Simvastatin-Nicotinamide Co-Crystals: Formation, Pharmaceutical Characterization and in vivo Profile.

PURPOSE: To enhance the solubility and dissolution profile of simvastatin (SIM) through co-crystallization with varying ratios of nicotinamide (NIC) using various co-methods. MATERIALS AND METHODS: Twelve SIM:NIC co-crystal formulations (F01-F12) were prepared using dry grinding, slurry, liquid-assisted grinding, and solvent-evaporation methods, and their properties compared. Optimized formulations were selected on the basis of dissolution profiles and solubility for in vivo studies. The angle of repose, Carr Index and Hausner ratio were calculated to evaluate flow properties. Differential light scattering (DLS) was used to estimate particle-size distribution. Scanning electron microscopy (SEM) was employed to evaluate surface morphology. Thermal analyses and Fourier-transform infrared (FTIR) spectroscopy were used to determine the ranges of thermal stability and physical interaction of formulated co-crystals. X-ray powder diffraction (XPD) spectroscopy was used to determine the crystalline nature. Solubility and dissolution studies were undertaken to determine in vitro drug-release behaviors. RESULTS: Micromeritic analyses revealed the good flow properties of formulated co-crystals. DLS showed the particle size of co-crystals to be in the nanometer range. SEM revealed that the co-crystals were regular cubes. Thermal studies showed the stability of co-crystals at >300°C. FTIR spectroscopy revealed minor shifts of various peaks. XPD spectroscopy demonstrated co-crystal formation. The formulations exhibited an improved dissolution profile with marked improvements in solubility. In vivo studies showed a 2.4-fold increase in Cmax whereas total AUC(0-∞) was increased 4.75-fold as compared with that of SIM tablets. CONCLUSION: Co-crystallization with NIC improved the solubility and dissolution profile and, hence, the bioavailability of the poorly water-soluble drug SIM.

Functional Roles of B-Vitamins in the Gut and Gut Microbiome.

The gut microbiota produce hundreds of bioactive compounds, including B-vitamins, which play significant physiological roles in hosts by supporting the fitness of symbiotic species and suppressing the growth of competitive species. B-vitamins are also essential to the host and certain gut bacterium. Although dietary B-vitamins are mainly absorbed from the small intestine, excess B-vitamins unable to be absorbed in the small intestine are supplied to the distal gut. In addition, B-vitamins are supplied from biosynthesis by distal gut microbiota. B-vitamins in the distal colon may perform many important functions in the body. They act as 1) nutrients for a host and their microbiota, 2) regulators of immune cell activity, 3) mediators of drug efficacy, 4) supporters of survival, or the fitness of certain bacterium, 5) suppressors of colonization by pathogenic bacteria, and 6) modulators of colitis. Insights into basic biophysical principles, including the bioavailability of B-vitamins and their derivatives in the distal gut are still not fully elucidated. Here, the function of single B-vitamin in the distal gut including their roles in relation to bacteria are briefly reviewed. The prospect of extending analytical methods to better understand the role of B-vitamins in the gut is also explored.

Imaging Biotin Trafficking In Vivo with Positron Emission Tomography.

The water-soluble vitamin biotin is essential for cellular growth, development, and well-being, but its absorption, distribution, metabolism, and excretion are poorly understood. This paper describes the radiolabeling of biotin with the positron emission tomography (PET) radionuclide carbon-11 ([11C]biotin) to enable the quantitative study of biotin trafficking in vivo. We show that intravenously administered [11C]biotin is quickly distributed to the liver, kidneys, retina, heart, and brain in rodents-consistent with the known expression of the biotin transporter-and there is a surprising accumulation in the brown adipose tissue (BAT). Orally administered [11C]biotin was rapidly absorbed in the small intestine and swiftly distributed to the same organs. Preadministration of nonradioactive biotin inhibited organ uptake and increased excretion. [11C]Biotin PET imaging therefore provides a dynamic in vivo map of transporter-mediated biotin trafficking in healthy rodents. This technique will enable the exploration of biotin trafficking in humans and its use as a research tool for diagnostic imaging of obesity/diabetes, bacterial infection, and cancer.

[Bioavailability of natural versus synthetic B vitamins and their effects on metabolic processes]. / Bioverfügbarkeit eines natürlichen versus eines synthetischen Vitamin-B- Komplexes und deren Auswirkungen auf metabolische Prozesse.

BACKGROUND: Owing to the widespread use of vitamin supplements to prevent and compensate for deficiencies, the equivalence of natural versus synthetic vitamins with respect to their bioavailability and metabolic influence is discussed controversially. METHOD: Thirty healthy female (n=22) and male participants (n=8) were investigated in a randomized, double-blind, cross-over study over a supplementation period of 6 weeks for each condition. The participants received a daily dose of a complex of the 8 natural B vitamins (group N), determined by the natural composition of quinoa seedlings, resp. synthetic B vitamins (group S), both corresponding to about 2.5 times the Recommended Dietary Allowance (RDA) of the national nutrition board. The primary criterion under investigation was changes in the blood levels of the individual B vitamins. Secondary criteria were the influence of both B complexes on homocysteine, antioxidant status, polyphenols, peroxide loading and peroxidase activity. RESULTS: Compared to baseline values, serum levels of all B vitamins measured increased: Vitamins B1 (N +23%; S +27%), B2 (N +14%; S +13%), B6 (N +101%; S +101%), B9 (N +86%; S +153%) and B12 (N +16%) were elevated at the end of the first supplementation period (p < 0.05), while serum levels of vitamins B1, B9 and B12 remained elevated compared to baseline even after the 2-week washout phase. During the second supplementation period, the vitamin concentrations in group N, with the exception of vitamin B1, could be increased once again (p < 0.05). In contrast, in group S only for vitamins B2 and B12 substantial increases (p < 0.05) were found. The influence of B vitamins on metabolic parameters such as homocysteine and polyphenols, which were markedly reduced, was also clearly measurable; however, total antioxidant capacity and peroxidase activity increased. The peroxide concentration remained almost unchanged in both groups. CONCLUSION: This clinical pilot study showed comparable bioavailability for both natural and synthetic B vitamins, with a 2.5-fold concentration of the RDA. Both vitamin B preparations showed a clear influence on metabolic parameters, whereas that of the natural B vitamins tended to have a slightly stronger effect than the synthetic analogues.

Experts' opinion on inositols in treating polycystic ovary syndrome and non-insulin dependent diabetes mellitus: a further help for human reproduction and beyond.

Introduction: This Experts' opinion provides an updated scientific support to gynecologists, obstetricians, endocrinologists, nutritionists, neurologists and general practitioners on the use of Inositols in the therapy of Polycystic Ovary Syndrome (PCOS) and non-insulin dependent (type 2) diabetes mellitus (NIDDM).Areas covered: This paper summarizes the physiology of Myo-Inositol (MI) and D-Chiro-Inositol (DCI), two important molecules present in human organisms, and their therapeutic role, also for treating infertility. Some deep differences between the physiological functions of MI and DCI, as well as their safety and intestinal absorption are discussed. Updates include new evidence on the efficacy exerted in PCOS by the 40:1 MI/DCI ratio, and the innovative approach based on alpha-lactalbumin to overcome the decreased therapeutic efficacy of Inositols in some patients.Expert opinion: The evidence suggests that MI, alone or with DCI in the 40:1 ratio, offers a promising treatment for PCOS and NIDDM. However, additional studies need to evaluate some still unresolved issues, such as the best MI/DCI ratio for treating NIDDM, the potential cost-effectiveness of reduced gonadotropins administration in IVF due to MI treatment, or the benefit of MI supplementation in ovulation induction with clomiphene citrate in PCOS patients.

Topical delivery of niacinamide: Influence of neat solvents.

Niacinamide (NIA) has been widely used in cosmetic and personal care formulations for several skin conditions. Permeation of topical NIA has been confirmed in a number of studies under infinite dose conditions. However, there is limited information in the literature regarding permeation of NIA following application of topical formulations in amounts that reflect the real-life use of such products by consumers. The aim of the present work was therefore to investigate skin delivery of NIA from single solvent systems in porcine skin under finite dose conditions. A secondary aim was to probe the processes underlying the previously reported low recovery of NIA following in vitro permeation and mass balance studies. The solubility and stability of NIA in various single solvent systems was examined. The solvents investigated included Transcutol® P (TC), propylene glycol (PG), 1-2 hexanediol (HEX), 1-2 pentanediol (1-2P), 1-5 pentanediol (1-5P), 1-3 butanediol (1-3B), glycerol (GLY) and dimethyl isosorbide (DMI). Skin permeation and deposition of the molecule was investigated in full thickness porcine skin in vitro finite dose Franz-type diffusion experiments followed by mass balance studies. Stability of NIA for 72 h in the solvents was confirmed. The solubility of NIA in the solvents ranged from 82.9 ± 0.8 to 311.9 ± 4.5 mg/mL. TC delivered the highest percentage permeation of NIA at 24 h, 32.6 ± 12.1% of the applied dose. Low total recovery of NIA after mass balance studies was observed for some vehicles, with values ranging from 55.2 ± 12.8% to 106.3 ± 2.3%. This reflected the formation of a number of NIA degradation by-products in the receptor phase during the permeation studies. Identification of other vehicles for synergistic enhancement of NIA skin delivery will be the subject of future work.

Rapidly dissolving bilayer microneedle arrays - A minimally invasive transdermal drug delivery system for vitamin B12.

Vitamin B12 plays an essential role in one-carbon metabolism in the human body. A deficiency in this vitamin can lead to severe haematopoietic and neuropsychiatric disorders and is currently treated by oral or parenteral administration of exogenous vitamin. Unfortunately, the absorption of orally taken vitamin B12 is low and highly variable, while injections can cause pain and anxiety. Thus, an efficient alternative drug delivery system for overcoming these shortcomings is highly desirable. Novel polymeric microneedle (MN) arrays have the potential for minimally invasive transdermal treatment of vitamin B12 deficiency. Bilayer dissolving MN arrays (19 × 19 needles, 600 µm height) containing 135 µg vitamin B12 were cast using two different aqueous polymer blends. MN arrays showed sufficient mechanical strength for skin insertion, dissolved rapidly and delivered 72.92% of their drug load in vitro over 5 h. Ultimately, the potential of delivering a therapeutically relevant dose of vitamin B12 transdermally was demonstrated in vivo in Sprague-Dawley rats by comparison to subcutaneous injections. Maximum plasma levels of 0.37 µg/mL occurred 30 min post-MN application, highlighting the ability of fabricated MN arrays to rapidly deliver vitamin B12 transdermally.

Metabolic consequences of discretionary fortified beverage consumption containing excessive vitamin B levels in adolescents.

Over the past decade, there has been a substantial increase in the number of beverage products containing added vitamins and minerals. Often viewed as a healthier choice by consumers, the metabolic impacts of excessive vitamin consumption are relatively unknown, especially in children. The aim of this study was to examine the effects of a widely available, vitamin fortified beverage (5h Energy Decaffeinated) on insulin sensitivity, metabolic hormones and serum metabolomic responses in adolescents. Twenty adolescents (13-19y, 10M/10F) completed two randomized trials, consuming either coloured water as placebo (PL) or a vitamin fortified, sugar free beverage (FB, 1.5ml/kg) 40min prior to a modified oral glucose tolerance test (OGTT, 1.75g/kg glucose). Samples were collected at baseline and at 30, 45, 60, 90 and 120min during the OGTT. No differences in blood glucose response were observed between the treatments. However, compared to PL, postprandial plasma C-peptide and insulin excursion was significantly greater with FB, resulting in a 28% decline in the insulin sensitivity index. This was accompanied by elevated GLP-1, glucagon and PYY responses with FB compared to PL. Serum metabolomics (1H-NMR) analysis also revealed perturbations to vitamin B-linked one carbon metabolism flux with FB consumption that became more pronounced over time. These included a transient reduction in homocysteine flux accompanied by increases in betaine, vitamin B6, vitamin B12, choline, folate and taurine. Although these impacts are likely short-lived, results show that beverages fortified with excessive amounts of vitamins are not metabolically inert, but likely result in greater insulin secretion, differential gut hormone secretion and elevated one-carbon flux to process the excessive vitamin loads.

A comparison of the in vitro permeation of niacinamide in mammalian skin and in the Parallel Artificial Membrane Permeation Assay (PAMPA) model.

The in vitro skin penetration of pharmaceutical or cosmetic ingredients is usually assessed in human or animal tissue. However, there are ethical and practical difficulties associated with sourcing these materials; variability between donors may also be problematic when interpreting experimental data. Hence, there has been much interest in identifying a robust and high throughput model to study skin permeation that would generate more reproducible results. Here we investigate the permeability of a model active, niacinamide (NIA), in (i) conventional vertical Franz diffusion cells with excised human skin or porcine skin and (ii) a recently developed Parallel Artificial Membrane Permeation Assay (PAMPA) model. Both finite and infinite dose conditions were evaluated in both models using a series of simple NIA solutions and one commercial preparation. The Franz diffusion cell studies were run over 24 h while PAMPA experiments were conducted for 2.5 h. A linear correlation between both models was observed for the cumulative amount of NIA permeated in tested models under finite dose conditions. The corresponding correlation coefficients (r2) were 0.88 for porcine skin and 0.71 for human skin. These results confirm the potential of the PAMPA model as a useful screening tool for topical formulations. Future studies will build on these findings and expand further the range of actives investigated.

A Randomized Pilot Trial to Evaluate the Bioavailability of Natural versus Synthetic Vitamin B Complexes in Healthy Humans and Their Effects on Homocysteine, Oxidative Stress, and Antioxidant Levels.

The vitamin B complex comprises 8 different water-soluble constituents that humans must sequester from the diet. This pilot study compared natural versus synthetic vitamin B complexes for their bioavailability, accumulation, and their impact on antioxidants, homocysteine levels, and oxidative stress. We conducted a double-blind randomized clinical trial with thirty healthy participants. They were randomly assigned to group N (natural) and group S (synthetic). Vitamin B was ingested daily for 6 weeks in the range of about 2.5 times above the recommended daily allowance. Blood samples were taken at baseline, 1.5 h, 4 h, 7 h (diurnal), 6 w (discontinuation of supplements), and 8 w (washout). Blood levels of thiamine (B1), riboflavin (B2), pyridoxine (B6), folic acid (B9), cobalamin (B12), homocysteine, total antioxidants, peroxidase activity, polyphenols, and total peroxides were determined. Compared to initial values, serum levels of each B vitamin increased at the end of the supplementation period: i.e., B1 (+23% N; +27% S), B2 (+14% N; +13% S), B6 (+101% N; +101% S), B9 (+86% N; +153% S), and B12 (+16% N) (p < 0.05). Homocysteine (-13% N) decreased, while peroxidase activity (+41% S) and antioxidant capacity increased (+26% N). Short-term effects were already observed after 1.5 h for B9 (+238% N; +246% S) and after 4 h for vitamin B2 (+7% N; +8% S), B6 (+59% N; +51% S), and peroxidase activity (+58% N; +58% S). During the washout period, serum levels of B vitamins decreased except for thiamine and peroxidase activity, which increased further. This clinical pilot study revealed comparable bioavailability for both natural and synthetic B vitamins but did not show statistically noticeable differences between groups despite some favourable tendencies within the natural vitamin group, i.e., sustained effects for cobalamin and endogenous peroxidase activity and a decrease in homocysteine and oxidative stress levels.

Gastrointestinal Handling of Water-Soluble Vitamins.

Nine compounds are classified as water-soluble vitamins, eight B vitamins and one vitamin C. The vitamins are mandatory for the function of numerous enzymes and lack of one or more of the vitamins may lead to severe medical conditions. All the vitamins are supplied by food in microgram to milligram quantities and in addition some of the vitamins are synthesized by the intestinal microbiota. In the gastrointestinal tract, the vitamins are liberated from binding proteins and for some of the vitamins modified prior to absorption. Due to their solubility in water, they all require specific carriers to be absorbed. Our current knowledge concerning each of the vitamins differs in depth and focus and is influenced by the prevalence of conditions and diseases related to lack of the individual vitamin. Because of that we have chosen to cover slightly different aspects for the individual vitamins. For each of the vitamins, we summarize the physiological role, the steps involved in the absorption, and the factors influencing the absorption. In addition, for some of the vitamins, the molecular base for absorption is described in details, while for others new aspects of relevance for human deficiency are included. © 2018 American Physiological Society. Compr Physiol 8:1291-1311, 2018.

Combination of 3D printing technologies and compressed tablets for preparation of riboflavin floating tablet-in-device (TiD) systems.

Gastric floating tablets are a multifunctional dosage form with the merits of long-term gastric retention, sustained release and improved bioavailability though floating time and sustained release are usually not satisfied. Here we designed a novel gastric floating system by combining compressed tablets with 3D printed devices, wherein a riboflavin tablet was filled into a device. The table-filled device can be called a tablet-in-device (TiD) system. Commercial poly(lactic acid) filaments were used for fused deposition modeling (FDM) 3D printing of the body and cap of the device. Four types of TiD systems were prepared. The basic structures of them involved non-net, centrally symmetric double-net (including a peripheral sealed air-filled chamber and a centric net-on-both-sides chamber), single-net (including a sealed air-filled chamber on the top side and a net-on-one-side chamber on the bottom side), and eccentric double-net (including an eccentric net-on-both-sides chamber and an air-filled chamber). They were exquisitely designed after precise calculations of every chamber parameters according to the buoyant principle. All of them showed good floating ability, although only the latter two TiD systems were selected due to appropriate drug release. Compressed riboflavin tablets, consisting of riboflavin, lactose, hydroxypropyl methylcellulose (HPMC) and magnesium stearate, were prepared with the direct compaction method. All the tablets showed rapid drug release though the release was highly hindered by the devices in the TiD systems due to the barrier effect of devices and the tablet slurry formation. The single-net and double-net TiD systems achieved the cumulative release of 41% and 62% at 72 h, respectively, along with simultaneously well floating. In vivo long-term (>72 h) gastric floating function of TiD systems was further demonstrated on the rabbit models by the CT investigation. TiD systems are appropriate for oral administration of drugs with super long-term floating and controlled release in the gastric route.

The effects of ligand valency and density on the targeting ability of multivalent nanoparticles based on negatively charged chitosan nanoparticles.

It has been shown that multivalent ligands could significantly enhance the binding avidity compared with the monovalent ones; therefore, once incorporated into nanoparticles, they promote superior targeting ability without increasing the ligand density. Although ligand valency and density play a key role on the targeting ability of corresponding nanoparticles, these facotrs remain largely unexplored and detailed studies are lacking. Herein, a series of multivalent ligands with certain valencies (FAn, n indicates the valency of ligand: n=3, 5, 7) has been conveniently synthesized by conjugating different copies of folate ligands with poly(acrylic acid) (PAA). Negatively charged chitosan nanoparticles (CTS-SA NPs) have been utilized as proper multivalent platforms because they can strongly suppress non-specific protein adsorption and cellular uptake without interfering with the targeting ability of multivalent ligands. Subsequently, the structure of CTS-SA NPs has been modified using different amounts of FAn to form multivalent nanoparticles (FAn-CTS-SA NPs) with various valencies and densities. A series of specific investigations of them suggested that the cellular uptake of multivalent nanoparticles has largely varied with the ligand valency variation even at similar ligand densities; and also largely varied with ligand density variation even at the same ligand valencies. The intermediate valency and density values determined in the current study (ie., 5 and 2.4wt%, respectively) have provided the best cellular uptake, facilitating superior targeting ability at relatively low ligand valency and density. Unexpectedly, no conspicuous difference has been observed during endocytotic inhibition assays with single inhibitors, which may be attributed to the synergetic endocytotic mechanism with multiple pathways of multivalent nanoparticles. The optimal multivalent nanoparticles have also exhibited excellent biocompatibility, long-term stability in vitro and enhanced circulation time in vivo, thus demonstrating their potential for targeted drug delivery.

Assessment of bioavailable B vitamin content in food using in vitro digestibility assay and LC-MS SIDA.

Standardized analytical methods, where each B vitamin is extracted from a given sample individually using separate procedures, typically ensure that the extraction conditions provide the maximum recovery of each vitamin. However, in the human gastrointestinal tract (GIT), the extraction conditions are the same for all vitamins. Here, we present an analytically feasible extraction protocol that simulates conditions in the GIT and provides a measure of the content of bioavailable vitamins using LC-MS stable isotope dilution assay. The results show that the activities of both human gastric and duodenal juices were insufficient to liberate absorbable vitamers (AV) from pure cofactors. The use of an intestinal brush border membrane (IBBM) fraction derived from the mucosal tissue of porcine small intestine ensured at least 70% AV recovery. The rate of AV liberation, however, was strongly dependent on the cofactor, e.g., in the case of NADH, it was magnitudes higher than in the case of thiamine diphosphate. For some vitamins in some food matrices, the use of the IBBM fraction assay resulted in lower values for the content of AV than conventional vitamin determination methods. Conventional methods likely overestimate the actual bioavailability of some vitamins in these cases. Graphical abstract Assessment of bioavailable B vitamin content in food.

Protective effect of vitamin B complex in diabetic peripheral neuropathy - Histopathological study

Vitamin B complex has been used for peripheral neuropathy for a long time and continues to be part of current practice despite lack of strong evidence for its use and its non-inclusion in treatment guidelines. So this study was carried out to verify the neuroprotective effect of vitamin B complex from morphological changes of the diabetic rat sciatic nerve. A total number of 30 adult male albino rats were used and divided into three groups. Group I: normal vehicle control (N=10). Group II: streptozotocin-induced diabetic rats (N=20), which is equally divided into two subgroups; IIa (diabetic vehicle control) and IIb (diabetic vitamin B complex-treated, at a dose of 1mg/kg/day for 6 weeks).Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ) at a dose of 80mg/kg. Specimens from sciatic nerve were processed for light, electron microscopy and immunohistochemistry investigations. Morphological indices including the average myelin sheath thickness, the average myelinated nerve fiber area, endoneurial capillary density and perineurial index were measured and statistically analysed. Vitamin B complex treatment for six weeks markedly protected the sciatic nerve from the deleterious effect of hyperglycemia and preserved normal structural features of the perineurium, Schwann cells and their myelin sheath, nerve fibers, blood capillaries and the interstitium. The results were verified by immunohistochemistry (using CD 31, CD 68 and anti caspase-3 antibodies) and the morphological indices including the myelin sheath thickness, perineurial index and endoneurial capillary density. In conclusion, vitamin B complex supplementation might provide a long-term, drug approach for protection from diabetic peripheral neuropathy

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Vitamin B12-Loaded Buccoadhesive Films as a Noninvasive Supplement in Vitamin B12 Deficiency: In Vitro Evaluation and In Vivo Comparative Study With Intramuscular Injection.

This study aimed to formulate and evaluate vitamin B12-loaded buccal mucoadhesive hydrogel films. Various film formulations were prepared using chitosan and polyvinyl alcohol. The prepared films were characterized for thickness, weight variation, drug content, percentage moisture uptake and moisture content, surface pH, mechanical properties, in vitro release, and mucoadhesion. Vitamin B12 bioavailability from the optimized formulation was studied on rabbits by the aid of enzyme-linked immunosorbent assay. Neuroton® I.M. injection was used for comparison. The films had acceptable mechanical and mucoadhesion properties. The percentages of moisture content of the optimized formulation were 3.2 ± 0.95, whereas the percentage drug released was 98.59 ± 1.41% at the end of 40 min. FTIR revealed the incidence of drug/polymer interaction. Differential scanning calorimetry revealed the possibility of the dispersion of cyanocobalamin in a molecular state with complete amorphization in the polymers. The estimated AUC0-8h showed 1.5-fold increases in the bioavailability of cyanocobalamin from the optimized formulation compared with the marketed I.M. injection. These findings warrant that vitamin B12 buccal film formulation can be considered as an effective alternative portal with noninvasive and more convenient characteristics compared with the I.M. injection dosage form.

Vitamin B12 deficiency evaluation and treatment in severe dry eye disease with neuropathic ocular pain.

PURPOSE: This study aims to understand the effect of vitamin B12 deficiency on neuropathic ocular pain (NOP) and symptoms in patients with dry eye disease (DED). METHODS: Patients with severe DED (without receiving topical artificial tears treatment) and ocular pain were enrolled (n = 90). Patients with severe DED and vitamin B12 deficiency (group 1, n = 45) received parenteral vitamin B12 supplement + topical treatment (artificial tears treatment + cyclosporine), and patients with severe DED and normal serum vitamin B12 level (group 2, n = 45) received only topical treatment (artificial tears treatment + cyclosporine). Patients were evaluated by the ocular surface disease index (OSDI) questionnaire, 3rd question (have you experienced painful or sore eyes during last week?) score of OSDI as a pain determiner and pain frequency measure), tear break up time (TBUT), and Schirmer's type 1 test. We compared the groups' OSDI, TBUT, and Schirmer's test recordings at the first visit and after 12 weeks retrospectively. RESULTS: The OSDI score, 3rd OSDI question score, TBUT, and Schirmer's test results improved after 12 weeks (p < 0.001 for each group). The mean vitamin B12 level at enrollment was 144.24 ±43.36 pg/ml in group 1 and 417.53 ±87.22 pg/ml in group 2. The mean vitamin B12 level in group 1 reached to 450 ±60.563 pg/ml after 12 weeks of treatment. The mean score changes between the groups were not statistically significant; however, the decrease in the OSDI questionnaire score (-30.80 ±5.24) and 3rd OSDI question score (-2.82 ±0.53) were remarkable in group 1 (Table 2). The mean TBUT increase was +7.98 ±2.90 s and Schirmer's test result increase was +12.16 ±2.01 mm in group 1. The mean TBUT increase was +6.18 ±1.49 s and Schirmer's test result increase was +6.71 ±1.47 mm in group 2. CONCLUSIONS: These findings indicate that vitamin B12 deficiency is related with NOP. It may be important to consider measuring the serum vitamin B12 level in patients with severe DED presenting with resistant ocular pain despite taking topical treatment.

Vitamin B-12-fortified toothpaste improves vitamin status in vegans: a 12-wk randomized placebo-controlled study.

Background: The oral application of vitamin B-12 may prevent its deficiency if the vitamin is absorbed via the mucosal barrier.Objectives: We studied the effect of the use of a vitamin B-12-fortified toothpaste on vitamin-status markers in vegans and assessed the efficiency of markers in the identification of vitamin-augmentation status.Design: In this 12-wk, double-blinded, randomized, placebo-controlled study, 76 vegans received either a placebo (n = 34) or vitamin B-12 (n = 42) toothpaste. Sixty-six subjects (n = 30 in the placebo arm; n = 36 in the vitamin B-12 arm) completed the intervention. Serum and plasma concentrations of vitamin B-12, holotranscobalamin, total homocysteine (tHcy), and methylmalonic acid (MMA) were measured before and after the intervention.Results: Both postintervention concentrations of vitamin B-12 and holotranscobalamin and their changes over 12 wk were higher in the vitamin B-12 group (mean ± SD change: 81 ± 135 pmol/L for vitamin B-12 and 26 ± 34 pmol/L for holotranscobalamin) than in the placebo group (-27 ± 64 and -5 ± 17 pmol/L, respectively) after adjustment for baseline concentrations. Postintervention concentrations of MMA and their changes differed significantly between groups (MMA changes: -0.169 ± 0.340 compared with -0.036 ± 0.544 µmol/L in vitamin B-12 and placebo groups, respectively; P < 0.001). After adjustment for baseline tHcy, postintervention concentrations of tHcy tended to be lower (P = 0.051), and the changes in tHcy (-0.7 ± 4.4 compared with 2.0 ± 5.6 µmol/L, respectively) were greater in the vitamin B-12 group than in the placebo group. Changes in vitamin B-12 markers were more prominent in vegans who reported that they had not taken vitamin B-12 supplements.Conclusion: Vitamin B-12 that is applied to the oral cavity via toothpaste enters the circulation and corrects the vitamin B-12 markers in the blood of vegans who are at higher risk of vitamin B-12 deficiency. This trial was registered at clinicaltrials.gov as NCT02679833.