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PubMed1984

Significance of isomerization in hydroxocobalamin.

Hydroxocobalamin is present in fairly large proportions both in foods and in the human body and apparently plays an important biological role. Since cyanocobalamin seems to play hardly any significant biochemical role in healthy humans, several physicians prefer to administer hydroxocobalamin to vitamin B12 deficient patients. We find that hydroxocobalamin in solution isomerizes very readily at room and lower temperatures. Our observations raise the question whether "Mother Nature" has gone awry in using an easily convertible substance like hydroxocobalamin or that the new isomeric forms play some significant role. These observations may also have a bearing on the reported occurrence of unidentified corrinoids in animal tissues, human red cells, liver and brain.

Chemical Phenomena↗

PubMed2006

Sodium thiosulfate or hydroxocobalamin for the empiric treatment of cyanide poisoning?

Cyanide poisoning must be seriously considered in victims of smoke inhalation from enclosed space fires; it is also a credible terrorism threat agent. The treatment of cyanide poisoning is empiric because laboratory confirmation can take hours or days. Empiric treatment requires a safe and effective antidote that can be rapidly administered by either out-of-hospital or emergency department personnel. Among several cyanide antidotes available, sodium thiosulfate and hydroxocobalamin have been proposed for use in these circumstances. The evidence available to assess either sodium thiosulfate or hydroxocobalamin is incomplete. According to recent safety and efficacy studies in animals and human safety and uncontrolled efficacy studies, hydroxocobalamin seems to be an appropriate antidote for empiric treatment of smoke inhalation and other suspected cyanide poisoning victims in the out-of-hospital setting. Sodium thiosulfate can also be administered in the out-of-hospital setting. The efficacy of sodium thiosulfate is based on individual case studies, and there are contradictory conclusions about efficacy in animal models. The onset of antidotal action of sodium thiosulfate may be too slow for it to be the only cyanide antidote for emergency use. Hydroxocobalamin is being developed for potential introduction in the United States and may represent a new option for emergency personnel in cases of suspected or confirmed cyanide poisoning in the out-of-hospital setting.

Animals↗

PubMed1999

Effects of hydroxocobalamin and carboxy-PTIO on nitrergic transmission in porcine anococcygeus and retractor penis muscles.

The effects of carboxy-PTIO and hydroxocobalamin were studied on nitrergic transmission in anococcygeus and retractor penis muscles taken during post mortem examination from young male pigs. In both muscles under resting conditions, electrical field stimulation (EFS) caused contractions that were sensitive to tetrodotoxin (1 microM) and were greatly inhibited by prazosin (1 microM) and guanethidine (10-30 microM), but were not significantly affected by atropine (1 microM). In the anococcygeus muscle, but not in the retractor penis muscle, guanethidine produced a prolonged contraction. After tone was raised by guanethidine in the anococcygeus or by phenylephrine (1 microM) in the presence of guanethidine in the retractor penis, EFS caused tetrodotoxin-sensitive relaxations. The EFS-induced relaxations were abolished by the NO synthase inhibitor N(G)-L-nitro-arginine methyl ester (L-NAME; 100 microM) and its effect was partly overcome by L-arginine (1 mM), indicating it was mediated by nitrergic nerves. Carboxy-PTIO (0.1-1 mM) had no significant effect in reducing stimulation-induced nitrergic relaxations in either muscle. However, hydroxocobalamin (0.1-1 mM) caused concentration-dependent reductions of nitrergic relaxations in both muscles. Relaxations to exogenous nitric oxide (1 microM) in both muscles were abolished by carboxy-PTIO (0.3 mM) and hydroxocobalamin (0.1 mM). There were no differences in reactivity to carboxy-PTIO or hydroxocobalamin between anococcygeus and retractor penis muscles from the same species (pig). The finding also confirms earlier observations that the nitrergic transmitter is generally resistant to the NO-scavenger carboxy-PTIO.

Animals↗

PubMed1998

Nasal absorption of hydroxocobalamin in healthy elderly adults.

AIMS: To investigate the nasal absorption of hydroxocobalamin in 10 healthy elderly adults. METHODS: In a cross-over study, blood samples were collected before administration of the drug and after 10, 20, 30, 40, 60, 120, 180 and 240 min. The plasma cobalamin concentration was determined by competitive radioisotope binding technique. RESULTS: The maximal plasma cobalamin concentration (Cmax) after nasal administration of 750 microg hydroxocobalamin was 1900 +/- 900 pmol l(-1) (mean +/- s.d.). The maximal plasma cobalamin concentration was reached in 35 +/- 13 min (t[max]). The Cmax after nasal administration of 1500 microg hydroxocobalamin was 3500 +/- 2500 pmol l(-1) with a t(max) of 28 +/- 16 min. Both the AUC(0,240 min) and AUC(0,00) increased significantly with an increase of the dose from 750 microg to 1500 microg (P = 0.037 and P = 0.028, respectively). The nasal spray was well tolerated. No signs of irritation or local sensitivity were noted. CONCLUSIONS: The nasal absorption of hydroxocobalamin in healthy elderly adults is rapid, high and well tolerated.

Absorption↗

PubMed1993

Differential effects of hydroxocobalamin on NO-mediated relaxations in rat aorta and anococcygeus muscle.

In rat aortic rings, hydroxocobalamin (10-30 microM) produced concentration-dependent reductions of the relaxant action of nitric oxide (NO) and the endothelium-dependent, NO-mediated, relaxant action of acetylcholine. In anococcygeus muscles, hydroxocobalamin (10-30 microM) reduced but also prolonged, NO-induced relaxations, but had no effect on non-adrenergic, non-cholinergic-mediated relaxations. Hydroxocobalamin had no effect on the NO-independent relaxant action of papaverine in either tissue. It is suggested that hydroxocobalamin sequesters NO by forming nitrosocobalamin. Nitrosocobalamin did not relax aortic rings, but produced a slowly developing and prolonged relaxation of anococcygeus muscles.

Acetylcholine↗

PubMedDate not supplied

[Interference of hydroxocobalamine treatment on commun biochemical determinations].

Hydroxocobalamin, antidote of the cyanide poisoning, is a red and water soluble pigment, which colors biological mediums. The interferences caused by this molecule are studied for plasma pools overloaded with hydroxocobalamin for concentrations from 0 to 1,125 mg.L-1. The results of 16 biochemical parameters on Vitros 750 XRC (Ortho-clinical Diagnostics) and of 23 biochemical parameters on Cobas Integra 700 (Roche Diagnostics) are examined. With this analytical system, unconjugated and conjugated bilirubin, creatinin, and CK results are changed as soon as plasma concentration of hydroxocobalamin reachs 124 mg.L-1. For the Vitros 750 XRC, ASAT, iron, creatinin, phosphorus are more sensitive to this interference. But, other results are changed for the two analytical systems for superior hydroxocobalamin concentrations.

Blood Chemical Analysis↗

PubMed1985

Depletion of extracellular cysteine with hydroxocobalamin and ascorbate in experimental murine cancer chemotherapy.

Treatment of mice bearing P388 lymphocytic leukemia with combined hydroxocobalamin (0.1 mmol/kg) and sodium ascorbate (1.0 mmol/kg) for 10 consecutive days resulted in 70% increase in survival. Treatment with dehydroascorbate (1.0 mmol/kg) similarly increased survival. The extended treatment for 15 days posttumor inoculation failed to improve survival as did lowering the tumor inocula from 10(6) to 10(4) cells in similarly treated mice. P388 cells in primary culture with cystine as a source of cysteine require exogenous thiols or disulfides for growth and also grow with cysteine but only when trace copper is sequestered with bathocuproine sulfonate. This is due to the copper catalyzed oxidation of cysteine to cystine, which these cells cannot utilize. Cells grew in medium preincubated for 8 h with cysteine and bathocuproine sulfonate, but lysed when the preincubated medium included hydroxocobalamin (10 microM) and sodium ascorbate (100 microM). This defect was corrected by resupplementation with cysteine or cystine plus bishydroxyethyl disulfide after addition of the cells. Further support for cysteine depletion as a factor in therapy is obtained by therapeutic interference with 4-thiamethionine (25 mumol/kg). This mixed disulfide of cysteine and methyl mercaptan enters cells as a methionine analogue, is reduced to supply cysteine, and thus withstands the oxidative environment that limits the utilization of cysteine as a nutrient. These results suggest that dehydroascorbate is generated from combined hydroxocobalamin and ascorbate and accounts for the thiol-prive activity of combined hydroxocobalamin and ascorbate therapy. The ultimate failure of therapy by thiol oxidation may be due to the increased availability of cysteine produced by host tissues, possibly infiltrating macrophages, that occurs independently of extended treatment and the size of the tumor inoculum.

Animals↗

PubMed1990

In vitro demonstration of the antidotal efficacy of hydroxocobalamin in cyanide poisoning.

The effects of sodium cyanide (1 mM) and the antidotal action of hydroxocobalamin (1 mM) were studied on rat cardiac papillary muscle. A 10-min period of exposure to cyanide induced a marked decrease in inotropy as shown by a decrease in the maximum unloaded shortening velocity (Vmax: 64 +/- 11% of precyanide values, p <0.01) and active isometric force (AF/s: 35 +/- 13%, p <0.01). The impairment of contraction-relaxation coupling under low load and the nearly complete disappearance of the load sensitivity of relaxation suggested a decrease in sarcoplasmic reticulum function. The proportional acceleration in isometric relaxation suggested a decrease in myofilament calcium sensitivity. There was a nearly complete recovery from cyanide poisoning after 5 min of exposure to hydroxocobalamin, whereas in a control group receiving cyanide alone, the mechanical parameters remained unchanged or were further impaired. The effects of hydroxocobalamin developed very quickly, beat to beat. The main toxic target of cyanide is brain and heart cytochrome oxidase, and brain damage appears only a few minutes after the onset of anoxia. Because hydroxocobalamin is a rapid and powerful antidote, it may be useful in the treatment of acute cyanide poisoning.

Journal Article↗

PubMed1995

Hydroxocobalamin and haemoglobin differentiate between exogenous and neuronal nitric oxide in the rat gastric fundus.

In longitudinal strips of rat gastric fundus, hydroxocobalamin (30 microM) significantly reduced relaxations to sodium nitroprusside (100 nM), nitric oxide (NO; 5 microM) and S-nitrosocysteine (3 microM), whereas responses to non-adrenergic, non-cholinergic (NANC) nerve stimulation were only slightly reduced. The stimulation-induced relaxations were markedly reduced by the NO synthase inhibitor NG-nitro-L-arginine (100 microM). Hydroxocobalamin (30 microM) enhanced relaxations to S-nitrosoglutathione (1 and 3 microM), and had no effect on responses to vasoactive intestinal polypeptide (1 nM). Haemoglobin (10 microM) significantly reduced relaxations to sodium nitroprusside, NO, S-nitrosocysteine and S-nitrosoglutathione, but did not affect responses to NANC nerve stimulation or vasoactive intestinal polypeptide. The results suggest that hydroxocobalamin and haemoglobin can differentiate between exogenous and neuronally released NO, and that the transmitter released from nitrergic nerves in the rat gastric fundus is not free NO or the nitrosothiols, S-nitrosocysteine and S-nitrosoglutathione.

Analysis of Variance↗

PubMed2005

Comparative effects of hydroxocobalamin and cyanocobalamin on plasma homocysteine concentrations in end-stage renal disease.

End-stage renal disease (ESRD) is associated with marked hyperhomocysteinemia which is only partially corrected by folic acid and pyridoxine supplementation. We and others have reported that various forms of parenteral cobalamin reduce plasma total homocysteine (tHcy) concentrations of patients with ESRD substantially below the lowest levels attainable with folic acid. We here report a 16-week randomized controlled crossover trial which directly compared the Hcy-lowering effect of intravenous hydroxocobalamin (HC) with that of cyanocobalamin (CC). Folic acid- and vitamin B12-replete maintenance hemodialysis patients were randomly assigned to receive either 1 mg intravenous HC weekly for 8 weeks followed by CC for a further 8 weeks, or CC for 8 weeks followed by HC for 8 weeks. Hydroxocobalamin increased serum cobalamin concentrations 40-fold, whereas CC increased them only 10-fold, but both treatments reduced plasma tHcy concentrations similarly by 33% (P < .001). Crossover to the alternate form of the vitamin greatly affected the serum cobalamin concentration but was without further effect on the plasma tHcy concentration. These results confirm that weekly cobalamin injections lower plasma tHcy concentrations of hemodialysis patients well below the level attainable with folic acid. Hydroxocobalamin and CC are equipotent despite producing very different serum cobalamin concentrations.

Cross-Over Studies↗

PubMed2004

Reductive dechlorination of alpha-, beta-, delta-, and gamma-hexachlorocyclohexane isomers by hydroxocobalamin in the presence of either dithiothreitol or titanium(III) citrate as reducing agents.

The effect of the reducing potential on the reductive dehalogenation of the different HCH (hexachlorocyclohexane) isomers has not yet been studied. In the present study, the potential for dehalogenation of (alpha-, beta-, delta-, and gamma-HCH isomers by the dithiothreitol (DTT) and titanium(III) citrate (reducing potential at pH 7, -0.33 and -0.48 V, respectively), with and without the addition of hydroxocobalamin was investigated. In the presence of DTT without catalyst, there was no disappearance of any of the HCH isomers studied after 1 h of treatment. However, disappearance of the gamma- and alpha-HCH isomers was observed during the same time period when titanium(III) citrate was used as the reductant in the absence of catalyst (62.9 and 16.6% disappearance, respectively). Addition of the hydroxocobalamin to the DTT system favored mainly the disappearance of gamma- and alpha-HCH (92.9 and 30.8% disappearance after 1 h, respectively); disappearance of delta-HCH and beta-HCH was small (11.9%) or negligible, respectively. Addition of the hydroxocobalamin to the titanium(III) citrate system favored the degradation of all HCH isomers under study: beta- and alpha-HCH completely disappeared to undetectable levels (<0.1%) after 1 and 2 min, respectively; degradation of delta-HCH and beta-HCH was slower than that of the other two isomers, although they had almost completely disappeared (99.9 and 99.6% disappearance, respectively) after 10 and 60 min, respectively. The order of disappearance, gamma-HCH > alpha-HCH > delta-HCH > beta-HCH, coincided with a decreasing order of the axially positioned Cl atoms of these isomers (considering their thermodynamically most stable configuration). This study is the first description of the rapid degradation of delta- and beta-HCH under abiotic conditions, and the results demonstrate the effect of the reducing potential on the reductive dehalogenation of HCH isomers.

Citric Acid↗

PubMed1999

Effect of hydroquinone, hydroxocobalamin and carboxy-PTIO on non-adrenergic non-cholinergic nerve mediated relaxations of the rat duodenum.

Relaxation induced by NANC-nerve stimulation is reduced by nitric oxide synthase (NOS) inhibitors but not by superoxide generators or NO scavengers, casting doubts on the precise nature of the neurotransmitter being released by these nerves. The lack of effect of superoxide anion generators to inhibit nitrergic nerve-mediated relaxations has been attributed to the protective action of high tissue levels of superoxide dismutase (SOD). The effects of hydroquinone, hydroxocobalamin and carboxy-PTIO, three NO inactivators which do not depend on superoxide anion generation, upon nitrergic nerve-mediated relaxations of the rat proximal duodenum were determined in order to elucidate whether they are mediated by free NO. GABA and nicotine caused relaxations of isolated segments of the rat proximal duodenum in a concentration-dependent manner that were abolished by tetrodotoxin (TTX). Similarly, transmural electrical stimulation (TES) caused frequency-dependent relaxations that were also abolished by TTX. The NOS inhibitors L-NAME and L-NOARG reduced in a concentration-dependent manner nerve-mediated relaxations elicited by TES, nicotine and GABA. The effect of NOS inhibitors was prevented by L-arginine but not D-arginine. NO caused concentration-dependent relaxations that were not affected by TTX or L-NOARG but were abolished by hydroquinone, hydroxocobalamin and carboxy-PTIO. In contrast, these compounds failed to affect TES-, nicotine- and GABA-induced relaxations. The lack of effect of hydroquinone, hydroxocobalamin and carboxy-PTIO upon nerve-mediated relaxations was unaltered by pretreatment with the SOD irreversible inhibitor DETCA. The present findings show that nitrergic nerve-mediated relaxations of the rat duodenum are unaffected by NO inactivators that do not generate superoxide anion. It is suggested that either a NO-containing molecule that is unreactive with the inactivators tested is the inhibitory neurotransmitter released by nitrergic nerves or that NOS activity fulfills another role in nitrergic nerves which could be related to the release of an still unidentified transmitter.

Animals↗

PubMed2002

Hydroxocobalamin, a nitric oxide scavenger, in the prophylaxis of migraine: an open, pilot study.

Drugs which directly counteract nitric oxide (NO), such as endothelial receptor blockers, NO-synthase inhibitors, and NO-scavengers, may be effective in the acute treatment of migraine, but are also likely to be effective in migraine prophylaxis. In the underlying pilot study the prophylactic effect of the NO scavenger hydroxocobalamin after intranasal administration in migraine was evaluated. Twenty patients, with a history of migraine of > 1 year and with two to eight migraine attacks per month, were included in an open trial. A baseline period was followed by an active treatment period of 3 months with 1 mg intranasal hydroxocobalamin daily. Patients were instructed to complete a diary in which details of each attack were described. A reduction in migraine attack frequency of >/ or = 50% was seen in 10 of 19 patients, which corresponds to 53% of the patients (responders). A reduction of > or = 30% was noted in 63% of the patients. The mean attack frequency in the total study population showed a reduction from 4.7 +/- 1.7 attacks per month to 2.7 +/- 1.6 (P < 0.001). For the responders the migraine attack frequency was reduced from 5.2 +/- 1.9 (baseline) to 1.9 +/- 1.3 attacks per month (P < 0.005), while for those who did not respond a non-significant reduction was found: 4.1 +/- 1.4 to 3.7 +/- 1.5 (P > 0.1). A reduction was also observed for the total duration of the migraine attacks per month, the total number of migraine days per month and the number of medication doses for acute treatment used per month. This is the first prospective, open study indicating that intranasal hydroxocobalamin may have a prophylactic effect in migraine. As a percentage of responders in prophylactic trials of > 35-40% is unlikely to be a placebo effect, a double-blind study is warranted.

Adult↗

PubMed1981

Effects of cyanide antidotes used with sodium nitroprusside infusions: sodium thiosulphate and hydroxocobalamin given prophylactically to dogs.

Cyanide antidotes were given to dogs before an infusion of sodium nitroprusside 1.5 mg kg-1 for 1 h. Dogs given thiosulphate 75 mg kg-1 had significantly lower plasma and red cell cyanide concentrations while plasma thiocyanate concentrations were significantly increased in comparison with control. These changes were associated with only minimal disturbance of tissue oxygenation. There was no effect on red cell cyanide or thiocyanate concentrations in dogs treated with hydroxocobalamin 1.5 mg kg-1, but plasma cyanide concentrations were significantly greater than in those receiving no antidote although there was less evidence of impaired oxygenation. There was no evidence of a synergistic action between thiosulphate and hydroxocobalamin. The vascular response to nitroprusside was unchanged in the thiosulphate-treated dogs, but was significantly greater in those given hydroxocobalamin. The implications for prophylaxis and treatment of cyanide poisoning following nitroprusside overdose are discussed.

Animals↗

PubMed1996

Blockade of nitrergic transmission by hydroquinone, hydroxocobalamin and carboxy-PTIO in bovine retractor penis: role of superoxide anion.

1. The effects of inhibiting endogenous Cu/Zn superoxide dismutase (SOD) with diethyldithiocarbamate (DETCA) were examined on the ability of hydroquinone, hydroxocobalamin and carboxy-PTIO to block nitrergic relaxation in the bovine retractor penis (BRP) muscle. 2. Incubation of strips of BRP with DETCA (3 mM) for 2 h reduced SOD activity from 73.1 +/- 15.7 to 8.2 +/- 1.9 units mg-1 protein. 3. Hydroquinone (10 microM--1 mM) produced weak inhibition of nitrergic (4 Hz, 10 s) relaxation in control strips of BRP, but powerful inhibition in strips treated with DETCA (3 mM, 2 h). Exogenous SOD (250 units ml--1) produced a partial blockade of the ability of hydroquinone to inhibit nitrergic relaxation in DETCA-treated strips. 4. In an assay of SOD-inhibitable reduction of cytochrome C, hypoxanthine (0.1 mM)/xanthine oxidase (16 munits ml-1) and pyrogallol (10 microM), led to the rapid generation of superoxide anion. Hydroquinone (10 microM) also led to the generation of the free radical, although the rate of generation was slower. 5. Two NO-scavenging agents, hydroxocobalamin (0.1 microM--1 mM) and carboxy-PTIO (0.1-1 mM), produced concentration-dependent blockade of nitrergic relaxation of the BRP. The magnitude of the blockade induced by these agents was unaffected following treatment with DETCA or SOD. 6. The findings with hydroquinone support our previous proposal that endogenous Cu/Zn SOD plays a vital role in protecting nitrergic neurotransmission from inactivation by superoxide anion. Results with hydroxocobalamin and carboxy-PTIO are consistent with the known ability of these agents to scavenge NO. The nitrergic neurotransmitter in the BRP thus appears to have the properties of NO.

Animals↗

PubMed1986

The use of hydroxocobalamin in the Schilling test.

Hydroxocobalamin and cyanocobalamin have been compared as the 'flushing dose' in the Schilling test. In healthy, haematologically normal subjects excretion of the test dose was greater following a hydroxocobalamin flushing dose than following a cyanocobalamin flushing dose, and to a lesser extent this was also true in patients requiring investigation. There were occasional discrepant results, but in general it appears that, although reference values differ, hydroxocobalamin is a suitable replacement for cyanocobalamin in the Schilling test.

Adult↗

PubMed1968

Microbial degradation of corrinoids. VI. Reduction of hydroxocobalamin by cell-free particles from Pseudomonas rubescens.

Cell-free particles from Pseudomonas rubescens have been shown to reduce hydroxocobalamin to vitamin B(12r). The particles are unable to reduce the B(12r) to B(12s). The reduction of hydroxocobalamin is dependent upon reduced nicotinamide adenine dinucleotide and is stimulated by flavin adenine dinucleotide. Cobinamide and diaquocobinamide were reduced at 25 and 10%, respectively, of the rate of hydroxocobalamin. Cyanocobalamin, coenzyme B(12), pseudovitamin B(12), and diaquopseudocobalamin were not reduced. Reduced nicotinamide adenine dinucleotide phosphate and flavin mononucleotide were not active. Diaphorase and xanthine oxidase activity were not present in the particulate fraction.

Cell-Free System↗

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↗