrombotic debris and/or disrupted end-organ metabolism. MC-1 is an investigational drug from Medicure, Inc. In preclinical models of ischaemia and ischaemia-reperfusion injury, treatment with MC-1 has demonstrated significant cardio- and neuroprotective effects. Although the pharmacological activity of MC-1 may involve multiple mechanisms, research suggests that at least part of the protective effect may be mediated through its actions on purinergic receptors. Early clinical experience with MC-1 also appears to be promising: in a recent Phase II evaluation, treatment with MC-1 was associated with a statistically significant reduction in periprocedural infarct size (as measured by area under the curve creatine kinase-myocardial band) among high-risk patients undergoing elective percutaneous coronary intervention. Based on these findings, larger, randomised trials to confirm the safety and efficacy of MC-1 in the setting of coronary artery revascularisation with coronary artery bypass graft, acute coronary syndromes and stroke are ongoing or in development. These forthcoming evaluations should clarify the safety and efficacy of MC-1 and improve the understanding regarding its potential therapeutic role in a variety of clinical settings and indications.

Manganese toxicity upon overexposure.

Manganese (Mn) is a required element and a metabolic byproduct of the contrast agent mangafodipir trisodium (MnDPDP). The Mn released from MnDPDP is initially sequestered by the liver for first-pass elimination, which allows an enhanced contrast for diagnostic imaging. The administration of intravenous Mn impacts its homeostatic balance in the human body and can lead to toxicity. Human Mn deficiency has been reported in patients on parenteral nutrition and in micronutrient studies. Mn toxicity has been reported through occupational (e.g. welder) and dietary overexposure and is evidenced primarily in the central nervous system, although lung, cardiac, liver, reproductive and fetal toxicity have been noted. Mn neurotoxicity results from an accumulation of the metal in brain tissue and results in a progressive disorder of the extrapyramidal system which is similar to Parkinson's disease. In order for Mn to distribute from blood into brain tissue, it must cross either the blood-brain barrier (BBB) or the blood-cerebrospinal fluid barrier (BCB). Brain import, with no evidence of export, would lead to brain Mn accumulation and neurotoxicity. The mechanism for the neurodegenerative damage specific to select brain regions is not clearly understood. Disturbances in iron homeostasis and the valence state of Mn have been implicated as key factors in contributing to Mn toxicity. Chelation therapy with EDTA and supplementation with levodopa are the current treatment options, which are mildly and transiently efficacious. In conclusion, repeated administration of Mn, or compounds that readily release Mn, may increase the risk of Mn-induced toxicity.

Seizures induced by intracerebral administration of pyridoxal-5'-phosphate: effect of GABAergic drugs and glutamate receptor antagonists.

Pyridoxal-5'-phosphate (PLP), the cofactor of glutamate decarboxylase, paradoxically induces convulsions when injected intracranially in adult mammals. We have tested the effect of some GABAergic and antiglutamatergic drugs on the behavioral and electroencephalographic (EEG) seizures produced by intracerebroventricular (i.c.v.) microinjection of 1 micromol PLP in the rat. PLP induced barrel turning, running fits and tonic-clonic convulsions, which started 5-10 min after recovery from the anesthesia (halothane), peaked at 20 min and disappeared at about 50 min. These symptoms were accompanied by frequent high amplitude EEG spike burst discharges. Pyridoxal, pyridoxamine-5'-phosphate or deoxypyridoxine were ineffective. The i.c.v. microinjection of the GABAergic compounds muscimol, isoguvacine, aminooxyacetic acid or GABA itself, significantly protected against PLP effects. In contrast, the NMDA receptor antagonists MK-801 and the non-NMDA receptor antagonist NBQX, failed to protect and induced motor alterations and mortality. We conclude that a temporary decrease of the GABA(A) receptor function is involved in the convulsant effect of PLP. This decrease might be due to the formation of a Schiff base between the carbonyl group of PLP and the epsilon-amino group of a functionally crucial lysine residue located in one extracellular loop of the GABA(A) receptor.

Efficacy and safety of mangafodipir trisodium (MnDPDP) injection for hepatic MRI in adults: results of the U.S. Multicenter phase III clinical trials. Efficacy of early imaging.

The efficacy of contrast-enhanced magnetic resonance imaging (MRI) for detecting and characterizing, or excluding, hepatic masses was assessed in 404 patients, following the intravenous administration of mangafodipir trisodium (MnDPDP) injection, a hepatic MRI contrast agent. An initial contrast-enhanced computed tomography (CT) examination was followed by unenhanced MRI, injection of MnDPDP (5 micromol/kg IV), and enhanced MRI at 15 minutes post injection. Agreement of the radiologic diagnoses with the patients' final diagnoses was higher for enhanced MRI and for the combined unenhanced and enhanced MRI evaluations than for unenhanced MRI alone or enhanced CT using the clinical diagnosis as the gold standard. Mangafodipir-enhanced MRI uniquely provided additional diagnostic information in 48% of the patients, and patient management was consequently altered in 6% of the patients. MnDPDP-enhanced MRI was comparable or superior to unenhanced MRI and enhanced CT for the detection, classification, and diagnosis of focal liver lesions in patients with known or suspected focal liver disease.

Safety and efficacy of mangafodipir trisodium (MnDPDP) injection for hepatic MRI in adults: results of the U.S. multicenter phase III clinical trials (safety).

The short-term safety of mangafodipir trisodium (MnDPDP) injection was studied in 546 adults with known or suspected focal liver lesions. An initial contrast-enhanced computed tomography examination was followed by unenhanced magnetic resonance imaging (MRI), injection of MnDPDP (5 micromol/kg), and enhanced MRI. Adverse events were reported for 23% of the patients; most were mild to moderate in intensity, did not require treatment, and were not drug related. The most commonly reported adverse events were nausea (7%) and headache (4%). The incidence of serious adverse events was low (nine events in six patients) and not drug related. Injection-associated discomfort was reported for 69% of the patients, and the most commonly reported discomforts included heat (49%) and flushing (33%). Changes in laboratory values and vital signs were generally transient, were not clinically significant, and did not require treatment. There were no clinically significant short-term risks from exposure to MnDPDP.

Safety of approved MR contrast media for intravenous injection.

In the last 10 years, the use of intravenous contrast media in magnetic resonance (MR) has become well-established clinical practice. Contrast media provide critical additional diagnostic information in many instances. The gadolinium chelates constitute the largest group of MR contrast media and are considered to be very safe. These agents are thought to be safer than nonionic iodinated contrast agents. Unlike x-ray agents, the gadolinium chelates are not nephrotoxic. Minor adverse reactions, including nausea (1%-2% for all agents) and hives (<1% for all agents), occur in a very low percent of cases. Health care personnel should be aware of the (extremely uncommon) potential for severe anaphylactoid reactions in association with the use of MR contrast media and be prepared should complications arise. The four gadolinium chelates currently available worldwide, gadopentetate dimeglumine, gadoteridol, gadodiamide, and gadoterate meglumine, cannot be differentiated on the basis of adverse reactions. Far fewer patients have been examined to date with the two other agents that have widespread approval, mangafodipir trisodium and ferumoxides. These latter two agents are considered to be very safe but have a higher percentage of associated adverse reactions (7%-17% with mangafodipir trisodium and 15% with ferumoxides). This review discusses the safety issues involved with administration of intravenous contrast media in MR imaging, focusing on the six agents (four gadolinium chelates, one manganese chelate, and the last a large iron particle) with widespread use world-wide.

MnDPDP for MR imaging of the liver. Results from the European phase III studies.

PURPOSE: To evaluate the diagnostic efficacy and safety of MnDPDP (Teslascan) in enhanced MR imaging. MATERIAL AND METHODS: In 2 multiple independent trials in Europe 624 patients were given MnDPDP intravenously at 5 mumol/kg b.w. Patients underwent an unenhanced MR examination comprising T1-weighted spin-echo and breath-hold gradient-echo sequences and a T2-weighted spin-echo sequence. The T1 sequences were repeated after the administration of MnDPDP. In a subgroup of 137 patients the results of the enhanced MR images were compared with the results of contrast-enhanced CT (CECT) images. RESULTS: For both types of T1-weighted sequences and when evaluating the maximum numbers of lesions seen in all imaging sequences, the total numbers of lesions seen were significantly higher in the MnDPDP-enhanced images than in the unenhanced images (p = 0.0005 and p = 0.0001, respectively). The investigators considered the enhanced images to contain "other additional information not found in the unenhanced images" in 279 (45%) of the 621 patients examined. The MnDPDP-enhanced images were also superior to the CECT images in the detection of lesions (p = 0.02). Adverse events were reported by 46 patients (7%) and infusion-associated discomfort by 26 (4%). Heart rates and systolic and diastolic blood pressures showed no clinically significant changes from baseline as a result of the administration of the contrast medium. CONCLUSION: MnDPDP was shown to be effective and safe in enhanced MR imaging of the liver.

Diagnostic efficacy of MnDPDP in MR imaging of the liver. A phase III multicentre study.

PURPOSE: To assess the diagnostic efficacy, safety and tolerability of mangafodipir trisodium (MnDPDP, Teslascan) in MR imaging of the liver. MATERIAL AND METHODS: Eighty-two patients from 4 centres underwent MR imaging with pre-contrast sequences including T1-weighted SE and GRE, and T2-weighted turbo SE sequences. MnDPDP at a dose of 5 mumol/kg b.w. was administered by slow i.v. infusion, and 20-60 min after infusion the T1-weighted SE and GRE sequences were repeated. Diagnostic efficacy was evaluated by counting the number of lesions and by evaluating whether more information for lesion characterisation was available in post-contrast images. Safety and tolerability were assessed by recording adverse events and infusion-related discomfort. RESULTS: Significantly more lesions were found in MnDPDP-enhanced T1-weighted SE and GRE images than in unenhanced images of the same sequences. More lesions were also found in these images compared with T2-weighted images at a level of marginal significance. More information was obtained from MnDPDP-enhanced images in 40 cases. Mild to moderate adverse events were experienced by 17% of the patients. CONCLUSION: MnDPDP-enhanced images can improve lesion detection in the liver and are helpful for lesion characterisation. To obtain optimal diagnostic information of liver lesions T2-weighted images are also valuable. MnDPDP is a safe contrast agent for MR imaging of liver lesions.

MR imaging properties and pharmacokinetics of MnDPDP in healthy volunteers.

PURPOSE: Thirteen male volunteers were studied to evaluate the MR imaging properties and pharmacokinetics of 10 mM mangafodipir trisodium infusion (MnDPDP, Teslascan). MATERIAL AND METHODS: Doses of 5 and 10 mumol/kg b.w. were administered by bolus injection (< 1 min) to 5 subjects, and by infusion (20 min) to 8 subjects, with a 3-week wash-out between doses. Infusion subjects underwent MR imaging. RESULTS: At 1 h after infusion, the plasma concentration of Mn was reduced to approximately 15% of the maximum value. Fifteen to 20% of Mn was recovered in the urine, and 50-60% was recovered in the faeces. The rapid initial plasma clearance of Mn is consistent with both rapid tissue uptake and rapid renal elimination. Increases in signal intensity were apparent on T1-weighted images of the liver, pancreas, spleen, renal cortex and the renal medulla, but not in regions of the brain protected by an intact blood-brain barrier. Increases were seen in the choroid plexus and pituitary. Contrast-related adverse events, only flushing of moderate intensity, occurred in bolus injection subjects. CONCLUSION: At 5 and 10 mumol/kg, mangafodipir produces relatively long-lasting enhancement of several abdominal organs, including the liver, pancreas and kidney.

Tissue distribution and general safety of MnDPDP in male beagle dogs, with or without total common bile duct obstruction.

PURPOSE: Evaluation of the tissue distribution of manganese (Mn) and general safety in normal and cholestatic male beagle dogs after i.v. administration of mangafodipir trisodium (MnDPDP, Teslascan). MATERIAL AND METHODS: Male beagle dogs, with or without surgical obstruction of the common bile duct, received a single i.v. bolus injection of saline (control), or MnDPDP at doses of 10 or 50 mumol/kg b.w. and were sacrificed 1 or 7 days after treatment. Toxicity was assessed and tissue concentrations of Mn were measured. RESULTS: Increased tissue Mn concentrations were found in all dogs treated with MnDPDP and were greatest in those with biliary obstruction. Although Mn concentrations decreased with time in most tissues in each of the treated groups, this was not the case for the brain and adrenal glands in dogs with total biliary obstruction in which further increases in Mn concentrations were seen at the later time point. This suggested a re-distribution of Mn from the major body depots such as the liver. There were no effects of MnDPDP on clinical signs/behaviour, organ weights, histomorphology or clinical biochemistry. CONCLUSION: These findings indicate that a single clinical dose of 5 mumol/kg MnDPDP is likely to be well tolerated in patients with cholestasis.

Magnesium pyridoxal-5'-phosphate glutamate, "A vitamin B6 derivative", does not affect lipoprotein levels in patients with familial hypercholesterolaemia.

OBJECTIVE: In this double-blind, randomized, placebo-controlled, dose-finding study we assessed the short-term efficacy and safety of increasing dosages of magnesium pyridoxal-5'-phosphate glutamate (MPPG) compared to placebo in patients with familial hypercholesterolaemia (FH). Twenty-three patients of either sex, over the age of 18 years and suffering from heterozygous FH, were treated with MPPG for a period of 16 weeks. RESULTS: Baseline characteristics and lipoprotein profiles of the patients were comparable in the two treatment groups. Overall compliance was 90%. Neither after the first 8 weeks treatment period with 450 mg MPPG daily nor after the second 8 weeks treatment period with 600 mg MPPG daily were statistically significant changes in plasma total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol or triglyceride levels observed between the treatment and placebo groups. Plasma levels of lipoprotein (Lp)(a), apolipoprotein (apo) A1, apo B100, very low density lipoprotein (VLDL) cholesterol and VLDL triglyceride also did not change. CONCLUSION: Although it has been demonstrated that MPPG improves lipoprotein levels in patients with different forms of dyslipidaemia, MPPG is not effective for the treatment of FH patients.

Tolerability and utility of mangafodipir trisodium injection (MnDPDP) at the dose of 5 mumol/kg body weight in detecting focal liver tumors: results of a phase III trial using an infusion technique.

PURPOSE: To evaluate the tolerability of mangafodipir trisodium (MnDPDP) and its utility for enhancing the ability of magnetic resonance (MR) imaging to detect focal hepatic lesions compared with non-enhanced MR and contrast-enhanced computed tomography (CT). MATERIALS AND METHODS: 119 patients with focal hepatic lesions were examined by MR and by contrast-enhanced CT. MR was performed before and after the infusion of 5 mumol/kg MnDPDP, at a concentration of 10 mumol/ml. Histologic confirmation was obtained in 79 patients. RESULTS: There were no severe adverse events. Five patients reported mild adverse events related to the infusion. MnDPDP-enhanced SE T1 and GE T1 sequences revealed more focal lesions than the same sequences before contrast infusion in, respectively 22.6 and 36.1% of the cases, and fewer focal lesions in, respectively 5.9 and 1.7% of the cases. Contrast-enhanced MR demonstrated more focal lesions than the SE T2 sequence in 29.4% of cases and fewer lesions in 5.9% of cases. MnDPDP-enhanced MR revealed more nodules than CT in 31.1% of cases and fewer nodules in 13.4% of cases. The additional information provided by MnDPDP enhancement led to modification of management for 12 patients (10.1%). CONCLUSION: MnDPDP is a well-tolerated contrast agent allowing better MR detection of focal hepatic lesions than non-enhanced MR or contrast-enhanced CT.