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Administration of high-dose vitamin K1 (VK1) overcomes coagulopathy and bleeding elicited by acute poisoning with long-acting anticoagulant rodenticides (LAARs). However, long-term (months) treatment is required due to long LAAR biological half-lives that may lead to poor compliance and recurrent coagulopathy. The half-lives of LAARs are extended by slow metabolism, and similar to warfarin, are thought to undergo enterohepatic recirculation. We now show that treatment with the bile acid sequestrant cholestyramine (CSA) administered concomitantly with VK1 decreases plasma LAAR levels and increases LAAR fecal excretion. Daily CSA treatment for 14 days did not reduce plasma VK1 levels, or increase prothrombin time. Collectively, these data show that CSA accelerates LAAR clearance from rabbits without adverse effects on VK1 anticoagulation, and could provide an additional therapeutic option for treatment of LAAR poisoning., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The possibility of controlling periorbital hyperpigmentation disorders is one of the most important research goals in cosmetic preparations. In the current investigation, 1% vitamin K (Vit K) was incorporated into a Chitosan/alginate hydrogel which aimed to increase the dermal delivery and anti-pigmentation effect. The Vit K-hydrogel was evaluated using several different tests, including volume expansion/contraction analysis, differential scanning calorimetry (DSC), scanning electron microscopy (SEM), ultraviolet (UV) absorbance spectroscopy, and attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy. Vit K hydrogel's drug release profile showed a steady increase over time. Furthermore, the modified Vit K hydrogel formulations showed no harmful effects in an in vitro cytotoxicity study. The Vit K hydrogel was tested for dermal irritation on Wistar rats, and the hydrogel was found to be non-irritating. Furthermore, Vit K-hydrogel inhibited melanin formation (31.76 ± 1.14%) and was remarkably higher than free Vit K. In addition, Vit K-hydrogel inhibited L-dopa auto-oxidation to a greater extent (94.80 ± 2.41%) in comparison with Vit K solution (73.95 ± 1.62%). Vit K-hydrogel enhanced percutaneous transport of Vit K, according to in vitro percutaneous absorption findings, suggesting that this innovative formulation may provide new therapeutic options for periorbital hyperpigmentation.

The available evidence on vitamin K status in cystic fibrosis (CF) is scarce, lacking data on vitamin K2 (menaquinones-MK). Therefore, we assessed vitamin K1, MK-4 and MK-7 concentrations (LC-MS/MS) in 63 pancreatic insufficient and modulator naïve CF patients, and compared to 61 healthy subjects (HS). Vitamin K1 levels did not differ between studied groups. MK-4 concentrations were higher (median <1st-3rd quartile>: 0.778 <0.589-1.086> vs. 0.349 <0.256-0.469>, p < 0.0001) and MK-7 levels lower (0.150 <0.094-0.259> vs. 0.231 <0.191-0.315>, p = 0.0007) in CF patients than in HS. MK-7 concentrations were higher in CF patients receiving K1 and MK-7 supplementation than in those receiving vitamin K1 alone or no supplementation. Moreover, vitamin K1 concentrations depended on the supplementation regime. Based on multivariate logistic regression analysis, we have found that MK-7 supplementation dose has been the only predictive factor for MK-7 levels. In conclusion, vitamin K1 levels in CF are low if not currently supplemented. MK-4 concentrations in CF patients supplemented with large doses of vitamin K1 are higher than in HS. MK-7 levels in CF subjects not receiving MK-7 supplementation, with no regard to vitamin K1 supplementation, are low. There do not seem to be any good clinical predictive factors for vitamin K status.

BACKGROUND Owing to its broad-spectrum antibacterial activity, strong antibacterial effects, and ß-lactamase stability, cefoperazone/sulbactam has been recognized as a first-line empirical drug for treating severe infections. However, its administration is also characterized by numerous adverse effects, including coagulation dysfunction. Here, we summarize past clinical treatment data to provide data support for clinical use of cefoperazone sulbactam. MATERIAL AND METHODS We retrospectively analyzed the clinical medical records of 820 patients treated with cefoperazone/sulbactam from January 2015 to December 2020. A retrospective cohort study design was used. We assessed the general data of patients, age and sex distribution, type of primary disease, and incidence and days of abnormal blood coagulation with cefoperazone sulbactam. The chi-square test and t test were used to analyze the effect of cefoperazone sulbactam on coagulation function and the effect of vitamin K intervention on prognosis. RESULTS The rate of coagulation dysfunction was 24.39% (200 patients). Among these 200 patients, 50 were treated with vitamin K1. With increasing patient age, the number of patients with cefoperazone/sulbactam-induced coagulation dysfunction increased (peak at 81-90 years). APACHE II of coagulation dysfunction (15.54±4.095) was significantly higher than that in the normal group. It occurred at days 2-19 after administration of 9.0 g/day of cefoperazone/sulbactam. Measured coagulation indices were significantly higher after treatment with cefoperazone/sulbactam than before treatment, including international normalized ratio, prothrombin time, and activated partial thrombin time (P<0.0001). CONCLUSIONS All coagulation indices decreased significantly after vitamin K1 intervention, indicating improved coagulation function, especially in patients with high APACHE II scores. Hence, regulated vitamin K1 administration can benefit patients with coagulation dysfunction in clinical treatment.

Background: Coronary and aortic artery calcifications are generally slow to develop, and their burden predicts cardiovascular disease events. In patients with diabetes mellitus, arterial calcification is accelerated and calcification activity can be detected using 18F-sodium fluoride positron emission tomography (18F-NaF PET)., Objectives: We aimed to determine whether vitamin K1 supplementation inhibits arterial calcification activity in individuals with diabetes mellitus., Methods: This was a post hoc analysis of the ViKCoVaC (effect of Vitamin-K1 and Colchicine on Vascular Calcification activity in subjects with Diabetes Mellitus) double-blind randomized controlled trial conducted in Perth, Western Australia. Individuals with diabetes mellitus and established coronary calcification (coronary calcium score > 10), but without clinical coronary artery disease, underwent baseline 18F-NaF PET imaging, followed by oral vitamin K1 supplementation (10 mg/d) or placebo for 3 mo, after which 18F-NaF PET imaging was repeated. We tested whether individuals randomly assigned to vitamin K1 supplementation had reduced development of new 18F-NaF PET positive lesions within the coronary arteries and aorta., Results: In total, 149 individuals completed baseline and follow-up imaging studies. Vitamin K1 supplementation independently decreased the odds of developing new 18F-NaF PET positive lesions in the coronary arteries (OR: 0.35; 95% CI: 0.16, 0.78; P = 0.010), aorta (OR: 0.27; 95% CI: 0.08, 0.94; P = 0.040), and in both aortic and coronary arteries (OR: 0.28; 95% CI: 0.13, 0.63; P = 0.002)., Conclusions: In individuals with diabetes mellitus, supplementation with 10 mg vitamin K1/d may prevent the development of newly calcifying lesions within the aorta and the coronary arteries as detected using 18F-NaF PET. Further long-term studies are needed to test this hypothesis.This trial was registered at anzctr.org.au as ACTRN12616000024448., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Vitamin K (VK) plays many important functions in the body. The most important of them include the contribution in calcium homeostasis and anticoagulation. Vascular calcification (VC) is one of the most important mechanisms of renal pathology. The most potent inhibitor of this process-matrix Gla protein (MGP) is VK-dependent. Chronic kidney disease (CKD) patients, both non-dialysed and hemodialysed, often have VK deficiency. Elevated uncarboxylated matrix Gla protein (ucMGP) levels indirectly reflected VK deficiency and are associated with a higher risk of cardiovascular events in these patients. It has been suggested that VK intake may reduce the VC and related cardiovascular risk. Vitamin K intake has been suggested to reduce VC and the associated cardiovascular risk. The role and possibility of VK supplementation as well as the impact of anticoagulation therapy on VK deficiency in CKD patients is discussed.

Growth arrest-specific gene 6 protein (Gas6) is avitamin K-dependent tissue bound protein. Gas6 has been shown to promote growth and therapy resistance among different types of cancer as well as thromboembolism. The aim of this prospective screening study: ClinicalTrials.gov; Identifier: NTC3782025, was to evaluate the effects of intravenously administered vitamin K1 on Gas6 and its soluble (s)Axl receptor plasma levels in intensive care patients. Vitamin K1 was intravenously injected in non-warfarin treated patients with prolonged Owren prothrombin time international normalized ratio (PT-INR) > 1.2 and blood samples were retrieved before and 20-28 h after injection. Citrate plasma samples from 52 intensive care patients were analysed for different vitamin K dependent proteins. There was a significant, but small increase in median Gas6. Only one patient had a large increase in sAxl, but overall, no significant changes in sAxl Gas6 did not correlate to PT-INR, thrombin generation assay, coagulation factors II, VII, IX and X, but to protein S and decarboxylated matrix Gla protein (dp-ucMGP). In conclusion, there was a small increase in Gas6 over 20-28 h. The pathophysiology and clinical importance of this remains to be investigated. To verify a true vitamin K effect, improvement of Gas6 carboxylation defects needs to be studied.

Reported associations between vitamin K 1 and both all-cause and cause-specific mortality are conflicting. The 56,048 participants from the Danish Diet, Cancer, and Health prospective cohort study, with a median [IQR] age of 56 [52-60] years at entry and of whom 47.6% male, were followed for 23 years, with 14,083 reported deaths. Of these, 5015 deaths were CVD-related, and 6342 deaths were cancer-related. Intake of vitamin K 1 (phylloquinone) was estimated from a food-frequency questionnaire (FFQ), and its relationship with mortality outcomes was investigated using Cox proportional hazards models. A moderate to high (87-192 µg/d) intake of vitamin K 1 was associated with a lower risk of all-cause [HR (95%CI) for quintile 5 vs quintile 1: 0.76 (0.72, 0.79)], cardiovascular disease (CVD)-related [quintile 5 vs quintile 1: 0.72 (0.66, 0.79)], and cancer-related mortality [quintile 5 vs quintile 1: 0.80 (0.75, 0.86)], after adjusting for demographic and lifestyle confounders. The association between vitamin K 1 intake and cardiovascular disease-related mortality was present in all subpopulations (categorised according to sex, smoking status, diabetes status, and hypertension status), while the association with cancer-related mortality was only present in current/former smokers (p for interaction = 0.002). These findings suggest that promoting adequate intakes of foods rich in vitamin K 1 may help to reduce all-cause, CVD-related, and cancer-related mortality at the population level., (© 2021. The Author(s).)

Abstract: Guidelines exist on the management of supratherapeutic/subtherapeutic international normalized ratio (INR) values for patients on warfarin. However, there is a paucity of the literature relating to an acute overdose of warfarin. This is a retrospective cohort study for all acute and acute-on-chronic (AOC) warfarin overdoses reported to the Maryland Poison Center in patients ≥12 years between January 1st, 2000, until October 31st, 2019, managed in a health care facility. The primary outcome was to determine the time after presentation to peak INR. Secondary outcomes included risk factors associated with INR >10 and describing patient characteristics. A total of 163 overdoses were included, 68 acute and 95 AOC. In patients who did not receive reversal therapies, INR peaked at a median value of 3.8 (interquartile range 2.6-5.5) between 24 and 36 hours. The median time to phytonadione was 22.0 hours. Most patients received phytonadione (62.0%), with fewer receiving blood products (16.6%). The median warfarin dose ingested was 75 mg. The AOC group had a greater mean age (56 vs. 43 years), median INR value (2.4 vs. 1.4), and men (62.1% vs. 41.2%). Factors associated with an INR > 10 included initial INR and reported quantity ingested. Peak INR was greater in the AOC than the acute overdose group (6.1 vs. 3.4), although the bleeding rate was similar. Peak INR values after warfarin overdose occur between 24 and 36 hours after presentation. Initial INRs and reported quantity ingested may be useful to predict those needing treatment., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background Dietary vitamin K (K 1 and K 2 ) may reduce atherosclerotic cardiovascular disease (ASCVD) risk via several mechanisms. However, studies linking vitamin K intake with incident ASCVD are limited. We aimed to determine the relationship between dietary vitamin K intake and ASCVD hospitalizations. Methods and Results In this prospective cohort study, participants from the Danish Diet, Cancer, and Health Study, with no prior ASCVD, completed a food-frequency questionnaire at baseline and were followed up for hospital admissions of ASCVD; ischemic heart disease, ischemic stroke, or peripheral artery disease. Intakes of vitamin K 1 and vitamin K 2 were estimated from the food-frequency questionnaire, and their relationship with ASCVD hospitalizations was determined using Cox proportional hazards models. Among 53 372 Danish citizens with a median (interquartile range) age of 56 (52-60) years, 8726 individuals were hospitalized for any ASCVD during 21 (17-22) years of follow-up. Compared with participants with the lowest vitamin K 1 intakes, participants with the highest intakes had a 21% lower risk of an ASCVD-related hospitalization (hazard ratio, 0.79; 95% CI: 0.74-0.84), after multivariable adjustments for relevant demographic covariates. Likewise for vitamin K 2 , the risk of an ASCVD-related hospitalization for participants with the highest intakes was 14% lower than participants with the lowest vitamin K 2 intake (hazard ratio, 0.86; 95% CI, 0.81-0.91). Conclusions Risk of ASCVD was inversely associated with diets high in vitamin K 1 or K 2 . The similar inverse associations with both vitamin K 1 and K 2 , despite very different dietary sources, highlight the potential importance of vitamin K for ASCVD prevention.

The aim of this study was to evaluate the effects of vitamin K1 on various vitamin K-dependent proteins in critically ill patients with prolonged Owren PT. We included critically ill non-bleeding adult patients without liver failure or anticoagulation treatment, with Owren PT > 1.2, who were prescribed intravenous vitamin K1. Blood was drawn at baseline and at 20-28 h after vitamin K1 administration. At both time points, we measured various vitamin K-dependent proteins and coagulation assays. ClinicalTrials.gov; Identifier: NTC3782025. In total, 52 patients were included. Intravenous vitamin K1 reduced Owren PT, Quick PT, protein induced by vitamin K absence/antagonist-II and desphospho-uncarboxylated matrix Gla protein (dp-ucMGP), but not to normal levels. Concomitantly, there were increases in thrombin generation and the activity of coagulation factors II, VII, IX and X that was only counteracted with a small increase in Protein C activity. In conclusion, the results suggest that vitamin K1 strengthens coagulation as measured by PT decrease and increases in the activity of vitamin K-dependent clotting factors and thrombin generation. The decreased dp-ucMGP, and its potential positive short- and long-term non-coagulative effects, merits further research.

Evidence suggests there are roles for vitamin K in various chronic disease outcomes, but population-level diet and supplement recommendations are difficult to determine due to high levels of variability in measures of status and response to intake compared to other nutrients. In this preliminary investigation, a blood-based epigenome-wide association study (EWAS) comparing responders and non-responders to phylloquinone (vitamin K1) supplementation (NCT00183001) was undertaken in order to better understand the molecular underpinnings of this observed variability. Responders (n = 24) and non-responders (n = 24) were identified in a prior 3-year phylloquinone supplementation trial based on their changes in plasma phylloquinone concentrations. Differential DNA methylation was identified in multiple regions with previously unknown relationships to phylloquinone absorption and metabolism, such as at the TMEM263 locus. A hypothesis-driven analysis of lipid-related genes highlighted a site in the NPC1L1 gene, supplementing existing evidence for its role in phylloquinone absorption. Furthermore, an EWAS for baseline plasma phylloquinone concentrations revealed a strong correlation between the epigenomic signatures of phylloquinone baseline status and response to supplementation. This work can guide future epigenomic research on vitamin K and contributes to the development of more personalized dietary recommendations for vitamin K.

Infection with Helicobacter pylori causes chronic inflammation and is a risk factor for gastric cancer. Antibiotic treatment or increased dietary folate prevents gastric carcinogenesis in male INS-GAS mice. To determine potential synergistic effects, H. pylori -infected male INS-GAS mice were fed an amino acid defined (AAD) diet with increased folate and were treated with antibiotics after 18 weeks of H. pylori infection. Antibiotic therapy decreased gastric pathology, but dietary folate had no effect. However, the combination of antibiotics and the AAD diet induced anemia, gastric hemorrhage, and mortality. Clinical presentation suggested hypovitaminosis K potentially caused by dietary deficiency and dysbiosis. Based on current dietary guidelines, the AAD diet was deficient in vitamin K. Phylloquinone administered subcutaneously and via a reformulated diet led to clinical improvement with no subsequent mortalities and increased hepatic vitamin K levels. We characterized the microbiome and menaquinone profiles of antibiotic-treated and antibiotic-free mice. Antibiotic treatment decreased the abundance of menaquinone producers within orders Bacteroidales and Verrucomicrobiales . PICRUSt predicted decreases in canonical menaquinone biosynthesis genes, menA and menD . Reduction of menA from Akkermansia muciniphila, Bacteroides uniformis , and Muribaculum intestinale were confirmed in antibiotic-treated mice. The fecal menaquinone profile of antibiotic-treated mice had reduced MK5 and MK6 and increased MK7 and MK11 compared to antibiotic-free mice. Loss of menaquinone-producing microbes due to antibiotics altered the enteric production of vitamin K. This study highlights the role of diet and the microbiome in maintaining vitamin K homeostasis.

Background: An outbreak of synthetic cannabinoid (SC)-associated coagulopathy and bleeding in Illinois, USA was determined to be due to inhalation of SC contaminated with brodifacoum (BDF), difenacoum (DiF), and bromadiolone (BDL), highly potent long-acting anticoagulant rodenticides (LAARs). Treatment with high-dose vitamin K1 (VK1) prevented mortality; however, plasma LAAR levels were not measured risking recurrence of coagulopathy and bleeding due to premature discontinuation. The goal of this study was to determine if plasma LAAR levels were reduced following standard of care treatment to normalize coagulopathy. Methods: Blood samples were collected from a cohort of 32 patients, and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis used to quantify plasma LAAR levels including enantiomers. Results: BDF was detected in 31 samples; 30 also contained DiF and 18 contained BDL. Initial plasma levels were 581 ± 87, 11.0 ± 1.9, and 14.9 ± 5.9 ng/mL for BDF, DiF, and BDL, respectively (mean ± SE). At discharge plasma, BDF levels remained elevated at 453 ± 68 ng/mL. Plasma half-lives for BDF, DiF, and BDL were 7.5 ± 1.3, 7.2 ± 1.9, and 1.8 ± 0.3 days, respectively. The half-life for trans-BDF enantiomers (5.7 ± 0.8 days) was shorter than for cis-enantiomers (7.6 ± 1.9 days). BDF half-lives were shorter, and coagulopathy normalized faster in patients receiving intravenous VK1 as compared to oral VK1. Patients prescribed VK1 at discharge had fewer re-admittances. Conclusions: These results demonstrate that plasma LAAR levels at discharge were elevated in poisoned patients despite normal coagulation, and that the route of VK1 administration affected LAAR pharmacokinetics and INR normalization. We propose plasma LAAR levels and coagulation be monitored concomitantly during follow-up of patients with LAAR poisoning. KEY POINTSIn patients treated with high-dose vitamin K1 for LAAR poisoning, plasma levels remained 40-fold above safe levels upon discharge from hospital.LAAR half-lives, normalization of coagulopathy, and readmittances were reduced by treatment with intravenous vitamin K1.

Purpose: The pathophysiologic relationship between vitamin K and glaucoma remains largely unknown. The aim of the study was to explore the effect of dietary vitamin K supplementation in a rat glaucoma model., Methods: Rats were randomly divided into two groups: standard diet and high vitamin K1 (VitK1) diet (300 mg VitK1/kg diet). Induction of chronic ocular hypertension by episcleral vein cauterization was performed on the right eye. The left eye with sham operation served as controls. Rats received standard or high VitK1 diets for 5 weeks after surgery until the end of experiment. Immunohistochemistry analyses of the retina and trabecular meshwork were performed. The change in coagulation function and IOP were evaluated., Results: We observed a significant declined IOP at 2 weeks after surgery in the high VitK1 group compared with the control group. High VitK1 showed no significant effect on the body weight, rat phenotypes, or coagulation function. High VitK1 significantly inhibited the loss of retinal ganglion cells in the retina and increased the expression of matrix gla protein. High VitK1 also ameliorated the collapsed trabecular meshwork structure and increased collagen staining in the trabecular meshwork., Conclusions: High VitK1 intake inhibited the loss of retinal ganglion cells during glaucomatous injury, probably by increasing the expression of matrix gla protein. A transient decrease in the IOP was observed in the high VitK1 group, implying a potential effect of VitK1 on aqueous outflow. Retinal ganglion cells protection by high VitK1 supplementation may be due to the IOP-lowering effects as well as neuroprotective effect. Further research is required to delineate these processes.

Vitamin K and its essential role in coagulation (vitamin K [Koagulation]) have been well established and accepted the world over. Many countries have a Recommended Daily Intake (RDI) for vitamin K based on early research, and its necessary role in the activation of vitamin K-dependent coagulation proteins is known. In the past few decades, the role of vitamin K-dependent proteins in processes beyond coagulation has been discovered. Various isoforms of vitamin K have been identified, and vitamin K2 specifically has been highlighted for its long half-life and extrahepatic activity, whereas the dietary form vitamin K1 has a shorter half-life. In this review, we highlight the specific activity of vitamin K2 based upon proposed frameworks necessary for a bioactive substance to be recommended for an RDI. Vitamin K2 meets all these criteria and should be considered for a specific dietary recommendation intake.

Due to the vitamin K 1 sensitizing potential, the oxidized-isoform of vitamin K 1 (vitamin K 1 oxide, VKO), has been recently used for treating laser-induced purpura and hyperpigmentation in cosmetics. The objective of this study was to formulate VKO in nanoliposomes by using Box-Behnken experimental design to obtain an optimized formula with higher efficiency. The ratio of phospholipid to cholesterol (PC/CHO ratio), VKO concentration and sonication time in low, medium, and high levels were independent variables, while the percent of VKO entrapment efficiency (EE%) and vesicle size were selected as dependent variables. Optimum desirability was identified and an optimized formulation was prepared, characterized, and selected for in vitro VKO release and ex vivo skin permeation. The PC/CHO ratio showed the greatest effect on both responses (P < 0.0001). This effect was positive on EE%, while a negative effect was shown on vesicle size. The optimized formulation showed controlled drug release of 79.2% through a silicon membrane, and achieved flux of 327.36 ± 22.1 μg/cm 2 through human skin after 24 h. So, nanoliposomes were proven as a suitable drug delivery system for topical delivery of VKO., 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 © 2020 Elsevier B.V. All rights reserved.)

The effectiveness of vitamin K1 for the treatment of liver failure has been controversial, and no studies have investigated the effect of vitamin K1 on the risk of death and coagulation function in patients with chronic liver failure. This study aimed to explore the effect of vitamin K1 on death risk and international normalized ratio in patients with chronic liver failure.From December 2013 to August 2017, this retrospective cohort study screened patients hospitalized for chronic liver failure (n = 80) who received routine treatment. The patients were categorized into the vitamin K1 and control groups according to whether they had received intramuscular injection of vitamin K1 on the basis of conventional treatment. Baseline data were analyzed with χ test and independent sample t-test; the survival curve of 48 weeks was created with Kaplan-Meier estimator. Correlation between death event and vitamin K1, age, sex, albumin (ALB), total bilirubin (TBIL), and alkaline phosphatase (ALP) was determined with the Cox proportional risk regression model.Fifty-seven Chinese patients were finally included in the analysis. Patients treated with vitamin K1 had a lower risk of death (hazards ratio [HR] 0.37, P = 0.009) than the control group (P = 0.006). Men had a higher risk of death (HR 2.97, P = 0.005). Age, ALB, TBIL, and ALP had a certain correlation with risk of death. Vitamin K1 reduced the international normalized ratio levels [P < 0.01 (95% confidence interval 0.000-0.002)].Vitamin K1 may reduce the risk of death in patients with chronic liver failure. Male sex, age, ALB, TBIL, and ALP are potential risk factors for increased risk of death in these patients. Based on these findings, vitamin k1 can be used in patients with chronic liver failure. Prospective studies are still needed, however, to validate the role of vitamin K1 in the chronic liver failure.

Background: Evidence suggests that lower serum undercarboxylated osteocalcin (ucOC) may be negatively associated with cardiometabolic health. We investigated whether individuals with a suppression of ucOC following an increase in dietary vitamin K1 exhibit a relative worsening of cardiometabolic risk factors., Materials and Methods: Men (n = 20) and women (n = 10) aged 62 ± 10 years participated in a randomized, controlled, crossover study. The primary analysis involved using data obtained from participants following a high vitamin K1 diet (HK; 4-week intervention of increased leafy green vegetable intake). High and low responders were defined based on the median percent reduction (30%) in ucOC following the HK diet. Blood pressure (resting and 24 h), arterial stiffness, plasma glucose, lipid concentrations, and serum OC forms were assessed., Results: Following the HK diet, ucOC and ucOC/tOC were suppressed more (p < 0.01) in high responders (41 and 29%) versus low responders (12 and 10%). The reduction in ucOC and ucOC/tOC was not associated with changes in blood pressure, arterial stiffness, plasma glucose, or lipid concentrations in the high responders (p > 0.05)., Discussion/conclusion: Suppression of ucOC via consumption of leafy green vegetables has no negative effects on cardiometabolic health, perhaps, in part, because of cross-talk mechanisms., (© 2020 S. Karger AG, Basel.)

Purpose: The study aimed to investigate strategies to prevent and treat cetuximab-induced skin reactions and their perceived effectiveness in patients with metastatic colorectal cancer (mCRC) and recurrent/metastatic squamous cell cancer of the head and neck (SCCHN)., Methods: This open-label, prospective observational study was conducted in Switzerland., Results: A total of 125 patients were included (n = 91 mCRC, n = 34 SCCHN; mean age 63.3 years; 73.6% males). The frequency of acneiform rash grade ≥ 2 increased from 12.6% at week 2 to 21.7% at week 16. The proportion of patients who reported no skin reaction decreased from 75.6% at week 2 to 43.3% at week 16. The most frequently used skin products at any time of observation were moisturizing (77.6%), lipid-regenerating (56.8%) or urea-containing products (52%), systemic antibiotics (49.6%), and vitamin K1 cream (43.2%). There was no clear effectiveness pattern for all product classes: in given patients, either the product showed no effect at all or a moderate/strong effect, consistently over time., Conclusions: A great variety of low-cost general skin care products were commonly used. According to physician's preference, systemic antibiotics and vitamin K1 cream are an appropriate approach to prevent or treat cetuximab-related skin toxicity.

Acne-like skin reactions frequently occur in patients undergoing treatment with drugs inhibiting the epidermal growth factor receptor. Recently, the effects of vitamin K1 containing cream (Reconval K1) as prophylactic skin treatment in addition to doxycycline were explored in a double-blind randomized phase II trial (EVITA) in patients with metastatic colorectal cancer receiving cetuximab. EVITA demonstrated a trend towards less severe skin rash in Reconval K1-treated patients using the tripartite WoMo skin reaction grading score as a thorough tool for quantification of drug related skin reactions. This gender-specific analysis of the EVITA trial evaluated the application of the WoMo score for assessment of epidermal growth factor receptor (EGFR)-related skin toxicities according to treatment arm and gender. To show the robustness of results parametric and non-parametric statistical analyses were conducted. All three parts of the WoMo score independently demonstrated the superiority of the treatment arm (Reconval K1) regarding a significant reduction in acneiform skin reactions in women. Men did not benefit from Reconval K1 cream at any time point in none of the WoMo score analyses. The treatment effect in women was confirmed by the use of skin rash categories based on the final WoMo overall score and mixed effect longitudinal multiple linear regression analysis. The WoMo score represents a sensitive tool for studies exploiting treatments against EGFR mediated acne-like skin rash. Part C of the WoMo score seems to be sufficient for quantification of drug related skin toxicities in further studies. Standard WoMo skin reaction score values for future studies are provided., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

A large-scale outbreak of life-threatening, inhaled synthetic cannabinoids (Spice/K2)-associated coagulopathy with bleeding complications was recently reported in Illinois. The causative agents were brodifacoum, difenacoum, and bromadiolone, potent, long-acting, 4-hydroxycoumarin anticoagulant rodenticides (LAAR) that were mixed with Spice/K2 products procured and then inhaled by the victims. We report on 3 poisoned patients who reside in underserved, socioeconomically disadvantaged neighborhoods of Chicago that were admitted and treated successfully at two inner-city, tertiary care hospitals in Chicago. The patients were discharged from the hospitals on daily long-term high-dose oral vitamin K 1 (VK 1 ), provided free of charge. However, 2 patients were lost to follow-up prior to safe discontinuation of oral VK 1 therapy. The third patient was treated and followed successfully for 7 months when VK 1 was discontinued. We conclude that prolonged oral VK 1 therapy and follow-up of acute, life-threatening LAAR poisoning are variable and present challenges to healthcare providers. Appropriate practice guidelines to improve patient access and adherence to daily high-dose oral VK 1 therapy and follow-up should be developed and implemented.

Background: Intracerebral hemorrhage (ICH) is a life-threatening complication of oral anticoagulant therapy that sometimes results in hematoma expansion after onset. Our facility did not have a standardized process for treating oral anticoagulant-associated ICH; this resulted in lag times from order to reversal agent administration., Purpose: The aim of this study was to examine the impact of a rapid anticoagulant reversal protocol, combined with warfarin and direct-acting oral anticoagulant therapy, in decreasing door to first intervention times., Methods: This study used a retrospective quality assessment research approach in examining an oral anticoagulant reversal protocol to compare the control and intervention groups. Phytonadione was the first intervention treatment for most study participants diagnosed with warfarin-associated ICH with an international normalized ratio greater than 1.4. Factor IX was the first intervention treatment for all but one study participant with DOAC-associated ICH., Results: Findings were statistically significant (P < .05) for door to first intervention treatments. Door to phytonadione in minutes decreased from 232.7 (SD, 199.4) to posttest findings of 111.4 (SD, 64.6). Door to factor IX in minutes decreased from 183.9 (SD, 230.2) to posttest findings of 116.6 (SD, 69.1)., Conclusion: Study findings support the hypothesis that the new protocol was associated with lower door-to-treatment times for eligible patients.

Background and Aim: Hip fracture patients are at great risk of malnutrition, but documentation of the effect of nutrition supplementation in this group is sparse and inconclusive. The aim of this study was to examine if personalized nutrition advice combined with vitamin K1, Ca and vitamin D could improve bone turnover 4 months after hip fracture., Design: This is a preplanned sub study of a randomized controlled trial of orthogeriatric care. The intervention group received orthogeriatric care, including nutrition advice and supplementation. The control group received usual care at the orthopedic ward. Blood was drawn for measurements of a number of vitamins and of bone turnover markers upon admission and at four months follow up., Results: 71 patients (31 in the intervention group and 40 controls) had available data at 4 months as well as at baseline. After four months, vitamin K1 and 25(OH)D were higher in the intervention group compared with controls; vitamin K1: 1.0 ± 1.2 vs 0.6 ± 0.6 ng/ml, p = 0.09, 25(OH)D: 60 ± 29 vs 43 ± 22 nmol/L, p = 0.01 when adjusted for baseline differences. In a secondary, unadjusted analysis, comprising all patients with available four months data (n = 136), the differences were statistically significant for vitamin K1 as well as 25(OH)D (p = 0.03 and p < 0.001, respectively). There was a non-significant increase in 25(OH)D in the intervention group from baseline to 4 months follow up, and a significant decrease in the control group. There was no difference in bone turnover markers between the two groups at 4 months follow up. A substantial loss of weight and physical function was found in both groups., Conclusions: The supplementation of 25(OH)D and vitamin K1 improved serum concentrations of these vitamins, but this did not translate into any improvement in the bone turnover markers. The RCT is registered in ClinicalTrials.govNCT01009268 and NCT01738776., (Copyright © 2017. Published by Elsevier Ltd.)

In the article intended for neonatologists, general practitioners and family doctors, the main causes of hemostatic disorders that lead to the development of hemorrhagic syndrome in newborns and infants are given. The emphasis is on the different forms of neonatal hemorrhagic disease (HD), which is based on the deficiency of vitamin K1, and therefore the bleeding that is observed in children who are breastfed in the first half of life is mostly associated, namely, with vitamin K deficiency. Risk factors of HD depending from the time of the beginning, of the action of one or another factor. The main clinical manifestations of both early and late forms of HD are described, it is shown which of them are mistakenly diagnosed that lead to the appointment of the wrong treatment. The assessment of the need for prevention of late form of bleeding associated with vitamin K deficiency is carried out by determining the concentration in the blood of a functional coagulation marker - PIVKA II. Modern methods of prevention of late bleeding associated with vitamin K1 deficiency, based on nosological units - chronic cholestasis, cystic fibrosis, are presented. The current recommendations on the use of vitamin K1 in newborns and infants of the American Academy of Pediatrics, the scientific community of Canada, Netherlands, Switzerland, Germany, France, the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), the World Health Organization, which are clearly followed by the effects of local peculiarities are described and interpreted. on approaches to the prevention of bleeding associated with vitamin K1 deficiency, which affects the choice of a single dose, the duration of the prophylactic course and the route of administration of vitamin in K1 (phytomenadion). The role of parents in the prevention of vitamin K deficiency is emphasized.

Background: Phylloquinone is the primary form of vitamin K in the diet and circulation. Large intra- and interindividual variances in circulating phylloquinone have been partially attributed to age. However, little is known about the nondietary factors that influence phylloquinone absorption and metabolism. Similarly, it is not known if phylloquinone absorption is altered by the individual's existing vitamin K status., Objective: The purpose of this secondary substudy was to compare plasma response with deuterium-labeled phylloquinone intake in older and younger adults after dietary phylloquinone depletion and repletion., Methods: Forty-two older [mean ± SD age: 67.2 ± 8.0 y; body mass index (BMI; in kg/m2): 25.4 ± 4.6; n = 12 men, 9 women] and younger (mean ± SEM age: 31.8 ± 6.6 y; BMI: 25.5 ± 3.3; n = 9 men, 12 women) adults were maintained on sequential 28-d phylloquinone depletion (∼10 µg phylloquinone/d) and 28-d phylloquinone repletion (∼500 µg phylloquinone/d) diets. On the 23rd d of each diet phase, participants consumed deuterated phylloquinone-rich collard greens (2H-phylloquinone). Plasma and urinary outcome measures over 72 h were compared by age group, sex, and dietary phase via 2-factor repeated-measures ANOVA., Results: The plasma 2H-phylloquinone area under the curve (AUC) did not differ in response to phylloquinone depletion or repletion, but was 34% higher in older than in younger adults (P = 0.02). However, plasma 2H-phylloquinone AUC was highly correlated with the serum triglyceride (TG) AUC (r2 = 0.45). After adjustment for serum TG response, the age effect on the plasma 2H-phylloquinone AUC was no longer significant., Conclusions: Plasma 2H-phylloquinone response did not differ between phylloquinone depletion and repletion in older and younger adults. The age effect observed was explained by the serum TG response and was completely attenuated after adjustment. Plasma response to phylloquinone intake, therefore, seems to be a predominantly lipid-driven effect and not dependent on existing vitamin K status. More research is required to differentiate the effect of endogenous compared with exogenous lipids on phylloquinone absorption. This trial was registered at clinicaltrials.gov as NCT00336232.

What Is Known and Objective: Renal transplant recipients receive immunosuppressive therapy to prevent acute rejection. We evaluated the immunopharmacological efficacy of vitamin K1 (VK1) and vitamin K2 (VK2) on T-cell mitogen-activated-peripheral lymphocytes of dialysis patients and healthy subjects., Methods: The effects of VK1 and VK2 on the T-cell mitogen-stimulated proliferation of peripheral blood mononuclear cells (PBMCs) obtained from 12 healthy subjects and 12 dialysis patients were estimated. Seven cytokines produced from the activated PBMCs were measured by a BD Cytometric Beads Array kit. Regulatory T cells (Tregs) in PBMCs were analysed as CD4 + CD25 + FoxP3 +  lymphocytes by flow cytometry., Results: VK2 dose-dependently suppressed the concanavalin A-stimulated proliferation of PBMCs from healthy subjects and dialysis patients, whereas VK1 had no significant effect on the PBMC proliferation. VK1 and VK2 did not influence the production of most of the Th1/Th2/Th17 cytokines from the activated PBMCs of these subjects, although VK2 increased the IL-4 production from PBMCs of healthy subjects. The Treg percentages in the PBMCs of dialysis patients were markedly decreased compared to healthy PBMCs after the treatment with relatively low concentrations of VK2., What Is New and Conclusion: The present data suggest that VK2 has immunosuppressive efficacy. VK2 may enhance the immunosuppressive efficacies of glucocorticoids while preventing osteoporosis caused by glucocorticoids., (© 2018 John Wiley & Sons Ltd.)

Background: Rheumatoid arthritis (RA) is an inflammatory disorder in which the disease severity might be decreased by anti-inflammatory agents. There are several lines of evidence which support anti-inflammatory effects of vitamin K. The aim of this study was to examine whether vitamin K is a useful strategy for reducing inflammation in RA subjects. Materials and methods: In this double-blind placebo controlled trial, 58 patients with definitive RA were randomly allocated into two groups to receive vitamin K 1 as phylloquinone [10 mg/day] or placebo pills for 8 weeks. Clinical status using disease activity score-28 (DAS-28) and serum concentrations of some inflammatory markers (IL-6, hs-CRP, TNFα) were assessed at baseline and at the end of intervention. Results: There were no significant differences between the two groups regarding any of the baseline characteristics. In the vitamin K 1 group, a 27 % decrease in serum levels of IL-6 (P = 0.006) and a 13 % decrease in DAS-28 (P = 0.041) were observed. However, after adjusting for relevant confounders, i. e.; duration of RA, intake of folic acid supplements, energy intake, weight and baseline values of each variable, by comparing the two groups, we found no significant reduction in these markers. Conclusion: Vitamin K 1 supplementation at 10 mg/day for 8 weeks had no significant effects on blood biomarkers of inflammation and disease severity of patients with rheumatoid arthritis compared with the placebo group.

Topical application of Vitamin K1 has been demonstrated to effectively treat papulopustular skin rash, a serious and frequently encountered side effect of Epidermal Growth Factor Inhibitors (EGFRIs). Systemic absorption of vitamin K1 from skin and the resultant consequence of antagonizing EGFRIs anticancer effects jeopardizes the clinical acceptability of this rather effective treatment. The purpose of the present study was to rationally formulate and evaluate the release rate and transdermal absorption of a wide range of Vitamin K1 dermal preparations with a variety of physiochemical properties. A library of 33 formulations with were compounded and tested for Vitamin K1 permeation using hydrophobic membranes and porcine skin mounted in a Fran diffusion cells. Our results demonstrate the lowest diffusion for water-in-oil emulsions, which also demonstrated a negligible transdermal absorption. The statistical analysis showed a significant correlation between in vitro and ex vivo results. While viscosity did not have a significant impact on the diffusion or absorption of vitamin K1, an increase in the lipid content was correlated with an increase in transmembrane diffusion (not with transdermal absorption). Overall, formulation design significantly impacts the release rate and transdermal absorption of vitamin K1, and confirms the possibility of minimal systemic distribution of this vitamin for this specific purpose., Competing Interests: The authors have declared that no competing interests exist.

Patients exposed to long acting anticoagulant rodenticides (LAARs) are typically administered large amounts of oral vitamin K1 (VK1) to counteract life-threatening anticoagulant effects. Although VK1 treatment effectively prevents mortality, additional methods are needed to reduce the long duration of VK1 treatment which can last for months at high expense. We developed a model of brodifacoum (BDF) poisoning, one of the most potent LAARs, in adult male New Zealand White (NZW) rabbits. The LD50 for oral BDF was determined to be 192 μg/kg, similar to that calculated for adult rats. However, in contrast to rats, NZW rabbits exhibited severe internal hemorrhage including in the brain, symptoms which mimic what occurs in cases of human poisoning. Similar to warfarin, BDF and other LAARs undergo enterohepatic recirculation which contributes to their long half-lives. We therefore tested effects of cholestyramine (CSA), an FDA-approved bile sequestrant, on BDF-induced mortality. When given daily (0.67 g/kg, oral) starting the day of BDF administration, CSA reduced mortality from 67% to 11%. At the same CSA prevented the increase in clotting time, and reduced the decrease in core body temperature due to BDF. Given its excellent safety record and that it is approved for children older than 6 years, these findings suggest CSA could be considered as an adjunct to VK1 for treatment of LAAR poisoning.

Rationale: Developing an optimal anticoagulant strategy poses a challenging task in patients with mechanical heart valves (MHVs) throughout their lifetime. We report an optimal anticoagulant therapy in a cancer patient with hepatic metastases after MHV replacement., Patient Concerns: A 68-year-old female with MHVs suffered from gallbladder cancer with hepatic metastases. Her international normalized ratio (INR) fluctuated owing to the declined hepatic function., Diagnoses: Gallbladder cancer and hepatic metastases, with a history of mechanic aortic valve replacement and mitral valve replacement., Interventions: Warfarin was discontinued and Vitamin K1 was immediately administrated via intravenous infusion. low-molecular-weight heparin (LMWH) was regarded as a preferable option, and nadroparin at the dosage of 4100IU daily was administered., Outcomes: No adverse event occurred during the patient's hospitalization and two-week follow up after discharge., Lessons: LMWH may represent a reasonable alternative regarding the inhibition of thrombus and bleeding in MHVs carriers with cancer and hepatic metastases.

Objective: Growth Arrest-Specific 6 (GAS6) is a vitamin K-dependent protein. Despite a similar structure to Protein S, it has no anticoagulant activity. An association between GAS6 and some diseases for adults has been reported. In the absence of prospective clinical studies of GAS6 in neonates, so far, the objective of this study is to obtain, for the first time, plasma GAS6 levels before and after vitamin K1 prophylaxis in full-term and pre-term newborns., Methods: 80 newborns (40 term and 40 preterm) were recruited for this study. Cord blood samples and peripheral blood samples 48 h after vitamin K1 injection were collected into EDTA-tubes. GAS6 levels were measured in platelet-poor plasma by ELISA., Results: Cord blood plasma GAS6 levels in preterm and term newborns were 9.07 ± 5.30 ng/mL and 9.75 ± 4.34 ng/mL, respectively. In response to vitamin K1 injection, GAS6 levels increased in preterm newborns (10.50 ± 5.28 ng/mL) (p < .05), but not in term newborns (9.12 ± 3.42 ng/mL, p > .05)., Conclusion: This pilot study provided, to the best of our knowledge, the first report that GAS6 levels increased significantly after vitamin K1 prophylaxis in preterm newborns but not in term infants. This study may serve as a first step toward more extensive studies in neonates.

Background: Acne-like skin rash is a frequently occurring adverse event associated with drugs against the epidermal growth factor receptor. This randomized vehicle-controlled study investigated the addition of vitamin K1 cream to doxycycline in patients with metastatic colorectal cancer treated with cetuximab., Patients and Methods: Patients receiving first-line cetuximab + FOLFIRI were randomly assigned to prophylactic treatment with doxycylin and vitamin K1 cream or doxycycline and the vehicle. The primary end point of the study was the incidence of grade ≥ 2 skin rash (NCI CTCAE version 4.02) during 8 weeks of skin treatment. Secondary end points comprised skin rash according to a more thorough tripartite skin toxicity score (WoMo), quality of life, efficacy, and compliance. The study had 80% power to show a 20% reduction of the incidence of grade ≥ 2 skin rash., Results: A total of 126 patients were analyzed. The incidence of skin rash grade ≥ 2 was comparable between the arms. Likewise, no difference was seen in the WoMo score with respect to the percentage of skin affected. However, starting in week 5 and increasing over time patients treated with vitamin K1 cream had less severe rash and fewer fissures. Quality of life as well as efficacy and compliance with study medication and anticancer treatment was comparable in both arms., Conclusion: The primary end point of decreasing grade ≥ 2 skin rash was not met. However, using vitamin K1 cream as part of prophylactic treatment decreased the severity of acne-like skin rash according to WoMo, an alternative and more thorough skin toxicity scoring tool.

Owing to its limited aqueous solubility, Phytomenadione (vitamin K) undergoes a low bioavailability (50%) with a large inter-individual variability after oral administration. Therefore, the aim of this work was to incorporate vitamin K into nanostructure lipid carrier systems to improve its aqueous solubility and bioavailability. Phytomenadione was used as a liquid lipid; Precirol ATO5, and Compritol ATO were used as solid lipids; Labrasol and Cremophore EL as water soluble surfactants; Capryol 90 and Lauroglycol as lipid soluble surfactants. Eight formulas were prepared and characterized for their particle sizes, zeta potential, entrapment efficiencies, and drug release. Those formulas had particle sizes ranging from 25.4 to 68.3 nm. The best formula, consisting of 15% Phytomenadione, 45% Precirol ATO5, 30% Cremophore EL, and 10% Lauroglycol 90, was selected for stability study and characterized by the techniques mentioned above and scanning electron microscopy. It had the highest drug loading and an acceptable in vitro release profile (94.54% within 30 min). This formula was also chemically and physically stable, and it recorded a relative bioavailability of 645.5% in rabbits compared to the commercial conventional tablet. This formula could be a promising carrier regarding its ease of preparation, dosage form versatility and enhanced bioavailability.

Background/objectives: This study aims to investigate the reproducibility and relative validity of the Dutch food frequency questionnaire (FFQ), to estimate intake of dietary phylloquinone and menaquinones compared with 24-h dietary recalls (24HDRs) and plasma markers of vitamin K status., Subjects/methods: In a cross-sectional study among 63 men and 58 women, the FFQ was completed three times over a 1-year period and the reproducibility was calculated over these measurements. Twelve-monthly 24HDR were collected to estimate relative validity. In addition, the relative validity of the FFQ, compared with plasma phylloquinone and desphospho-uncarboxylated matrix Gla protein (dpucMGP), was assessed cross-sectionally among 507 postmenopausal women., Results: Intraclass correlations showed a good reproducibility, with correlations ranging from 0.65 to 0.83. The relative validity for phylloquinone intake compared with 24HDR was lower for women (r s =0.28) than men (r s =0.40). The relative validity, compared with 24HDR, for intake of short-chain menaquinones were ranging between 0.30 and 0.34. Long-chain menaquinones showed good relative validity (r s =0.60-0.69). Plasma phylloquinone concentrations were weakly correlated with phylloquinone intake (r s =0.16 (0.07-0.24). Plasma dpucMGP was negatively but weakly correlated with phylloquinone intake (r s =-0.09 (-0.18; -0.01)) and long-chain menaquinones (r s =-0.13 (-0.21; -0.04)), but not with short-chain menaquinones (r s =-0.04 (-0.13; 0.05))., Conclusions: The FFQ is reproducible to rank subjects for phylloquinone and menaquinone intake.The relative validity of our FFQ, compared with 24HDR, to estimate intake of phylloquinone and short-chain menaquinones was low, but the relative validity for long-chain menaquinones was good. The relative validity of our FFQ, compared with plasma phylloquinone and dpucMGP, was relatively low for both phylloquinone and menaquinone intake.

Background: Associations between childhood vitamin K consumption and cardiac structure and function have not been investigated., Objective: We determined associations between phylloquinone (vitamin K-1) intake and left ventricular (LV) structure and function in adolescents., Methods: We assessed diet with three to seven 24-h recalls and physical activity (PA) by accelerometry in 766 adolescents (aged 14-18 y, 50% female, 49% black). Fat-free soft tissue (FFST) mass and fat mass were measured by dual-energy X-ray absorptiometry. LV structure [LV mass (g)/height (m)2.7 (LV mass index) and relative wall thickness] and function [midwall fractional shortening (MFS) and ejection fraction] were assessed by echocardiography. Associations were evaluated by comparing the LV structure and function variables across tertiles of phylloquinone intake. Prevalence and OR of LV hypertrophy (LV mass index >95th percentile for age and sex) were also assessed by phylloquinone tertiles., Results: The prevalence of LV hypertrophy progressively decreased across tertiles of phylloquinone intake (P-trend < 0.01). Multinomial logistic regression-adjusting for age, sex, race, Tanner stage, systolic blood pressure, FFST mass, fat mass, socioeconomic status, PA, and intakes of energy, fiber, calcium, vitamin C, vitamin D, and sodium-revealed that compared with the highest phylloquinone intake tertile (reference group), the adjusted OR for LV hypertrophy was 3.3 (95% CI: 1.2, 7.4) for those in the lowest phylloquinone intake tertile. When LV structure variables were compared across phylloquinone intake tertiles adjusting for the same covariates, there were significant linear downward trends for LV mass index (6.5% difference, tertile 1 compared with tertile 3) and relative wall thickness (9.2% difference, tertile 1 compared with tertile 3; both P-trend ≤ 0.02). Conversely, significant linear upward trends across phylloquinone intake tertiles were observed for MFS (3.4% difference, tertile 1 compared with tertile 3) and ejection fraction (2.6% difference, tertile 1 compared with tertile 3; both P-trend < 0.04)., Conclusion: Our adolescent data suggest that subclinical cardiac structure and function variables are most favorable at higher phylloquinone intakes., (© 2017 American Society for Nutrition.)

Vitamin K1 injection induces severe dose-related anaphylactoid reactions and overdose for the treatment of vitamin K deficiency. We aimed to find an optimal and small dose of vitamin K1 injection to treat vitamin K deficiency and avoid anaphylactoid reactions in animal. Rats were administered a vitamin K-deficient diet and gentamicin to establish vitamin K deficiency model. Behaviour tests were performed in beagle dogs to observe anaphylactoid reactions. The results showed an increased protein induced by vitamin K absence or antagonist II (PIVKA-II) levels, a prolonging of prothrombin time (PT) and activated partial thromboplastin time (APTT) and a decrease in vitamin K-dependent coagulation factor (F) II, VII, IX and X activities in the model group. In vitamin K1 0.01 mg/kg group, the liver vitamin K1 levels increased fivefold and the liver vitamin K2 levels increased to the normal amount. Coagulation markers PT, APTT, FVII and FIX activities returned to normal. Both in the 0.1 and 1.0 mg/kg vitamin K1 groups, coagulation functions completely returned to normal. Moreover, the amount of liver vitamin K1 was 40 (0.1 mg/kg) or 100 (1.0 mg/kg) times as in normal. Vitamin K2 was about 4 (0.1 mg/kg) or 5 (1.0 mg/kg) times as the normal amount. There was no obvious anaphylactoid symptom in dogs with the dose of 0.03 mg/kg, which is equivalent to the dose of 0.01 mg/kg in rats. These results demonstrated that a small dose of vitamin K1 is effective to improve vitamin K deficiency and to prevent anaphylactoid reactions, simultaneously., (© 2017 Société Française de Pharmacologie et de Thérapeutique.)

Background & Aims: Vitamin K has been associated with various health outcomes, including non-fatal cardiovascular diseases (CVD) and cancer. However, little is known about the association between vitamin K intake and all-cause and cause specific mortality. This study aims to investigate the association between vitamin K intake and all-cause and cause-specific mortality., Methods: This prospective cohort study included 33,289 participants from the EPIC-NL cohort, aged 20-70 years at baseline and recruited between 1993 and 1997. Dietary intake was assessed at baseline with a validated food frequency questionnaire and intakes of phylloquinone, and total, short chain and long chain menaquinones were calculated. Information on vital status and causes of death was obtained through linkage to several registries. The association between the different forms of vitamin K intake and mortality was assessed with Cox proportional hazards, adjusted for risk factors for chronic diseases and nutrient intake., Results: During a mean follow-up of 16.8 years, 2863 deaths occurred, including 625 from CVD (256 from coronary heart disease (CHD)), 1346 from cancer and 892 from other causes. After multivariable adjustment, phylloquinone and menaquinones were not associated with all-cause mortality with hazard ratios for the upper vs. the lowest quartile of intake of 1.04 (0.92;1.17) and 0.94 (0.82;1.07) respectively. Neither phylloquinone intake nor menaquinone intake was associated with risk of CVD mortality. Higher intake of long chain menaquinones was borderline significantly associated (p trend  = 0.06) with lower CHD mortality with a HR 10μg of 0.86 (0.74;1.00). None of the forms of vitamin K intake were associated with cancer mortality or mortality from other causes., Conclusions: Vitamin K intake was not associated with all-cause mortality, cancer mortality and mortality from other causes., (Copyright © 2016. Published by Elsevier Ltd.)

A 28-year-old female Andean condor (Vultur gryphus) housed in an outside exhibit at the National Aviary in Pittsburgh, PA, began showing signs of weakness. Toxicosis with an anticoagulant rodenticide was suspected because its mate had died 1 day earlier from possible brodifacoum poisoning. A rapid decline in the packed cell volume, despite vitamin K 1 treatment, necessitated a blood transfusion with blood from bald eagles (Haliaeetus leucocephalus) and Steller's sea eagles (Haliaeetus pelagicus). Supportive therapy after transfusion included vitamin K 1 (5 mg/kg IM q12h) as well as enrofloxacin, vitamin B complex, selenium and vitamin E, and subcutaneous fluids as needed. After a 39-day treatment period, a tapering dosage of vitamin K 1 was initiated, and treatment ended after 17 weeks. However, 2 weeks later, the bird suffered from a potential relapse. It was successfully treated with a repeat tapering vitamin K 1 regimen lasting a total of 4 months.

Purpose: The change in turnaround time of 4-factor prothrombin complex concentrate (PCC) when managed by the pharmacy department compared to blood bank management was evaluated., Methods: A retrospective analysis evaluated blood bank versus pharmacy management of PCC. Blood bank management was evaluated from November 2014 to November 2015, and pharmacy management was evaluated from December 2015 to July 2016. Chart review was performed on all patients who received PCC during these study periods. The primary outcome was the difference in median time from order entry to administration between management groups. Comparisons were made for the appropriateness of clinical use, length of stay, and discharge status. The primary outcome was analyzed using a Mann-Whitney U test. Secondary outcomes were analyzed using the chi-square test or Fisher's exact test. Descriptive statistics were utilized to analyze secondary outcomes., Results: Forty-three patients received PCC in the blood bank group, and 22 patients received PCC in the pharmacy group. Median turnaround time of PCC was lower in the pharmacy group (43 minutes; interquartile range [IQR], 32-65 minutes) compared to the blood bank group (62 minutes; IQR; 39-110 minutes; p = 0.032). PCC use was clinically appropriate for 55% of patients ( n = 12) in the pharmacy group compared with 37% of patients ( n = 16) in the blood bank group ( p = 0.182). There were no significant differences between the blood bank and pharmacy groups with regard to hospital length of stay or in-hospital mortality., Conclusion: Conversion of PCC management from the blood bank to the pharmacy was associated with a significant decrease in time to PCC administration., Competing Interests: DisclosuresThe authors have declared no potential conflicts of interest., (Copyright © 2017 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

Vitamin K plays important biological roles in maintaining normal blood coagulation, bone mineralization, soft tissue physiology, and neurological development. Menaquinone-7 is a form of vitamin K2 that occurs naturally in some animal-derived and fermented foods. It is also available as an ingredient of dietary supplements. Menaquinone-7 has greater bioavailability than other forms of vitamin K, which has led to increasing sales and use of menaquinone-7 supplements. This special article reviews the chemistry, nomenclature, dietary sources, intake levels, and pharmacokinetics of menaquinones, along with the nonclinical toxicity data available and the data on clinical outcomes related to safety (adverse events). In conclusion, the data reviewed indicate that menaquinone-7, when ingested as a dietary supplement, is not associated with any serious risk to health or with other public health concerns. On the basis of this conclusion, US Pharmacopeia monographs have been developed to establish quality standards for menaquinone-7 as a dietary ingredient and as a dietary supplement in various dosage forms., (© The Author(s) 2017. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Phylloquinone is the most abundant form of vitamin K in US diets. Green vegetables are considered the predominant dietary source of phylloquinone. As our food supply diversifies and expands, the food groups that contribute to phylloquinone intake are also changing, which may change absolute intakes. Thus, it is important to identify the contributors to dietary vitamin K estimates to guide recommendations on intakes and food sources. Objective: The purpose of this study was to estimate 1 ) the amount of phylloquinone consumed in the diet of US adults, 2 ) to estimate the contribution of different food groups to phylloquinone intake in individuals with a high or low vegetable intake (≥2 or <2 cups vegetables/d), and 3 ) to characterize the contribution of different mixed dishes to phylloquinone intake. Methods: Usual phylloquinone intake was determined from NHANES 2011-2012 (≥20 y old; 2092 men and 2214 women) and the National Cancer Institute Method by utilizing a complex, stratified, multistage probability-cluster sampling design. Results: On average, 43.0% of men and 62.5% of women met the adequate intake (120 and 90 μg/d, respectively) for phylloquinone, with the lowest self-reported intakes noted among men, especially in the older age groups (51-70 and ≥71 y). Vegetables were the highest contributor to phylloquinone intake, contributing 60.0% in the high-vegetable-intake group and 36.1% in the low-vegetable-intake group. Mixed dishes were the second-highest contributor to phylloquinone intake, contributing 16.0% in the high-vegetable-intake group and 28.0% in the low-vegetable-intake group. Conclusion: Self-reported phylloquinone intakes from updated food composition data applied to NHANES 2011-2012 reveal that fewer men than women are meeting the current adequate intake. Application of current food composition data confirms that vegetables continue to be the primary dietary source of phylloquinone in the US diet. However, mixed dishes and convenience foods have emerged as previously unrecognized but important contributors to phylloquinone intake in the United States, which challenges the assumption that phylloquinone intake is a marker of a healthy diet. These findings emphasize the need for the expansion of food composition databases that consider how mixed dishes are compiled and defined., Competing Interests: Author disclosures: SGH, EGF, KJB, RLB, DBH, CHG, and SLB, no conflicts of interest., (© 2017 American Society for Nutrition.)

Five dogs were presented with clinical signs compatible with upper airway obstruction, including stridor, stertor, coughing, gagging, and varying degrees of respiratory distress. All dogs had radiographic findings of soft tissue opacity in the area of the pharynx, larynx, or trachea, and several had narrowing of the tracheal lumen. Coagulation abnormalities (prolonged prothrombin time, activated partial thromboplastin time) were present in the four dogs that underwent testing. Four of five dogs were treated for the coagulopathy, presumably due to anticoagulant rodenticide toxicosis, and survived to discharge.Upper airway obstruction is an unusual presentation for anticoagulant rodenticide toxicosis in dogs. Raising the index of suspicion for this treatable condition may help clinicians to identify this sooner.

Purpose: Cetuximab-induced skin rash Gd3+ occurs in ≥16% patients (pts) (Heinemann et al., Lancet Oncol 15(10):1065-1075, 2014; Van Cutsem et al. J Clin Oncol 27(19):3117-25; 2009b). Survival, response, and toxicity parameters were re-evaluated under a pre-defined skin prophylaxis consistent of vitamin K1 ointment and oral doxycycline., Methods: This is a national, multicenter, phase 4, first-line mCRC (K-RAS wt) trial. Pts received irinotecan 180 mg/m² (d1), FA 400 mg/m² (d1), 5-FU 400 mg/m² (d1), 5-FU 2400 mg/m² (d1-2), and cetuximab [400 mg/m² (d1), and then 250 mg/m² qw], prophylactic 0.1% vitamin K1 ointment qd, and oral doxycycline 100 mg bid., Primary Objective: 1-year PFS rate; secondary objectives: skin side-effects (grade, onset), objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) time, and overall survival (OS) time and safety., Results: Twenty centers recruited 55 patients. Recruitment started Q1 2011 and ended Q3 2013 due to slow accrual. Characteristics were in line with CRYSTAL trial except for age and colonic location. 1-year PFS rate was 25.9%, mOS 21.8 months (m), and mPFS 8.5 m. ORR was 63.0%, DCR 77.8%. Rash Gd2+ occurred in 42.6% [median onset was 4.0 weeks (w)]; paronychia Gd2+ occurred in 22.2% (median onset 15.4w.); skin fissures Gd2+ occurred in 31.5% (median onset 19.9 weeks) 7% pts abandoned cetuximab treatment due to toxicity., Conclusion: Our data reveal encouraging improvements in skin reactions and their time to occurrence due to a pre-defined skin care.

Importance: Cataract, one of the most frequent causes of blindness in developed countries, is strongly associated with aging. The exact mechanisms underlying cataract formation are still unclear, but growing evidence suggests a potential role of inflammatory and oxidative processes. Therefore, antioxidant and anti-inflammatory factors of the diet, such as vitamin K1, could play a protective role., Objective: To examine the association between dietary vitamin K1 intake and the risk of incident cataracts in an elderly Mediterranean population., Design, Setting, and Participants: A prospective analysis was conducted in 5860 participants from the Prevención con Dieta Mediterránea Study, a randomized clinical trial executed between 2003 and 2011. Participants were community-dwelling men (44.2%) and women (55.8%), and the mean (SD) age was 66.3 (6.1) years., Main Outcomes and Measures: Dietary vitamin K1 intake was evaluated using a validated food frequency questionnaire. The time to the cataract event was calculated as the time between recruitment and the date of the occurrence to cataract surgery, the time to the last visit of the follow-up, date of death, or the end of the study. Hazard ratios and 95% CIs for cataract incidence were estimated with a multivariable Cox proportional hazards model., Results: Participants were community-dwelling men (44.2%; n = 868) and women (55.8%; n = 1086), and the mean (SD) age was 66.3 (6.1) years. After a median of 5.6 years follow-up, we documented a total of 768 new cataracts. Participants in the highest tertile of dietary vitamin K1 intake had a lower risk of cataracts than those in the lowest tertile (hazard ratio, 0.71; 95% CI, 0.58-0.88; P = .002), after adjusting for potential confounders., Conclusions and Relevance: High intake of dietary vitamin K1 was associated with a reduced risk of cataracts in an elderly Mediterranean population even after adjusting by other potential confounders., Trial Registration: isrctn.org: ISRCTN35739639.

Combination therapy is one of the best methods to manage the fatality rate in hepatocellular carcinoma (HCC). This study aimed to formulate a synergistic combination of synthetic and herbal compounds for the treatment of HCC as well as to elucidate a possible signalling mechanism. MTT and enzymatic assay were performed to determine the synergistic effect of drug combination (sorafenib, vitamin K1 and trans-chalcone) on HepG2 cell lines after intoxication with H 2 O 2 . Protein-protein interaction and docking studies were performed using Pathwaylinker2.0 and Schrödinger's software application to find out the mechanism of action and major targets for drug combination. The overall in vitro result showed that combination of trans-chalcone, vitamin K1 and sorafenib (10, 5 and 5 μM concentration, respectively) enhanced the resistance against oxidative stress generated by H 2 O 2 . The interaction studies helped in identification of few targets for docking of ligands (trans-chalcone, vitamin K1 and sorafenib). The study reports the synergistic effects of the formulation that can protect the cells from oxidative stress and restore normal levels of cellular enzymes in HepG2 cell line. We were able to determine the mechanism of action of herbal and synthetic formulation through in silico studies. Finally, docking studies confirmed potential targets for inhibition of hepatocarcinogenesis., (© 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

The levels of 63 cytokines, chemokines, and growth factors were measured in the serum of four patients with idiopathic morphea and of one patient with vitamin K 1 -induced morphea employing a multiplex assay to identify the role of inflammatory/immunologic events in their pathogenesis. Full-thickness skin biopsies of affected skin were analyzed by histopathology. Luminex assays for 63 cytokines, chemokines, and growth factors were performed in the sera from four patients with idiopathic morphea and in two different samples of serum obtained in two separate occasions from one patient with vitamin K 1 -induced morphea. The serum values of numerous inflammatory cytokines and growth factors including IL-2, IL-4, IL-6, and IFNβ were markedly increased in the serum of patients with idiopathic morphea, whereas, these values were normal in the serum of the patient with vitamin K 1 -induced morphea. In contrast, serum eotaxin levels were greater than threefold higher in the patient with vitamin K 1 -induced morphea compared to patients with idiopathic morphea. The results demonstrated remarkable increases in the levels of numerous cytokines and chemokines in the serum samples of all patients with idiopathic morphea indicative of a prominent role of inflammatory/immunologic events in its pathogenesis. The results also showed statistically significant differences between idiopathic morphea and vitamin K 1 -induced morphea suggesting that their development involves different pathogenetic mechanisms.