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At least 19 recordsLinked to original sources
PubMed1991

Effects of hydroxocobalamin on rat cardiac papillary muscle.

Hydroxocobalamin is a rapid and powerful antidote in acute cyanide poisoning. The effects of hydroxocobalamin (0.1, 0.3, and 1 mM) on intrinsic myocardial contractility were studied on isolated rat cardiac papillary muscles (n = 10). Whatever the concentration, hydroxocobalamin did not modify the active isometric force and a slight increase in maximum unloaded shortening velocity was noted at 1 mM. Only 0.3 mM significantly impaired contraction-relaxation coupling under low load, suggesting a slight decrease in sarcoplasmic reticulum function. No changes in contraction-relaxation coupling under heavy load were noted, suggesting the lack of modification of myofilament calcium sensitivity. These results suggest that hydroxocobalamin does not induce noticeable changes in intrinsic myocardial contractility. An indirect mechanism might be involved in the previously reported decrease in cardiac function at supratherapeutic concentrations of hydroxocobalamin.

Animals↗
PubMed1978

Prevention of nitroprusside-induced cyanide toxicity with hydroxocobalamin.

To investigate hydroxocobalamin's role in preventing cyanide intoxication from sodium nitroprusside, we studied two groups of patients. One group received nitroprusside alone, and the other received nitroprusside and hydroxocobalamin. Red-cell and plasma cyanide levels were 83.44 +/- 23.12 and 3.51 +/- 1.01 microgram per 100 ml after nitroprusside alone and were 33.18 +/- 17.29 and 2.18 +/- 0.65 microgram per 100 ml after nitroprusside plus hydroxocobalamin. Acidosis developed in patients with red-cell cyanide levels higher than 75 microgram per 100 ml. When hydroxocobalamin infusion was stopped before sodium nitroprusside infusion was discontinued, blood cyanide levels and base deficit increased in a manner similar to that in the untreated group. The dose of nitroprusside used in each group did not differ statistically. These data show that hydroxocobalamin prevents cyanide transfer from red cells and plasma to tissue after nitroprusside metabolism, and thereby prevents cyanide toxicity from large intravenous doses of the drug.

Adult↗
PubMed1991

Enzymologic studies on patients with methylmalonic aciduria: basis for a clinical trial of deoxyadenosylcobalamin in a hydroxocobalamin-unresponsive patient.

Eleven patients with methylmalonic aciduria have been classified on the basis of detailed enzymology on cultured skin fibroblasts. Nine were classified as mutase deficiencies and were unresponsive to hydroxocobalamin in vivo or in vitro. One was classified as a Cbl A variant and was responsive to hydroxocobalamin therapy in vitro and in vivo. Patient 11 was classified as having deoxyadenosyltransferase deficiency (Cbl B). However, a clinical therapeutic trial of deoxyadenosylcobalamin resulted in no clinical or biochemical improvement. Further studies on the patient's cultured fibroblasts suggested that deoxyadenosylcobalamin fails to reach the mitochondria in an intact form. These studies show that detailed enzymologic classification is essential for the reliable evaluation of the response to therapeutic maneuvers; complementation studies alone may be inadequate to completely classify these patients. Therapy with deoxyadenosylcobalamin offers no advantages over the use of hydroxocobalamin in the treatment of patients with methylmalonic aciduria.

Alkyl and Aryl Transferases↗
PubMed1976

Nitroprusside-induced cyanide poisoning: antidotal effect of hydroxocobalamin.

Sodium nitroprusside was investigated as a potential source of cyanide poisoning, Whole-blood cyanide determinations were performed on arterial samples from baboons receiving nitroprusside while anesthetized. There was a statistically significant increase in cyanide levels, as well as development of tachyphylaxis and severe metabolic acidosis. Hydroxocobalamin (vitamin B12a) infused simultaneously with nitroprusside significantly lessened the increase in cyanide levels and eliminated the development of metabolic acidosis. Nitroprusside can cause cyanide intoxication in the baboon, and hydroxocobalamin appears to be an effective antidote.

Acid-Base Equilibrium↗
PubMed1976

Uptake of hydroxocobalamin by rat liver mitochondria. Binding to a mitochondrial protein.

Lysosome-free preparations of rat liver mitochondria take up hydroxo[57Co]cobalamin by a process which is dependent on mitochondrial swelling, rather than on energy or ion fluxes. The uptake system is saturable and unidirectional, leading to inside/outside concentration ratios of 17. The process also exhibits specificity: cyano[57Co]cobalamin is taken up less rapidly and to a lesser extent than hydroxocobalamin; methylcobalamin and adenoslcobalamin inhibit hydroxocobalamin uptake markedly, while cyanocobalamin does not. The [57Co]cobalamin ([57Co]Cbl) taken up is bound to a mitochondrial protein whose apparent molecular weight is 120,000 by Sephadex G-150 chromatography. Double reciprocal plots of bound [57Co]Cbl versus medium [57Co]Cbl concentration yield estimates for bound Cblmax of 29 pmol/mg of protein and for Kd is 8.2 muM. We conclude that mitochondrial uptake of cobalamins occurs via the diffusion of free cobalamins into the mitochondria and their subsequent binding to a high affinity mitochondrial protein(s) which we propose to be the source of the unidirectional character, the saturability, and the specificity of the uptake system.

Acid Phosphatase↗
PubMed1976

Hydroxocobalamin therapy of cyanide intoxication in guinea pigs.

The efficacy of hydroxocobalamin (vitamin B12a) as a specific, nontoxic antidote in acute cyanide poisoning was tested. Guinea pigs receiving lethal intravenous NaCN injections were treated with either vitamin B12a or saline solution. There was a statistically significant antidotal effect of the vitamin. No toxic effect was observed with large doses of the vitamin.

Animals↗
PubMed1992

[Do antidotes have a future? The example of 4-methylpyrazole and hydroxocobalamin].

In all probability the future progress in the "molecular" approach of therapy in acute poisoning within the next 20 years or so will be more rapid than the "mechanistic" approach, which undoubtedly has brought considerable improvements in the overall survival of these patients in the past. Principally molecular antidotes can act on three different levels, a) prior to the cellular targets (e.g. through modifications of toxokinetics), b) at specific cellular receptors through competition for binding (e.g. naloxone and flumazenil), and c) after the receptor sites through unspecific counteraction of toxic effects (e.g. betablockers for intoxications with theophylline). Immune-antidotes act prior to cellular receptors. Examples are the digoxin antibodies and the anti-venoms as well as the very recently developed and not yet clinically tested antibodies against antidepressive drugs and against colchicine. Two newer antidotes, the 4-methylpyrazole and the hydroxocobalamin, act also prior the cellular targets of the corresponding toxic compounds. Thus, 4-Methylpyrazole decreases the degradation of ethylene-glycol by inhibiting alcohol dehydrogenase, which results in a higher excretion of unchanged ethylene-glycol in urine. Hydroxycobalamin complexes with cyanides to form the physiologic vitamin B12. In order to allow an equimolar neutralization of ingested cyanides a concentrated preparation containing 5 g of hydroxycobalamin was developed, the pharmacokinetic properties of which are discussed.

Antidotes↗
PubMed1977

Intracellular binding of radioactive hydroxocobalamin to cobalamin-dependent apoenzymes in rat liver.

We identified previously an intracellular cobalamin (Cbl) binding protein(s) in cultured human fibroblasts, distinct from known Cbl "R" binders and absent from mutant cells deficient in the synthesis of the two Cbl coenzymes. In order to further characterize this binding activity, we have investigated its homologue in rat liver. After being transported to the liver by the serum protein transcobalamin II, [57Co]Cbl was bound by at least two distinct proteins, one cytosolic, the other mitochondrial. Labeled Cbl bound to cytosolic protein faster than or prior to the mitochondrial protein. With time there was a decline in radioactivity associated with the cytosolic binder and a coordinate increase in that associated with the mitochondrial binder. Although both proteins cochromatographed on Sephadex G-150 and had apparent molecular weights of 120,000, they were separated into two discrete components by polyacrylamide gel electrophoresis and by DEAE-cellulose chromatography. The cytosolic binder cochromatographed with N5-methyltetrahydrofolate:homocysteine methyltransferase activity (5-methyltetrahydropteroyl-L-glutamate:L-homocysteine S-methyltransferase, EC 2.1.1.13); the mitochondrial one with methylmalonyl CoA mutase activity (methylmalonyl-CoA CoA-carbonylmutase, EC 5.4.99.2). These proteins were distinguished further by the chemical forms of [57Co]Cbl found with them, hydroxocobalamin and methylcobalamin with the cytosolic protein and adenosylcobalamin with the mitochondrial one. These results suggest that intracellular Cbl binding activity in rat liver can be accounted for by attachment of Cbl to the two known Cbl-dependent apoenzymes, methylmalonyl CoA mutase and methyltetrahydrofolate methyltransferase. The mechanism and significance of the observered binding protein deficiency in mutant human fibroblasts must, therefore, be re-evaluated.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1977

Conversion of hydroxo(aquo) cobalamin to sulfitocobalamin in the absence of light: a reaction of importance in the identification of the forms of vitamin B12, with possible clinical significance.

During determinations of the forms of vitamin B12 in foods and human tissues several samples yielded a growth zone on bioautography which was distinct from those due to methylcobalamin, adenosylcobalamin, hydroxocobalamin, or cyanocobalamin. The material responsible for this growth zone was identified as sulfitocobalamin and the mechanisms in its formation from hydroxocobalamin involve absence of light and the presence of bisulphite ions derived from atmospheric sulfur dioxide or indigenous sulfite ions. The formation of sulfitocobalamin during the extraction of cobalamins from foods and tissues can be prevented by reception and homogenization of the material in an ammonia buffer instead of water; the hydroxocobalamin is then converted to ammonia cobalamin, which is more resistant to attack by (bi)sulfite ions. The conversion of hydroxo(aquo)cobalamin to sulfitocobalamin in the dark can be rapid, and materials for analysis should be placed in the ammonia buffer before darkroom work is begun. The rapid conversion of hydroxo(aquo)cobalamin to sulfitocobalamin in the dark raises the possibility that hydroxocobalamin in foods may be converted to the less well absorbed sulfitocobalamin in the upper gastrointestinal tract.

Animals↗
PubMed1979

Tobacco amblyopia: the effect of treatment on the electroretinogram.

In seven recently diagnosed and untreated patients with tobacco amblyopia the light and dark adapted electroretionograms were recorded together with visual acuity, central fields and the Farnsworth-Munsell 100-Hue test. After 3 months treatment with injections of hydroxocobalamin all these tests were repeated. An improvement in visual acuity resulted in all cases. A significant reduction in the Farnsworth-Munsell total error score of the seven patients was noted (p less than 0.01). A significant increase in the amplitude of the light adapted b-wave of the ERG was found (0.01 less than p less than 0.02) following the course of hydroxocobalamin injections. No other significant changes in the ERG were demonstrated. It is suggested that the ERG changes demonstrated an improvement in an abnormal biochemical state in those bipolar and perhaps Müller cell of the inner nuclear layer of the retina which make electrophysiological connnections chiefly with foveal cones.

Aged↗
PubMed1976

The forms of vitamin B12 in foods.

1. The forms of vitamin B12 were determined in foods, most of which had been prepared for consumption. 2. Five forms were detected: adenosylcobalamin, hydroxocobalamin, methylcobalamin, cyanocobalamin and sulphitocobalamin. Adenoxylcobalamin and hydroxocobalamin were the predominant forms. 3. The intestinal absorption of [57Co]sulphitocobalamin was estimated and found to be lower than that of [58Co]cyanocobalamin.

Adult↗
PubMed1979

Inborn errors of cobalamin metabolism: effect of cobalamin supplementation in culture on methylmalonyl CoA mutase activity in normal and mutant human fibroblasts.

We have examined the effect of addition of hydroxocobalamin to growth medium on the activity of the adenosylcobalamin-requiring enzyme methylmalonyl CoA mutase in normal human fibroblasts and in mutant human fibroblasts derived from patients with inherited methylmalonicacidemia. The mutant cell lines were assigned to four distinct genetic complementation groups (cbl A, cbl B, cbl C, and cbl D), each deficient in some step in the synthesis of adenosylcobalamin from hydroxocobalamin. After control cells were grown in cobalamin-supplemented medium, mutase holoenzyme activitiy increased markedly in a time- and concentration-dependent fashion. Growth in cobalamin-supplemented medium had no effect on mutase activity in some mutant lines belonging to the cbl B group, while activity increased severalfold in other cbl B mutants and in all cbl A, cbl C, and cbl D mutants examined, although mutase activity was still less than 10% of control. Comparison of mutase holoenzyme activity and total propionate pathway activity suggests that enhancement of mutase activity in mutant cells after cobalamin supplementation to values 5--10% of control may be sufficient to overcome the inherited metabolic block and to restore total pathway activity to normal.

Amino Acid Metabolism, Inborn Errors↗
PubMed1976

Tissue distribution of endogenous cobalamins and other corrins in the rat, cat and guinea pig.

1. Methylcobalamin, adenosylcobalamin, hydroxocobalamin and cyanocobalamin have been estimated by a chromato-bioautographic techniques in 16 tissues from healthy rats and in five guinea pig tissues. 2. Plasma and erythrocyte cobalamins have been estimated in rats, cats and guinea pigs and the results compared with those in man. 3. Unidentified corrins were detected in 8 of the 16 rat tissues and in 3 of the 5 guinea pig tissues analysed, but were not present in tissues from specific pathogen-free rats nor in the standard laboratory diet. 4. Adenosylcobalamin was the major corrin in 8 of the 16 rat tissues. In the remainder hydroxocobalamin predominated or was present in equal proportions with adenosylcobalamin. Methylcobalamin was detected in the majority of rat tissues but at levels much lower than those in human tissues. Small amounts of cyanocobalamin were detected also and levels were higher than those of methylcobalamin in 8 of the 16 tissues. 5. In the rat, cat and guinea pig, levels of methylcobalamin and hydroxobalamin were higher in erythrocytes than in plasma, a pattern almost the complete reverse of that in man.

Adrenal Glands↗
PubMed1979

Interference by methylcobalamin analogues with synthesis of cobalamin coenzymes in human lymphocytes in vitro.

1. 72 h uptake of cyano[57Co]cobalamin and formation of 57Co-labelled methylcobalamin, adenosylcobalamin and hydroxocobalamin has been estimated with and without the addition of methylcobalamin analogues in phytohaemagglutinin-stimulated lymphocytes from healthy human subjects. 2. Difluorochloromethylcobalamin reduced cell uptake of cyanocobalamin and caused a disproportionate reduction in synthesis of adenosylcobalamin. 3. Methylcobalamin-palladium trichloride reduced cell uptake of cyanobalamin more effectively than did difluorochloromethylcobalamin and reduced the formation of methylcobalamin, adenosylcobalamin and hydroxocobalamin in proportion. 4. The results suggest that in addition to inhibiting uptake of cyanocobalamin, one or both compounds may have interfered directly with the mechanism of synthesis of the cobalamin coenzymes.

Cobamides↗