A randomized, double-blind, crossover study on the pharmacokinetics of a novel formulation of CoQ10 with pyridoxal 5'-phosphate and phosphatidyl choline.

The pharmacokinetics of a single 30-mg dose of a novel enteric-coated coenzyme Q10 (CoQ(10)) formulation with pyridoxal 5'-phosphate and phosphatidyl choline (CoQ(10)-P5P-PC) was investigated against two comparators CoQ(10) (NPN 02176955) and CoQ(10) (DIN 02231736) in 21 healthy volunteers, with screening CoQ(10) levels of 0.8 ± 0.2 mg/L. A randomized, double-blind, crossover study was designed with a washout period of 2 weeks between each formulation and blood sampled at 2, 4, 5, 6, 8, 12, 24, 48 and 72 hr postdose. Significantly, higher plasma concentrations were demonstrated for the CoQ(10) (NPN 02176955) formulation at 6 and 8 hr postdose (p = .010 and p = .042, respectively). There were no significant differences between formulations with respect to the area under the curve, AUC((0-72 hr)), or the maximum plasma concentration (C(max)). Total CoQ(10) (T(max)) reached maximum plasma concentrations at 6.4 ± 2.5 hr after supplementation with CoQ(10) (NPN 02176955), 8.0 ± 9.8 hr with CoQ(10)-P5P-PC, and 9.5 ± 9.3 hr with CoQ(10) (DIN 02231736). The estimated elimination half-life (t(1/2)) was 92.3 hr after a single oral dose of CoQ(10)-P5P-PC, 38.2 hr with CoQ(10) (NPN 02176955), and 80.7 hr with CoQ(10) (DIN 02231736). The results suggest that CoQ(10) is available for a longer time in subjects' administered with CoQ(10)-P5P-PC in comparison with the other two formulations studied. There were no significant differences in adverse events, by severity, causality, or organ system. The CoQ(10)-P5P-PC formulation was found to be superior in the t(1/2), and it may be suggested that fewer doses are required to maintain healthy circulatory CoQ(10) levels.

Effects of consecutive high-dose alcohol administration on the utilization of sulfur-containing amino acids by rats.

In this study, we attempted to evaluate changes in sulfur-containing amino acid (SCAA) metabolism after short-term high-dose alcohol ingestion. At the beginning of the study, six animals were sacrificed as the baseline group and then other animals in the experiment were consecutively gavaged with alcohol (30%, 3 g/kg) for 7 days. Animals (n=6 each) were subsequently sacrificed at the time points of Days 1 (Group E1), 3 (Group E3) and 7 (Group E7). Blood samples and selected tissues were collected at each time interval. SCAA, pyridoxal phosphate (PLP) and glutathione (GSH) levels were analyzed. Results showed that taurine levels of tissues (brain, liver, heart and kidneys) all declined after the ethanol intervention and continued to decrease in selected tissues except the brain during the experiment. Furthermore, the trends of plasma taurine and PLP contents were highly correlated (r=.98, P=.045). A similar utilization pattern of plasma taurine and PLP indicated that transsulfuration preferred taurine production to GSH synthesis. The trend of plasma taurine levels being positively correlated with PLP levels reveals that dramatic transsulfuration occurred to meet the urgent demand for taurine by brain cells. In conclusion, we reported that continual alcohol ingestion alters SCAA utilization, especially by depletion of taurine and hypotaurine and by elevation of S-adenosyl homocysteine in the selected organs.

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.

Mechanisms of action of liver contrast agents: impact for clinical use.

New contrast agents for magnetic resonance imaging are continually being developed by pharmaceutical companies in order to better image the liver. These agents can be divided into hepatobiliary agents directed to the hepatocytes and nanoparticulate agents directed to the reticulo-endothelial system. After intravenous injection, all these agents concentrate in the liver and induce profound changes in signal intensity. Particulate agents induce predominantly a darkening of the liver parenchyma, while hepatobiliary agents induce a brightening. In both cases, liver-lesion conspicuity is enhanced, leading to a better visualization of the lesion. After a brief description of the principal characteristics of the agents, this paper will attempt to summarize the utility of these agents for the detection and characterization of focal liver disease.

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.