Intramuscular cobinamide as an antidote to methyl mercaptan poisoning.

BACKGROUND: Methyl mercaptan occurs naturally in the environment and is found in a variety of occupational settings, including the oil, paper, plastics, and pesticides industries. It is a toxic gas and deaths from methyl mercaptan exposure have occurred. The Department of Homeland Security considers it a high threat chemical agent that could be used by terrorists. Unfortunately, no specific treatment exists for methyl mercaptan poisoning. METHODS: We conducted a randomized trial in 12 swine comparing no treatment to intramuscular injection of the vitamin B12 analog cobinamide (2.0 mL, 12.5 mg/kg) following acute inhalation of methyl mercaptan gas. Physiological and laboratory parameters were similar in the control and cobinamide-treated groups at baseline and at the time of treatment. RESULTS: All six cobinamide-treated animals survived, whereas only one of six control animals lived (17% survival) (p = 0.0043). The cobinamide-treated animals returned to a normal breathing pattern by 3.8 ± 1.1 min after treatment (mean ± SD), while all but one animal in the control group had intermittent gasping, never regaining a normal breathing pattern. Blood pressure and arterial oxygen saturation returned to baseline values within 15 minutes of cobinamide-treatment. Plasma lactate concentration increased progressively until death (10.93 ± 6.02 mmol [mean ± SD]) in control animals, and decreased toward baseline (3.79 ± 2.93 mmol [mean ± SD]) by the end of the experiment in cobinamide-treated animals. CONCLUSION: We conclude that intramuscular administration of cobinamide improves survival and clinical outcomes in a large animal model of acute, high dose methyl mercaptan poisoning.

Antidotal efficacies of the cyanide antidote candidate dimethyl trisulfide alone and in combination with cobinamide derivatives.

Formulation optimization and antidotal combination therapy are the two important tools to enhance the antidotal protection of the cyanide (CN) antidote dimethyl trisulfide (DMTS). The focus of this study is to demonstrate how the formulation with polysorbate 80 (Poly80), an excipient used in pharmaceutical technology, and the combinations with other CN antidotes having different mechanisms of action enhance the antidotal efficacy of the unformulated (neat) DMTS. The LD50 for CN was determined by the statistical Dixon up-and-down method on mice. Antidotal efficacy was expressed as antidotal potency ratio (APR). CN was injected subcutaneously one minute prior to the antidotes' injection intramuscularly. The APR values of 1.17 (dose: 25 mg/kg bodyweight) and 1.45 (dose: 50 mg/kg bodyweight) of the neat DMTS were significantly enhanced by the Poly80 formulation at both investigated doses to 2.03 and 2.33, respectively. The combination partners for the Poly80 formulated DMTS (DMTS-Poly80; 25 and 50 mg/kg bodyweight) were 4-nitrocobinamide (4NCbi) (20 mg/kg bodyweight) and aquohydroxocobinamide (AHCbi; 50, 100, and 250 mg/kg bodyweight). When DMTS-Poly80 (25 and 50 mg/kg bodyweight; APR = 2.03 and 2.33, respectively) was combined with 4NCbi (20 mg/kg bodyweight; APR = 1.35), significant increase in the APR values were noted at both DMTS doses (APR = 2.38 and 3.12, respectively). AHCbi enhanced the APR of DMTS-Poly80 (100 mg/kg bodyweight; APR = 3.29) significantly only at the dose of 250 mg/kg bodyweight (APR = 5.86). These studies provided evidence for the importance of the formulation with Poly80 and the combinations with cobinamide derivatives with different mechanisms of action for DMTS as a CN antidote candidate.

Intramuscular cobinamide sulfite in a rabbit model of sublethal cyanide toxicity.

STUDY OBJECTIVE: Exposure to cyanide in fires and industrial exposures and intentional cyanide poisoning by terrorists leading to mass casualties is an ongoing threat. Current treatments for cyanide poisoning must be administered intravenously, and no rapid treatment methods are available for mass casualty cyanide exposures. Cobinamide is a cobalamin (vitamin B(12)) analog with an extraordinarily high affinity for cyanide that is more water-soluble than cobalamin. We investigate the use of intramuscular cobinamide sulfite to reverse cyanide toxicity-induced physiologic changes in a sublethal cyanide exposure animal model and determine the ability of an intramuscular cobinamide sulfite injection to rapidly reverse the physiologic effects of cyanide toxicity. METHODS: New Zealand white rabbits were given 10 mg sodium cyanide intravenously over 60 minutes. Quantitative diffuse optical spectroscopy and continuous-wave near-infrared spectroscopy monitoring of tissue oxyhemoglobin and deoxyhemoglobin concentrations were performed concurrently with blood cyanide level measurements and cobinamide levels. Immediately after completion of the cyanide infusion, the rabbits were injected intramuscularly with cobinamide sulfite (n=6) or inactive vehicle (controls, n=5). RESULTS: Intramuscular administration led to rapid mobilization of cobinamide and was extremely effective at reversing the physiologic effects of cyanide on oxyhemoglobin and within deoxyhemoglobin extraction. Recovery time to 63% of their baseline values in the central nervous system occurred within a mean of 1,032 minutes in the control group and 9 minutes in the cobinamide group, with a difference of 1,023 minutes (95% confidence interval 116 to 1,874 minutes). In muscle tissue, recovery times were 76 and 24 minutes, with a difference of 52 minutes (95% confidence interval 7 to 98 minutes). RBC cyanide levels returned toward normal significantly faster in cobinamide sulfite-treated animals than in control animals. CONCLUSION: Intramuscular cobinamide sulfite rapidly and effectively reverses the physiologic effects of cyanide poisoning, suggesting that a compact cyanide antidote kit can be developed for mass casualty cyanide exposures.

Intramuscular cobinamide versus saline for treatment of severe hydrogen sulfide toxicity in swine.

INTRODUCTION: Hydrogen sulfide (H2S) is found in petroleum, natural gas, and decaying organic matter. Terrorist groups have attempted to use it in enclosed spaces as a chemical weapon. Mass casualty scenarios have occurred from industrial accidents and release from oil field sites. There is no FDA approved antidote for sulfide poisoning. We have previously reported that intravenous cobinamide is effective for sulfide poisoning. A rapid-acting antidote that is easy to administer intramuscularly (IM) would be ideal for use in a prehospital setting. In this study, we assessed survival in sulfide-poisoned swine treated with IM cobinamide. METHODS: Eleven swine (45-55 kg) were anesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring. After stabilization, anesthesia was adjusted such that animals ventilated spontaneously with a FiO2 of 0.21. Sodium hydrosulfide (NaHS, 8 mg/mL) was infused intravenously at 0.9 mg/kg.min until apnea or severe hypotension. Animals were randomly assigned to receive cobinamide (4 mg/kg), or no treatment at the apnea/hypotension trigger. The NaHS infusion rate was sustained for 1.5 min post trigger, decreased to 0.2 mg/kg.min for 10 min, and then discontinued. RESULTS: The amount of NaHS required to produce apnea or hypotension was not statistically different in both groups (cobinamide: 9.0 mg/kg ±6.1; saline: 5.9 mg/kg ±5.5; mean difference: -3.1, 95% CI: -11.3, 5.0). All of the cobinamide treated animals survived (5/5), none of the control (0/6) animals survived (p < .01). Mean time to return to spontaneous ventilation in the cobinamide treated animals was 3.2 (±1.1) min. Time to return to baseline systolic blood pressure (±5%) in cobinamide-treated animals was 5 min. CONCLUSION: Intramuscular cobinamide was effective in improving survival in this large swine model of severe hydrogen sulfide toxicity.

Aortic pathology from protein kinase G activation is prevented by an antioxidant vitamin B12 analog.

People heterozygous for an activating mutation in protein kinase G1 (PRKG1, p.Arg177Gln) develop thoracic aortic aneurysms and dissections (TAAD) as young adults. Here we report that mice heterozygous for the mutation have a three-fold increase in basal protein kinase G (PKG) activity, and develop age-dependent aortic dilation. Prkg1R177Q/+ aortas show increased smooth muscle cell apoptosis, elastin fiber breaks, and oxidative stress compared to aortas from wild type littermates. Transverse aortic constriction (TAC)-to increase wall stress in the ascending aorta-induces severe aortic pathology and mortality from aortic rupture in young mutant mice. The free radical-neutralizing vitamin B12-analog cobinamide completely prevents age-related aortic wall degeneration, and the unrelated anti-oxidant N-acetylcysteine ameliorates TAC-induced pathology. Thus, increased basal PKG activity induces oxidative stress in the aorta, raising concern about the widespread clinical use of PKG-activating drugs. Cobinamide could be a treatment for aortic aneurysms where oxidative stress contributes to the disease, including Marfan syndrome.

The nitric oxide scavenger cobinamide profoundly improves survival in a Drosophila melanogaster model of bacterial sepsis.

Septic shock has an extremely high mortality rate, with approximately 200,000 people dying from sepsis annually in the U.S. The high mortality results in part from severe hypotension secondary to high serum NO concentrations. Reducing NO levels should be beneficial in sepsis, but NOS inhibitors have had a checkered history in animal models, and one such agent increased mortality in a clinical trial. An alternative approach to reduce NO levels in sepsis is to use an NO scavenger, which should leave sufficient free NO for normal physiological functions. Using a well-established model of bacterial sepsis in Drosophila melanogaster, we found that cobinamide, a B(12) analog and an effective NO scavenger in vitro, dramatically improved fly survival. Cobinamide augmented the effect of an antibiotic and was beneficial even in immune-deficient flies. Cobinamide's mechanism of action appeared to be from reducing NO levels and improving cardiac function.

Efficacy of Intravenous Cobinamide Versus Hydroxocobalamin or Saline for Treatment of Severe Hydrogen Sulfide Toxicity in a Swine (Sus scrofa) Model.

BACKGROUND: Hydrogen sulfide (H2 S) is a potentially deadly gas that naturally occurs in petroleum and natural gas. The Occupational Health and Safety Administration cites H2 S as a leading cause of workplace gas inhalation deaths. Mass casualties of H2 S toxicity may be caused by exposure from industrial accidents or release from oil field sites. H2 S is also an attractive terrorism tool because of its high toxicity and ease with which it can be produced. Several potential antidotes have been proposed for hydrogen sulfide poisoning but none have been completely successful. OBJECTIVE: The objective was to compare treatment response assessed by the time to spontaneous ventilation among groups of swine with acute H2 S-induced apnea treated with intravenous (IV) cobinamide (4 mg/kg in 0.8 mL of 225 mmol/L solution), IV hydroxocobalamin (4 mg/kg in 5 mL of saline), or saline alone. METHODS: Twenty-four swine (45-55 kg) were anesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring. After stabilization, anesthesia was adjusted such that animals would spontaneously ventilate with an FiO2 of 0.21. Sodium hydrosulfide (NaHS; concentration of 8 mg/mL) was begun at 1 mg/kg/min until apnea was confirmed for 20 seconds by capnography. This infusion rate was sustained for 1.5 minutes postapnea and then decreased to a maintenance rate for the remainder of the study to replicate sustained clinical exposure. Animals were randomly assigned to receive cobinamide (4 mg/kg), hydroxocobalamin (4 mg/kg), or saline and monitored for 60 minutes beginning 1 minute postapnea. G* power analysis using the Z-test determined that equal group sizes of eight animals were needed to achieve a power of 80% in detecting a 50% difference in return to spontaneous ventilations at α = 0.05. RESULTS: There were no significant differences in baseline variables. Moreover, there were no significant differences in the mg/kg dose of NaHS (5.6 mg/kg; p = 0.45) required to produce apnea. Whereas all of the cobinamide-treated animals survived (8/8), none of the control (0/8) or hydroxocobalamin (0/8)-treated animals survived. Mean (±SD) time to spontaneous ventilation in the cobinamide-treated animals was 3.2 (±1.1) minutes. CONCLUSIONS: Cobinamide successfully rescued the severely NaHS-poisoned swine from apnea in the absence of assisted ventilation.

PainVision® Apparatus for Assessment of Efficacy of Pulsed Radiofrequency Combined with Pharmacological Therapy in the Treatment of Postherpetic Neuralgia and Correlations with Measurements.

Objective. PainVision device was a developed application for the evaluation of pain intensity. The objective was to assess the efficacy and safety of pulsed radiofrequency (PRF) combined with pharmacological therapy in the treatment of postherpetic neuralgia (PHN). We also discussed the correlation of the measurements. Method. Forty patients with PHN were randomized for treatment with PRF combined with pharmacological therapy (PRF group, n = 20) or pharmacological therapy (control group, n = 20) at postoperative 48 hours. The efficacy measure was pain degree (PD) that was assessed by PainVision and visual analog scale (VAS), short form Mcgill pain questionnaire (SF-Mcgill), and numeric rate scale sleep interference score (NRSSIS). Correlations between PD, VAS, SF-Mcgill, and NRSSIS were determined. Results. The PD for persistent pain (PP) and breakthrough pain (BTP) at postoperative 48 hours assessed by PainVision were significantly lower in PRF group than in control group (PD-PP, P < 0.01; PD-BTP, P < 0.01). PD and VAS were highly correlated for both persistent pain (r = 0.453, ρ = 0.008) and breakthrough pain (r = 0.64, ρ = 0.001). Conclusion. PRF was well tolerated and superior to isolated pharmacological therapy in the treatment of PHN. PainVision device showed great value in the evaluation of pain intensity and PD had an excellent correlation with VAS and SF-Mcgill.

Treatment of vitamin B12 deficiency-methylcobalamine? Cyancobalamine? Hydroxocobalamin?-clearing the confusion.

Vitamin B12 (cyancobalamin, Cbl) has two active co-enzyme forms, methylcobalamin (MeCbl) and adenosylcobalamin (AdCbl). There has been a paradigm shift in the treatment of vitamin B12 deficiency such that MeCbl is being extensively used and promoted. This is despite the fact that both MeCbl and AdCbl are essential and have distinct metabolic fates and functions. MeCbl is primarily involved along with folate in hematopiesis and development of the brain during childhood. Whereas deficiency of AdCbl disturbs the carbohydrate, fat and amino-acid metabolism, and hence interferes with the formation of myelin. Thereby, it is important to treat vitamin B12 deficiency with a combination of MeCbl and AdCbl or hydroxocobalamin or Cbl. Regarding the route, it has been proved that the oral route is comparable to the intramuscular route for rectifying vitamin B12 deficiency.

Decellularized skeletal muscle as an in vitro model for studying drug-extracellular matrix interactions.

Several factors can affect drug absorption after intramuscular (IM) injection: drug solubility, drug transport across cell membranes, and drug metabolism at the injection site. We found that potential interactions between the drug and the extracellular matrix (ECM) at the injection site can also affect the rate of absorption post-injection. Using decellularized skeletal muscle, we developed a simple method to model drug absorption after IM injection, and showed that the nature of the drug-ECM interaction could be investigated by adding compounds that alter binding. We validated the model using the vitamin B12 analog cobinamide with different bound ligands. Cobinamide is being developed as an IM injectable treatment for cyanide poisoning, and we found that the in vitro binding data correlated with previously published in vivo drug absorption in animals. Commercially available ECM products, such as collagen and GelTrex, did not recapitulate drug binding behavior. While decellularized ECM has been widely studied in fields such as tissue engineering, this work establishes a novel use of skeletal muscle ECM as a potential in vitro model to study drug-ECM interactions during drug development.

Nitrocobinamide, a new cyanide antidote that can be administered by intramuscular injection.

Currently available cyanide antidotes must be given by intravenous injection over 5-10 min, making them ill-suited for treating many people in the field, as could occur in a major fire, an industrial accident, or a terrorist attack. These scenarios call for a drug that can be given quickly, e.g., by intramuscular injection. We have shown that aquohydroxocobinamide is a potent cyanide antidote in animal models of cyanide poisoning, but it is unstable in solution and poorly absorbed after intramuscular injection. Here we show that adding sodium nitrite to cobinamide yields a stable derivative (referred to as nitrocobinamide) that rescues cyanide-poisoned mice and rabbits when given by intramuscular injection. We also show that the efficacy of nitrocobinamide is markedly enhanced by coadministering sodium thiosulfate (reducing the total injected volume), and we calculate that ∼1.4 mL each of nitrocobinamide and sodium thiosulfate should rescue a human from a lethal cyanide exposure.

Biodistribution of radiolabeled adenosylcobalamin in patients diagnosed with various malignancies.

OBJECTIVE: To study the biodistribution of a vitamin B12 analog, indium In 111-labeled diethylenetriaminepentaacetate adenosylcobalamin (In 111 DAC), in patients recently diagnosed as having primary or recurrent malignancy. PATIENTS AND METHODS: Thirty patients (14 women and 16 men) with radiographically or clinically diagnosed breast, lung, colon, sarcomatous, thyroid, or central nervous system malignancies were studied prior to definitive surgery or biopsy. A maximum of 650 microCi (2.2 microg) of In 111 DAC was administered intravenously. Vitamin B12 and folate levels were determined prior to injection. Serum clearance and urinary and stool excretion of the tracer were measured. Images were routinely obtained at 0.5, 3 to 5, and 20 to 24 hours after injection. Biodistribution of In 111 DAC was determined by computer analysis of regions of interest. RESULTS: Serum T1/2 clearance was 7 minutes. Average urinary and stool excretion of the injected dose over 24 hours was 26.1% and 0.4%, respectively. The greatest focal uptake of In 111 DAC occurred in the liver and spleen, followed by the nasal cavity and salivary and lacrimal glands. The average tumor uptake of the injected dose was 2% at 30 minutes and 1.5% at 24 hours. High-grade primary and metastatic breast, lung, colon, thyroid, and sarcomatous malignancies were all imaged at 3 to 5 hours after injection. Central nervous system tumors and advanced metastatic prostate cancer were best identified at 24 hours. Mammographically occult, palpable, and nonpalpable breast cancers were delineated by In 111 DAC. Low-grade malignancies as well as early skeletal metastatic disease were not effectively imaged by the vitamin B12 tracer. Patients with elevated baseline vitamin B12 or those concurrently taking corticosteroids appeared to have optimal visualization of their malignancies. CONCLUSION: Vitamin B12 may be a useful vehicle for delivering diagnostic and therapeutic agents to various malignancies. Further evaluation of cobalamin analogs and their interaction with transport proteins and cellular receptors within malignant tissue and infection is warranted.

Treatment of pustulosis palmaris et plantaris with large doses of vitamin B12.

Thirty-three patients with pustulosis palmaris et plantaris were treated with large doses of vitamin B12 (cyanocobalamin and/or coenzyme B12). Those patients receiving large doses for a long period of time showed a better response than those who received small doses for a shorter period.

Effect of factor B on vitamin B12 status and propionate metabolism in sheep.

Growing lambs fed diets containing two concentrations of Co (basal and basal plus 1 ppm) were injected with Factor B (cobinamide) or saline during an 8-wk trial conducted to determine the effects of Factor B on liver B12 levels and on propionate metabolism. At the end of the trial, lambs given Factor B had lower (P less than .05) liver vitamin B12 concentrations and higher (P less than .05) Factor B concentrations than controls fed the high Co diet. The high Co diet did not enhance liver B12 levels in the lambs treated with Factor B. Feed intake and body weight gain were not significantly affected by treatment. Plasma propionate increased (P less than .05) with time on experiment, and concentrations during the final period were negatively correlated (r = -.45; P less than .05) with liver B12 levels. When the lambs were loaded with propionate, a similar correlation (r = -.59; P less than .05) was observed between log plasma level at t = 20 and liver B12 levels. Liver B12 levels (.2 to 1.1 micrograms/g) were all within what is usually considered a normal range. . No significant relationship between plasma propionate and liver Factor B levels were observed.

[Study of the effect of Stressen on homocysteine blood levels in patients affected by vascular disease]. / Studio dell'effetto della specialità medicinale "Stressen" sui livelli ematici di omocisteina in pazienti con patologia vascolare.

OBJECTIVE: This study was carried out to confirm the results obtained in a previous trial, where Stressen had reduced homocysteinemia in patients with elevated concentrations of this amino acid and affected by vascular disease. MATERIALS AND METHODS: 50 patients were enrolled and they received Stressen twice daily for 30 days. Basal levels of homocysteinemia were determined and, after the treatment, evaluation of this parameter was repeated. RESULTS: At enrollment homocysteinemia was 23.44 +/- 7.24 micromol/l; at the end of the treatment with Stressen it was reduced to 10.22 +/- 3.41 micromol/l, corresponding to a decrease of 56.4% (p<0.0001). No significant difference between sexes was noted. CONCLUSIONS: The results of this study confirm the efficacy of Stressen on homocysteine plasma levels and agree with literature about the relationship among vitamin B12, folate and homocysteine; the activity of the drug was therefore predictable considering its composition, constituted of cobamamide, calcium folinate and arginine glutamate.

[Effect of Stressen on homocysteine blood levels in patients with cardiovascular disease or at risk by familial anamnesis]. / Studio dell'effetto della specialità medicinale Stressen sui livelli ematici di omocisteina in pazienti affetti da patologia cardiovascolare o a rischio per anamnesi familiare.

OBJECTIVE: Moderate hyperhomocysteinemia, important risk factor for cardiovascular disease, produces an endothelial damage due to oxidative stress; high plasma levels of homocysteine can be related either to genetic aberrations or to reduced blood concentrations of folate and vitamin B12. The aim of this study is to evaluate the effect of Stressen on blood levels of this amino acid in patients affected by cardiovascular disease or in healthy hyperhomocysteinemic subjects, considered at risk of coronary diseases, due to familiar anamnesis. MATERIALS AND METHODS: Homocysteinemia was evaluated by means of an immunoenzymatic method in 26 subjects with basal values > 15 micromol/l and treated with Stressen, a 10 ml bottle twice daily. RESULTS: After 30 days of drug consumption, mean value of total homocysteinemia was 11.6 +/- 1.86 micromol/l, corresponding to a statistically significant mean reduction of 42.8% of basal values. CONCLUSIONS: Stressen significantly decreased total homocysteinemia in this studied population, showing to be suitable for prevention of cardiovascular and thromboembolic diseases.

[Controlled study of the effect of Stressen on homocysteine blood levels in patients with vascular disease]. / Studio controllato dell'effetto della specialità medicinale "Stressen" sui livelli ematici di omocisteina in pazienti con patologia vascolare.

OBJECTIVE: Plasma levels of folate and vitamin B12 are inversely related to homocysteinemia and nowadays a further supplement of these vitamins, other than diet, is considered useful for lowering homocysteine blood levels. Stressen possesses the requirements for the control of this biochemical parameter; this study had the purpose to verify the activity of the product in patients affected by vascular disease. MATERIALS AND METHODS: 40 patients have taken a bottle of Stressen twice daily for 30 days and 20 subjects, suffering from the same pathology and non treated with the drug, have been considered as controls. Homocysteinemia was evaluated at the beginning and at the end of the treatment. RESULTS: Stressen determined a statistical reduction of 51.1% of basal concentration (p<0.0001), while levels of controls remained unchanged after the 30 days period. CONCLUSIONS: Supplement of vitamin B12 and folate, consisting in Stressen administration, normalized homocysteinemia. Furthermore, arginine glutamate, in the composition of the product, represents substrate for NO synthase and could be particularly useful for the treatment of vascular disease, improving endothelial-dependent dilation.

[Intragastric sinusoidal modulated-current electrophoresis of cobamamide as a method in the pathogenetic therapy of chronic atrophic gastritis]. / Vnutrizheludochnyi SMT-élektroforez kobamamida kak metod patogeneticheskoi terapii khronicheskogo atroficheskogo gastrita.

Therapy of patients with chronic atrophic gastritis using intragastric SMC-electrophoresis of cobamamide resulted in a marked clinical effect. Altogether 82 patients were investigated. Protein metabolism using I131-albumin and reparative regeneration (histochemical and electron microscopy methods) was studied in the course of treatment. A positive time course of protein metabolism determined by albumin and improvement of reparation of specialized epitheliocytes in the mucous membrane of the stomach were noted as a result of therapy.

[Vitamin B 12 metabolism and the status of sulfhydryl groups in protein-choline deficiency in rats. Effects of methyl- and adenosylcobalamins]. / Obmen vitamina B 12 i sostoianie SH-grupp pri belkovo-kholinovoi nedostatochnosti u krys. Vliianie metil i adenozilkobalaminov.

The effect of low protein choline-deficient diet on total vitamin B12 content and individual cobalamin level in the blood serum and liver of rats was determined. Moreover the total and non-protein SH-group content and glutathione transferase activity in the liver of rats were studied. Total cobalamin content increased in the blood serum, but it did not change in the liver of rats fed choline-deficient low protein diet. Total and non-protein SH-group level as well as glutathione transferase activity in the liver decreased significantly. The causes of changes revealed are discussed. Methylcobalamin (but not adenosylcobalamin) administration normalized individual cobalamin level in the blood serum. Administration of both methylcobalamin and adenosyl-cobalamin resulted in total SH-group content restoration whereas non-protein SH-group level and glutathione transferase activity were restored only in methylcobalamin-treated rats.