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PubMed2004

Dietary secoisolariciresinol diglucoside and its oligomers with 3-hydroxy-3-methyl glutaric acid decrease vitamin E levels in rats.

Secoisolariciresinol diglucoside (SDG) is an important dietary lignan that is found at very high levels in flaxseed (1-4 %, w/w). Flaxseed lignans have received much research interest in recent years because of reported phyto-oestrogenic, anticarcinogenic, and anti-atherogenic effects. Previously, flaxseed feeding has been shown to decrease vitamin E concentrations in rats despite the antioxidant potential of SDG in vitro. Sesamin, a sesame lignan, on the other hand has been shown to increase vitamin E concentrations in rats. The aim of the present study was to investigate the effect of dietary SDG and its oligomers on vitamin E and cholesterol concentrations in rats. SDG was extracted from defatted flaxseed flour with a dioxane-ethanol mixture and purified by silica column chromatography. The major oligomers with 3-hydroxy-3-methyl glutaric acid, containing a high ratio of SDG to p-coumaric and ferulic acid glucosides, were purified from the extracts by reversed-phase liquid chromatography. When fed to rats at 0.1 % in the diet for 27 d, both SDG and its oligomers had no effect on animal performance but caused an increase in liver cholesterol and a 2-fold reduction in the levels of alpha- and gamma-tocopherols in rat plasma and liver. It is notable that a phenolic antioxidant, such as SDG, causes a vitamin E-lowering effect in rats. This cannot be explained at present, but warrants further investigations with respect to the magnitude, mechanism, and significance of the observed effect for human nutrition.

Animals↗

PubMed2003

Magnetic resonance imaging of the brain in glutaric acidemia type I: a review of the literature and a report of four new cases with attention to the basal ganglia and imaging technique.

RATIONALE AND OBJECTIVES: In glutaric acidemia type I (GA I), a pediatric neurometabolic disease that may be mistaken for nonaccidental trauma, expeditious detection is critical as early treatment may substantially improve psychomotor dysfunction. In this study, we examine in depth the magnetic resonance (MR) findings, with special attention to the basal ganglia, in 4 new cases and compare the findings with those described in the literature. METHODS: MR studies of 4 children, diagnosed to have GA I via cultured fibroblast enzyme studies or urine metabolite assays, were performed on a 1.5 T system in the axial plane using spin echo T(1)-weighted, fast spin echo T(2)-weighted, and fluid-attenuated inversion recovery (FLAIR) technique. Three of 4 patients were followed with serial exams to document temporal evolution of the disease. RESULTS: On T(2)-weighted images, abnormal increased signal intensity was seen in both the putamen and globus pallidus in all cases. However, in contradistinction to cases reported in the literature, involvement of the caudate nucleus was minimal or absent even on serial MR exams. In children 15 months and older, FLAIR improved recognition of basal ganglia and white matter abnormalities. The previously described widened cerebrospinal fluid spaces anterior to the temporal lobes, increased T(2)-weighted signal intensity in the periventricular white matter, and widened sylvian fissures characteristic of GA I were noted in all patients. CONCLUSIONS: Abnormalities of the caudate nucleus are not a prominent presentation of these patients and the absence of this finding should not exclude a diagnosis of GA I. FLAIR scans, as an adjunct to more conventional T(1)- and T(2)-weighted sequences, can play an important role in children 15 months or older despite immature myelination in these patients.

Basal Ganglia↗

PubMed2004

Pharmacokinetics, safety, and efficacy of a liposome encapsulated thymidylate synthase inhibitor, OSI-7904L [(S)-2-[5-[(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl]amino-1-oxo-2-isoindolynl]-glutaric acid] in mice.

OSI-7904L [(S)-2-[5-[(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl]amino-1-oxo-2-isoindolynl]-glutaric acid] is a liposomal formulation of the highly specific, noncompetitive, thymidylate synthase inhibitor OSI-7904 (also known as GW1843, 1843U89, and GS7904). The liposome formulation was developed to enhance the therapeutic index and dose schedule convenience of this potent antifolate compound. The studies presented here were conducted to determine the antitumor efficacy, distribution, pharmacokinetics, and safety of OSI-7904L in mice. In a human colon adenocarcinoma xenograft model in mice, OSI-7904L demonstrated superior antitumor efficacy compared with OSI-7904 or 5-fluorouracil. Furthermore, OSI-7904L could be administered less frequently than OSI-7904 although still generating greater tumor growth inhibition. Distribution studies confirmed that OSI-7904L-treated animals had much greater plasma, tissue, and tumor exposure than did OSI-7904-treated animals. Tumor exposures, based on area under the curve, in OSI-7904L-treated mice were increased over 100-fold compared with tumor exposures in OSI-7904-treated mice. Plasma exposures following OSI-7904L administration were greater than dose proportional consistent with saturation of plasma clearance mechanisms. OSI-7904L was much more toxic than OSI-7904 in the mouse with primary toxicities to the intestines, bone marrow, and thymus. Minimal toxicity to the lungs and liver was noted. These data clearly demonstrated that in mice, OSI-7904L has an increased plasma residence time as well as increased tissue and tumor exposure compared with OSI-7904, thus resulting in increased potency and toxicity. Potential benefits of OSI-7904L include improved efficacy and a more convenient schedule of administration.

Animals↗

PubMedDate not supplied

Neurophysiologic features in glutaric aciduria type I.

Neurophysiologic abnormalities are frequently seen in organic acidemias, but knowledge of the specific changes in the different types of organic acidemias is lacking. We studied electroencephalogram (EEG), visual evoked potential (VEP) and brain-stem auditory evoked response (BAER) in seven children with glutaric aciduria type I (GA1) to assess the neurophysiologic features in this rare inborn error of metabolism. Age at the time of the diagnosis ranged between 3 months and 36 months. Age at the time of neurophysiologic evaluation ranged between 11 months and 36 months. At the time of neurophysiologic evaluation, severe global developmental delay was seen in four patients, dystonia in four patients, motor delay in two patients, and axial hypotonia in two patients; macrocephaly, spasticity, moderate mental retardation and borderline intelligence were each seen in one patient. One patient had autistic features characterized by lack of language and social skills, poor eye contact and stereotypical behavior. Three of seven patients showed abnormal EEG findings. Two patients showed asymmetry with intermittent occipital delta slowing in one hemisphere. This finding probably indicates underlying cerebral dysfunction, and is not a specific feature. However, it suggests that these patients may develop abnormal EEG features during the course of the disease, and thus a baseline EEG may be useful for comparison over time. One patient showed high amplitude bursts of beta in the occipital regions with left predominance while on clonazepam and baclofen. We believe this finding was due to medication effect, and that what we observed was an exaggarated response to benzodiazepine. The clinical significance of this finding is unclear. VEP and BAER were available in four patients, and we found abnormalities in three of them. Neurophysiologic evaluation may be helpful in patients with GA1 as in other types of organic acidemias to help detect subtle changes that are not reflected by neurological examination or neuroimaging studies, and it may guide future treatment plans. Detailed neurophysiologic analysis in a large series of GA1 may yield further information regarding the extent of cerebral dysfunction.

Amino Acid Metabolism, Inborn Errors↗

PubMed1986

Glutaric acidemia type II. Phenotypic findings and ultrastructural studies of brain and kidney.

In a patient with nonketotic hypoglycemia, hyperammonemia, and a urinary organic acid pattern characteristic of glutaric acidemia type II, dysmorphic facial features and kidneys with multiple cortical cysts were the characteristic phenotypic findings. Electron microscopy revealed characteristic cytoplasmic, homogeneous, moderately electron-dense bodies with a limiting membrane. This specific lesion was noted in both central nervous system and renal tissues.

Acidosis↗

PubMed1996

Glutaric aciduria type I in the Arab and Jewish communities in Israel.

Mutation analysis was performed in eight families (16 patients) with glutaric aciduria type I (GA-I), which were all the families diagnosed in Israel in the years 1987-1994. Six families were of Moslem origin and two were non-Ashkenazi Jews. The entire coding region of the cDNA of the glutaryl-CoA dehydrogenase gene was sequenced in one patient of each family. Seven new mutations were identified in 15 of 16 mutated alleles, including six point mutations: T416I (4 alleles), G390R (1 allele), and S305L, A293T, L283P, and G1O1R (2 alleles each). In addition, a 1-bp deletion at position 1173 was identified in two alleles. These findings do not provide a molecular basis for the clinical variability in GA-I families. The occurrence of multiple novel mutations in a small geographic area may be explained by their recent onset in isolated communities with a high consanguinity rate.

Adult↗

PubMed1963