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PubMed1998

Randomized, double-blind, placebo-controlled study of the safety and efficacy of vitamin B complex in the treatment of nocturnal leg cramps in elderly patients with hypertension.

Nocturnal leg cramps is a common and troublesome problem in elderly individuals, and their etiology is unknown. Treatment with quinine is a common practice, but the effectiveness of the drug is doubtful and adverse drug effects are common. This randomized, double-blind, placebo-controlled study was conducted to evaluate the safety and efficacy of vitamin B complex capsules (fursulthiamine 50 mg, hydroxocobalamin 250 micrograms, pyridoxal phosphate 30 mg, and riboflavin 5 mg) in 28 elderly patients with hypertension who had severe nocturnal leg cramps that disturbed their sleep. Self-reported ratings of leg cramp frequency, duration, and intensity were used to evaluate severity of nocturnal leg cramps. Both the patients taking vitamin B capsules (n = 14) and those taking placebo (n = 14) received medications three times daily, and were examined regularly at 2-week intervals for 3 months. After 3 months, 86% of the patients taking vitamin B had prominent remission of leg cramps, whereas those taking placebo had no significant difference from baseline. Treatment with vitamin B complex significantly reduced the frequency, intensity, and duration of nocturnal leg cramps. Because quinine is not without potential for side effects, and vitamin B complex is a relatively safe and effective alternative, clinicians should reconsider the treatment of choice for nocturnal leg cramps.

Aged↗
PubMed2001

Evidence for the interaction between nitric oxide and vasoactive intestinal polypeptide in the mouse gastric fundus.

The involvement of nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) in nonadrenergic noncholinergic (NANC) nerve-induced relaxation and the interaction between NO and VIP were investigated in the mouse gastric fundus. N(omega)-nitro-L-arginine (L-NOARG; 100 microM) completely inhibited the NANC relaxations induced by electrical stimulation (ES) (0.5, 1, 2, 4, and 8 Hz; 25 V; 1 ms; 15-s trains). Hemoglobin (20 microM), hydroxocobalamin (100 microM), and 1H-[1,2,4,]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 microM) diminished ES-induced relaxations, but alpha-chymotrypsin (10 U/ml) and VIP antiserum (1/200 dilution) had no effect on NANC relaxations. L-NOARG (100 microM) did not have any effect, whereas ODQ (10 microM) attenuated sodium nitroprusside (SNP; 100 nM)-induced relaxations. alpha-Chymotrypsin (10 U/ml) had no effect on the response to SNP. Furthermore, alpha-chymotrypsin (10 U/ml) abolished and VIP antiserum (1/200 dilution) diminished VIP (50 nM)-induced relaxations. L-NOARG (100 microM) caused an inhibition of VIP-induced relaxation that was reversed by L-arginine (1 mM) but not by D-arginine (1 mM). Similarly, ODQ (10 microM) inhibited the responses to VIP. 2-Amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (5 microM) had no effect on these relaxations. L-NOARG (100 microM) and ODQ (10 microM) did not affect isoproterenol (10 nM)-induced relaxations. In conclusion, these results provide evidence that NO is involved in NANC nerve-induced relaxation and the participation of VIP (and related neuropeptides) cannot be excluded in causing relaxation of mouse gastric fundus muscle strips. These findings support the idea that VIP directly stimulates the production of NO by increasing NOS activity and thereby activating soluble guanylyl cyclase in smooth muscle.

Adrenergic beta-Agonists↗
PubMed2004

Chromatographic study of photolysis of aqueous cyanocobalamin solution in presence of vitamins B and C.

Aqueous cyanocobalamin solutions (pH 1-7) have been photolysed in the presence of individual B (thiamine HCl, riboflavin, nicotinamide and pyridoxine HCl) and C (ascorbic acid) vitamins with visible light. The degraded solutions were subjected to thin-layer chromatography using several solvent systems and the Rf values of the vitamins and their photoproducts were determined. The major photoproducts have been identified by comparison of their Rf values with those of the authentic compounds. Cyanocobalamin leads to the formation of hydroxocobalamin. Thiamine HCl gives rise to 4-methyl-5-(Beta-hydroxyethyl) thiazole and 2-methyl-4-amino-5-hydroxymethyl-pyrimidine in trace amounts whereas riboflavin degrades extensively to formylmethylflavin and lumichrome, and to a smaller extent to lumiflavin and carboxymethylflavin. Ascorbic acid is oxidized to dehydroascorbic acid. Nicotinamide and pyridoxine HCl do not undergo any degradation. The extent of degradation depends upon the pH.

Journal Article↗
PubMed1993

Stabiliiy of cyanocobalamin solutions insunlight and artificial light.

A comparison of the degradation of cyanocobalamin (vitamin B(12)) solutions on exposure to sunlight and artificial light has been made using two concentrations, i.e. 950 mug/ml (corresponding to parenteral solutions) and 95 mu/ml (1:10 dilution) at pH 4.0, 5.5 and 7.0. Cyanocobalamin and the photoproduct, hydroxocobalamin (vitamin B(12b)), have been determined by a two component spectrophotometric method at 550 and 525 nm. Cyanocobalamin loss (950 mug/ml and 95 mug/ml) on exposure to sunlight for 2 hours amounts to 14.7-21.0% and 56.3-81.5% respectively indicating that light intensity is the rate determining factor in the reaction. In artificial light for 2 hours B(12) (950 mug/ml and 95 mug/ml) loses 2.7.19.4% and 1.5-27.7% respectively. Thus B(12) degradation in sunlight is greater compared to that of the artificial light, with the formation of some oxidation products, in addition to B(12b).

Journal Article↗
PubMed1991

Mechanism of conversion of human apo- to holomethionine synthase by various forms of cobalamin.

Methionine synthase catalyzes the conversion of N5-methyltetrahydrofolate and homocysteine to tetrahydrofolate and methionine. Methylcobalamin (Me-Cbl) is tightly bound to methionine synthase and is required for enzymatic activity. When added to crude tissue homogenates, Me-Cbl stimulates methionine synthase but similar stimulation is observed with hydroxocobalamin, cyanocobalamin (CN-Cbl), and adenosyl-Cbl, although the mechanisms involved are unknown. We prepared human apomethionine synthase and studied its activation in the presence of [14C]CN-Cbl and [14CH3]Me-Cbl with concentrations of 2-mercaptoethanol ranging from 0.15 to 100 mM. We observed that the removal of the labeled upper axial ligands from CN-Cbl and Me-Cbl both paralleled the activation of human apomethionine synthase. Spectral studies employing CN-Cbl and Me-Cbl showed that both forms of Cbl must be converted to Cob(II)alamin before they can bind to human apomethionine synthase and convert it to its activated holoenzyme form. Studies with 14 different Cbl analogues with alterations in various portions of the corrin ring and the nucleotide showed that all of the analogues were able to fully activate human methionine synthase when they were reduced with 2-mercaptoethanol. Full activation occurred at lower concentrations of many of the Cbl analogues than occurred with Cbl itself. We conclude that Me-Cbl and other forms of Cob(III)alamin do not bind to human apomethionine synthase and that all must first be reduced to Cob(II)alamin before such binding can occur. The fact that human methionine synthase shows little absolute specificity for alterations in various portions of the Cbl molecule suggests that the potent inhibition of mammalian methionine synthase activity observed in vivo with various Cbl analogues is due to inhibition of intracellular Cbl transport or to inhibition of the enzymatic formation of Cob(II)alamin rather than to direct inhibition of mammalian methionine synthase itself.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1977

[The present state of hypotension (author's transl)].

The study was made of the recent literature on controlled hypotension and its place in modern anaesthetic practice. The effects of the different techniques and drugs are outlined in this paper. The results of investigation revealed that the circulation of heart, brain, liver, and kidneys is able to tolerate a wide range of deviation of blood pressure. Hypotension induced by high doses of halothane alone, which used to be considered as an adequate measure, has recently been shown to cause such serious side-effects that it can no longer be recommended. Halothane lowers blood pressure almost exclusively by means of a reduction of the contractility of the heart muscle. Ganglionic blocking agents alone should not be used either because of their depressing effect on the heart; moreover their hypotensive effects are hard to control. The sole exception is trimetaphan but it produces other severe side-effects such as liberation of histamine. On the other hand ganglionic blocking agents combined with halothane can be recommended. The combined administration of these drugs allow an easy control of hypotension and the side effects are minimal. Only sodium-nitroprusside meets all the requirements of a hypotensive drug. It operates selectively in a peripheral vasoplegic manner without effecting the cerebral centres. Regarding the heart, no side-effect is known apart from tachycardia; cardiac output is not altered. The metabolism of sodium-nitroprusside requires precaution in dosage, as degradation takes place via the toxic compounds of cyanide. Therefore liver disease and disturbances in vitamin B12 utilisation are regarded as contraindications for the use of nitroprusside. That is also the reason why a maximum allowable dose of 10-15 gamma/kg body weight and minute should not be exceeded. Prophylactic administration of vitamin B 12a (hydroxocobalamin) should be considered in every case when nitroprusside is used.

Cardiac Output↗
PubMed1977

Metabolic fate of cyanocobalamin taken up by Spirometra mansonoides spargana.

Analysis of tissue from Spirometra mansonoides spargana has shown that cyanocobalamin (vitamin B12) is metabolized to adenosylcobalamin and hydroxocobalamin. No methylcobalamin was detected. When the tissues were examined for enzymes which are known to utilize coenzyme forms of vitamin B12, only methylmalonyl CoA mutase, which requires adenosylcobalamin was found. The enzyme, tetrahydropteroylglutamate methyltransferase, which requires methylcobalamin as a cofactor, was not detected. A sizable portion of the cyanocobalamin taken up was bound to ammonium sulfate-precipitable material, suggesting that the binding substance is a protein. Vitamin B12 taken up by spargana was found to be released in vivo with a biological half-life of about 7 weeks.

Animals↗
PubMed1990

Effects of various known and potential cyanide antagonists and a glutathione depletor on acute toxicity of cyanide in mice.

To compare the protective potencies of a large number of known and potential cyanide antagonists in one stock of mice, groups (N = 10) of male CF-1 Swiss-Webster mice were given a single maximal or near-maximal intraperitoneal injection of each substance. Ethyl maleate, a glutathione (GSH) depletor and potential enhancer of cyanide toxicity, was given to other groups. Thirty min later, the mice were given subcutaneous injections of graded doses of KCN. In untreated control mice, the 24-hr median lethal dose (LD50) of KCN was 11 mg/kg of body weight (potency ratio, PR = 1.0). In comparison, protective effects of traditional antagonists thiosulfate and nitrite produced PR values of 1.48 and 2.95, respectively. Tetrathionate, sulfate, dithionite, methionine, hydroxocobalamin, ascorbate, pyridoxal phosphate, alpha-ketoglutarate, alpha-ketobutyrate, GSH, GSH disulfide (GSSG) and selenite were similar in efficacy to thiosulfate (P less than 0.05; PR values 1.35-1.59). Cysteine, diethyldithiocarbamate (DEDC), and cobaltous chloride were more effective than thiosulfate (PR values 1.68, 1.69, and 1.85, respectively). Phentolamine and dicobalt EDTA were ineffective, whereas papaverine enhanced toxicity (PR 0.72). Agents with significant PR values (greater than or equal to 1.14) but which were less effective than thiosulfate included sulfite, dimercaptosuccinic acid, pyruvate, citrate, alpha-ketovalerate, naloxone, and corn oil. Ethyl maleate in corn oil markedly enhanced KCN lethality (PR 0.57 compared to corn oil alone), and caused prolonged illness in several mice. Vitamin E in corn oil had no effect. Dual mixtures of thiosulfate with other selected substances were also tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

[Acquired von Willebrand syndrome associated with Hashitoxicosis and pernicious anemia combined].

A new case of acquired von Willebrand syndrome (AvWS) with Hashitoxicosis and pernicious anemia combined in a 73-years-old male is reported. He was admitted because of appetite loss and general malaise. Physical examination showed severe anemia and general edema. The red-cell count was 103 X 10(4)/microliters with a MCV of 122 fl; the white-cell count was 2,900/microliters with 24.5% hypersegmented neutrophils; the platelet count was 17.2 X 10(4)/microliters. the lactate dehydrogenase was 9,513 U/ml and vitamin B12 was 87 pg/dl. An aspirated specimen of bone marrow was diagnostic of megaloblastic anemia. The thyroid hormones were decreased with the thyroid stimulating hormone increased. From the immunological findings, the thyroid-test, microsome-test, and anti-intrinsic factor were positive, but M proteinemia and Bence Jones proteinuria were absent. Histology of the thyroid gland and the gastric mucosa established the diagnosis of chronic thyroiditis and chronic atrophic gastritis. Subcutaneous hemorrhages after veni-puncture were observed on admission. He had a normal bleeding time, but the coagulation studies indicated the presence of von Willebrand disease, but as his family and past history were negative, this suggested the presence of an AvWS. The analysis of von Willebrand factor (vWF) multimeric composition had showed the lack of the larger multimers in the plasma, but it was normalized after the administration of levothyroxine sodium and hydroxocobalamin with vWF: Ag/RCo ratio paralleled. As far as we know, this is the first report of AvWS with Hashitoxicosis and pernicious anemia combined.

Aged↗
PubMedDate not supplied

Suspected cyanide poisoning in smoke inhalation: complications of sodium nitrite therapy.

A 78 year old man was found comatose, apneic, and asystolic after closed-space smoke inhalation. He was successfully resuscitated to pulse and blood pressure at the scene. A cyanide component to the poisoning was suspected and two 300 mg doses of sodium nitrite were administered, resulting in significant hypotension. Although high methemoglobin levels were not induced, when added to simultaneously obtained carboxyhemoglobin levels, the total amount of non-oxygen transporting hemoglobin remained nearly constant for about 4-1/2 hours before hyperbaric oxygen (HBO) therapy could be administered. The patient later died in multi-organ system failure. Admission whole blood cyanide level was only 0.34 mcg/mL. These sodium nitrite adverse effects can be avoided by slow intravenous infusion and by administering only recommended doses. In smoke inhalation victims with suspected cyanide poisoning, sodium thiosulfate should be administered first, and sodium nitrite withheld until after the patient is receiving HBO therapy. When available, hydroxocobalamin (which neither induces methemoglobinemia nor causes hypotension) may be the specific cyanide antidote of choice for victims of smoke inhalation.

Aged↗
PubMed1979

[Granulocyte dysfunction in transcobalamin II deficiency].

Granulocytes from a boy with congenital transcobalamin II (TC II) deficiency were found to have abnormally low antibacterial activity against Staphylococcus aureus. Transfusion of normal plasma supplemented with hydroxocobalamin temporarily restored granulocyte bactericidal activity to normal. Granulocyte function was also temporarily restored by oral leucovorin. The defect appears to be causally related to the patient's TC II deficiency and indirectly to an intracellular deficiency of cobalamin and folate coenzymes [1].

Blood Bactericidal Activity↗
PubMed1977

Studies on the mechanism of the adenosylcobalamin-dependent diol dehydrase reaction by the use of analogs of the coenzyme.

A series of 16 analogs of 5'-deoxy-5'-adenosylcobalamin (adenosylcobalamin) were examined for their effects on the diol dehydrase system of Klebsiella pneumoniae (Aerobacter Aerogenes). Four analogs, ara-adenosyl-, aristeromycyl-, 3-isoadenosyl-, and nebularylcobalamin, were able to function as coenzymes in the diol dehydrase reaction, coenzyme activity decreasing in that order. Like the native holoenzyme, complexes of the enzyme with these four analogs show a cob(II)alamin-like absorption peak or shoulder in the presence of 1,2-propanediol. Analogs containing hypoxanthine, cytosine, or benzimidazole do not function as coenzymes, but are weak competitive inhibitors in the presence of adenosylcobalamin. Analogs in which the D-ribosyl moiety is replaced by L-ribose or by an alkyl chain of 2 to 6 carbons are inactive as coenzymes, but act as competitive inhibitors with extremely high affinity for the apoenzyme. Complexes with the inactive analogs showed visible spectra similar to those of the corresponding free cobalamins. Upon anaerobic photolysis and subsequent aeration, complexes with the first group of inactive analogs produced unusually stabilized cob(II)alamin, while complexes with the second group of inactive analogs were readily photolyzed to a hydroxocobalamin-enzyme complex. Complexes with adeninylpentyl- and L-adenosylcobalamin were stable to light under the same conditions. These findings suggest that both the ribose and the adenine moiety of the nucleoside participate in enzyme-coenzyme interaction, involving not only the binding to the apoenzyme but also the activation of the carbon-cobalt bond.

Apoenzymes↗
PubMed1987

Activation and cleavage of the carbon-cobalt bond of adeninylethylcobalamin by diol dehydrase.

Adeninylethylcobalamin (AdeEtCbl) underwent cleavage of the C-Co bond by interaction with apoprotein of diol dehydrase from Klebsiella pneumoniae ATCC 8724, although this analog was quite inactive as coenzyme. Spectroscopic observation indicates that AdeEtCbl was converted to the enzyme-bound hydroxocobalamin without intermediates. The conversion was stoichiometric (1:1) and obeyed the second-order reaction kinetics (k = 0.027 min-1 microM-1 at 37 degrees C) depending upon concentrations of apoprotein and AdeEtCbl. This suggests that the complex formation is the rate-determining step and that AdeEtCbl undergoes rapid C-Co bond cleavage once it binds to the apoenzyme. Substrates and oxygen did apparently not affect the rate of the C-Co bond cleavage. The experiments using [adenine-U-14C]AdeEtCbl and [1(3)-3H]glycerol demonstrated that 9-ethyladenine was the only product formed from the adeninylethyl group of AdeEtCbl during the conversion and that an additional hydrogen atom in the 9-ethyladenine is not derived from the substrate. 1H NMR measurement of the 9-ethyladenine formed enzymatically from AdeEtCbl and DL-1,2-[1,1,2-2H3]propanediol also led to the same conclusion. All of these results indicate that the C-Co bond of AdeEtCbl is activated by diol dehydrase and undergoes heterolysis forming Co(III) and a carbanion or a carbanion-like species, in clear contrast to the homolysis of the C-Co bond of adenosylcobalamin in the normal catalytic process. 9-Ethyladenine formed remained tightly associated with the enzyme. Longer chain homologs, i.e. adeninylpropylcobalamin, adeninylbutylcobalamin, and adeninylpentylcobalamin did not undergo such cleavage of the C-Co bond by diol dehydrase.

Adenine↗
PubMed1988

Heteronuclear NMR studies of cobalamins. 31P NMR observations of cobalamins bound to a haptocorrin from chicken serum.

A vitamin B12-binding protein (haptocorrin) from chicken serum has been purified to homogeneity by photodissociative affinity chromatography and characterized by gel electrophoresis and UV-visible spectrophotometry of its aquocobalamin, hydroxocobalamin, and cyanocobalamin complexes. The haptocorrin is a glycoprotein with a molecular mass of about 70 kDa and a protein moiety of about 40 kDa. 31P NMR resonances of the haptocorrin-cobalamin complexes are relatively broad singlets (with or without proton decoupling) shifted downfield by 0.7-1.0 ppm from the position of the free cobalamin resonances. From the line width data, the relaxation of the phosphorus nucleus is found to be dominated by chemical shift anisotropy with a very minor (13%) component from dipolar interaction with the two nearest neighbor protons. The rotational correlation time of the haptocorrin at 25 degrees C is estimated to be 85 ns and the activation energy for rotational correlation 3.9 +/- 0.3 kcal mol-1. The downfield shift of the 31P resonances of cobalamins upon binding to the haptocorrin cannot be due to hydrogen bonding phosphodiester moiety or displacement of the axial base by a group on the protein. Calculations also show that the downfield shift is very unlikely to be due to dipolar deshielding of the phosphorus nucleus by the ring current of an aromatic residue of the protein. It is concluded that the downfield shift of the 31P resonance must be due to sterically induced changes in phosphodiester conformation which may, or may not, involve steric compression of the axial Co-N bond.

Algorithms↗
PubMed1988

Improvement in bronchial squamous metaplasia in smokers treated with folate and vitamin B12. Report of a preliminary randomized, double-blind intervention trial.

To test whether changes in folate and vitamin B12 nutrition modify the severity of potentially premalignant lesions identified by cytology in sputum samples of smokers, we conducted a randomized, controlled prospective intervention trial in smokers with bronchial squamous metaplasia. Seventy-three men with a history of 20 or more pack-years of cigarette smoking who had metaplasia on one or more sputum samples were stratified according to smoking level and randomly assigned to four months' treatment with either placebo or 10 mg of folate plus 500 micrograms of hydroxocobalamin. Direct cytological comparison of the two groups after four months showed significantly greater reduction of atypia in the supplemented group. This provides preliminary evidence that atypical bronchial squamous metaplasia may be reduced by supplementation with folate and vitamin B12. However, the significance of these findings is tempered by substantial spontaneous variation in sputum cytologies, the small study population, the short duration of the trial, and the supraphysiological doses of folate and B12 used. The results should not be construed as pointing to a potential way of preventing lung cancer in individuals who continue to smoke or as supporting self-medication with large doses of folate or B12 by smokers.

Bronchi↗
PubMed1986

Clinical features and management of cyanide poisoning.

The pathophysiology, clinical features, and management of cyanide toxicity are reviewed and sources of cyanide are listed. Cyanide is a deadly poison that is found in many foods and household and industrial products, including some that are readily available. Cyanide binds with cytochrome oxidase, the enzyme responsible for oxidative phosphorylation, and paralyzes cellular respiration. Because the tissues cannot use oxygen that is delivered, aerobic metabolism ceases. The signs and symptoms of cyanide poisoning reflect the extent of cellular hypoxia. Manifestations may include respiratory abnormalities (progressing from tachypnea and dyspnea to respiratory depression and apnea), hemodynamic instability, metabolic acidosis, and, possibly, local irritant effects after oral ingestion of cyanide. The mainstays of therapy are 100% oxygen and specific antidotes to cyanide. Sequential treatment with amyl nitrite by inhalation, intravenous sodium nitrite 3%, and intravenous sodium thiosulfate 25% is directed toward decreasing the amount of cyanide available for cellular binding. Nitrites convert hemoglobin to methemoglobin, which reacts with cyanide to form cyanomethemoglobin. Sodium thiosulfate serves as a source of sulfur groups, which are needed for conversion of cyanide to thiocyanate, a compound that is relatively less toxic and is excreted renally. Supportive care also is important. Cobalt EDTA, hydroxocobalamin, and aminophenols have also been used but are not considered standard treatments. Cyanide poisoning is a medical emergency that requires prompt recognition and immediate and aggressive treatment.

Antidotes↗
PubMed1987

Cobalamin derivatives in subcellular fractions of porcine ileal enterocytes.

The distribution of cobalamin derivatives in porcine enterocytes was studied using thin-layer chromatography and bioautography. Compared with the original homogenate, adenosyl-cobalamin (Ado-Cbl) was concentrated 5-10 times in the mitochondrial fraction. Cyanocobalamin was found in the lysosomal fraction, but was not detected in the mitochondria. Methyl-cobalamin (Me-Cbl) was found only in the sap fraction and could not be detected in the total homogenate. Hydroxocobalamin was the main form of Cbl in the lysosomal fraction. These results provide indirect evidence that in enterocytes methylmalonyl-CoA mutase, the coenzyme of which is Ado-Cbl, is located in the mitochondrial fraction and that methionine synthetase, the coenzyme of which is Me-Cbl, is located in the sap fraction. These enzymes thus appear to be distributed in the same way as in liver cells.

Animals↗