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Facial paralysis results in the decline in the generation of facial expressions and is attributed to several causes. Intractable facial paralysis has a poor prognosis, and new treatments are required. Facial paralysis results in the decline in the generation of facial expressions and is attributed to several causes. Reactive oxygen species can inhibit peripheral nerve regeneration after injury. Therefore, the administration of an appropriate antioxidant can promote nerve regeneration. Silicon (Si)-based agents can react with water to generate antioxidant hydrogen. Oral administration of Si-based agents can effectively alleviate symptoms of disease models associated with oxidative stress. Thus, we orally administered a Si-based agent to a facial paralysis model mice to investigate whether promotion of nerve regeneration occurred. The combined administration of methylcobalamin (MeCbl) with the Si-based agent was also investigated. The Si-based agent improved the clinical score evaluation of facial paralysis. Electroneuronography and immunostaining showed that the Si-based agent promoted myelination and recovery of facial nerve function. Furthermore, in the drug-administered group, oxidative stress associated with facial nerve injury was reduced more than that in the non-administered group. The clinical score evaluation, neuroregeneration effect, and reduction of oxidative stress were improved in the combination group compared to the single administration group. The Si-based agent could rapidly improve the disappearance of facial expressions by promoting myelin sheath formation and alleviating oxidative stress. Combination therapy with a Si-based agent and MeCbl should improve the prognosis and treatment of intractable facial paralysis.

Methylcobalamin (MBL) is a vitamin B12 coenzyme and is effective for treating peripheral neuropathies. Little is known about pharmacokinetics (PK) of MBL in animals, we have developed a simple assay for MBL by using only 0.01 mL of plasma for PK of MBL in rats. Under minimal light exposure (<5 lx), MBL was extracted by a simple protein precipitation using methanol and detected by liquid chromatography with tandem mass spectrometry. MBL in rat plasma at 20-10,000 ng/mL was quantified using only 0.01 mL of plasma. Relative error and relative standard deviation met the acceptance criteria in reproducibility assessments, indicating the robustness of the assay. PK of MBL was evaluated after intravenous, intramuscular, and subcutaneous administration. PK of MBL was dose proportional at 5-20 mg/kg in both intramuscular and subcutaneous administrations. Bioavailability after the two dosing routes was complete (ca. 100 %). The incurred sample reanalysis also supported that the assay is robust. The established assay was successfully applied to PK studies in rats to find that MBL showed high bioavailability after intramuscular and subcutaneous administrations., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024. Published by Elsevier Inc.)

Objective: In attempt to conquer the major concerns of oral duloxetine hydrochloride (like low bioavailability, intolerable side-effects and no regeneration of demyelinated nerve fibres) for the management of chemotherapy-induced peripheral neuropathy (CIPN), an alternative delivery of duloxetine hydrochloride was aimed for in-vivo optimization. Methods: A film forming dermal gel consisting of duloxetine hydrochloride was formulated and enriched with methylcobalamin and geranium oil. The formulated gel successfully qualified the various pharmaceutical characteristics of gel. Administration of paclitaxel (8 mg/kg/i.p. in four divided doses) for 4 alternate days induced the symptoms of peripheral neuropathy in rats. On 14th day, the responses to noxious stimulus (mechanical hyperalgesia, cold allodynia, and heat hyperalgesia) were increased and reached to its maximum. Thereafter, drug treatment with formulated dermal gel and oral duloxetine hydrochloride (30 mg/kg, once daily) was initiated for 2 weeks in different group of animals. On the 28th day animals were sacrificed to isolate sciatic nerve, to assess biochemical changes (TBARS, reduced GSH, total protein, TNF-α, IL-6) and for histopathological examinations of nerve sections using Hematoxylin-Eosin and Toludine blue staining methods. Results: Application of formulated dermal gel to paclitaxel-treated rats significantly improved paw-withdrawal latency responses during noxious stimulus testing, reduced the levels of TBARS, TNF-α, IL-6 and elevated the levels of reduced GSH as compared to paclitaxel treated rats. Histographs also indicated marked regeneration of the damaged nerve fibers. Topical delivery of duloxetine hydrochloride produced similar results in disparity to oral route. However, no significant disparity in responses was obtained with twice application of formulated dermal gel when compared to once daily application. Conclusion: Tremendous recovery from nociception, oxidation and inflammation in addition to nerve degeneration was achieved through dermal application of duloxetine hydrochloride in peripheral neuropathy.

Photodegradation of drug substances leads to the formation of known and unknown degradation products. These unknown degradation products interfere and give erroneous results because of absorption on analytical wavelengths. This interference could be eliminated using the correction of irrelevant absorbancies. This study is based on the application of linear and non-linear correction of irrelevant absorption for the determination of methylcobalamin (MC) and hydroxocobalamin in the photolytic degradation assisted by ascorbic acid (AH 2 ). MC follows first-order degradation kinetics and the rate of degradation (k obs ) ranges from 1.99-2.34 × 10 -2 , min -1 at pH 2.0-12.0. The second-order rate constants (k 2 ) for the photochemical interaction of MC and AH 2 are in the range of 17.9-60.3 × 10 -2 M -1 , min -1 (acidic region) and 10.3-24.6 × 10 -2 M -1 , min -1 (alkaline region). The k 2 -pH profile was found to be bell-shaped and the maximum rate of degradation in the presence of AH 2 is at pH 5.0 (60.3 × 10 -2 M -1 , min -1 ) due to the protonation of MC. However, in alkaline pH, the rate of photodegradation decreases due to the ionization form of AH 2 which is AH - species., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Postherpetic pain (PHP) is difficult to control. Although Neurotropin® (NTP) and methylcobalamin (MCB) are often prescribed to treat the pain, the efficacy of combined treatment for PHP remains imcompletely understood., Objective: In this study, we investigate the combined effects of NTP and MCB on PHP in mice., Methods: NTP and MCB were administered from day 10-29 after herpes simplex virus type-1 (HSV-1) infection. The pain-related responses were evaluated using a paint brush. The expression of neuropathy-related factor (ATF3) and nerve repair factors (GAP-43 and SPRR1A) in the dorsal root ganglion (DRG) and neurons in the skin were evaluated by immunohistochemical staining. Nerve growth factor (NGF) and neurotrophin-3 (NT3) mRNA expression levels were evaluated using real-time PCR., Results: Repeated treatment with NTP and MCB after the acute phase inhibited PHP. Combined treatment with these drugs inhibited PHP at an earlier stage than either treatment alone. In the DRG of HSV-1-infected mice, MCB, but not NTP, decreased the number of cells expressing ATF3 and increased the number of cells expressing GAP-43- and SPRR1A. In addition, MCB, but not NTP, also increased and recovered non-myelinated neurons decreased in the lesional skin. NTP increased the mRNA levels of NTF3 in keratinocytes, while MCB increased that of NGF in Schwann cells., Conclusion: These results suggest that combined treatment with NTP and MCB is useful for the treatment of PHP. The combined effect may be attributed to the different analgesic mechanisms of these drugs., Competing Interests: Declaration of Competing Interest The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. This study was funded by Nippon Zoki Pharmaceutical Co., Ltd., (Copyright © 2024 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

The growing production of pharmaceuticals and nutraceuticals, e.g., methylcobalamin supplements, improves the health of people. This study assesses the environmental footprint of chewable methylcobalamin supplements in four packaging types: blister packs or bottles made of HDPE, PET, or glass. A cradle-to-grave life cycle assessment is conducted to evaluate the supply to Belgian consumers of the recommended daily dose of methylcobalamin supplementation (1.2 mg) in case of deficiency. The impact of methylcobalamin manufacturing in major producing countries (China as baseline and France) is analyzed based on detailed synthesis modeling of data points coming from patents. The overall carbon footprint (CF) is dominated by the transport of consumers to the pharmacy and methylcobalamin powder manufacturing in China (while its mass share per supplement is only 1 %). The impact is the lowest for supplements in HDPE bottles (6.3 g CO 2 eq) and 1 %, 8 %, and 35 % higher for those in PET bottles, glass bottles, and blister packs, respectively. Tablets in blister packs have for other investigated impact categories (fossil resource footprint (FRF); acidification; eutrophication: freshwater, marine, and terrestrial; freshwater ecotoxicity; land use; and water use) the highest footprint and those in HDPE and PET bottles for most the lowest. The CF of methylcobalamin powder manufacturing in France is 22 % lower than in China (2.7 g CO 2 eq), while the FRF is similar in both locations (26-27 kJ). The FRF and the difference in the CF are chiefly due to energy use and solvent production emissions. Similar trends as the CF are found for other investigated impact categories. Valuable conclusions are drawn for environmental studies on pharmaceuticals and nutraceuticals: (i) including accurate data on consumer transport, (ii) using more environmentally-friendly active ingredients, (iii) choosing appropriate packaging types considering multiple aspects: convenience, environmental footprint, etc., and (iv) providing a holistic picture through assessing various impact categories., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Vitamin B12 (cobalamin, Cbl) is represented by several molecular variants distinguished by the exchangeable ligand X coordinated to cobalt ion (XCbl). The most typical XCbl-forms are cyanocobalamin (CNCbl), hydroxocobalamin (HOCbl), methylcobalamin (MeCbl) and 5'-deoxydeoxyadenosylcobalamin (AdoCbl). Cells convert the "inactive" vitamins CNCbl and HOCbl to the two critically important coenzymes AdoCbl or MeCbl. Surprisingly, little or no MeCbl is usually uncovered in the tissue samples, as compared to AdoCbl and HOCbl. We hypothesized that a low level of MeCbl is an artifact of "harsh" extractions, leading to degradation of MeCbl and/or its conversion to other XCbl-forms., Methods: We designed a "mild" extraction protocol, including homogenization of rat liver in ammonium acetate (pH 4.6), dilution with EtOH (final 60%) and heating for 10 min at 70 °C. The XCbls were separated by HPLC and quantified by isotope dilution assays., Results: A "mild" extraction revealed the following composition of Cbls: 37% AdoCbl, 35% MeCbl, 15% HOCbl and 13% CNCbl. The usual "harsh" protocol (pH 7, 20 min at 80 °C) changed this balance to 33%, 5%, 43% and 17%, respectively. A model assay revealed that MeCbl underwent demethylation and conversion to HOCbl at pH 3 and pH > 7, when heated with thiols. Other changes included decyanation of CNCbl and destruction of HOCbl., Conclusions: Our procedure reveals a high content of MeCbl in rat liver., General Significance: This result challenges previous data and pinpoints the need for new studies to characterize the endogenous Cbl-forms in health and disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Vitamin B-12 deficiency is widespread in many parts of the world, affecting all age groups and increasing with age. It is primarily due to a low intake of animal source foods or malabsorption. The measurement of bioavailability of vitamin B-12 is etiologically important in deficiency but is limited due to the use of radioactive isotopes like [57Co]- or [14C]-cyanocobalamin., Objectives: The aim of this study was to measure the bioavailability of [13C]-cyanocobalamin in humans and to assess the effect of parenteral replenishment of vitamin B-12 on the bioavailability., Methods: We synthesized a stable isotope-labeled vitamin B-12, [13C]-cyanocobalamin, using Salmonella enterica by providing [13C2]-ethanolamine as a sole carbon source. After purification and mass spectrometry-based characterization, its oral bioavailability was measured in the fasted state with high and low oral doses, before and after parenteral replenishment of vitamin B-12 stores, from the kinetics of its plasma appearance in a 2-compartment model., Results: [13C]-cyanocobalamin was completely decyanated to [13C]-methylcobalamin describing metabolic utilization, and its plasma appearance showed early and late absorption phases. At a low dose of 2.3 µg, the mean bioavailability was 46.2 ± 12.8 (%, mean ± SD, n = 11). At a higher dose of 18.3 µg, the mean bioavailability was 7.6 ± 1.7 (%, mean ± SD, n = 4). Parenteral replenishment of the vitamin B-12 store in deficient individuals prior to the measurement resulted in a 1.9-fold increase in bioavailability., Conclusions: Vitamin B-12 bioavailability is dose dependent and at a low dose that approximates the normal daily requirement (46%). The stable isotope method described here could be used to define the etiology of deficiency and to inform the dietary requirement in different physiologic states as well as the dose required for supplementation and food fortification. This trial was registered at the Clinical Trials Registry of India as CTRI/2018/04/012957., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Peripheral nerve injury is one of common traumas. Although injured peripheral nerves have the capacity to regenerate, axon regeneration proceeds slowly and functional outcomes are often poor. Pharmacological enhancement of regeneration can play an important role in increasing functional recovery. In this study, we developed a novel electrospun nanofiber sheet incorporating methylcobalamin (MeCbl), one of the active forms of vitamin B12 homologues, to deliver it enough locally to the peripheral nerve injury site. We evaluated whether local administration of MeCbl at the nerve injury site was effective in promoting nerve regeneration. Electrospun nanofiber sheets gradually released MeCbl for at least 8weeks when tested in vitro. There was no adverse effect of nanofiber sheets on function in vivo of the peripheral nervous system. Local implantation of nanofiber sheets incorporating MeCbl contributed to the recovery of the motor and sensory function, the recovery of nerve conduction velocity, and the promotion of myelination after sciatic nerve injury, without affecting plasma concentration of MeCbl., Statement of Significance: Methylcobalamin (MeCbl) is a vitamin B12 analog and we previously reported its effectiveness in axonal outgrowth of neurons and differentiation of Schwann cells both in vitro and in vivo. Here we estimated the effect of local administered MeCbl with an electrospun nanofiber sheet on peripheral nerve injury. Local administration of MeCbl promoted functional recovery in a rat sciatic nerve crush injury model. These sheets are useful for nerve injury in continuity differently from artificial nerve conduits, which are useful only for nerve defects. We believe that the findings of this study are relevant to the scope of your journal and will be of interest to its readership., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Aims: This study investigated the efficacies of gliclazide (GLZ), methylcobalamin (MCA), and GLZ+MCA combination therapy on DPN by evaluating the treatment-related changes in peripheral nerve function, the polyol pathway, and oxidative stress in the sciatic nerve of streptozotocin-induced diabetic rats., Materials and Methods: The rat model of streptozotocin-induced diabetes was orally given GLZ (25mg/kg/day), MCA (175μg/kg/day), and GLZ+MCA (25mg/kg/day+175μg/kg/day) combination therapy for 8weeks, in order to observe its effects on the motor nerve conduction velocity (MNCV), on the activities of Na(+), K(+)-ATPase, aldose reductase(AR), AR mRNA expression, on the polyol contents, antioxidative enzyme activities and peroxidation products in the sciatic never tissue., Key Findings: Most of the indicators of DPN, such as delayed MNCV, altered/damaged nerve structure, inhibited Na(+),K(+)-ATPase activity, enhanced AR activity and AR mRNA expression, increased polyol contents, altered Cu,Zn-superoxide dismutase, catalase, and glutathione-peroxidase activities, and elevated malondialdehyde level in the sciatic nerves of the diabetic rats, were significantly ameliorated by treatment with either GLZ or MCA. Moreover, the combination of GLZ and MCA was found to enhance the curative effect on DPN in parts of above-mentioned parameters as compared to monotherapy., Significance: Monotherapy with GLZ or MCA, and especially the combined application of GLZ and MCA, could be efficient therapeutic strategies for combating experimental DPN in diabetic rats., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: High-dose of methylcobalamin promotes nerve regeneration in rats with acrylamide neuropathy. A double-blind controlled trial suggested that high-dose methylcobalamin could increase compound muscle action potentials in patients with amyotrophic lateral sclerosis (ALS). A large-scale extended period human trial is now on-going in ALS (Clinicaltrial.govNCT00444613). We attempted to study whether high-dose methylcobalamin can improve symptoms or retard progression of motor dysfunction in the wobbler mouse model of ALS., Methods: After initial diagnosis of the disease at the postnatal age of 3-4 weeks, wobbler mice received methylcobalamin (3 or 30 mg/kg, n=10/group) or vehicle (n=10), daily for 4 weeks by intraperitoneal administration in a blinded fashion. We compared clinical symptoms and pathological changes among all groups. Vitamin B12 concentrations were measured in the serum, the skeletal muscle and the spinal cord of three groups (n=5/group)., Results: In comparison with vehicle, mice treated with ultra-high dose (30 mg/kg) of methylcobalamin significantly inhibited muscle weakness and contracture in the forelimb, and increased the weight of the bicep muscles and the number of musculocutaneous nerves. Methylcobalamin-treated mice significantly elevated vitamin B12 concentrations of the serum, the bicep muscle and the spinal cord compared to vehicle., Conclusion: Our results suggest that treatment with methylcobalamin could delay progression of motor symptoms and neuropathological changes in wobbler mouse motor neuron disease if very high doses are used., (Copyright © 2015. Published by Elsevier B.V.)

The aim of this work was to evaluate the vitamin B12 content and profile of cobalamin bioactive forms in raw and cooked beef. The study showed that vitamin B12 distribution is unequal among beef muscles. The content of this nutrient ranges from 0.7 to 1.5 μg/100 g of tissue. In beef, three biologically active forms of vitamin B12 were determined, i.e.: methylcobalamin, adenosylcobalamin and hydroxycobalamin; the dominating form of vitamin B12 was adenosylcobalamin (68% of total cobalamins). The process of roasting and grilling had little effect on the vitamin B12 content in the final product as compared to the raw meat. The fried product was characterised by about a 32% lower content of cobalamins than in raw meat., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Methylcobalamin (MeCbl) is a vitamin B12 analog that has some positive effects on peripheral nervous disorders. Although some previous studies revealed the effects of MeCbl on neurons, its effect on the muscle, which is the final target of motoneuron axons, remains to be elucidated. This study aimed to determine the effect of MeCbl on the muscle. We found that MeCbl promoted the proliferation and migration of C2C12 myoblasts in vitro and that these effects are mediated by the Erk1/2 signaling pathway without affecting the activity of the Akt signaling pathway. We also demonstrated that MeCbl inhibits C2C12 cell apoptosis during differentiation. Our results suggest that MeCbl has beneficial effects on the muscle in vitro. MeCbl administration may provide a novel therapeutic approach for muscle injury or degenerating muscle after denervation., (Copyright © 2013 Elsevier Inc. All rights reserved.)