Vitamin K1 Treatment Research Articles

Safety of Vitamin K in mechanical heart valve patients with supratherapeutic INR: A systematic review and meta-analysis.

Patients who had mechanical heart valves and an international normalized ratio (INR) of >5.0 should be managed by temporary cessation of vitamin K antagonist. This study aimed to investigate the safety of low-dose vitamin K1 in patients with mechanical heart valves who have supratherapeutic INR. CINAHL, Cochran Library, Clinical trial.gov, OpenGrey, PubMed, ScienceDirect, and Scopus were systematically searched from the inception up to October 2021 without language restriction. Studies comparing the safety of low-dose vitamin K1 treatment in patients with placebo or other anticoagulant reversal agents were included. We used a random-effect model for the meta-analysis. Publication bias was determined by a funnel plot with subsequent Begg's test and Egger's test. From 7529 retrieved studies, 3 randomized control trials were included in the meta-analysis. Pooled data demonstrated that low-dose vitamin K was not associated with thromboembolism rate (risk ratio [RR] = 0.94; 95% CI: 0.19-4.55) major bleeding rate (RR = 0.58; 95% CI: 0.07-4.82), and minor bleeding rate (RR = 0.60; 95% CI: 0.07-5.09). Subgroup and sensitivity analysis demonstrated the nonsignificant effect of low-dose vitamin K on the risk of thromboembolism. Publication bias was not apparent, according to Begg's test and Egger's test (P = .090 and 0.134, respectively). The current evidence does not support the role of low-dose vitamin K as a trigger of thromboembolism in supratherapeutic INR patients with mechanical heart valves. Nevertheless, more well-designed studies with larger sample sizes are required to justify this research question.

Randomized, placebo-controlled trial of orally administered vitamin K1 for warfarin-associated coagulopathy in Chinese patients with mechanical heart valves.

Warfarin-associated coagulopathy commonly occurs in patients undergoing treatment with this anticoagulant. This trial aimed to determine the efficacy of using low-dose orally administered vitamin K1 to lower international normalized ratio (INR) values into the target range in a cohort of Chinese patients with mechanical heart valves. This was a double-blind, placebo-controlled, randomized trial. Chinese patients with mechanical heart valves who were undergoing warfarin treatment and who had INR values from 4.0 to 10.0 without bleeding were the subjects of this study. These patients were randomized into two treatment groups and were orally administered either vitamin K1 (2.5mg) or placebo. Warfarin was discontinued in both groups until INR values were ≤ 2.5. INR values on the day following treatment were the primary study outcome, with INR values on the following days and adverse clinical events over a 3-month follow-up serving as secondary study outcomes. In total, 80 patients were enrolled in the present study, and 40 patients each were assigned to the placebo and vitamin K1 treatment groups. Patients administered vitamin K1 exhibited a quick reduction in INR values relative to patients administered placebo (29 of 40 [72.5%] vs. 0 of 44 [0%] patients exhibiting INR values from 1.5-2.5 on the day following treatment, respectively, p = 0.000). Lower bleeding incidence was observed among patients administered vitamin K1 relative to those administered placebo during follow-up (4 [10%] vs. 12 [30%] patients, respectively, p = 0.045). There were no instances of thromboembolic complications or warfarin resistance in either group. Low-dose oral vitamin K1 can be effectively administered to Chinese patients with mechanical heart valves taking warfarin to rapidly reduce elevated INR values.

Effects of vitamin K1 treatment on plasma concentrations of long-acting anticoagulant rodenticide enantiomers following inhalation of contaminated synthetic cannabinoids

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.

Vitamin K1 Inhibition of Renal Crystal Formation through Matrix Gla Protein in the Kidney

Background and Objectives: Vitamin K (VK) plays a major role in modifying the binding of calcium in bones and blood vessels. Understanding the effect of VK on crystal formation in the kidney would contribute to advancing the treatment and prevention of kidney stones. Methods: Rats were treated with vitamin K1 (VK1) for 8 weeks. VK1 levels were detected and crystal formation were observed. HK2 cells were exposed to calcium oxalate monohydrate crystals. Apoptosis and cell viability were detected. Crystal deposition was analyzed using atomic absorption assay. The adenovirus vectors expressing matrix Gla protein (MGP) and siMGP were constructed to elucidate the effect and mechanism of VK1 on crystal formation. MGP expression in vivo and in vitro was analyzed by Western blot. The mRNA levels of monocyte chemoattractant protein-1 (MCP-1) and collagen I was measured by semiquantitative RT-PCR. Results: The concentrations of VK1 in whole blood and kidney tissues rose under treatment with VK1. Crystal formation was inhibited from the second to the 6th week, the frequency and quality of crystal formation decreased significantly, and the location of crystal formation was limited to a greater extent in the rats treated by VK1 compared to the control group. Warfarin treatment in the crystals-exposed HK2 cells significantly increased the number of crystals adhering to cells and the number of apoptotic cells and reduced cell viability. VK1 treatment reversed warfarin’s above influence. VK1 inhibited the upregulations of MCP-1 and collagen I in kidney tissues under crystal load. VK1 treatment increased MGP expression in vivo and in vitro, and MGP is necessary for VK1 to play a role in crystal deposition in cells. Conclusions: VK1 treatment can inhibit the formation of renal crystals in vivo. VK1 increases MGP expression and functions through MGP to reduce crystal deposition in cells and provide cell protection. Our findings suggest that VK1 treatment could be a potential strategy for the treatment and prevention of nephrolithiasis.

The Bile Sequestrant Cholestyramine Increases Survival in a Rabbit Model of Brodifacoum Poisoning.

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.

Treatment for long acting anticoagulant rodenticide poisoning – beyond INR monitoring?

Poisoning by long acting anti-coagulant rodenticides (LAARs) requires long-term treatment with oral vitamin K1 (VK1). However, discontinuing treatment based on normalization of INR, may leave some patients with serum LAAR concentrations above a level considered safe. To address this, we carried out a retrospective analysis of 21 case reports of LAAR poisoning having at least two serum LAAR concentrations quantified during treatment with oral VK1. We identified the case reports by survey of existing peer-reviewed literature in which a patient presented to emergency department exhibiting bleeding or elevated International Normalized Ratio (INR), and had quantitative measurements of serum LAAR concentrations. Of 21 case reports, measurement of serum LAAR concentrations following VK1 treatment showed that over half (n = 11) had serum LAAR concentrations that were above a concentration considered to be safe (10 ng/mL), despite having received higher daily and total VK1 dosing, over an equivalent treatment duration. Since residual amounts of serum and tissue LAAR could contribute to symptom recurrence and repeated hospitalization, these results indicate that normalization of INR is not a sufficient criterion to discontinue VK1 treatment and that measurements of serum LAAR concentrations should be included to help guide decisions to continue or discontinue VK treatment.

Phylloquinone supplementation improves glycemic status independent of the effects of adiponectin levels in premonopause women with prediabetes: a double-blind randomized controlled clinical trial.

BackgroundVitamin K, as a cofactor in the gamma carboxylation of certain glutamic acid (Gla) residues, has been related to glucose metabolism and insulin sensitivity. Osteocalcin, also known as bone γ-carboxyglutamic acid, increases β-cell proliferation as well as insulin and adiponectin secretion, which improve glucose tolerance and insulin sensitivity. Thus, the purpose of the present study was to examine the possible role of adiponectin as a mediator of glucose homeostasis following phylloquinone supplementation in premonopause women with prediabetes.MethodsEighty two women were randomized to consume vitamin k1 supplement (n = 39) or placebo (n = 43) for four weeks. Participants in vitamin K1 treatment group received one pearl softgel capsule containing 1000 micrograms phylloquinone while the placebo group received one placebo capsules daily for four weeks. The Blood samples were collected at baseline and after a four-week intervention to quantify osteocalcin, adiponectin, leptin and relevant variables.ResultsPhylloquinone supplementation significantly increased serum adiponectin concentration (1.24 ± 1.90 compared with −0.27 ± 1.08 μg/ml), and did not alter total osteocalcin (0.50 ± 4.11 compared with 0.13 ± 1.85 ng/ml) and leptin (−0.29 ± 8.23 compared with −1.15 ± 5.25 ng/ml) compared with placebo. Adjustments for total osteocalcin and adiponectin using analysis of covariance (ANCOVA) did not affect the association of glycemic status with related variables.ConclusionsIn conclusion our study demonstrated that phylloquinone supplementation improved glycemic status in premonopausal prediabetic women independent of adiponectin.Trial registrationThis trial was registered in Iranian Registry of Clinical Trials with ID number of IRCT2013120915724N1.

Vitamin K1 exerts antiproliferative effects and induces apoptosis in three differently graded human colon cancer cell lines.

Vitamin K1 has been demonstrated as having anticancer potentiality mainly in liver cancer cells. Beyond the reported mechanisms of cancer inhibition (cell cycle arrest and induction of apoptosis), a possible control by vitamin K1 on molecules affecting cell growth could be hypothesized. In the literature, few (if any) data are available on its antitumor effects on colon cancer cells. Therefore, the aims of the study were to investigate in three differently graded human colon cancer cell lines (Caco-2, HT-29, and SW480) the effects of increasing concentrations of vitamin K1 (from 10 μM to 200 μM) administered up to 72 h on (1) cell proliferation, (2) apoptosis with the possible involvement of the MAPK pathway, and (3) polyamine biosynthesis. Vitamin K1 treatment caused a significant antiproliferative effect and induced apoptosis in all the cell lines, with the involvement of the MAPK pathway. A concomitant and significant decrease in the polyamine biosynthesis occurred. This is the first study demonstrating a significant polyamine decrease in addition to the antiproliferative and proapoptotic effects following vitamin K1 administration to colon cancer cell lines. Therapeutically, combinations of vitamin K1 with polyamine inhibitors and/or analogues may represent a suitable option for chemoprevention and/or treatment in future strategies for colorectal cancer management.

Vitamin K1 alleviates streptozotocin-induced type 1 diabetes by mitigating free radical stress, as well as inhibiting NF-κB activation and iNOS expression in rat pancreas

ObjectiveThe aim of this study was to understand the mechanism of action of vitamin K1 against streptozotocin (STZ)-induced diabetes. MethodsMale Wistar rats were administered 35 mg/kg STZ and after 3 d were treated with vitamin K1 (5 mg/kg, twice a week) for 3 months. Blood glucose was monitored twice a month. At the end of the study, animals were sacrificed and pancreas dissected out and analyzed for free radicals, antioxidants, metabolic enzymes related to glucose, membrane ATPases, histopathological evaluation, and expression of nuclear factor (NF)-κB and inducible nitric oxide synthase (iNOS). Glycated hemoglobin, plasma insulin, and islet area were determined at the end of the study. ResultsTreatment of STZ-induced type 1 diabetic rats with vitamin K1 reduced oxidative stress, enhanced antioxidants, and inhibited aldose reductase in pancreas. Vitamin K1 administration rescued endocrine pancreas from STZ-induced cell death, resulting in enhanced insulin secretion and normal blood glucose and glycosylated hemoglobin levels. Histologic analyses also showed the antidiabetic potential of vitamin K1. Measure of pancreatic islet area showed an increase in the islet area upon vitamin K1 treatment when compared with the STZ-administered group, suggesting the possibility of regeneration. To understand the mechanism involved in vitamin K1 mediated changes, we performed immunohistochemical analyses for NF-κB and iNOS enzyme. Vitamin K1 was shown to suppress NF-κB activation and iNOS expression in the islets upon administration of STZ. ConclusionThis work shows, to our knowledge for the first time, the mechanism of action of vitamin K1 against type 1 diabetes and the possible therapeutic use of this vitamin in stimulating islet cell proliferation/regeneration.

Vitamin K1 attenuates bile duct ligation-induced liver fibrosis in rats

Vitamin K1 is used as a liver protection drug for cholestasis-induced liver fibrosis in China, but the mechanism of vitamin K1's action in liver fibrosis is unclear. In this study, a model of liver fibrosis was achieved via bile duct ligation in rats. The rats were then injected with vitamin K1, and the levels of serum aspartate aminotransferase, alanine transaminase, total bilirubin and the fibrotic grade score, collagen content, the expressions of α-smooth muscle actin (SMA) and cytokeratin 19 (CK19) were measured on day 28 after ligation. The levels of the biochemical parameters, fibrotic score and collagen content were significantly reduced by treatment with vitamin K1 in bile duct-ligated rats. In addition, α-SMA and CK19 expression was significantly reduced by vitamin K1 treatment in bile duct-ligated rats. These results suggested that vitamin K1 may attenuate liver fibrosis by inhibiting hepatic stellate cell activation in bile duct-ligated rats.

Vitamin K1 enhances sorafenib-induced growth inhibition and apoptosis of human malignant glioma cells by blocking the Raf/MEK/ERK pathway

BackgroundThe combined effects of anticancer drugs with nutritional factors against tumor cells have been reported previously. This study characterized the efficacy and possible mechanisms of the combination of sorafenib and vitamin K1 (VK1) on glioma cell lines.MethodsWe examined the effects of sorafenib, VK1 or their combination on the proliferation and apoptosis of human malignant glioma cell lines (BT325 and U251) by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, flow cytometry and 4′,6-diamidino-2-phenylindole (DAPI) assay. The signaling pathway changes were detected by western blotting.ResultsSorafenib, as a single agent, showed antitumor activity in a dose-dependent manner in glioma cells, but the effects were more pronounced when used in combination with VK1 treatment. Sorafenib in combination with VK1 treatment produced marked potentiation of growth inhibition and apoptosis, and reduced expression of phospho-mitogen-activated protein kinase kinase (MEK) and phospho-extracellular signal-regulated kinase (ERK). Furthermore, the expression levels of antiapoptotic proteins Bcl-2 and Mcl-1 were significantly reduced.ConclusionsOur findings indicated that VK1 enhanced the cytotoxicity effect of sorafenib through inhibiting the Raf/MEK/ERK signaling pathway in glioma cells, and suggested that sorafenib in combination with VK1 maybe a new therapeutic option for patients with gliomas.

Abstract 5407: Inhibitory Raf-1 phosphorylations at Ser-43 and Ser-259 are induced in vitamin K1 enhancement of Sorafenib-mediated HCC cell growth inhibition

Abstract Sorafenib, a multi-kinase inhibitor, is an FDA-approved agent for treatment of human hepatocellular carcinoma (HCC). However, tumor shrinkage is minor. K vitamins can activate protein kinase A (PKA), which in turn can mediate inhibitory Raf phosphorylation. We developed a new strategy to combine naturally occurring K vitamins with Sorafenib to treat HCC, and found that K vitamins were able to enhance the inhibition of HCC cell growth in vitro and in vivo by Sorafenib. To explore the mechanisms involved, we examined the role of Raf-1 kinase, because it has been reported that Sorafenib inhibits tumor cell growth as a direct inhibitor of Raf, whereas vitamin K2 can induce PKA activity, which is a Raf-1 upstream kinase. We found that while lower doses of vitamin K1 (10 μM) or Sorafenib (2.5 μM) alone slightly induced Raf-1 phosphorylation at both Ser-43 and Ser-259 in Hep3B cells, combination vitamin K1 plus Sorafenib treatment resulted in strong Raf-1 phosphorylation at these two Raf-inhibitory serine residues. Raf-1 protein kinase activity assay showed that lower concentrations of vitamin K1 or Sorafenib alone had little, if any effects on Raf-1 activity, combination vitamin K1 plus Sorafenib at the same low concentrations significantly inhibited Raf-1 activity, judged by strong inhibition of MEK, and of ERK phosphorylation, its down stream targets. Since Raf-1 phosphorylation at Ser-43 and Ser-259 can be regulated by either PKA or Akt kinase, we examined the effects of both vitamin K1 and Sorafenib on their phosphorylation. Although both vitamin K1 and Sorafenib alone induced PKA phosphorylation, no synergistic phosphorylation effects on PKA were found using the combination. However, vitamin K1 enhanced Sorafenib-induced Akt phosphorylation, which was associated with enhanced c-Met tyrosine phosphorylation at Tyr-1349, a known phospho-Akt regulator. Our data suggest that enhanced inhibitory Raf-1 phosphorylation at Ser-43 and Ser-259 may play a central role in vitamin K1 plus Sorafenib synergy in inhibiting HCC cell growth. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5407.

Lack of Drug‐Drug Interaction Between ATI‐5923, a Novel Vitamin K Epoxide Reductase Inhibitor, and Amiodarone, in Beagle Dog

ATI‐5923 is a novel oral anticoagulant and like warfarin, is a vitamin K epoxide reductase inhibitor. Unlike warfarin, which is metabolized by CYP2C9 and CYP3A4, ATI‐5923 is metabolized by carboxylesterases. These studies compared the efficacy of ATI‐5923 to that of warfarin, when administered either intravenously (IV) or once a day orally, to produce stable anticoagulation in beagle dogs. The drug‐drug interaction potential was assessed using co‐administration with amiodarone, an inhibitor of CYP3A4 and CYP2C9, with either ATI‐5923 or warfarin. Effects on coagulation were assessed by measuring Factor VII and X levels and prothrombin times (PT). Continuous IV infusions and oral administration of ATI‐5923 or warfarin caused a dose‐dependent decrease in plasma concentrations of Factor VII and Factor X, and an associated increase in PT. On a dose basis, ATI‐5923 was a more potent anticoagulant than warfarin. Intravenous fresh frozen canine plasma or subcutaneous vitamin K1 treatment reversed the anticoagulant effects of orally‐administered ATI‐5923 in beagle dogs. Co‐administration of amiodarone (40mg/kg for 2 days, 20mg/kg for 6 days) significantly increased the plasma levels and anticoagulation effect of warfarin (0.25mg/kg) in beagle dogs, as measured by an increase in PT and decrease in factor VII and X. In contrast, amiodarone had no effect on the anticoagulation parameters and plasma levels of ATI‐5923 (0.3mg/kg). We conclude that ATI‐5923, via a vitamin K‐dependent mechanism, causes changes in key parameters of hemostasis in beagle dogs that are consistent with effective anticoagulation without the important drug‐drug interaction commonly observed with amiodarone in warfarin‐treated patients.

Lack of Drug-Drug Interaction Between ATI-5923, a Novel Vitamin K Epoxide Reductase Inhibitor, and Amiodarone, in Beagle Dog

ATI-5923 is a novel oral anticoagulant that is being developed to prevent thromboembolic events associated with atrial fibrillation, prosthetic heart valves, and deep venous thrombosis. Like warfarin, it is a vitamin K epoxide reductase inhibitor. Unlike warfarin, which is metabolized by CYP2C9 and CYP3A4, ATI-5923 is metabolized by carboxylesterases. Our hypothesis is that ATI 5923 will lead to superior INR (international normalized ratio) control compared to warfarin as it will not be subject to pharmacokinetic interactions observed with many of the drugs that affect warfarin metabolism, leading to either excessive or suboptimal anticoagulation resulting in bleeding or thrombotic complications, respectively. These studies compared the efficacy of ATI-5923 to that of warfarin, when administered either intravenously (IV) or once a day orally, to produce stable anticoagulation in beagle dogs. The drug-drug interaction potential was assessed using co-administration with amiodarone, an inhibitor of CYP3A4 and CYP2C9, with either ATI-5923 or warfarin. Effects on coagulation were assessed by measuring Factor VII and X levels and prothrombin times (PT). Continuous IV infusions (5 to 9 days per dose) and oral administration of ATI 5923 and warfarin (5 to 10 days per dose) caused a dose-dependent decrease in plasma concentrations of Factor VII and Factor X, and an associated increase in PT. On a dose basis, ATI 5923 was a more potent anticoagulant than warfarin. Intravenous fresh frozen canine plasma or subcutaneous vitamin K1 treatment reversed the anticoagulant effects of orally-administered ATI-5923 in adult beagle dogs. Co-administration of amiodarone (40mg/kg for 2 days, 20mg/kg for 6 days) significantly increased the plasma levels and anticoagulation effect of warfarin (0.25mg/kg) in beagle dogs, as measured by increase PT and decrease in factor VII and X. In contrast, amiodarone had no effect on the anticoagulation parameters and plasma levels of ATI-5923 (0.3mg/kg). We conclude that ATI-5923, via a vitamin K-dependent mechanism, causes changes in key parameters of hemostasis in beagle dogs that are consistent with effective anticoagulation but without the important drug-drug interaction commonly observed with amiodarone in warfarin-treated patients.

Pharmacological prevention and regression of arterial remodeling in a rat model of isolated systolic hypertension.

Isolated systolic hypertension (ISH) is the predominant form of hypertension in the elderly population and drug treatment is unsatisfactory. We compared the efficacy of an endothelin-receptor antagonist (darusentan), an angiotensin-receptor blocker (irbesartan) and a thiazide diuretic (hydrochlorothiazide, HCTZ) to prevent and regress pulse pressure (PP) elevation and remodeling of large and small arteries, in a rat model of ISH obtained by the chronic administration of warfarin and vitamin K1 (WK). Warfarin and vitamin K1 treatment for 4 or 8 weeks led to an elevation of PP, associated with increases in aortic calcium deposition and the ratio of collagen to elastin (C/E). Despite these changes in the composition of the aortic wall, the global structure of the aorta was unchanged. In contrast, an outward hypertrophic remodeling was observed in the middle cerebral artery. An early treatment with all drugs (darusentan, irbesartan, HCTZ) prevented PP elevation, changes of aortic media composition and the development of vascular remodeling. However, after 4 weeks of ISH, only darusentan and irbesartan reduced PP when administered from week 4 to 8. Darusentan was the most effective to regress existent aortic calcification, while only irbesartan reversed small artery hypertrophic remodeling. During the development of ISH, drug treatment appears more beneficial when started early. Indeed, the three agents prevented PP elevation, aortic calcification and C/E increase in the aorta, and hypertrophy in small arteries. In contrast, once the disease is established, endothelin appears crucial in the maintenance of aortic calcification, while angiotensin II sustains small artery hypertrophy.

Influence of a single treatment with vitamin E or K (hormonal imprinting) of neonatal rats on the sexual behavior of adults.

The effect of a single neonatal treatment (imprinting) with vitamin E or vitamin K1 on the sexual activity of three-month old rats, was studied. In female animals vitamin E treatment significantly lowered the Meyerson index and lordosis quotient, among males there were significantly more inactive animals and no multiple ejaculations could be observed. Vitamin K1 treatment caused only slight changes in the same direction, in both sexes. Considering also earlier results concerning vitamin A and D neonatal treatments (alterations in receptor binding capacity, sex hormone levels and sexual behavior), and receptorial changes caused by neonatal vitamin E and K1 treatments, the present experiment also calls attention to the lifelong effects of perinatal treatment with lipid soluble vitamins.

Plasma superwarfarin levels and vitamin K1 treatment in dogs with anticoagulant rodenticide poisoning

Summary The plasma concentration, plasma half‐life (t1/2), and mean residence time (MRT) of rodenticide anticoagulants were determined in 21 dogs in which a preliminary diagnosis of anticoagulant rodenticide poisoning had been made. Brodifacoum, difethialone, and difenacoum were detected by high‐performance liquid chromatography (HPLC) in the plasma of 13, 3, and 2 dogs, respectively. At presentation the plasma concentration ranged from below the detection limit (10 ng/L) to 851 ng/L. Toxin could not be detected in 3 dogs, despite these animals showing characteristic coagulation disturbances and a positive response to therapy with vitamin K1. Two dogs died during emergency treatment. Treatment in the remaining 19 dogs consisted of the administration of vitamin K1 and supportive therapy. The dose of vitamin K1 was reduced in a stepwise manner as long as the prothrombin time remained within physiological limits. The variation in initial plasma concentrations of the anticoagulants combined with the results of treatment support the idea that an individual therapeutic approach is warranted.

Supplementation of vitamin K in pregnant women receiving anticonvulsant therapy prevents neonatal vitamin K deficiency

The null hypothesis of this study is that extra vitamin K administered to pregnant women on a regimen of enzyme-inducing anticonvulsant therapy will not decrease the frequency of symptoms of vitamin K deficiency in their neonates. A multicenter case-control study was performed on 16 pregnant women on anticonvulsant therapy who received 10 mg of vitamin K1 daily from 36 weeks of pregnancy onward. Concentrations of PIVKA-II (protein induced by vitamin K absence for factor II) and of vitamin K1 were determined in cord blood and compared with those in 20 controls. In none of 17 cord samples was PIVKA-II detectable, compared with 13 of 20 in controls (chi 2, p < 0.001). Median cord vitamin K1 level was 530 pg/ml compared with below detection limit in most controls. Antenatal vitamin K1 treatment decreases the frequency of vitamin K deficiency in neonates of mothers on anticonvulsant therapy.

The Effects of Vitamin K1 and Warfarin on Prothrombin Expression in Human Hepatoblastoma (HepG2) Cells

Cultures of human hepatoblastoma (HepG2) cells were treated with vitamin K1 or warfarin and prothrombin antigen and mRNA levels were determined. With 3 and 6 h of 10 micrograms vitamin K1 treatment secreted prothrombin antigen levels, relative to total secreted protein levels, were increased 1.5-fold and 2.1-fold, respectively, over ethanol-treated control levels as determined by an enzyme-linked immunosorbent assay. Dose-response analysis with 3 h of 25 micrograms/ml vitamin K1 treatment demonstrated a maximal increase of 2.0-fold in secreted prothrombin antigen levels, relative to total secreted protein levels, over ethanol-treated control levels. Pulse-chase analysis with 35S-methionine and immunoprecipitation of 35S-labelled prothrombin demonstrated that, with vitamin K1 treatment (25 micrograms/ml, 3 h), the rate of prothrombin secretion increased approximately 2-fold and the total amount (intra- and extracellular) of prothrombin synthesized increased approximately 50% over ethanol-treated control levels. Warfarin treatment (1, 5, or 10 micrograms/ml, 24 h) resulted in decreases in secreted prothrombin antigen levels, relative to total protein levels to approximately 85%, 87% or 81% of ethanol-treated control levels. Analysis of total RNA isolated from these cultures by Northern and solution hybridization techniques demonstrated that prothrombin mRNA was approximately 2.1 kb and that neither vitamin K1 nor warfarin treatment affected the quantity of prothrombin mRNA (ranging from 240-350 prothrombin mRNA molecules per cell). These results demonstrate that vitamin K1 and warfarin, in addition to effects on gamma-carboxylation, affect prothrombin synthesis post-transcriptionally, perhaps influencing translation, post-translational processing and/or secretion mechanisms.

Coagulopathic Effects and Therapy of Brodifacoum Toxicosis in Dogs

The clinical signs and laboratory changes of brodifacoum (BDF) intoxicated dogs and their response to vitamin K1 treatment were examined. Brodifacoum, a second-generation anticoagulant rodenticide, was fed to four dogs for 3 consecutive days producing a cumulative dose of 1.1 mg BDF/kg body weight. Clinical observations of the animals were made daily throughout the study. Monitored laboratory parameters included: one-stage prothrombin time (OSPT), activated partial thromboplastin time (APTT), activated coagulation time (ACT), complete blood counts, thrombocyte counts, and serum chemistry values. Response to vitamin K1 therapy was evaluated clinically and by laboratory tests. Serum BDF concentrations were monitored. Inappetence and hemorrhagic tendencies were exhibited by day 5 postrodenticide exposure. One-stage prothrombin time, APTT, and ACT were 25% greater than time zero values at 24, 24, and 72 hours postdosing, respectively. All laboratory parameters returned to normal within 48 hours of initiating vitamin K1 therapy (0.83 mg/kg orally, TID for 5 days). Serum brodifacoum concentrations were highest (1065-1215 ng/mL) during the 3 days after BDF dosing and were detectable (3.0-7.5 ng/mL) until day 24 postexposure. A mean BDF elimination half-life of 6 +/- 4 days was observed.