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Background: Cefoperazone/sulbactam is commonly prescribed for the treatment of infected patients with cirrhosis., Aim: To investigate the effect of cefoperazone/sulbactam on coagulation in cirrhotic patients and assess the effectiveness of vitamin K1 supplementation in preventing cefoperazone/sulbactam-induced coagulation disorders., Method: This retrospective cohort study compared coagulation function in 217 cirrhotic patients who received cefoperazone/sulbactam with and without vitamin K1 supplementation (vitamin K1 group, n = 108; non-vitamin K1 group, n = 109). Propensity score matching (PSM) was used to to reduce confounders' influence, the SHapley additive exPlanations (SHAP) model to explore the importance of each variable in coagulation disorders., Results: In the non-vitamin K1 group, the post-treatment prothrombin time (PT) was 16.5 ± 6.5 s and the activated partial thromboplastin time (aPTT) was 34.8 ± 9.4 s. These were significantly higher than pre-treatment values (PT: 14.6 ± 2.4 s, p = 0.005; aPTT: 30.4 ± 5.9 s, p < 0.001). In the vitamin K1 group, no differences were observed in PT, thrombin time, or platelet count, except for a slightly elevated post-treatment aPTT (37.0 ± 10.4 s) compared to that of pre-treatment (34.4 ± 7.2 s, p = 0.033). The vitamin K1 group exhibited a lower risk of PT prolongation (OR: 0.211, 95% CI: 0.047-0.678) and coagulation disorders (OR: 0.257, 95% CI: 0.126-0.499) compared to that of the non-vitamin K1 group. Propensity score matching analysis confirmed a reduced risk in the vitamin K1 group for prolonged PT (OR: 0.128, 95% CI: 0.007-0.754) and coagulation disorders (OR: 0.222, 95% CI: 0.076-0.575). Additionally, the vitamin K1 group exhibited lower incidences of PT prolongation, aPTT prolongation, bleeding, and coagulation dysfunction compared to the non-vitamin K1 group., Conclusion: Cefoperazone/sulbactam use may be linked to a higher risk of PT prolongation and coagulation disorders in cirrhotic patients. Prophylactic use of vitamin K1 can effectively reduce the risk., Competing Interests: Conflicts of interest No conflicts of interest have been declared., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: Information regarding the relationship between epilepsy and vitamin K1 remains unclear. We aimed to assess the association between dietary vitamin K1 intake and epilepsy., Methods: Data was obtained from the National Health and Nutrition Examination Survey (NHANES) conducted from 2013 to 2018. The study enrolled participants aged ≥ 18 years that provided complete information on their dietary vitamin K1 intake and epilepsy status. Weighted multivariable regression and subgroup analyses were performed to detect the association between dietary vitamin K1 intake and epilepsy., Results: In total, 10 137 participants (mean age, 48 years) were enrolled. Among them, 84 (0.83%) participants were identified as having epilepsy, whereas 10 053 (99.17%) were included in the non-epilepsy group, with an average dietary vitamin K1 intake of 67.2 ± 6.9 and 105.5 ± 1.5 µg/d, respectively. Each unit (10 µg/d) increase in vitamin K1 intake was associated with a 7% decrease in the odds of epilepsy (odds ratio = 0.93, 95% confidence interval: 0.88-0.98, p = 0.011). Multivariate logistic regression analysis revealed that participants in the higher quartile had lower odds of epilepsy than those in the first quartile of vitamin K1 intake. Subgroup analysis showed a stable and consistent inverse association between dietary vitamin K1 intake and epilepsy., Conclusion: Higher dietary vitamin K1 intake was associated with lower incidence of epilepsy. Our study did not establish a cause-and-effect relationship. Further large-scale prospective studies and randomized trials are warranted to confirm our findings., Competing Interests: Declarations Ethics approval and consent to participate The National Center for Health Statistics and Research Ethics Review Committee approved the use of human participants for the NHANES study. In addition, written informed consent was provided by each participant. Due to the retrospective nature of this study (publicly available NHANES data), the requirement for an institutional review board approval was waived. Consent for publication NA. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

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 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.)

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.

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.

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.

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.

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.)

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.

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.)

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.

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.

Renal diets for advanced chronic kidney disease (CKD) are structured to achieve a lower protein, phosphate and sodium intake, while supplying adequate energy. The aim of this nutritional intervention is to prevent or correct signs, symptoms and complications of renal insufficiency, delaying the start of dialysis and preserving nutritional status. This paper focuses on three additional aspects of renal diets that can play an important role in the management of CKD patients: the vitamin K1 and fiber content, and the alkalizing potential. We examined the energy and nutrients composition of four types of renal diets according to their protein content: normal diet (ND, 0.8 g protein/kg body weight (bw)), low protein diet (LPD, 0.6 g protein/kg bw), vegan diet (VD, 0.7 g protein/kg bw), very low protein diet (VLPD, 0.3 g protein/kg bw). Fiber content is much higher in the VD and in the VLPD than in the ND or LPD. Vitamin K1 content seems to follow the same trend, but vitamin K2 content, which could not be investigated, might have a different pattern. The net endogenous acid production (NEAP) value decreases from the ND and LPD to the vegetarian diets, namely VD and VLPD; the same finding occurred for the potential renal acid load (PRAL). In conclusion, renal diets may provide additional benefits, and this is the case of vegetarian diets. Namely, VD and VLPD also provide high amounts of fibers and Vitamin K1, with a very low acid load. These features may have favorable effects on Vitamin K1 status, intestinal microbiota and acid-base balance. Hence, we can speculate as to the potential beneficial effects on vascular calcification and bone disease, on protein metabolism, on colonic environment and circulating levels of microbial-derived uremic toxins. In the case of vegetarian diets, attention must be paid to serum potassium levels.

Background & Aims: Vitamin K acts as a coenzyme in the γ-carboxylation of vitamin K-dependent proteins, including coagulation factors, osteocalcin, matrix Gla protein (MGP), and the growth arrest-specific 6 (GAS6) protein. Osteocalcin is a key factor for bone matrix formation. MGP is a local inhibitor of soft tissue calcification. GAS6 activity prevents the apoptosis of vascular smooth muscle cells. Few data on vitamin K intake in chronic kidney disease patients and no data in patients on a Mediterranean diet are available. In the present study, we evaluate the dietary intake of vitamin K1 in a cohort of patients undergoing haemodialysis., Methods: In this multi-centre controlled observational study, data were collected from 91 patients aged >18 years on dialysis treatment for at least 12 months and from 85 age-matched control subjects with normal renal function. Participants completed a food journal of seven consecutive days for the estimation of dietary intakes of macro- and micro-nutrients (minerals and vitamins)., Results: Compared to controls, dialysis patients had a significant lower total energy intake, along with a lower dietary intake of proteins, fats, carbohydrates, fibres, and of all the examined minerals (Ca, P, Fe, Na, K, Zn, Cu, and Mg). With the exception of vitamin B12, vitamins intake followed a similar pattern, with a lower intake in vitamin A, B1, B2, C, D, E, folates, K1 and PP. These finding were confirmed also when normalized for total energy intake or for body weight. In respect to the adequate intakes recommended in the literature, the prevalence of a deficient vitamin K intake was very high (70-90%) and roughly double than in controls. Multivariate logistic model identified vitamin A and iron intake as predictors of vitamin K deficiency., Conclusions: Haemodialysis patients had a significantly low intake in vitamin K1, which could contribute to increase the risk of bone fractures and vascular calcifications. Since the deficiency of vitamin K intake seems to be remarkable, dietary counselling to HD patients should also address the adequacy of vitamin K dietary intake and bioavailability. Whether diets with higher amounts of vitamin K1 or vitamin K supplementation can improve clinical outcomes in dialysis patients remains to be demonstrated., (Copyright © 2016 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Purpose: Patients with diabetes (DM) and chronic kidney disease (CKD) are at increased risk for suboptimal bone health. The study objective was to investigate the relationships between vitamin D (vitD), vitamin K1 (vitK 1 ), and calcium intake with bone mineral density (BMD) and vitamin D status in an ambulatory population with DM and CKD., Methods: Adults (age 18-80 years; n = 62) with DM and CKD (stages 1-4) were recruited from the Northern Alberta Renal Program. Primary outcome variables included vitD, vitK 1 , and calcium intake; serum 25(OH)D, 1,25(OH) 2 D; and BMD as measured by dual X-ray absorptiometry. Statistical significance was determined at P < 0.05., Results: Participants met the estimated average requirement or adequate intake for vitD, vitK 1 , and calcium intake in 73% (n = 45), 66% (n = 39), and 52% (n = 31), respectively, with a combined intake of micronutrient supplementation and diet. Participants had serum 25(OH)D concentrations ≥75 nmol/L (n = 41), normal BMDs (n = 48), and 66% (n = 41/62) were taking vitD supplements (>1000 IU/D). BMD was positively influenced by serum 25(OH)D. However, serum 25(OH) ≥100 nmol/L was associated with lower BMD (absolute and T-scores) for whole-body and spine (P ≤ 0.05). VitK 1 intake (≥200 μg/day) was associated with higher whole-body and femoral-neck BMDs (absoluteand T-scores; P ≤ 0.05)., Conclusion: VitD status and BMD in adults with DM and CKD was influenced by vitD supplementation and vitK 1 intake.

Currently, there are few guidelines for the use of vitamin K1 in the maintenance treatment of long-acting anticoagulant rodenticide (LAAR) poisonings. We explored factors in the treatment of LAAR poisoning during the maintenance period in order to suggest feasible treatment models.Data from 24 cases of anticoagulant rodenticide poisoning in our hospital were collected from January 2013 to May 2016. The patients' sex, age, coagulation function, total time from poisoning to treatment with vitamin K1 (prehospital time), vitamin K1 sustained treatment time (VKSTT), anticoagulant rodenticide category, and specific poison dosage were collected. Multivariate analysis was used to evaluate the correlation between vitamin K1 dosage and other factors during the maintenance period.Only VKSTT (partial regression coefficient -1.133, 0.59, P = 0.035) had an obvious influence on the therapeutic dose of vitamin K1 required during the maintenance period.After an initial pulse therapy, the bleeding and coagulation functions were stabilized, and the patients were subsequently treated with vitamin K1 during the maintenance period. Over time, the maintenance dose of vitamin K1 (10-120 mg/d, intravenous drip) was gradually decreased and was not related to toxicant concentration., Competing Interests: The authors have no conflicts of interest to disclose.

Background: Data from a nationally representative sample of 18- to 64-y-old Irish adults conducted in 1999 highlighted low phylloquinone intakes. That survey, however, did not include older adults (aged ≥65 y), a subgroup that is potentially at higher risk of low phylloquinone intakes, or a biomarker of vitamin K status., Objectives: The objectives of this work were to measure the phylloquinone intake and its adequacy and the serum percentage of undercarboxylated osteocalcin (%ucOC), a vitamin K status biomarker, in a nationally representative sample of Irish adults aged 18-90 y, and to compare these newer data on dietary phylloquinone in adults aged 18-64 y with those from the previous survey., Methods: Data and biobanked serum samples from the National Adult Nutrition Survey, a randomly selected sample of Irish adults aged 18-90 y (N = 1500), were accessed. Phylloquinone intakes were estimated from 4-d food diary data and were compared across age groups (18-35, 36-50, 51-64, and ≥65 y). Serum %ucOC was assessed by immunoassay (n = 692)., Results: The mean ± SD intake of phylloquinone from all sources was 85.2 ± 59.1 μg/d, 99% of which was derived from food. Phylloquinone intakes and serum %ucOC were significantly (P < 0.05) lower (14-25%) and higher (27-39%), respectively, in the 18- to 35-y age group than in the 36- to 50-y, 51- to 64-y, and ≥65-y age groups (no differences between these 3 groups; P > 0.2 in all cases). Mean phylloquinone intakes had increased (P < 0.01) modestly (6 μg/d) in 18-64-y-olds across a decade. Of the total study population, 55% had phylloquinone intakes below the United Kingdom recommended intake of 1 μg ⋅ kg body weight -1 ⋅ d -1 CONCLUSION: Our study shows that younger adults (aged 18-35 y) appear to be at higher risk of inadequate vitamin K intake and lower vitamin K status, the health implications of which are unclear and warrant further investigation., (© 2016 American Society for Nutrition.)

Suboptimal vitamin D status is common among humans, and might increase bone resorption with subsequent negative effects on bone health. Fatty fish, including Atlantic salmon, is an important dietary vitamin D source. However, due to a considerable change in fish feed composition, the contribution of vitamin D from salmon fillet has been reduced. The main objective was to investigate if intake of vitamin D3 enriched salmon or vitamin D3 tablets decreased bone biomarkers (urinary N-telopeptides, deoxypyridinoline, serum bone-specific alkaline phosphatase, and osteocalcin) compared to a low vitamin D3 intake. The 122 healthy postmenopausal women included in this 12 weeks intervention trial were randomized into four groups: three salmon groups (150 grams/two times/week) and one tablet group (800 IU vitamin D and 1000 mg calcium/day). The salmon groups also received calcium supplements. The salmon had three different vitamin D3/vitamin K1 combinations: high D3+high K1, low D3+high K1, or high D3+low K1. Increased intake of salmon containing high levels of vitamin D3 (0.35-0.38 mg/kg/fillet) and supplements with the same weekly contribution had a positive influence on bone health as measured by bone biomarkers in postmenopausal women. Consequently, an increased level of vitamin D3 at least to original level in feed for salmonids will contribute to an improved vitamin D3 status and may improve human bone health.

Vitamin K1 (VK1) is a natural and lipophilic compound currently used in dermatological formulations. In this work, nanoemulsions containing VK1 have been proposed to overcome some issues associated to semisolid VK1-incorporating formulations. The study has been focused on the design of a lipid-free aqueous formulation, easy to prepare and with low cost of production. Thus, a simply protocol, using a low-energy method, has been used to spontaneously form the nanoemulsions. The nanoemulsion composition has been optimized to improve its physical stability during storage in different conditions. Then, the possibility to administer VK1-containing nanoemulsions by nebulization without significant alteration of the formulation was tested. Moreover, the VK1 accumulation into the skin layers have been evaluated through permeation experiments on Franz cells, ATR-FITR analysis, confocal laser scanning microscopy (CLSM) observations, and high performance liquid chromatography (HPLC) analysis. The study demonstrated that NEs represent an interesting option for the commercial development of an aqueous spray formulation for the topical delivery of VK1., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objectives: Rheumatoid arthritis (RA) is an autoimmune disease characterized by an increase in some autoantibodies and proteolytic enzymes, leading to joint destruction. Although recent investigations have considered vitamin K as an anti-inflammatory nutrient with an important role in bone metabolism, there is currently limited information on its efficacy in RA. We aimed to examine the effects of vitamin K1 (phylloquinone) on the biomarker of joint destruction and autoantibody in patients with RA., Materials and Methods: This was a randomized clinical trial in which 64 women with RA who fulfilled the eligibility criteria were randomly allocated to an intervention or a control group. Vitamin K1 or placebo was administered to the participants for 8 weeks. Baseline characteristics and anthropometric measures were obtained. Clinical status using disease activity score in 28 joints (DAS-28), serum levels of matrix metalloproteinase-3 (MMP-3), and rheumatoid factor (RF) were assessed before and after the intervention., Results: The serum level of MMP-3 compared with the baseline values did not change significantly in the groups. However, the serum concentration of RF decreased significantly in the vitamin K1 group (p = 0.041). Intergroup comparison showed no significant change in RF serum level after adjusting for relevant confounders (p > 0.05)., Conclusions: Vitamin K1 supplementation at 10 mg/day for 8 weeks did not alter joint destruction and immune status in the patients with RA compared with the controls.

Purpose: Functional vitamin K deficiency (both K1 and K2) is postulated to be one of the most relevant links between chronic kidney disease and vascular calcification in hemodialysis (HD) patients. Recommended dietary restrictions in HD patients superimposed on diversity of eating habits across the countries may affect the prevalence of functional vitamin K deficiency. The aim of this study was to determine the level of functional vitamin K deficiency and its relation to vitamin K1 intake in HD patients in Upper Silesia in Poland., Methods: Protein-induced vitamin K absence or antagonist-II (PIVKA-II) and undercarboxylated matrix Gla protein (ucMGP) were assessed by ELISA in 153 stable, prevalent HD patients and 20 apparently healthy adults (to establish normal ranges for PIVKA-II and ucMGP). Daily phylloquinone intake was assessed using a food frequency questionnaire., Results: PIVKA-II and ucMGP levels were increased in 27.5 and 77.1 % of HD patients in comparison with the reference ranges in apparently healthy controls, respectively. In 45 % of cases, the increased PIVKA-II level was explained by insufficient phylloquinone intake for Polish population (recommended intake: >55 μg for women and >65 µg for men). Applying ROC analysis, we showed that vitamin K1 intake below 40.2 µg/day was associated with increased PIVKA-II levels. There was no correlation between vitamin K1 intake and plasma concentration of ucMGP, or between PIVKA-II and ucMGP., Conclusions: (1) Functional vitamin K1 deficiency is explained by low vitamin K1 intake in less than half of HD patients. (2) Undercarboxylated matrix Gla protein level is a poor surrogate for functional vitamin K1 deficiency.

Purpose: Vitamin K1 (VK1) is a molecule abundant in some species of leaf vegetables with beneficial effects in humans following administration on the skin. This work investigates the possibility to use formulations based on lipid vesicles, namely liposomes, transfersomes and ethosomes, suitable to be administered on the skin by nebulization and alternative to fat semisolid preparations present on the market., Methods: Lipid vesicles encapsulating VK1 were prepared and characterized. Ex-vivo experiments on Franz cells were carried out to study the VK1 accumulation/permeation in/through the skin. Vesicles interaction with the skin was investigated by confocal laser scanning microscopy (CLSM) and attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy., Results: All developed carriers were stable following long-term storage and were not altered following nebulization. In ex-vivo experiments, vesicles with the highest deformability index, namely transfersomes and ethosomes, led to an enhanced VK1 accumulation/permeation into/through the skin. Interestingly, the nebulization of the vesicles led to a further increase of VK1 accumulation into the skin., Conclusions: In conclusion, to achieve a local effect of VK1 on the skin, the topical nebulization of VK1-containing transfersomes could offer a good compromise between a high VK1 penetration into the skin and a limited permeation through it.

Whether through the vitamin K-dependent proteins or the individual K vitamers, vitamin K (VK) is associated with a number of age-related conditions (e.g., osteoporosis, atherosclerosis, insulin resistance, cognitive decline). In light of this, we investigated the influence of lifetime dietary VK exposure on the tissue distribution of phylloquinone (K₁) and menaquinone-4 (MK-4) vitamers in 3-, 12- and 22-month-old male and female rats fed different K₁ diets since weaning or subjected to a 40% calorie restricted diet (CR) since adulthood. Dietary K₁ intakes around the minimal amount required for normal blood coagulation had no significant influence on body weights of both male and female rats at different life stages. Tissue contents of the K vitamers differed according to organs, were generally higher in females than in males, and increased with K₁ intake. The MK-4/total VK ratios tended to be increased in old age possibly reflecting an increased physiological demand for MK-4 during aging. Our study also confirmed the greater susceptibility of male rats to low VK containing diet, notably at a younger age. Despite lifelong higher K₁ intakes per unit body weight, tissue K₁ and MK-4 contents at 20 months were generally lower in CR rats compared to their ad libitum (AL) counterparts. Whether the lower tissue MK-4 content is the result of lower synthesis from K₁ or greater tissue utilization remains to be determined. However, the more youthful coagulation profile observed in old CR rats (vs. AL rats) tends to support the notion that CR is associated with greater utilization of the K vitamers to sustain physiological functions.

This institutional review board-approved retrospective cohort study evaluated the impact of intravenous versus subcutaneous phytonadione on length of stay in hospitalized patients requiring urgent warfarin reversal. All patients were 18 years or older, on warfarin therapy with an international normalized ratio (INR) between 3.1 and 10.0, and had warfarin therapy restarted at discharge. Patients who received intramuscular or oral phytonadione, phytonadione by more than 1 route, fresh frozen plasma, or any other blood products containing clotting factors, patients with active or severe liver disease, and patients who received other forms of anticoagulation were excluded. A total of 4425 patients receiving phytonadione were evaluated and 79 patients were included. Baseline characteristics were similar between the intravenous and subcutaneous groups, including mean age, gender, warfarin indication, Charlson comorbidity index, and indication for phytonadione. Geometric mean length of stay in the intravenous group was 211.7 hours compared with 191.0 hours in the subcutaneous group (P = 0.47). Though intravenous phytonadione administration resulted in significantly lower INRs at all time points <36 hours, geometric mean time to restart of warfarin therapy was not impacted (66.3 hours vs. 64.1 hours, P = 0.72). Despite demonstrating significantly greater INR reductions, hospital length of stay and time to restart of warfarin therapy were not improved with the administration of intravenous over subcutaneous phytonadione.