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Biomedical subjects

C R Roe

Publications and source records attributed to C R Roe.

At least 91 records · Page 5Linked to original sources
PubMed1985

Valproylcarnitine: a novel drug metabolite identified by fast atom bombardment and thermospray liquid chromatography-mass spectrometry.

Urine samples from three children at different stages of chronic valproate therapy were partially purified using a cation exchange column. A signal consistent with either valproylcarnitine or octanoylcarnitine was observed in one of these extracts by direct fast atom bombardment-mass spectrometry analysis. These isomeric acylcarnitines were synthesized, separated and characterized by thermospray high performance liquid chromatography-mass spectrometry. This new technique was then employed to positively identify intact valproyl-carnitine in the patients' urine samples. The implications of this finding with regard to a mechanism to account for carnitine deficiency in patients receiving valproate are discussed.

Adolescent↗
PubMed1985

Diagnostic and therapeutic implications of medium-chain acylcarnitines in the medium-chain acyl-coA dehydrogenase deficiency.

The medium-chain acyl-coA dehydrogenase deficiency is one of several metabolic disorders presenting clinically as Reye syndrome. Evidence is presented for a characteristic organic aciduria that distinguishes this disorder from Reye syndrome and other masqueraders characterized by dicarboxylic aciduria. The key metabolites, suberylglycine and hexanoylglycine, are excreted in high concentration only when the patients are acutely ill. More significantly, using novel techniques in mass spectrometry, the medium-chain defect is shown to be characterized by excretion of specific medium-chain acylcarnitines, mostly octanoylcarnitine, without significant excretion of a normal metabolite, acetylcarnitine, in four patients with documented enzyme deficiency. Similar studies on the urine of two patients reported with Reye-like syndromes of unidentified etiology have suggested the retrospective diagnosis of medium-chain acyl-coA dehydrogenase deficiency. Administration of L-carnitine to medium-chain acyl-coA dehydrogenase deficiency patients resulted in the enhanced excretion of medium-chain acylcarnitines. Octanoylcarnitine is prominent in the urine both prior to and following L-carnitine supplementation. The detection of this metabolite as liberated octanoic acid, following ion-exchange chromatographic purification and mild alkaline hydrolysis, provides a straightforward diagnostic procedure for recognition of this disorder without subjecting patients to the significant risk of fasting. In view of the carnitine deficiency and the demonstrated ability to excrete the toxic medium-chain acyl-coA compounds as acylcarnitines, a combined therapy of reduced dietary fat and L-carnitine supplementation (25 mg/kg/6 h) has been devised and applied with positive outcome in two new cases.

Acyl-CoA Dehydrogenase↗
PubMed1985

Creatine kinase brain isoenzyme: relationship of cerebrospinal fluid concentration to the neurologic condition of newborns and cellular localization in the human brain.

Immunocytochemical study of human brain showed creatine kinase brain isoenzyme (CKBB) present in both neurons and astrocytes. Because creatine kinase brain isoenzyme is an intracellular enzyme that might be released with brain injury, its concentration in the CSF of newborns was measured using a radioimmunoassay. Infants who suffered a documented neurologic insult (a cerebroventricular hemorrhage or a CNS infection) were found to have a greater mean CSF creatine kinase brain isoenzyme concentration than those without a history of neurologic insult. Infants with a high concentration had a poor short-term outcome (death or neurologic abnormality when discharged) more frequently than did those with a lower concentration. Infants with a grade 3 or 4 cerebroventricular hemorrhage had a higher mean concentration than did those with a grade 1 or 2 hemorrhage. These data are consistent with the hypothesis that CSF creatine kinase brain isoenzyme is a metabolic indicator of brain damage in newborns.

Astrocytes↗
PubMed1984

L-carnitine: therapeutic strategy for metabolic encephalopathy.

The organic anion transport system in the choroid plexus is responsible for excretion of organic anions from brain to plasma. Disruption of this system could then result in accumulation of encephalopathic acyl groups in brain in a variety of metabolic disorders. Octanoate produced inhibition of this transport system associated with disruption of mitochondrial ultrastructure. Octanoylcarnitine and L-carnitine had no effect. These compounds represent those seen in the medium chain acyl CoA dehydrogenase deficiency. L-Carnitine may be useful for protecting the central nervous system through formation of the non-toxic acylcarnitine in this and other metabolic disorders characterized by accumulation of encephalopathic metabolites.

Animals↗
PubMed1984

Application of high resolution fast atom bombardment and constant B/E ratio linked scanning to the identification and analysis of acylcarnitines in metabolic disease.

Acylcarnitines, a biologically important group of metabolites which have thus far eluded characterization by mass spectrometry, exhibit very intense fast atom bombardment mass spectra dominated by parent cations. The combination of high resolution selected ion detection and daughter ion analysis using the linked scan at constant B/E ratio has enabled the unequivocal identification of the acylcarnitines in the urine of children with propionic acidemia, methylmalonic aciduria and Reye's Syndrome. Quantitative analysis of acetylcarnitine and propionylcarnitine in selected samples was accomplished by isotope dilution, utilizing (2H3)acetyl- and (2H5)propionylcarnitines as internal standards. These techniques will allow assessment of the therapeutic use of L-carnitine in these disorders.

Acetylcarnitine↗
PubMed1984

L-carnitine enhances excretion of propionyl coenzyme A as propionylcarnitine in propionic acidemia.

Treatment with L-carnitine greatly enhanced the formation and excretion of short-chain acylcarnitines in three patients with propionic acidemia and in three normal controls. The use of fast atom bombardment mass spectrometry and linked scanning at constant magnetic (B) to electric (E) field ratio identified the acylcarnitine as propionylcarnitine in patients with propionic acidemia. The normal children excreted mostly acetylcarnitine. Propionic acidemia and other organic acidurias are characterized by the intramitochondrial accumulation of short-chain acyl-Coenzyme A (CoA) compounds. The substrate specificity of the carnitine acetyltransferase enzyme and its steady state nature appears to facilitate elimination of propionyl groups while restoring the acyl-CoA:free CoA ratio in the mitochondrion. We suggest that L-carnitine may be a useful therapeutic approach for elimination of toxic acyl CoA compounds in several of these disorders.

Acyl Coenzyme A↗
PubMed1984

L-carnitine therapy in isovaleric acidemia.

Isovaleric acidemia, resulting from isovaleryl-coenzyme A dehydrogenase deficiency, is associated with marked reduction of free carnitine in both plasma and urine. Fast atom bombardment-mass spectrometry, hydrolysis, and gas chromatography/mass spectrometry have unequivocally identified the existence of isovalerylcarnitine, a new metabolite specific for this disorder. Administration of equimolar amounts of glycine or L-carnitine separately with leucine demonstrated that isovaleryl-coenzyme A is removed by supplemental L-carnitine in the form of isovalerylcarnitine as effectively as it is by glycine, in the form of isovalerylglycine. When L-carnitine is given alone, excretion of isovalerylglycine decreases in preference to enhanced excretion of isovalerylcarnitine and hippurate. Treatment with L-carnitine alone has proven effective in preventing further hospitalizations in a patient with this genetic disorder.

Amino Acid Metabolism, Inborn Errors↗
PubMed1984

Urinary excretion of l-carnitine and acylcarnitines by patients with disorders of organic acid metabolism: evidence for secondary insufficiency of l-carnitine.

Concentrations of l-carnitine and acylcarnitines have been determined in urine from patients with disorders of organic acid metabolism associated with an intramitochondrial accumulation of acyl-CoA intermediates. These included propionic acidemia, methylmalonic aciduria, isovaleric acidemia, multicarboxylase deficiency, 3-hydroxy-3-methylglutaric aciduria, methylacetoacetyl-CoA thiolase deficiency, and various dicarboxylic acidurias including glutaric aciduria, medium-chain acyl-CoA dehydrogenase deficiency, and multiple acyl-CoA dehydrogenase deficiency. In all cases, concentrations of acylcarnitines were greatly increased above normal with free carnitine concentrations ranging from undetectable to supranormal values. The ratios of acylcarnitine/carnitine were elevated above the normal value of 2.0 +/- 1.1. l-Carnitine was given to three of these patients; in each case, concentrations of plasma and urine carnitines increased accompanied by a marked increase in concentrations of short-chain acylcarnitines. These acylcarnitines have been examined using fast atom bombardment mass spectrometry in some of these diseases and have been shown to be propionylcarnitine in methylmalonic aciduria and propionic acidemia, isovalerylcarnitine in isovaleric acidemia, and hexanoylcarnitine and octanoylcarnitine in medium-chain acyl-CoA dehydrogenase deficiency. The excretion of these acylcarnitines is compatible with the known accumulation of the corresponding acyl-CoA esters in these diseases. In this group of disorders, the increased acylcarnitine/carnitine ratio in urine and plasma indicates an imbalance of mitochondrial mass action homeostasis and, hence, of acyl-CoA/CoA ratios. Despite naturally occurring attempts to increase endogeneous l-carnitine biosynthesis, there is insufficient carnitine available to restore the mass action ratio as demonstrated by the further increase in acylcarnitine excretion when patients were given oral l-carnitine.(ABSTRACT TRUNCATED AT 250 WORDS)

Acyl-CoA Dehydrogenases↗
PubMed1983

Effect of increasing carbon chain length on organic acid transport by the choroid plexus: a potential factor in Reye's syndrome.

Transport of the anionic herbicide 2,4-dichlorophenoxyacetic acid by choroid plexus is inhibited significantly by several short and medium chain acids. For both monocarboxylic and dicarboxylic homologs, inhibition clearly increases with chain length. It appears that organic acid compounds of longer chain length, higher brain uptake index, and highest inhibition of choroid plexus transport would be the ones producing the most significant increases in intracranial pressure in metabolic encephalopathy such as Reye's syndrome.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1983

Metabolic response to carnitine in methylmalonic aciduria. An effective strategy for elimination of propionyl groups.

Patients with methylmalonic aciduria have an excessive intramitochondrial accumulation of acylcoenzyme A compounds that may reduce the availability of free coenzyme A (CoA) for normal metabolic requirements, producing profound metabolic disturbances. Giving carnitine to a patient with methylmalonic aciduria produced an increase in hippurate excretion (an index of intramitochondrial adenosine triphosphate (ATP) and CoA availability), a large increase in short chain urinary acylcarnitines, and a reduction in excretion of methylmalonate and methylcitrate. These acylcarnitines were shown by fast atom bombardment and B/E linked scan mass spectrometry to be propionylcarnitine and acetylcarnitine. Carnitine acts by removing (detoxifying) propionyl groups, thereby releasing CoA and restoring ATP biosynthesis and concentrations towards normal. L-carnitine may play a central role in maintenance of mitochondrial and cellular homoeostasis in methylmalonic aciduria and propionic acidaemia. These principles may provide an approach to the treatment of this and other disorders, inherited and acquired, in which accumulation of acyl CoA metabolites results in sequestration of free CoA, thereby perturbing metabolic homoeostasis.

Acetylcarnitine↗
PubMed1983

Saturable accumulation of the anionic herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D), by rabbit choroid plexus: early developmental origin and interaction with salicylates.

Transport of the anionic herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D) was examined in vitro via the isolated choroid plexus of adult and neonatal rabbits and in vivo via ventriculocisternal perfusion. In vitro, the facilitated transport of 2,4-D by the choroid plexus was established in the rabbit by as early as 3 days of age. Uptake in both adults and neonates took place against a concentration gradient via a saturable process that was inhibited by ouabain and hypothermia (0 degrees C). Probenecid and hippuric acid were effective dose-dependent inhibitors of 2,4-D transport in vitro. The major metabolite of salicylate, salicyluric acid, was also an effective inhibitor, more than its precursor, salicylate, or gentisic acid, a second salicylate metabolite. Neither phenol, acetaminophen nor glycine inhibited 2,4-D transport. Thus, the effects appear specific for those compounds which share the organic acid transport system. The role of carrier-mediated transport in the clearance of 2,4-D from cerebrospinal fluid (CSF) was also evaluated in vivo by ventriculocisternal perfusion. Steady-state clearance of 2,4-D from CSF exceeded that of inulin and was reduced in a dose-dependent fashion in the presence of salicylate. Neither CSF formation nor absorption rates were changed. These results indicate that 2,4-D is transported from the CSF via the organic anion transport system, and that inhibitors of this transport system may block its elimination from the brain in vivo, just as they block its transport by the isolated choroid plexus.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1982

Myocardial infarct extension: incidence and relationship to survival.

Myocardial infarct extension, defined as reelevation or reappearance of creatine phosphokinase-MB (CK-MB) 48 hours after the onset of symptoms, was evaluated prospectively in 56 consecutive patients with acute myocardial infarction. Myocardial infarct extension occurred in eight patients (14%). The sensitivity, specificity and predictive accuracy in the diagnosis of myocardial infarct extension were 63%, 85% and 42%, respectively, for recurrent chest pain requiring morphine; 50%, 65% and 19% for recurrent ST-segment elevation on routine 12-lead ECGs; and 88%, 63% and 28% for reelevation of total CK. Three of the eight episodes of extension were clinically silent. Four of eight patients (50%) with extension died, compared with one of 46 patients (2%) without extension (p = 0.0009). CK-MB persisted for 72 hours or longer in 16 patients and identified seven of eight patients who subsequently had infarct extension. We conclude that myocardial infarct extension is an infrequent complication of acute myocardial infarction and is associated with a very high mortality rate. Persistence of CK-MB for 72 hours or more identifies a subgroup of patients at high risk for subsequent infarct extension and death.

Creatine Kinase↗