vitamin-k-semiquinone-radical and Body-Weight

Obesity is an epidemic with rising prevalence, and obese patients are predisposed to comorbid conditions that increase risk for thromboembolic events. It is critical to identify safe and effective anticoagulation therapy for use in this population. Direct oral anticoagulants (DOACs) are a preferred option for anticoagulation in patients of normal weight due to many benefits and equivalent safety and efficacy to their vitamin K antagonist counterparts. However, the safety and efficacy of DOACs in obese patients is not well understood. This review describes recent studies on the pharmacokinetics, safety and efficacy, and clinical outcomes of the DOACs apixaban, rivaroxaban, edoxaban and dabigatran in obese patient populations. DOACs may be a beneficial alternative to vitamin K antagonist therapy in obese patient populations.. The incidence of obesity within the USA is on the rise, as is that of the medical conditions that often accompany it. These include conditions that can predispose individuals to forming clots in the blood, such as atrial fibrillation, which is a form of an abnormal heartbeat, and nonalcoholic fatty liver disease, which is caused by fat buildup around the liver. Therefore, it is important that we have effective medicines that can prevent clotting in an obese patient population. Direct oral anticoagulants are a new, preferred medication option for this, but it is unclear how safe or effective they are in obese people; there is some concern that because of increased body weight, individuals may not get enough medicine to effectively prevent clots from forming, which would ultimately put them at risk for clotting and serious adverse health outcomes such as stroke. This review describes recent studies on the use of the direct oral anticoagulants apixaban, rivaroxaban, edoxaban and dabigatran in obese patients, and whether they are a safe and effective form of anticoagulation in this population.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Body Mass Index; Body Weight; Dabigatran; Hemorrhage; Humans; Obesity; Pyridones; Rivaroxaban; Stroke; Vitamin K

The non-vitamin K antagonist oral anticoagulants (NOACs) exert their anticoagulant effect closely related to their plasma concentrations. Since their distribution volume is related to body weight (and its correlates, i.e., surface area and body mass index, BMI), extremes in body weight may affect their efficacy or safety. Four NOACs are currently available for long-term use, with few exceptions, in atrial fibrillation and venous thromboembolism: the direct thrombin inhibitor dabigatran etexilate, and the factor (F) Xa inhibitors rivaroxaban, apixaban, and edoxaban. Experience in patients with low (<50 kg) or extremely high (>150 kg) body weight is still quite limited, as such patients were rare in registration trials and sometimes directly excluded. In general, increased bleeding and higher mortality rates are observed in patients weighing <50 kg compared with patients weighing 50-100 kg. This may however also be explained by the presence of underlying conditions such as cancer. At the opposite end of the spectrum of body weight, lower antithrombotic efficacy may occur, perhaps due to the dilutional effect of a higher distribution volume. In this article, we review the pertinent literature and analyze the effects of low or high body weight on anticoagulant activity and clinical outcomes of the NOACs, their dose recommendations, and areas of uncertainty.

Topics: Administration, Oral; Anticoagulants; Body Weight; Dose-Response Relationship, Drug; Humans; Venous Thromboembolism; Vitamin K

Atrial fibrillation (AF) is associated with an increased risk of ischemic stroke or systemic embolism compared with normal sinus rhythm. These strokes may efficiently be prevented in patients with risk factors using oral anticoagulant therapy, with either vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs) (i.e., direct thrombin inhibitors or direct factor Xa inhibitors). Owing to their specific risk profiles, some AF populations may have increased risks of both thromboembolic and bleeding events. These AF patients may be denied oral anticoagulants, whilst evidence shows that the absolute benefits of oral anticoagulants are greatest in patients at highest risk. NOACs are an alternative to VKAs to prevent stroke in patients with "non-valvular AF", and NOACs may offer a greater net clinical benefit compared with VKAs, particularly in these high-risk patients. Physicians have to learn how to use these drugs optimally in specific settings. We review concrete clinical scenarios for which practical answers are currently proposed for use of NOACs based on available evidence for patients with kidney disease, elderly patients, women, patients with diabetes, patients with low or high body weight, and those with valve disease.

Topics: Administration, Oral; Aging; Anticoagulants; Antithrombins; Atrial Fibrillation; Body Weight; Diabetes Mellitus; Factor Xa Inhibitors; Heart Valve Diseases; Hemorrhage; Humans; Kidney Diseases; Risk Factors; Stroke; Vitamin K

Since direct oral anticoagulants (DOAC) have become available, use of anticoagulant treatment has become easier and safer-for patients suffering from thromboembolic diseases as well as for patients with atrial fibrillation: Because of constant bioavailability, fixed dose regimen treatment is possible, monitoring not necessary and severe bleeding complications-particularly intracranial hemorrhages-rare in comparison to vitamin K anticoagulants. To gain all these advantages, it is essential to give DOAC in the correct dosage. Dose reduction of single DOAC has to be considered depending on underlying disease, body weight and renal function. DOAC are not allowed in patients with artificial heart valves, in pregnancy and in children. In case of severe bleeding complications under DOAC treatment, prothrombin complex concentrates is one treatment option. For dabigatran an antidote is available.

Topics: Administration, Oral; Anticoagulants; Antidotes; Atrial Fibrillation; Biological Availability; Body Weight; Dabigatran; Humans; Thromboembolism; Vitamin K

The choice for oral anticoagulant (OAC) therapy was previously limited to the vitamin K antagonists (VKAs). The advent of the direct oral anticoagulants (DOACs) brought with it the expectation that oral anticoagulation would become simpler (with the elimination of routine monitoring and introduction of a fixed-dose anticoagulant), and that the use of VKAs would be slowly phased out. Although DOACs have made anticoagulation more convenient and accessible, we are now faced with what can be described as a tyranny of choice, together with many unanswered questions relating to DOAC use. These include optimal DOAC selection and dosing, use in complex 'real-world' patients, the role for monitoring and issues surrounding adherence. Warfarin remains the anticoagulant of choice in certain scenarios (e.g. metallic heart valves). The future holds much excitement: clinical studies are underway to expand the indications for DOACs and experience continues to grow outside the trials setting.

Topics: Administration, Oral; Anticoagulants; Body Weight; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Gastrointestinal Hemorrhage; Humans; Medication Adherence; Venous Thromboembolism; Vitamin K; Warfarin; Women's Health

Management of patients with a major bleed while on vitamin K antagonist (VKA) is a common clinical challenge. Prothrombin Complex Concentrates (PCC) provide a rapid reversal of VKA induced coagulopathy. However, a well-defined PCC dosing strategy, especially in emergency setting, is still lacking. We performed a systematic review to describe the currently used PCC dosing strategies and to present their efficacy in terms of target INR achievement and clinical outcome. We used outcome definitions as used in the individual studies. MEDLINE and EMBASE databases were searched for studies reporting the use of PCC for emergency VKA reversal. Twenty-eight studies, including 4 randomized trials, were found. In these, fifteen different PCC dosing protocols were identified in which the PCC dose ranged from 8 to 50IU factor IX/kg. These strategies were based on: bodyweight; bodyweight and initial INR; bodyweight and initial INR and target INR; individual doctors decision; or a fixed dose. Study quality was moderate with large variation in outcome definitions. Relatively good clinical and INR outcomes were reported with the use of any treatment protocol while less good results were reported for INR outcome when a predefined protocol was missing (doctor strategy). Lowest PCC dosages were infused in the fixed dose strategy. In emergency VKA reversal, a predefined PCC dosing protocol seems essential. We found no evidence that one dosing strategy is superior. Future studies should be designed to investigate if body weight and INR are relevant for PCC dosing. In these, we need uniform outcome definitions.

Topics: Blood Coagulation Factors; Body Weight; Drug Administration Schedule; Humans; International Normalized Ratio; Prothrombin; Randomized Controlled Trials as Topic; Treatment Outcome; Vitamin K

To evaluate the effect of body weight (BW) on safety and efficacy of direct oral anticoagulants (DOACs).. We performed a meta-analysis of randomized controlled trials (RCTs) comparing DOACs with vitamin K antagonists (VKA) in patients with venous thromboembolism (VTE). Efficacy (prevention of recurrent VTE or VTE-related death) and safety (occurrence of major or clinically relevant non-major bleeding) outcomes were stratified according to patients' BW (low, normal, and high).. Six RCTs with a total of 27,023 patients were included. DOACs showed a similar efficacy to VKA in patients with high BW, normal BW, and low BW (RR 0.98, 95% CI 0.72, 1.35; RR 0.91, 95% CI 0.75, 1.09; and RR 0.84, 95% CI 0.57, 1.24, respectively). Safety was comparable among DOACs and VKA in patients with high BW and low BW (RR 0.93, 95% CI 0.65, 1.32; and RR 0.80, 95% CI 0.54, 1.20), whereas DOACs were marginally safer than VKA in normal-BW subjects (RR 0.82, 95% CI 0.67, 1.00). However, the difference among DOACs and VKA in the rate of bleeding episodes appeared similar in the three BW groups.. Results of our meta-analysis suggested that DOACs might be a safe and effective therapeutic option for the treatment of acute VTE even in the patients with extreme body weights. However, other studies with larger study populations are warranted to confirm our findings.

Topics: 4-Hydroxycoumarins; Acute Disease; Administration, Oral; Anticoagulants; Body Weight; Female; Humans; Indenes; Male; Middle Aged; Randomized Controlled Trials as Topic; Treatment Outcome; Venous Thromboembolism; Vitamin K

Numerous factors are well documented to affect the response to vitamin K antagonists (VKA), including dietary vitamin K, other drugs, age, pharmacogenetics, and disease states. Body weight is perhaps not as well known as a variable affecting VKA dose. Our aim was to review the literature regarding body weight and VKA dose requirements.. We reviewed the English-language literature via PubMed and Scopus using the search terms VKA, warfarin, acenocoumarol, phenprocoumon, fluindione, AND body weight.. Among 32 studies conducted since the widespread use of the international normalized ratio, 29 found a correlation with body weight or body surface area and VKA dose requirement. Warfarin was evaluated in 27 studies and acenocoumarol, phenprocoumon, or fluindione were assessed in 5 investigations.. Because of varying study methodologies, further study is warranted. Based on current evidence, clinicians should include body weight, along with other established variables when dosing VKA. Most important, obese and morbidly obese patients may require a 30% to 50% increase with the initial dosing of VKA.

Topics: Acenocoumarol; Anticoagulants; Body Weight; Comorbidity; Drug Dosage Calculations; Humans; Obesity; Obesity, Morbid; Phenindione; Phenprocoumon; Vitamin K; Warfarin

Lifestyle factors play a role in both the genesis and recovery from fragility fracture. The purpose of this review is to summarize recent evidence for exercise and nutrition in the management of hip fracture.. Recent randomized controlled trials of exercise have primarily consisted of isolated resistance training or multimodal home-based programs. More robust, long-term, or supervised training is generally associated with greater clinical benefits, including muscle strength, mobility, and function. Recent nutritional interventions have included multinutrient supplements, nutritional counseling and support, and vitamin D/calcium supplementation. Isolated nutritional interventions have not consistently shown significant impact on long-term outcomes after hip fracture, although improvements in body weight, biochemical indices, complication rates, and mobility have been reported. Overall, there is marked heterogeneity in the robustness of responses seen to hip fracture treatment studies. Few large, long-term, multicomponent interventions with clinically relevant outcomes of functional independence, need for residential care, mortality, and quality of life have been reported.. Evidence-based approaches to hip fracture should include comprehensive risk-factor assessment and treatment for sarcopenia/dynapenia, balance impairment, undernutrition of protein, energy, vitamin D and calcium, depression, cognitive impairment, sensory impairment, social isolation, and comorbid illness with exercise, nutrition and other modalities.

Topics: Body Weight; Bone and Bones; Calcium, Dietary; Dietary Proteins; Dietary Supplements; Evidence-Based Medicine; Exercise; Hip Fractures; Humans; Life Style; Malnutrition; Neuropsychology; Nutritional Status; Randomized Controlled Trials as Topic; Risk Factors; Sarcopenia; Vitamin D; Vitamin K

Cystic fibrosis children tend to have a low birth weight and their mean height and weight during childhood is below that for the general population. They also tend to have a delayed bone age and puberty. The degree of underweight correlates more closely with the respiratory condition than with the degree of malabsorption. There is evidence that their nutritional requirements are increased, perhaps up to 150% of the recommended daily allowance, but in later childhood their food intake is frequently low and maybe the major reasons for their poor growth and development. Specific deficiencies of vitamins, minerals and essential fatty acids occasionally present as clinical problems. New approaches to nutrition include increasing dietary fat, which was traditionally low because of malabsorption, and this change has been made possible with the development of modern pancreatic supplements. Supplementary nutrition with elemental diets or intravenous hyperalimentation have given promising results in some studies and might be expected to improve the patient's resistance to infection as well as his nutritional state. The place of oral essential fatty acid supplements is still being evaluated, but intravenous infusions of fat emulsion are not justifiable in themselves.

Topics: Age Determination by Skeleton; Body Height; Body Weight; Child; Cystic Fibrosis; Energy Intake; Fatty Acids, Essential; Humans; Infant, Low Birth Weight; Infant, Newborn; Iron; Nutritional Physiological Phenomena; Puberty, Delayed; Vitamin A; Vitamin D; Vitamin E; Vitamin K; Zinc

Topics: Adolescent; Adult; Age Factors; Ascorbic Acid; Body Weight; Child; Child Nutritional Physiological Phenomena; Child, Preschool; Female; Growth; Humans; Infant; Infant Nutritional Physiological Phenomena; Infant, Newborn; Male; Nutritional Requirements; Physical Exertion; Pregnancy; Sex Factors; Vitamin A; Vitamin B Complex; Vitamin D; Vitamin E; Vitamin K; Vitamins

Topics: Ascorbic Acid; Birth Weight; Body Height; Body Weight; Calcium, Dietary; Diet; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Eclampsia; Energy Transfer; Female; Germany, West; Humans; Lactation; Maternal Mortality; Nutritional Physiological Phenomena; Obesity; Obstetric Labor, Premature; Pre-Eclampsia; Pregnancy; Prenatal Care; Vitamin A; Vitamin B Complex; Vitamin D; Vitamin E; Vitamin K

Topics: Adult; Age Factors; Animals; Blood Coagulation Factors; Body Weight; Chickens; Depression, Chemical; Female; Humans; Male; Metabolism; Middle Aged; Prothrombin; Prothrombin Time; Sex Factors; Stimulation, Chemical; Time Factors; Vitamin K; Vitamin K 1; Warfarin

To determine if a fixed dose of 1000 IU of 4-factor prothrombin complex concentrate (4F-PCC) is as effective as traditional variable dosing based on body weight and international normalized ratio (INR) for reversal of vitamin K antagonist (VKA) anticoagulation.. In this open-label, multicenter, randomized clinical trial, patients with nonintracranial bleeds requiring VKA reversal with 4F-PCC were allocated to either a 1,000-IU fixed dose of 4F-PCC or the variable dose. The primary outcome was the proportion of patients with effective hemostasis according to the International Society of Thrombosis and Haemostasis definition. The design was noninferiority with a lower 95% confidence interval of no more than -6%. When estimating sample size, we assumed that fixed dosing would be 4% superior.. From October 2015 until January 2020, 199 of 310 intended patients were included before study termination due to decreasing enrollment rates. Of the 199 patients, 159 were allowed in the per-protocol analysis. Effective hemostasis was achieved in 87.3% (n=69 of 79) in fixed compared to 89.9% (n=71 of 79) in the variable dosing cohort (risk difference 2.5%, 95% confidence interval -13.3 to 7.9%, P=.27). Median door-to-needle times were 109 minutes (range 16 to 796) in fixed and 142 (17 to 1076) for the variable dose (P=.027). INR less than 2.0 at 60 minutes after 4F-PCC infusion was reached in 91.2% versus 91.7% (P=1.0).. The large majority of patients had good clinical outcome after 4F-PCC use; however, noninferiority of the fixed dose could not be demonstrated because the design assumed the fixed dose would be 4% superior. Door-to-needle time was shortened with the fixed dose, and INR reduction was similar in both dosing regimens.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Factors; Body Weight; Drug Administration Schedule; Equivalence Trials as Topic; Female; Hemorrhage; Hemostatics; Humans; International Normalized Ratio; Male; Middle Aged; Vitamin K

The pharmacokinetics of oral rivaroxaban are highly predictable and only affected to a limited extent by bodyweight; therefore, dose adjustments for bodyweight are not required. However, this raises concerns among physicians for potential under- or overdosing. This substudy of the randomised EINSTEIN DVT and EINSTEIN PE trials, which compared rivaroxaban with enoxaparin/vitamin K antagonist (VKA) therapy, aimed to determine the incidence of major bleeding in patients with a low bodyweight and recurrent venous thromboembolism (VTE) in patients with a high bodyweight during rivaroxaban or enoxaparin/VKA therapy. More than 8,000 patients with objectively diagnosed deep-vein thrombosis or pulmonary embolism were included. Adjusted hazard ratios for recurrent VTE and bleeding were calculated using the Cox proportional hazards model. Analyses were performed for both the first 21 days of treatment and the whole treatment period. For rivaroxaban recipients, there was no association between bodyweight or body mass index (BMI) and risk of recurrent VTE (ptrend=0.87 and 0.62, respectively), major bleeding (ptrend=0.24 and 0.36, respectively) or clinically relevant bleeding (ptrend=0.17 and 0.63, respectively). Major bleeding events were numerically lower in rivaroxaban patients across all bodyweight and BMI categories. Hazard ratios for rivaroxaban vs enoxaparin/VKA were similar in all bodyweight and BMI categories, both during the first 21 days and the whole treatment period. The fixed-dose rivaroxaban regimen is not associated with an increased risk of major bleeding or recurrent VTE in patients with either a low or high bodyweight. A high BMI was not associated with an increased risk of recurrent VTE during anticoagulation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Body Weight; Enoxaparin; Female; Humans; Male; Middle Aged; Recurrence; Rivaroxaban; Venous Thromboembolism; Vitamin K; Young Adult

Serum level of under-carboxylated osteocalcin (ucOC) is considered a sensitive measure of vitamin K status, and ucOC levels are associated with bone mineral density (BMD) and fracture risk in elderly persons. The aim of this study was to assess the relationship between ucOC and BMD in early menopausal women.. The data reported here come from the enrollment in a double-blinded placebo-controlled randomized trial comprising 334 healthy Norwegian women between 50 and 60 years, 1-5 years after menopause, not using warfarin or medication known to affect bone metabolism. Total hip, femoral neck, lumbar spine, and total body BMD and serum level of ucOC and total osteocalcin were measured, and information of lifestyle was collected through questionnaires. The association between ucOC and BMD at all measurement sites was assessed by multiple regression analyses adjusting for possible confounding variables.. The absolute serum level of ucOC was significantly and negatively associated with BMD at all measurements sites, both in univariate analyses (p < 0.01) and in multivariate analyses adjusting for years since menopause, smoking status and weight (p < 0.01). However, serum ucOC, expressed as percentage of the total osteocalcin level, was not associated with BMD at any site.. Achievement of adequate vitamin K nutritional intake is important, but ucOC expressed as percentage of total osteocalcin levels as reflection of vitamin K status does not seem to play a central role in determining BMD levels in early menopausal women.

Topics: Body Height; Body Mass Index; Body Weight; Bone Density; Double-Blind Method; Female; Femur Neck; Humans; Lumbar Vertebrae; Menopause; Middle Aged; Norway; Osteocalcin; Regression Analysis; Surveys and Questionnaires; Vitamin K

Osteocalcin (OC) is a vitamin K-dependent protein found in bone and in circulation. High serum γ-carboxylated OC reflects a high, and high uncarboxylated OC (ucOC) reflects a low vitamin K status. A revolutionary hypothesis is that ucOC acts as a hormone improving glucose handling and reducing fat mass. The objective was to test the logical extrapolation of the ucOC hormone hypothesis to humans that elevated ucOC is associated with higher body weight, BMI and fat mass. In a cross-sectional analysis, the associations of vitamin K status with circulating adiponectin and body composition were investigated in 244 postmenopausal women (study I). The effects of vitamin K treatment on adiponectin, body weight and BMI were investigated in archived samples from forty-two young men and women who received varying doses of menaquinone-7 during 12 weeks (study II) and from a cohort of 164 postmenopausal women who participated in a 3-year placebo-controlled trial on 45 mg menaquinone-4 (MK-4) (study III). No association was found between vitamin K status and circulating adiponectin before or after vitamin K supplementation. A higher carboxylation of OC was significantly correlated with lower body weight, BMI and fat mass of the trunk. Women taking MK-4 maintained their baseline body weight and BMI, whereas women taking placebo showed significant increases in both indices. These findings demonstrate that a high vitamin K status of bone has no effect on circulating adiponectin in healthy people and long-term vitamin K supplementation does not increase weight in healthy postmenopausal women.

Topics: Adiponectin; Adiposity; Adult; Aged; Body Composition; Body Weight; Cohort Studies; Cross-Sectional Studies; Dietary Supplements; Double-Blind Method; Female; Humans; Male; Middle Aged; Osteocalcin; Postmenopause; Premenopause; Retrospective Studies; Severity of Illness Index; Vitamin K; Vitamin K Deficiency; Young Adult

Despite years of experience with vitamin K antagonist-associated bleeding events, there is still no evidence to help identify the optimal treatment with prothrombin complex concentrates. Variable dosing and fixed dose strategies are being used. In this observational prospective two-cohort study, we aimed to assess the non-inferiority of a low fixed PCC dose (1,040 IU Factor IX) compared to the registered variable dosing regimen based on baseline International Normalized Rate, bodyweight, and target International Normalized Rate, to counteract vitamin K antagonists in a bleeding emergency in a daily clinical practice setting.. Non-inferiority of the fixed prothrombin complex concentrate dose was hypothesized with a margin of 4%. Main end points were proportion of patients reaching the target International Normalized Rate (< 2.0) after prothrombin complex concentrate treatment, and successful clinical outcome.. Target International Normalized Rate was reached in 92% of the fixed dose patients (n=101) versus 95% of variable dose patients (n=139) resulting in a risk difference of -2.99% (90% CI: - 8.6 to 2.7) (non-inferiority not confirmed). Clinical outcome was successful in 96% and 88% of fixed versus variable dose, respectively, with a risk difference of 8.3% (90% CI: 2.7-13.9; non-inferiority confirmed).. Although a lower fixed prothrombin complex concentrate dose was associated with successful clinical outcome, fewer patients reached the target International Normalized Rate.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Factors; Body Weight; Emergencies; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Prospective Studies; Time Factors; Treatment Outcome; Vitamin K

CYP2C9 and VKORC1 genotypes could be used to predict warfarin requirement. The objective was to develop and validate a warfarin dosing algorithm using genetic, clinical and demographic data of Chinese patients from an anticoagulation clinic in Hong Kong. Blood samples were collected from 100 patients on stable maintenance dose of warfarin, recruited from an anticoagulation clinic, for genotyping CYP2C9 and VKORC1. Clinical and demographic data were obtained by face-to-face interview and medical chart review. Data of 80 patients (study cohort) were randomly selected for deriving a dosing algorithm. Comparison between predicted dose and actual stable doses was conducted in a validation cohort (n = 20). Sixty-nine (69%) of all 100 patients were homozygous for VKORC1 1173-TT, 25 (25%) were VKORC1 1173-CT heterozygotes and six (6%) were homozygous for VKORC1 1173-CC. 6 (6%) patients were CYP2C9 1*/3* and 94 (94%) were CYP2C9 1*/1*. CYP2C9 and VKORC1 genotype, age, weight and vitamin K intake were identified by stepwise regression modelling to produce the best model for estimating warfarin dose (R (2) = 68%, P < 0.001). In the validation cohort (n = 20), actual stable dose was significantly associated with predicted dose (R = 0.6, P = 0.005). Five of 11 (45.6%) and 5/9 (55.6%) patients whose mean warfarin requirements were ≤ 3 mg/day and >3 mg/day, respectively, were within <20% of actual doses. In conclusion, a genotype-guided dosing algorithm for warfarin therapy was developed for Chinese patients to explain 68% of dosage variation. The predicted doses differed from the actual doses by no more than 20% in 50% of patients.

Topics: Age Factors; Aged; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Asian People; Body Weight; Cross-Sectional Studies; Cytochrome P-450 CYP2C9; Female; Follow-Up Studies; Genotype; Hong Kong; Humans; Male; Middle Aged; Mixed Function Oxygenases; Vitamin K; Vitamin K Epoxide Reductases; Vitamins; Warfarin

To corroborate results obtained in The Netherlands with PPSB-SD, showing a safe acute reversal of anticoagulation within 15 minutes of administration.. PPSB-SD is a concentrate prothrombin complex containing a relatively constant high level of vitamin K-dependant coagulation factors II, VII, IX and X. PPSB-SD was administered to 14 patients treated with oral anticoagulants, according the patient's weight, the initial and the target INR (< 2.0 for moderate haemorrhage and abdominal surgery, or < 1.5 for severe haemorrhage and cardio-vascular interventions). INR values were measured with the Coagucheck Pro (Roche Diagnostics) upon admission and at 15 minutes, 1, 3 and 5 hours after treatment, and confirmed by the hospitals' laboratory.. Within 15 minutes 11 patients out of 12 reached their INR target (data were missing for 2 patients). INR decreased rapidly, then remained stable for the next 5 hours. All patients had a favourable outcome: bleeding was stopped and no haemorrhage occurred during surgery. Only one adverse event was reported, but it was not related to the PPSB-SD treatment. No sign of disseminated intravascular coagulation was observed during this study. The administration of PPSB-SD along with vitamin K and dosed according to body weight and initial and target INR allowed for optimal reversal of anticoagulation, as no second infusion was necessary. The recommended dosing worked also very well for patients with high initial INR (9.2 to 22.8) who were brought down to normal values (0.9 to 1.1) within 15 minutes.. PPSB-SD can safely be used for the rapid reversal of anticoagulation as needed in emergency situations.

Topics: Abdomen; Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Factors; Blood Loss, Surgical; Body Weight; Coagulants; Emergencies; Female; Follow-Up Studies; Gastrointestinal Hemorrhage; Hip Fractures; Humans; International Normalized Ratio; Male; Middle Aged; Time Factors; Treatment Outcome; Vitamin K

The current standard initial therapies for deep venous thrombosis are low-molecular-weight heparin and unfractionated heparin. In a dose-ranging study of patients with symptomatic deep venous thrombosis, fondaparinux had efficacy and a safety profile similar to those of low-molecular-weight heparin (dalteparin).. To evaluate whether fondaparinux has efficacy and safety similar to those of enoxaparin in patients with deep venous thrombosis.. Randomized, double-blind study.. 154 centers worldwide.. 2205 patients with acute symptomatic deep venous thrombosis.. Fondaparinux, 7.5 mg (5.0 mg in patients weighing <50 kg and 10.0 mg in patients weighing >100 kg) subcutaneously once daily, or enoxaparin, 1 mg/kg of body weight, subcutaneously twice daily for at least 5 days and until vitamin K antagonists induced an international normalized ratio greater than 2.0.. The primary efficacy outcome was the 3-month incidence of symptomatic recurrent venous thromboembolic complications. The main safety outcomes were major bleeding during initial treatment and death. An independent, blinded committee adjudicated all outcomes.. 43 (3.9%) of 1098 patients randomly assigned to fondaparinux had recurrent thromboembolic events compared with 45 (4.1%) of 1107 patients randomly assigned to enoxaparin (absolute difference, -0.15 percentage point [95% CI, -1.8 to 1.5 percentage points]). Major bleeding occurred in 1.1% of patients receiving fondaparinux and 1.2% of patients receiving enoxaparin. Mortality rates were 3.8% and 3.0%, respectively.. Follow-up was incomplete in 0.4% of fondaparinux-treated patients and 1.0% of enoxaparin-treated patients.. Once-daily subcutaneous fondaparinux was at least as effective (not inferior) and safe as twice-daily, body weight-adjusted enoxaparin in the initial treatment of patients with symptomatic deep venous thrombosis.

Topics: Aged; Body Weight; Cause of Death; Double-Blind Method; Drug Administration Schedule; Enoxaparin; Female; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Kidney; Male; Middle Aged; Polysaccharides; Recurrence; Treatment Outcome; Venous Thrombosis; Vitamin K

Body weight-adjusted subcutaneous low-molecular-weight heparin (LMWH) has been proven to be at least as effective and safe as dose-adjusted intravenous unfractionated heparin (UFH) for the treatment of patients with venous thromboembolism. However, body weight-adjusted dosage of low-molecular-weight heparin may be cumbersome and could lead possibly to incorrect dosing. Therefore a fixed LMWH dose, independent of body-weight, might rationalize initial treatment for venous thromboembolism.. Patients with proven proximal deep-vein thrombosis were randomly assigned to fixed dose subcutaneous LMWH Certoparin (8,000 anti-factor Xa U b.i.d.; 265 patients) or to adjusted dose i.v. UFH (273 patients) for 12 days. Vitamin K antagonists were started between day 3 and 7 and continued for up to 6 months. The primary outcome measure was a 30 percent or greater improvement in the Marder Score, as revealed by repeated venography on day 12 (end of the initial treatment). The secondary composite outcome measure included death, recurrent venous thromboembolism and major bleeding and was assessed at day 12 and after 6 months by a blinded adjunction committee.. The Marder score improved by 30% or more in 30.3% and 25.0% of patients assigned to LMWH (198 paired venograms) and UFH (192 paired venograms), respectively (2p = 0.26). At the end of the initial treatment, the composite outcome was observed in 4 of the 265 patients (1.5%) randomized to LMWH, as compared with 14 of the 273 patients (5.1%) randomized to UFH (2p = 0.03). At 6 months these figures were 6.8% and 12.8%, respectively (risk reduction 0.53, confidence interval 0.31-0.90, 2p = 0.02).. Fixed dose subcutaneous LMWH certoparin is at least as efficacious as UFH in resolving proximal vein thrombosis.

Topics: Acute Disease; Adult; Aged; Anticoagulants; Body Weight; Cohort Studies; Female; Hemorrhage; Heparin; Heparin, Low-Molecular-Weight; Humans; Injections, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Phlebography; Popliteal Vein; Postoperative Complications; Recurrence; Treatment Outcome; Venous Thrombosis; Vitamin K

A synergistic interplay between vitamins K and D appears to exist. We aimed to investigate for the first time whether the associations of dietary vitamin K intake and circulating 25(OH)D with serum lipoprotein levels are influenced by the existence of deficiency of either or both vitamins K and D. Sixty individuals [24 males, 36(18-79) years old] were examined. Vitamin deficiency of K1 and D were defined as vitamin K1 intake/body weight (BW)<1.00 μg/kg/day and circulating 25(OH)D<20 ng/ml, respectively. In individuals with vitamin K1 deficiency, the vitamin K1 intake/BW correlated positively with high density lipoprotein-cholesterol (HDL-C) (r=0.509, p=0.008) and negatively with serum triglycerides (TG) (r=-0.638, p=0.001), whereas circulating 25(OH)D correlated negatively with TG (r=-0.609, p=0.001). In individuals with vitamin D deficiency, the vitamin K1 intake/BW correlated positively with HDL-C (r=0.533, p=0.001) and negatively with TG (r=-0.421, p=0.009), while circulating 25(OH)D correlated negatively with TG (r=-0.458, p=0.004). The above-mentioned associations of vitamin K1 intake/BW and circulating 25(OH)D with serum lipoproteins were not detected in individuals without vitamin K1 deficiency or the ones without vitamin D deficiency. The vitamin K2 intake/BW correlated negatively with low density lipoprotein-cholesterol (LDL-C) (r=-0.404, p=0.001). In conclusion, the associations of vitamin K1 intake with TG and HDL-C and of circulating 25(OH)D with TG were more pronounced in individuals with deficiency of either or both vitamins K1 and D. Increased dietary vitamin K2 intake was associated with decreased LDL-C.

Topics: Adolescent; Adult; Aged; Avitaminosis; Body Weight; Cholesterol, HDL; Cholesterol, LDL; Humans; Male; Middle Aged; Vitamin D Deficiency; Vitamin K; Vitamin K 1; Vitamin K 2; Vitamins; Young Adult

Potassium bromate (KBrO3) has been reported to be toxic, adversely affecting many body tissues and organs. The aim of this study was to determine the blood coagulation effect of Parkia biglobosa (P. biglobosa) seed on potassium bromate induced coagulopathy.. P. biglobosa was extracted with soxhlet extractor with ethanol as the solvent. Twenty-four adult male Wistar rats were acclimatized under laboratory conditions and were randomly grouped into A, B, C and D. Group A was given distilled water orally. Animals in groups B, C and D were administered 100 mg/kg body weight of potassium bromate, but groups C and D were also treated with 100 and 200 mg/kg body weight of P. biglobosa respectively. Both potassium bromate and P. biglobosa were freshly prepared on daily basis and administered to rats by oral gavage for 28 days. At the end of the treatment period, blood samples were collected in sodium citrate bottles and were used for analysis of Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT), Thrombin Time (TT), fibrinogen and vitamin K levels using standard methods.. Administration of potassium bromate increased Prothrombin Time (PT) from 11.67±2.15 seconds (in control animals) to 19.53±2.83 seconds. Treatment with 100 and 200 mg/kg body weight of P. biglobosa seed extract neutralized this effect in a dose-dependent manner. Likewise, KBrO 3 was observed to have significantly elevated Activated Partial Thromboplastin Time (APTT) from 29.67±3.93 to 41.10±4.79 seconds and Thrombin Time (TT) from 15.36±2.06 to 25.43±2.83 seconds when compared with those in the control group. The result further showed that exposure of animals to KBrO3 significantly declined the levels of fibrinogen (from 4.05±0.72 to 2.59±0.30 g/dL) and vitamin K (from 3.18±0.73 to 1.84±0.18 ng/mL) when compared with the untreated animals. The effect of KBrO 3 on PT, APTT, TT, Fibrinogen and vitamin k were attenuated by P. biglobosa in a dose-dependent manner.. The results of this investigation demonstrated that potassium bromate caused prolongation of PT, aPTT and TT and decreased levels of fibrinogen and vitamin K, but P. biglobosa treatment counteracted these effects. Thus, it is recommended that these results be investigated in clinical trials in human volunteers.. On a signalé que le bromate de potassium (KBrO3) est toxique et qu’il a des effets néfastes sur de nombreux tissus et organes du corps. Le but de cette étude était de déterminer l’effet de la graine de Parkia biglobosa (P. biglobosa) sur la coagulopathie induite par le bromate de potassium.. P. biglobosa a été extrait à l’aide d’un extracteur soxhlet avec de l’éthanol comme solvant. Vingt-quatre rats Wistar mâles adultes ont été acclimatés dans des conditions de laboratoire et ont été répartis au hasard en groupes A, B, C et D. Le groupe A a reçu de l’eau distillée par voie orale. Les animaux des groupes B, C et D ont reçu 100 mg/kg de poids corporel de bromate de potassium, mais les groupes C et D ont également été traités avec 100 et 200 mg/kg de poids corporel de P. biglobosa respectivement. Le bromate de potassium et P. biglobosa ont été fraîchement préparés quotidiennement et administrés aux rats par gavage oral pendant 28 jours. A la fin de la période de traitement, des échantillons de sang ont été collectés dans des bouteilles de citrate de sodium et ont été utilisés pour l’analyse du temps de prothrombine (PT), du temps de thromboplastine partielle activée (APTT), du temps de thrombine (TT), du fibrinogène et des niveaux de vitamine K en utilisant des méthodes standard.. L’administration de bromate de potassium a augmenté le temps de prothrombine (PT) de 11,67±2,15 secondes (chez les animaux témoins) à 19,53±2,83 secondes. Un traitement avec 100 et 200 mg/kg de poids corporel a neutralisé cet effet de manière dose-dépendante. De même, on a observé que le KBrO3 augmentait significativement le temps de thromboplastine partielle activée (TCA) de 29,67±3,93 à 41,10±4,79 secondes et le temps de thrombine (TT) de 15,36±2,06 à 25,43±2,83 secondes par rapport aux animaux du groupe témoin. Le résultat a également montré que l’exposition des animaux au KBrO3 a réduit de manière significative les niveaux de fibrinogène (de 4,05±0,72 à 2,59±0,30 g/dL) et de vitamine K (de 3,18±0,73 à 1,84±0,18 ng/mL) par rapport aux animaux non traités. L’effet du KBrO3 sur le PT, l’aPTT, le TT, le Fibrinogène et la vitamine K a été atténué par P. biglobosa de manière dose-dépendante.. Les résultats de cette étude ont démontré que le bromate de potassium a provoqué une prolongation du PT, de l’aPTT et du TT et a diminué les niveaux de fibrinogène et de vitamine K, mais le traitement par P. biglobosa a contrecarré cet effet. Il est donc recommandé que ces résultats soient étudiés dans des essais cliniques sur des volontaires humains.. Coagulation sanguine, Coagulopathie, Parkia biglobosa, Bromate de potassium.

Topics: Adult; Animals; Blood Coagulation; Body Weight; Fibrinogen; Humans; Male; Rats; Rats, Wistar; Vitamin K

Micronutrients consumed in excess or imbalanced amounts during pregnancy may increase the risk of metabolic diseases in offspring, but the mechanisms underlying these effects are unknown. Serotonin (5-hydroxytryptamine, 5-HT), a multifunctional indoleamine in the brain and the gut, may have key roles in regulating metabolism. We investigated the effects of gestational micronutrient intakes on the central and peripheral serotonergic systems as modulators of the offspring's metabolic phenotypes. Pregnant Wistar rats were fed an AIN-93G diet with 1-fold recommended vitamins (RV), high 10-fold multivitamins (HV), high 10-fold folic acid with recommended choline (HFolRC), or high 10-fold folic acid with no choline (HFolNC). Male and female offspring were weaned to a high-fat RV diet for 12 weeks. We assessed the central function using the 5-HT2C receptor agonist, 1-(3-chlorophenyl)piperazine (mCPP), and found that male offspring from the HV- or HFolRC-fed dams were less responsive (P < 0.05) whereas female HFolRC offspring were more responsive to mCPP (P < 0.01) at 6 weeks post-weaning. Male and female offspring from the HV and HFolNC groups, and male HFolRC offspring had greater food intake (males P < 0.001; females P < 0.001) and weight gain (males P < 0.0001; females P < 0.0001), elevated colon 5-HT (males P < 0.01; females P < 0.001) and fasting glucose concentrations (males P < 0.01; females P < 0.01), as well as body composition toward obesity (males P < 0.01; females P < 0.01) at 12 weeks post-weaning. Colon 5-HT was correlated with fasting glucose concentrations (males R2=0.78, P < 0.0001; females R2=0.71, P < 0.0001). Overall, the serotonergic systems are sensitive to the composition of gestational micronutrients, with alterations consistent with metabolic disturbances in offspring.

Topics: Animals; Body Weight; Diet, High-Fat; Female; Folic Acid; Glucose; Humans; Male; Maternal Nutritional Physiological Phenomena; Micronutrients; Phenotype; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Serotonin; Vitamin A; Vitamin K; Vitamins; Weaning

Despite an increase in the use of fixed-dose protocols of 4-factor prothrombin complex concentrate (4F-PCC) for the reversal of vitamin K antagonists (VKAs), there remains a paucity of data in obese patients. In this study, we aimed to compare the proportion of patients attaining international normalized ratio (INR) goals using a weight-based dosing strategy versus a fixed-dose regimen of 4F-PCC.. This was a retrospective study conducted in patients 18 years of age or older, weighing ≥ 100 kg, who received either a weight-based dose or fixed dose of 4F-PCC (2000 units) for the reversal of VKA, and had a documented baseline and post-treatment INR. The primary outcome was the proportion of patients achieving an INR of < 2 for all indications of warfarin reversal, except in patients with intracranial hemorrhage, where the goal was an INR of < 1.5.. A total of 44 patients met the inclusion criteria; 25 patients in the weight-based dosing group and 19 patients in the fixed-dose group. The median baseline INR was similar in both groups (weight-based dosing group 3.2 [interquartile range {IQR} 2.8-3.7] vs fixed-dose group 3.0 [IQR 2.7-4.9], p = 1). The median post-treatment INR was significantly lower in the weight-based dosing group compared to the fixed-dose group (1.3 [IQR 1.2-1.5] vs 1.6 [IQR 1.5-1.9], p < 0.01). However, there was no significant difference in the primary outcome between both groups (weight-based dosing strategy 84% vs fixed dose strategy 90%, p = 0.68).. Our findings suggest that a fixed-dose regimen of 2000 units in obese patients weighing ≥ 100 kg is adequate to achieve these INR goals.

Topics: Aged; Anticoagulants; Blood Coagulation Factors; Body Weight; Clinical Protocols; Dose-Response Relationship, Drug; Female; Humans; International Normalized Ratio; Male; Obesity; Retrospective Studies; Time-to-Treatment; Vitamin K

One of the well-known toxicants of the mammary tissue is 7,12-dimethylbenz[a]anthracene (DMBA). This study was carried out to investigate the possible prophylactic's role of increased dietary intake of vitamin K on the induction of toxicity in the lung tissue. Twenty-eight Wistar albino rats (120-150 g) were randomly divided into different groups. Group 1 served as the control and were fed with a normal diet (containing the recommended daily allowance of vitamin K (0.0075%)). Groups 2 and 3 received a single dose of DMBA (80 mg/kg body weight) intragastically. In addition, group 3 rats were maintained on surplus vitamin K diet (0.075% diet) as against the group 2 animals that were on a normal diet. Group 4 rats were on surplus vitamin K diet (0.075% diet) throughout the experimental period of 16 weeks. Our results revealed that supplementation of diet with surplus vitamin K significantly increased the activities of catalase. Superoxide dismutase, glutathione-S-transferase, and glutathione peroxidase were significantly increased in the serum and lungs when compared with the DMBA-treated group, which was maintained on a normal diet. Significant alterations in malondialdehyde, nitric oxide, granulocyte-macrophage colony-stimulating factor, and interleukin 17F were observed in rats challenged with DMBA-fed normal diets but were normalized in rats with surplus vitamin K. These alterations and reversal were confirmed by histopathology studies. This suggests the prophylactic benefit of increased dietary intake of vitamin K without any observed deleterious effect on DMBA-induced pulmonary toxicity.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antioxidants; Body Weight; Dietary Supplements; Lung; Rats; Rats, Wistar; Vitamin K

Prothrombin Complex Concentrates (PCC) are prescribed for emergent warfarin reversal (EWR). The comparative effectiveness and safety among PCC products are not fully understood.. Patients in an academic level one trauma center who received PCC3 or PCC4 for EWR were identified. Patient characteristics, PCC dose and time of dose, pre- and post-INR and time of measurement, fresh frozen plasma and vitamin K doses, and patient outcomes were collected. Patients whose pre-PCC International Normalized Ratio (INR) was > 6 h before PCC dose or the pre-post PCC INR was > 12 h were excluded. The primary outcome was achieving an INR ≤ 1.5 post PCC. Secondary outcomes were the change in INR over time, post PCC INR, thromboembolic events (TE), and death during hospital stay. Logistic regression modelled the primary outcome with and without a propensity score adjustment accounting for age, sex, actual body weight, dose, initial INR value, and time between INR measurements. Data are reported as median (IQR) or n (%) with p < 0.05 considered significant.. Eighty patients were included (PCC3 = 57, PCC4 = 23). More PCC4 patients achieved goal INR (87.0% vs. 31.6%, odds ratio (OR) = 14.4, 95% CI: 3.80-54.93, p < 0.001). This result remained true after adjusting for possible confounders (AOR = 10.7, 95% CI: 2.17-51.24, p < 0.001). The post-PCC INR was lower in the PCC4 group (1.3 (1.3-1.5) vs. 1.7 (1.5-2.0)). The INR change was greater for PCC4 (2.3 (1.3-3.3) vs. 1.1 (0.6-2.0), p = 0.003). Death during hospital stay (p = 0.52) and TE (p = 1.00) were not significantly different.. PCC4 was associated with a higher achievement of goal INR than PCC3. This relationship was observed in the unadjusted and propensity score adjusted results.

Topics: Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Factors; Body Weight; Emergencies; Female; Humans; International Normalized Ratio; Male; Middle Aged; Plasma; Propensity Score; Retrospective Studies; Time Factors; Trauma Centers; Vitamin K; Warfarin

Topics: Anticoagulants; Body Weight; Humans; Vitamin K

High intakes of multivitamins (HV) during pregnancy by Wistar rats increase food intake, body weight, and characteristics of the metabolic syndrome in male offspring. In this study, high-fat soluble vitamins were fed in combination during gestation to test the hypothesis that they partially account for the effects of the HV diet. Pregnant Wistar rats (14-16/group) were fed a recommended multivitamin diet (1-fold all vitamins) or high-fat soluble vitamin diet (HFS; 10-fold vitamins A, D, E, and K) during pregnancy. Offspring body weight, food intake, and preference as well as expression of selected genes in the hypothalamus and hippocampus were evaluated at birth, weaning, and 14 weeks postweaning. Body weight and food intake were not affected but sucrose preference decreased by 4% in those born to dams fed the HFS gestational diet. Gene expressions of the hypothalamic anorexogenic pro-opiomelanocortin (Pomc) and orexogenic neuropeptide Y (Npy) (∼30% p = 0.008, ∼40% p = 0.007) were increased in weaning and adult rats, respectively. Hippocampal dopaminergic genes (35%-50% p < 0.05) were upregulated at birth and 14 weeks postweaning. DNA hypermethylation (2% p = 0.006) was observed in the dopamine receptor 1 (Drd1) promoter region. We conclude that a gestational diet high in vitamins A, D, E, and K does not show the effects of the HV diet on body weight or food intake but may affect the development of higher hedonic regulatory pathways associated with food preference.

Topics: Animals; Animals, Newborn; Body Weight; Diet; DNA Methylation; Female; Food Preferences; Gene Expression; Hippocampus; Hypothalamus; Male; Maternal Nutritional Physiological Phenomena; Neuropeptide Y; Pregnancy; Pro-Opiomelanocortin; Rats; Rats, Wistar; Receptors, Dopamine D1; Sucrose; Up-Regulation; Vitamin A; Vitamin D; Vitamin E; Vitamin K; Vitamins; Weaning

Optimal dosing of prothrombin complex concentrate (PCC) has yet to be defined and varies widely due to concerns of efficacy and thrombosis. We hypothesized a dose of 15 IU/kg actual body weight of a three-factor PCC would effectively correct coagulopathy in acute care surgery patients. Retrospective review of 41 acute care surgery patients who received 15 IU/kg (± 10%) actual body weight PCC for correction of coagulopathy. Demographics, laboratory results, PCC dose, blood and plasma transfusions, and thrombotic complications were analyzed. We performed subset analyses of trauma patients and those taking warfarin. Mean age was 69 years (18-94 years). Thirty (73%) trauma patients, 8 (20%) emergency surgery patients, 2 (5%) burns, and 1 (2%) nontrauma neurosurgical patient were included. Mean PCC dose was 1305.4 IU (14.2 IU/kg actual body weight). Mean change in INR was 2.52 to 1.42 (p 0.00004). Successful correction (INR <1.5) was seen in 78 per cent. Treatment failures had a higher initial INR (4.3 vs 2.03, p 0.01). Mean plasma transfusion was 1.46 units. Mean blood transfusion was 1.61 units. Patients taking prehospital warfarin (n = 29, 71%) had higher initial INR (2.78 vs 1.92, p 0.05) and received more units of plasma (1.93 vs 0.33, p 0.01) than those not taking warfarin. No statistical differences were seen between trauma and nontrauma patients. One thrombotic event occurred. Administration of low-dose PCC, 15 IU/kg actual body weight, effectively corrects coagulopathy in acute care surgery patients regardless of warfarin use, diagnosis or plasma transfusion.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Transfusion; Body Weight; Burns; Drug Dosage Calculations; Emergencies; Humans; International Normalized Ratio; Middle Aged; Plasma; Retrospective Studies; Surgical Procedures, Operative; Thrombosis; Vitamin K; Warfarin; Wounds and Injuries; Young Adult

Here we assessed how intake reductions induced by Roux-en-Y gastric bypass surgery (RYGB) occur within and across access periods by examining drinking microstructure. After training, RYGB (n = 8-10) or sham-operated (SHAM, n = 12) rats were given 60-min access first to 0.3 M sucrose, then to 5% Intralipid, and finally to milk-chocolate Ensure Plus across 5 days each. Initially, total licks taken during the first meal of sucrose and Intralipid by RYGB and SHAM rats did not differ, but, across subsequent test periods, RYGB rats licked less than SHAM rats. First Ensure meal size also did not differ between RYGB and SHAM rats, but SHAM rats increased licking across test periods while the behavior of RYGB rats remained stable. The intake differences between the surgical groups, when they occurred, were most often due to smaller burst sizes in RYGB rats. Importantly, the surgical-group difference in sucrose and Intralipid intakes could not be explained by altered palatability of these solutions because, throughout testing, both groups had similar early meal licking behavior thought to represent the motivational potency of stimulus orosensory features. Although, overall, RYGB rats displayed lower early meal licking of Ensure relative to the SHAM rats, this appeared to be driven primarily by increases in the latter group across test periods; the RYGB group stayed relatively stable. Collectively, these results suggest that some level of postoral experience with these stimuli and/or their components is necessary before intake differences emerge between surgical groups, and, even when differences occur, often immediate taste-motivated ingestive behavior remains unaltered.

Topics: Animals; Body Weight; Dietary Fats; Emulsions; Feeding Behavior; Gastric Bypass; Male; Phospholipids; Rats; Rats, Sprague-Dawley; Soybean Oil; Sucrose; Sweetening Agents; Vitamin K

Indandione VKAs have been widely used for decades, especially in Eastern Europe and France. Contrary to coumarin VKAs, the relative contribution of individual factors to the indandione-VKA response is poorly known. In the present multicentre study, we sought to develop and validate a model including genetic and non-genetic factors to predict the daily fluindione dose requirement in elderly patients in whom VKA dosing is challenging. We prospectively recorded clinical and therapeutic data in 230 Caucasian inpatients mean aged 85 ± 6 years, who had reached international normalized ratio stabilisation (range 2.0-3.0) on fluindione. In the derivation cohort (n=156), we analysed 13 polymorphisms in seven genes potentially involved in the pharmacological effect or vitamin-K cycle (VKORC1, CYP4F2, EPHX1) and fluindione metabolism/transport (CYP2C9, CYP2C19, CYP3A5, ABCB1). We built a regression model incorporating non-genetic and genetic data and evaluated the model performances in a separate cohort (n=74).Body-weight, amiodarone intake, VKORC1, CYP4F2, ABCB1 genotypes were retained in the final model, accounting for 31.5% of dose variability. None influence of CYP2C9 was observed. Our final model showed good performances: in 83.3% of the validation cohort patients, the dose was accurately predicted within 5 mg, i.e.the usual step used for adjusting fluindione dosage. In conclusion, in addition to body-weight and amiodarone-intake, pharmacogenetic factors (VKORC1, CYP4F2, ABCB1) related to the pharmacodynamic effect and transport of fluindione significantly influenced the dose requirement in elderly patients while CYP2C9 did not. Studies are required to know whether fluindione could be an alternative VKA in carriers of polymorphic CYP2C9 alleles, hypersensitive to coumarins.

Topics: Aged; Aged, 80 and over; Amiodarone; Body Weight; Drug Dosage Calculations; Female; Gene-Environment Interaction; Genotype; Heart Rate; Humans; Inactivation, Metabolic; Male; Models, Biological; Pharmacogenetics; Phenindione; Polymorphism, Genetic; Vascular Resistance; Vitamin K

Suboptimal vitamin K nutriture is evident during rapid growth. We aimed to determine whether vitamin K(2) (menaquinone-4 [MK-4]) supplementation is beneficial to bone structure and intrinsic bone tissue properties in growing rats. Male Wistar rats (5 weeks old) were assigned to either a control diet (n = 8) or an MK-4-supplemented diet (22 mg d(-1) kg(-1) body weight, n = 8). After a 9-week feeding period, we determined the serum concentration ratio of undercarboxylated osteocalcin to γ-carboxylated osteocalcin and the urinary deoxypyridinoline level. All rats were then euthanized, and their tibiae were analyzed by micro-computed tomography for trabecular architecture and synchrotron radiation micro-computed tomography for cortical pore structure and mineralization. Fourier transform infrared microspectroscopy and a nanoindentation test were performed on the cortical midlayers of the anterior and posterior cortices to assess bone tissue properties. Neither body weight nor tibia length differed significantly between the 2 groups. Dietary MK-4 supplementation decreased the ratio of undercarboxylated osteocalcin to γ-carboxylated osteocalcin but did not affect deoxypyridinoline, indicating a positive effect on bone formation but not bone resorption. Trabecular volume fraction and thickness were increased by MK-4 (P < .05). Neither the cortical pore structure nor mineralization was affected by MK-4. On the other hand, MK-4 increased mineral crystallinity, collagen maturity, and hardness in both the anterior and posterior cortices (P < .05). These data indicate the potential benefit of MK-4 supplementation during growth in terms of enhancing bone quality.

Topics: Algorithms; Amino Acids; Animals; Biomarkers; Body Weight; Bone Development; Bone Resorption; Calcification, Physiologic; Diet; Male; Mechanical Phenomena; Organ Size; Osteocalcin; Rats; Rats, Wistar; Spectroscopy, Fourier Transform Infrared; Tibia; Tomography, X-Ray Computed; Trabecular Meshwork; Vitamin K; Vitamins

Initiation of warfarin therapy is complicated by its narrow therapeutic index and inter-patient dose-effect variability. A '10-mg nomogram' warfarin initiation protocol permits safe therapeutic anticoagulation in outpatients started on warfarin. We aimed to develop a safe and effective warfarin maintenance dose prediction tool in these patients.. Baseline potential predictor variables were collected on a retrospective cohort of outpatients initiated on warfarin for venous thromboembolism treatment. The primary outcome was the warfarin maintenance dose, defined as mean warfarin dose over the last 10 days of the first month of warfarin treatment. Univariate and multivariate analyses were performed to determine which baseline variables were warfarin maintenance dose predictors. An independent cohort of patients validated the derived warfarin maintenance dose prediction rule.. Patient's age and weight, cumulative dose of warfarin over the first week of induction and international normalized ratio (INR) on days 3, 5 and 8 were statistically significant predictors of the warfarin maintenance dose. Our final prediction rule reads: maintenance dose (in mg) = 2.5 + 10% of the first week cumulative dose - INR value at day 8 + 1.5 if INR was below 2.0 at day 5. In the validation cohort, the predicted dose was strongly correlated with the actual maintenance dose (r = 0.88, P < 0.0001). The mean difference between observed and predicted dose was not clinically significant: -0.1 +/- 1.1 mg.. In outpatients initiated on warfarin using a '10-mg nomogram', a simple prediction rule can accurately predict warfarin maintenance dose. Prospective studies employing the rule are indicated.

Topics: Administration, Oral; Adult; Age Factors; Aged; Ambulatory Care; Anticoagulants; Blood Coagulation; Body Weight; Drug Administration Schedule; Drug Dosage Calculations; Drug Monitoring; Female; Genotype; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Nomograms; Phenotype; Predictive Value of Tests; Reproducibility of Results; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Venous Thromboembolism; Vitamin K; Warfarin

Topics: Body Weight; Breast Feeding; Female; Hospitalization; Humans; Infant; Infant Care; Infant, Newborn; Jaundice, Neonatal; Postnatal Care; Practice Guidelines as Topic; Pregnancy; Vitamin K

Despite administration of vitamin K (VK), some infants show lower activity of VK-dependent coagulation factors and they could develop intracranial hemorrhage. For preventing VK deficiency bleeding (VKDB) in infants, oral administration of VK and a screening test for VK deficiency are carried out in Japan. For the screening, the total activity of VK-dependent coagulation factors is measured using a commercial product, Normotest. This study was undertaken to clarify the importance of the following genetic and environmental factors on the coagulation status in one-month-old infants: two polymorphisms in the factor VII gene, -323P0/10 (a 10-bp insertion in the promoter region at position -323) and R353Q (the replacement of arginine [R] with glutamine [Q] at residue 353) and sex, age, gestational age, birth weight, and feeding regimen. Two hundred Japanese infants (34.6 +/- 4.0 days old) were screened for VK-dependent coagulation activity with Normotest and were genotyped for the two polymorphisms. Among the subjects screened, 18 infants (9%) carried the P10 allele and 26 (13%) carried the R353Q allele. Multiple regression analysis showed that the 10-bp inserted (P10) allele or the Q allele was associated with the lower coagulation activities. The coagulation activities for the R/Q genotype were significantly lower than those for the R/R genotype and those for the P0/P10 genotype were significantly lower than those for the P0/P0 genotype. Therefore, infants who carry the P10 allele or the Q allele show lower activity of VK-dependent coagulation factors. These infants may have a higher risk of VKDB manifestation.

Topics: Birth Weight; Blood Coagulation; Blood Coagulation Factors; Blood Coagulation Tests; Body Weight; Bottle Feeding; Breast Feeding; Factor VII; Female; Gene Frequency; Genotype; Gestational Age; Humans; Infant; Infant, Newborn; Male; Polymorphism, Genetic; Regression Analysis; Sex Factors; Vitamin K; Vitamin K Deficiency; Vitamin K Deficiency Bleeding

To identify factors related to children's bone mineral indexes at age 8 years, and to assess bone mineral indexes in the same children at ages 6 and 8 years.. Bone mineral content (BMC [g]) and bone mineral density (BMD; calculated as g/cm 2 ) were measured by dual-energy x-ray absorptiometry (DEXA) in children and their mothers when the children were 8 years of age. A subset of children had an earlier DEXA assessment at age 6 years. Children's dietary intake, height, weight, and level of sedentary activity were assessed as part of a longitudinal study from ages 2 months to 8 years.. Fifty-two healthy white children (25 male, 27 female) and their mothers. Main outcome measures Children's total BMC and BMD at age 8 years.. Correlations and stepwise multiple regression analyses.. Factors positively related to children's BMC at age 8 years included longitudinal intakes (ages 2 to 8 years) of protein, phosphorus, vitamin K, magnesium, zinc, energy, and iron; height; weight; and age ( P < or = .05). Factors positively related to children's BMD at age 8 years included longitudinal intakes of protein and magnesium ( P < or = .05). Female sex was negatively associated with BMC and BMD at age 8 years ( P < or = .05). Children's bone mineral indexes at ages 6 and 8 years were strongly correlated ( r =0.86, P < .0001 for BMC; r =0.92, P <.0001 for BMD).. Because many nutrients are related to bone health, children should consume a varied and nutrient-dense diet.

Topics: Absorptiometry, Photon; Age Factors; Body Height; Body Weight; Bone Density; Calcium, Dietary; Child; Diet; Dietary Proteins; Energy Intake; Exercise; Female; Humans; Iron, Dietary; Life Style; Longitudinal Studies; Magnesium; Male; Phosphorus, Dietary; Regression Analysis; Sex Factors; Vitamin K; Zinc

alpha-Methylacyl-CoA racemase (Amacr) deficiency in humans leads to sensory motor neuronal and liver abnormalities. The disorder is recessively inherited and caused by mutations in the AMACR gene, which encodes Amacr, an enzyme presumed to be essential for bile acid synthesis and to participate in the degradation of methyl-branched fatty acids. To generate a model to study the pathophysiology in Amacr deficiency we inactivated the mouse Amacr gene. As per human Amacr deficiency, the Amacr(-/-) mice showed accumulation (44-fold) of C27 bile acid precursors and decreased (over 50%) primary (C24) bile acids in bile, serum and liver, however the Amacr(-/-) mice were clinically symptomless. Real-time quantitative PCR analysis showed that, among other responses, the level of mRNA for peroxisomal multifunctional enzyme type 1 (pMFE-1) was increased 3-fold in Amacr(-/-) mice. This enzyme can be placed, together with CYP3A11 and CYP46A1, to make an Amacr-independent pathway for the generation of C24 bile acids. Exposure of Amacr(-/-) mice to a diet supplemented with phytol, a source for branched-chain fatty acids, triggered the development of a disease state with liver manifestations, redefining the physiological significance of Amacr. Amacr is indispensable for the detoxification of dietary methyl-branched lipids and, although it contributes normally to bile acid synthesis from cholesterol, the putative pMFE-1-mediated cholesterol degradation can provide for generation of bile acids, allowing survival without Amacr. Based upon our mouse model, we propose elimination of phytol from the diet of patients suffering from Amacr deficiency.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Bile Acids and Salts; Body Weight; Cholesterol; Cholesterol 24-Hydroxylase; Clofibrate; Cytochrome P-450 CYP3A; Deficiency Diseases; Deoxyribonucleases, Type II Site-Specific; Dietary Fats; Disease Models, Animal; Female; Gene Expression Regulation; Hypolipidemic Agents; Kidney; Lipids; Liver; Male; Membrane Proteins; Mice; Mice, Mutant Strains; Oxidoreductases, N-Demethylating; Phytol; Racemases and Epimerases; Steroid Hydroxylases; Vitamin K

Topics: Aged; Body Weight; Cause of Death; Double-Blind Method; Drug Administration Schedule; Enoxaparin; Female; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Humans; Kidney; Male; Middle Aged; Polysaccharides; Recurrence; Treatment Outcome; Venous Thrombosis; Vitamin K

To identify patient-specific factors predictive of maintenance warfarin dosage requirements >5 mg/d.. One hundred forty-six adults taking warfarin were identified from a community hospital and an outpatient anticoagulation clinic. Patient demographics and data on warfarin doses, laboratory results, and medication use were obtained by abstracting patient records. Estimates of vitamin K intake were obtained using a questionnaire and structured interview. Multiple logistic regression was used to identify patient characteristics independently predictive of warfarin maintenance requirements >5 mg/d. An assessment tool for estimating an individual patient's likelihood of requiring warfarin maintenance doses >5 mg/d was derived from the logistic regression model and was assessed in both the study cohort and a separate historical validation cohort of 125 patients.. Five factors were independently associated with warfarin requirements >5 mg/d: age <55 years, male gender, African American ethnicity, vitamin K intake >400 micro g/d, and body weight >or=91 kg. The assessment tool derived from these factors correctly classified semiquantitative warfarin requirements as non-high-dose in 84 of 93 study cohort patients and 71 of 78 validation cohort patients, and correctly classified requirements as high-dose in 10 of 13 study cohort patients and 11 of 15 validation cohort patients.. African American ethnicity is a newly identified predictor of warfarin requirements >5 mg/d and is independent of dietary vitamin K intake. An assessment tool incorporating this and other predictors can estimate a patient's likelihood of requiring such dosages.

Topics: Age Factors; Aged; Anticoagulants; Black People; Body Weight; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Models, Biological; Multivariate Analysis; Sex Factors; Vitamin K; Warfarin; White People

Topics: Blood Coagulation; Body Weight; Humans; Injections, Subcutaneous; International Normalized Ratio; Vitamin K

There is strong evidence supporting the importance of vitamin K in bone health and the aetiological role of vitamin K deficiency in osteoporosis. In view of the common occurrence of osteoporosis among older subjects in Hong Kong, we have studied the dietary vitamin K intakes in 100 residents of a nursing home (43 men, 57 women; median age 81.0 years) and 88 free-living subjects attending a day care centre (13 men, 75 women; median age 71.5 years). The subjects were interviewed and the average vitamin K intake in the preceding week was estimated, using a diet recall questionnaire modified from our previous surveys of dietary patterns in local Chinese people. The median vitamin K intake was much lower in nursing home residents than in free-living subjects (4.50 vs 488.09 microg/day or 0.13 vs 8.74 microg/kg/day, P<0.001). An intake that was below the recommended daily intake was far more common among nursing home residents (86.0 vs 11.4%, P < 0.001). Among nursing home residents, there was a negative correlation between age and vitamin K intake (r = -0.217, P = 0.030), but there was a positive correlation between body weight and vitamin K intake (r = 0.244, P = 0.015). No such relationship was seen among free-living subjects. Elderly nursing home residents in this study generally had a poor dietary vitamin K intake and might therefore be predisposed to osteoporosis. The importance of green leafy vegetables as a rich source of vitamin K should be emphasised.

Topics: Adult; Aged; Aged, 80 and over; Body Weight; Feeding Behavior; Female; Homes for the Aged; Hong Kong; Humans; Male; Middle Aged; Nursing Homes; Surveys and Questionnaires; Vitamin K; Vitamin K Deficiency

To determine the influence of body weight on the international normalized ratio (INR) response to a fixed dose of vitamin K in overanticoagulated patients.. Retrospective review of records of patients who received 1 mg of vitamin K subcutaneously to correct excessive INR. Dose of vitamin K in milligrams per kilograms plotted against change in INR in 24 hours.. Fifteen patients were identified who met all inclusion criteria. Linear regression analysis plotted INR response at 24 hours versus dose of vitamin K adjusted for body weight. Pearson's product moment correlation (R = 0.85) indicated a significant relationship between INR response at 24 hours to an adjusted body weight dose of subcutaneous vitamin K (P = 0.0000523). A strong correlation (r = 0.69) also existed between INR response at 24 hours and the actual body weight dose of subcutaneous vitamin K (P = 0.004).. In overanticoagulated patients, variability in response to vitamin K may be explained by variability in body weight. Dosing vitamin K according to body weight may result in a more predictable INR response.

Topics: Blood Coagulation; Body Weight; Humans; Injections, Subcutaneous; International Normalized Ratio; Linear Models; Retrospective Studies; Vitamin K

Menatetrenone, a vitamin K2 with four isoprene units, has been reported to improve osteoporotic bone loss. The purpose of this investigation was to clarify the effect of menatetrenone on the three-dimensional (3D) trabecular microarchitecture in ovariectomized (OVX) rats by using microcomputed tomography (MCT). Forty-two 13-week-old female rats were used and divided into four groups: the OVX (OVX + MK-4) group treated with menatetrenone, the (OVX untreated) group, the sham-operated (Sham + MK-4) group treated with menatetrenone, and the sham-operated group not treated with menatetrenone (Sham untreated) group. OVX rats were fed a calcium-deficient diet. Menatetrenone treatment was begun just after the ovariectomy, and the mean menatetrenone oral intake over the 8-week period was adjusted to 30 mg/kg BW per day. The proximal metaphyseal region of the right tibia was evaluated by dual X-ray absorptiometry (DXA) and MCT. A parametric analysis of the reconstructed trabecular volume was carried out using bone volume fractions, the fractal dimension calculated by the 3D box-counting method, and the connectivity density as determined by topological analysis. Menatetrenone significantly increased the trabecular bone volume, fractal dimension, and connectivity in the OVX + MK-4 group compared with the OVX-untreated group (p < 0.01). Our results suggest that an 8-week administration of menatetrenone protects against the loss of trabecular bone volume and its connectivity when treatment is begun just after the ovariectomy. Despite this apparent protection, it remains unknown whether it is possible to reestablish trabecular connectivity if therapeutic intervention occurs after the trabecular connectivity has been lost.

Topics: Alkaline Phosphatase; Animals; Anthropometry; Body Weight; Bone Density; Calcium; Computer Simulation; Disease Models, Animal; Female; Humans; Osteoporosis, Postmenopausal; Ovariectomy; Rats; Rats, Inbred F344; Reproducibility of Results; Tibia; Tomography, X-Ray Computed; Vitamin K; Vitamin K 2

Two experiments were carried out in 4-week-old rats. First, the effect of dietary calcium (Ca) content (0.05, 0.1, 0.2, 0.5 and 1.16%) on bone loss was assessed for 3 weeks. Dry weight of the femur showed a Ca-content-dependent decrease. Significant decrease in body weight and plasma Ca level was observed in the 0.05 and 0.1% Ca diet groups, but not in other groups. Second, the curative effect of V.K2 on bone strength was examined. After being fed a 0.2%-Ca diet for 3 weeks, rats were fed 0.2%- or 0.5%-Ca diets for the next 6 weeks with or without V.K2 treatment. At the beginning and after 3 and 6 weeks of treatment, femurs and lumbar vertebra (L3) were collected. In the 0.2%-Ca group, bone mineral density (BMD) and bone strength in the femur gradually increased, but were much lower than those in the intact group. In the 0.5%-Ca group, both parameters in the femur and L3 were rapidly increased. V.K2 treatment did not affect the BMD or bone strength in the femur at either point. However, the bone strength in L3 in the V.K2 group was higher than that in the 0.5%-Ca group at 3 weeks and in the 0.2%-Ca group at 6 weeks than that in the respective control group. These findings suggest that V.K2 has curative effect on bone strength in the vertebra.

Topics: Animals; Body Weight; Bone and Bones; Bone Density; Calcium; Femur; Lumbar Vertebrae; Male; Rats; Rats, Sprague-Dawley; Vitamin K; Vitamin K 2

Menadione induced oxidative stress in cells. The acute and cumulative toxic effects of menadione were evaluated by intravenous injection of the drug in Wistar rats. For evaluation of acute toxicity, single bolus doses of 25, 50, 100 and 150 mg/kg menadione were used. For evaluation of cumulative toxicity, five doses of 100 and 150 mg/kg menadione were injected every other day. Histologic and ultrastructural examinations were made from tissues of kidney, heart, liver, lung, skeletal muscle of foreleg and smooth muscle of stomach. A dose-response relationship was observed in rats whether treated with single or five doses of menadione. Menadione at a dose of 25 mg/kg produced minimal granular degeneration in the tubular cells of the kidney. Menadione at a dose of 50 mg/kg produced minimal granular degeneration in the tubular cells of the kidney and mild pulmonary hemorrhage in the lung. Menadione at doses of 100 and 150 mg/kg produced lesions in the kidney, heart, liver and lung. The characteristic lesions in the kidney included tubular dilatation, formation of protein casts in the lumen of renal tubules, Ca2+ mineralization, vacuolization in proximal and distal tubules, granular degeneration in the cortex and necrosis. Apoptosis was very obvious in kidney from rats treated at 100 and 150 mg/kg menadione. Lesions found in the heart included inflammation, hemorrhage, vacuolization, edema and necrosis. Mitochondria were swollen. Hepatic changes included inflammation, degeneration, vacuolization and necrosis. The only lesion observed in lung was hemorrhage. At the same dose of menadione, structural damage was more severe in kidney than in other organs. The lesions produced by one dose of single injection of the drug were more severe than five doses of multiple injection of menadione in all observed tissues. We conclude that the acute toxicity of menadione is more severe than the cumulative toxicity of menadione.

Topics: Animals; Body Weight; Calcium; Glutathione; Heart; Kidney; Liver; Male; Myocardium; Rats; Rats, Wistar; Vitamin K

A review of 127 infants with haemorrhagic disease of the newborn (HDN) is presented. The case definition of HDN used in the selection of patients was bleeding during the 1st week of life in a newborn with normal platelet count, normal peripheral blood smear and complete clinical response to parenteral vitamin K. Equivocal cases with respect to cause of bleeding were excluded. The eligible cases consisted of 0.9% of all admissions to the unit and the male:female ratio was 1.8:1. Most were from families of low economic status and poor educational background. Omission of vitamin K prophylaxis and exclusive breastfeeding were the commonest antecedents. The mean (SE) gestation and admission weight were 39.3 (0.2) weeks and 2981 (78) g, respectively. One hundred and two (80.3%) had classical HDN with a mean (SE) age at onset of 63 (4.4) hours. Gastro-intestinal bleeding was the commonest observation. Thirty-three infants (26%) died, most of them from exsanguination. There is a need for well designed work to determine the magnitude of the problem, including that of late-onset HDN, the antecedent risk factors, the preferred route for administering prophylactic vitamin K and a clear policy guideline on prevention of the disease.

Topics: Body Weight; Breast Feeding; Educational Status; Ethiopia; Female; Gastrointestinal Hemorrhage; Humans; Infant, Newborn; Male; Socioeconomic Factors; Vitamin K; Vitamin K Deficiency Bleeding

Young chicks were fed a vitamin K-deficient soybean concentrate basal diet containing graded levels of menadione from menadione nicotinamide bisulfite (MNB) or menadione dimethyl-pyrimidinol bisulfite (MPB) to assess prothrombin time as a function of menadione intake. Prothrombin time decreased linearly as menadione dose increased from 0 to 400 micrograms/kg. Multiple linear regression slope-ratio calculations indicated that both sources of menadione were of equal potency. To assess niacin bioactivity of MNB, graded doses of nicotinamide (0 to 5 mg/kg) from MNB or nicotinamide were added to a niacin-deficient diet based upon corn, corn gluten meal and vitamin-free casein. Weight gain increased linearly as a function of nicotinamide dose, and multiple linear regression analysis of weight gain as a function of supplemental nicotinamide intake revealed no significant differences in slope between the two sources of nicotinamide. Using excess doses, MNB was compared with MPB in acute (single crop intubation) or chronic (fed in the diet for 14 d) toxicity trials. With a single menadione dose of 1600 mg/kg body wt, weight gain in the subsequent 14-d period was reduced by MNB but not by MPB. Mortality rates of 25 and 17% occurred for MPB and MNB, respectively, at this dose level. Doses lower than 1600 mg/kg body wt caused neither morbidity nor mortality. When provided in the diet for a 14-d feeding period, menadione doses of 3000 mg/kg diet from MNB reduced gain, feed intake, gain:feed ratio and blood hemoglobin concentration. Menadione doses of 6000 mg/kg diet were required to produce morbidity of this type when MPB was fed.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Animals; Body Weight; Chickens; Dose-Response Relationship, Drug; Male; Niacin; Niacinamide; Prothrombin Time; Vitamin K; Vitamin K 3

Newborn infants are susceptible to bleeding disorders caused by a vitamin K deficiency, so called 'haemorrhagic disease of the newborn' (HDN). These bleedings often occur in infants after medication of the mother with antiepileptics, such as phenobarbital or phenytoin. It has been suggested that an increase in the late type of HDN in exclusively breast-fed infants might be related to the presence of cytochrome P450-inducing polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) in human milk. In order to study this possible mechanistic relationship 5-week-old, germfree, female WAG/Rij-rats were exposed to a single oral dose of either 1 microgram 2,3,7,8-tetrachlorodibenzo-p-dioxin/kg body weight (TCDD) or 30 mg 2,2',4,4',5,5'-hexachlorobiphenyl/kg body weight (HxCB), representing cytochrome P-450 1A (3-methylcholanthrene type) and 2B (phenobarbital type) inducers. During the experiment blood coagulation time from each rat was measured. Also, hepatic 7-ethoxy-(EROD) and 7-pentoxyresorufin O-dealkylating (PROD) activities and total cytochrome P450 content were measured. Blood coagulation time (Thrombotest) in the HxCB-treated rats was significantly prolonged and positively correlated to PROD activity and total P450 content. No clear effect of TCDD on coagulation time could be observed under these experimental conditions. These results suggest involvement of P450 2B isoenzymes in vitamin K metabolism.

Topics: Animals; Blood Coagulation; Body Weight; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP2B1; Cytochrome P-450 Enzyme System; Female; Gas Chromatography-Mass Spectrometry; Germ-Free Life; Liver; Microsomes, Liver; Organ Size; Oxidoreductases; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Prothrombin Time; Rats; Rats, Inbred Strains; Vitamin K; Vitamin K Deficiency

Inducibility of oxidative stress in rat liver in vivo by menadione-associated redox cycling activation under redox enzyme modulating conditions was examined by monitoring hepatocyte injury and 8-hydroxydeoxyguanosine (8-OHdG) levels of liver DNA. In addition, the treatment-associated liver tumor initiating activity was assessed in terms of development of gamma-glutamyl-transpeptidase (GGT)- and glutathione S-transferase placental form (GST-P)-positive foci and hyperplastic nodules. With or without following menadione treatment (50 mg/kg, i.g.), redox enzyme modulations of increased cytochrome P450 reductase activity induced by phenobarbital (PB)-Na (100 mg/kg, i.p. for 5 days), inhibition of DT-diaphorase by dicumarol (25 mg/kg, i.p.) and depletion of glutathione by phorone (200 mg/kg, i.p.), with or without further supplement of iron EDTA-Na-Fe(III) (70 mg/kg, i.p.), caused both substantial hepatocyte necrosis and 8-OHdG production in Fischer 344 male rats. Subsequent feeding with a 0.05% PB diet for 64 weeks resulted in slightly increased development of GGT-positive foci but not GST-P positive lesions or hyperplastic nodules, suggesting a lack of tumor-initiating activity of the oxidative DNA damage associated with redox enzyme modulations with or without menadione.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Body Weight; Cytochrome Reductases; Deoxyguanosine; Dicumarol; DNA; DNA Damage; gamma-Glutamyltransferase; Glutathione; Iron; Ketones; Liver; Liver Neoplasms, Experimental; Male; NAD(P)H Dehydrogenase (Quinone); Necrosis; Neoplasms, Experimental; Organ Size; Oxidation-Reduction; Phenobarbital; Quinone Reductases; Rats; Rats, Inbred F344; Time Factors; Vitamin K

The objective of the experiment was to study the influence of a high but nontoxic dietary level of menadione (vitamin K3) on the incidence of leiomyomas and leiomyosarcomas in the oviduct of females from various lines of Japanese quail. Analyzed values of vitamin K3 per 1,000 kg of feed were 7.37 g in the control diet, and 149.6, 1,722, and 3,722 g for the experimental diets from 0 to 4, 5 to 8, and after 8 wk of age, respectively. Females were killed after they had been in production for 158 days. Females from three large-bodied lines had a greater incidence of smooth muscle tumors than those from a smaller randombred control line. The high dietary level of vitamin K3 had no influence on tumor development.

Topics: Animals; Bird Diseases; Body Weight; Coturnix; Female; Genital Neoplasms, Female; Leiomyoma; Leiomyosarcoma; Oviposition; Vitamin K

Topics: 4-Hydroxycoumarins; Animals; Anticoagulants; Antidotes; Body Burden; Body Weight; Dogs; Eating; Female; Liver; Male; Partial Thromboplastin Time; Pesticide Residues; Prothrombin Time; Rodenticides; Vitamin K

The present study describes the effect of high doses of vitamin K3 (8-30 mg/kg) administered daily by intramuscular injection during seven days; on blood smear, red blood cells (RBC) and concentration of hemoglobin (Hb) counts, value of hematocrit (Ht), mean corpuscular hemoglobin concentration (MCHC), reticulocyte and erythroblast counts, total and differential counting of leukocytes (WBC) and total and fractionated serum bilirubin concentration of albino male rats. Results were then compared with findings in normal rats treated with the same doses of sodium bisulfite. In animals treated with vitamin K3 a statistically significant decrease in the number of erythrocytes and in the concentration of Hb, Ht and MCHC was found together with a concomitant increase of erythroblast and reticulocyte counting. In regard to the blood smear, it was observed that erythrocytes vary in their hemoglobin content, size, shape and in their staining properties (polychromatophilia) where as the leukocytes were found to be morphologically normal, but in an increased number. Lymphocytes occasionally showed azurophil granules. Platelets assumed irregular shape and in normal amounts. The leukocytes count showed leukocytosis with marked neutrophilia, eosinophilia, lymphocytosis and monocytosis. Also, the presence of clinical jaundice with an increase of the serum "indirectly-reacting" bilirubin was also observed. These findings indicate that hypervitaminosis K3 induces a marked hemolytic microcytic hypochromic anemia and changes in the white blood cells count. Further studies will be pursued in order to obtain a better understanding of the causes and/or the mechanisms that induce these alterations in the blood cells.

Topics: Analysis of Variance; Anemia, Hemolytic; Animals; Bilirubin; Body Weight; Epidemiologic Methods; Erythrocyte Indices; Hematocrit; Hemoglobins; Injections, Intramuscular; Leukocyte Count; Male; Rats; Rats, Inbred Strains; Venezuela; Vitamin K

Three groups of beagle dogs (five/sex/group) were fed olestra, a mixture of octa-, hepta- and hexa-esters of sucrose formed with long-chain fatty acids, at 0, 5 or 10% of the diet for 20 months. The objective of the study was to assess the potential chronic toxicity of olestra in a non-rodent species. The feed was supplemented with vitamins A and E to ensure that the diets were nutritionally adequate and comparable for all groups. The levels of supplementation were established in a 91-day feeding study. Survival was 100% and growth was not affected by olestra. Olestra-fed animals consumed more feed than controls, apparently to compensate for the caloric dilution of the diet by olestra, but the increases were generally not statistically significant. No biologically significant changes were seen in haematological or serum biochemical parameters or in vitamin D and vitamin K status of the animals. Histopathology revealed no olestra-related effects. Isolated incidences of soft stools, apparently resulting from the large amounts of undigested olestra, were noted in olestra-fed animals. The results of this study indicate that olestra was not toxic when fed to dogs at up to 10% of the diet for 20 months.

Topics: Animal Feed; Animals; Anticholesteremic Agents; Body Weight; Dietary Fats, Unsaturated; Dogs; Dose-Response Relationship, Drug; Eating; Fatty Acids; Female; Leukocyte Count; Liver; Male; Sex Characteristics; Sucrose; Triglycerides; Vitamin A; Vitamin D; Vitamin E; Vitamin K

Cardiotoxic mechanisms induced by anthracyclines are not clearly determined. A possible hypothesis is free radical formation and cell damage due to the quinone part of the molecule. We have studied the effect of menadione on myocardial structure and function. The effect on the red blood cells has been also determined. Groups of rats were treated orally with increasing doses (5 mg/kg/d, increased to 20 mg/kg/d and 40 mg/kg/d in the 3rd and 5th w, respectively). Duration of treatment was 6 w. ECG and blood pressure changes and blood cell count, including Heinz-Ehrlich bodies and reticulocytes, hemoglobin and hematocrit, were determined before and after treatment weekly and every 2 w, respectively. At the end of the experiment, the hearts of 2 rats/group were processed for electron microscopy. Heart, spleen and liver weights were determined. Heart, spleen, liver and kidney were subjected to histopathological examinations. Menadione treatment did not affect growth. No significant ECG changes were obtained; only significant changes of wave amplitude were observed. Menadione caused no relevant hematological changes but there were some blood pressure alterations. Morphological changes in myocardial tissue were observed including a small disorganization of myofibrils and mitochondria crystolisis. Z-lines appear forming zigzags. There were differences in organ weights. This study showed the damage induced by menadione was less than injury induced by anthracyclines.

Topics: Animals; Body Weight; Electrocardiography; Heart; Male; Microscopy, Electron; Mitochondria, Heart; Myocardium; Pilot Projects; Rats; Rats, Inbred Strains; Vitamin K

The mechanism of induction of vitamin K (VK) deficiency in newborn babies and antibiotics-treated patients has not entirely been clarified because of the difficulty in preparing the true VK deficient model-animals and the complication in an assay system for VK derivatives and of their metabolites until now. Germfree animal is thought to be an useful tool to establish a primary VK deficiency not caused by VK antagonists etc., because of the lack of their intestinal flora. Germfree (GF) and conventional (CV) ICR/JCL male mice, 12-13 week-old were used in this experiment. VK deficient (K-Def), menaquinone-4 (MK-4) supplemented (MK-4), and VK3 (menadione) supplemented diet (K3) were fed to the mice in both GF and CV states. After 8 days, severe VK deficient symptoms were occurred only in GF-K-Def group, whereas not at all in CV-K-Def group. Both prothrombin time (PT) and activated partial thromboplastin time (APTT) were also prolonged only in GF-K-Def group. From the HPLC analysis of MK-4 content in liver, it was suspected that the content of MK-4 which has been thought to be an active form of VK was not necessarily paralleled with the degree of VK deficiency.

Topics: Animals; Body Weight; Disease Models, Animal; Germ-Free Life; Hemorrhage; Liver; Male; Mice; Mice, Inbred ICR; Organ Size; Partial Thromboplastin Time; Prothrombin Time; Vitamin K; Vitamin K Deficiency

The influence on the survival of ascitic liver tumor (TLT)-bearing mice of combined vitamins C and K3 administered before or after a single i.p. dose of 6 different cytotoxic drugs, all commonly used in human cancer therapy, was investigated. Combined i.p. administration of these vitamins produced a distinct chemotherapy-potentiating effect for all drugs examined, especially when injected before chemotherapy. This potentiating treatment did not increase the general and organ toxicity that accompanies cancer chemotherapy. The possible generation of peroxides followed by membrane lipid alteration, DNase activation and DNA destruction by combined vitamin C and K3 in catalase-deficient cancer cells might be involved in the mechanisms of this selective potentiation.

Topics: Animals; Antineoplastic Agents; Ascorbic Acid; Body Weight; Catalase; Cyclophosphamide; Deoxyribonucleases; DNA Damage; Drug Synergism; Enzyme Activation; Liver Neoplasms; Male; Mice; Organ Size; Vitamin K

In vivo synergy was demonstrated with vitamin K3 (menadione) and methotrexate in rats bearing the Walker 256 im carcinosarcoma, without concomitant increase in toxicity. Synergy is defined as a combined antitumor effect which exceeds the sum of the individual antitumor effects. It is suggested that such synergy, extended to human neoplasms, may significantly increase the effectiveness of methotrexate as a chemotherapeutic agent.

Topics: Animals; Body Weight; Carcinoma 256, Walker; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Synergism; Methotrexate; Rats; Vitamin K; Vitamin K 3

Studies have been done to determine the optimal dosage of vitamin E. Vitamin E is generally considered to be relatively nontoxic at high dosage in spite of the fact that it is a fat-soluble vitamin. From our experiments using mice, when various dosages of all-rac-alpha-tocopherol were injected into the intraperitoneal cavity every day, 1) the body weight decreased when the dose was more than 100 IU/kg per day, and all the mice died within 3 days at 400 IU/kg per day; 2) immune responses investigated by lymphoproliferative assays with phytohemagglutinin, concanavalin A and lipopolysaccharide were enhanced significantly between 5 and 20 IU/kg per day, but were inhibited by 80 IU/kg per day. When the immunopotentiation effect of vitamin E was discernible, serum tocopherol levels were about twice the control values. From our results, the optimal dosage of vitamin E was between 5 and 20 IU/kg per day, and dosages over 80 IU/kg per day were toxic to mice. We then experimented similarly with vitamin K, which is fat soluble and possesses a quinone structure resembling vitamin E. When doses between 12.5 and 150 mg/kg per day of vitamin K were injected into the intraperitoneal cavity daily fore 14 days, increase of body weight was generally inhibited. This did not depend on the dose, and there was no definite relationship between mitogen responses and vitamin K.

Topics: Adjuvants, Immunologic; alpha-Tocopherol; Animals; Body Weight; Dose-Response Relationship, Drug; Lymphocyte Activation; Male; Mice; Mice, Inbred Strains; Stereoisomerism; Tocopherols; Vitamin E; Vitamin K

Prenatal exposure to oral anticoagulants during pregnancy may result in defective fetal development or life-threatening hemorrhage. Fetal exposure during the first eight weeks of pregnancy may cause abnormal development of the facial structures, hypoplastic digits, strippled epiphyses, and mental retardation. Midtrimester exposure may result in optic atrophy, faulty brain growth, and developmental retardation. Third-trimester exposure may produce fetal anticoagulation, predisposing the infant to life-threatening hemorrhage in the perinatal period. Anticoagulation with heparin sodium does not provide a clearly safe alternative, since this therapy has been associated with excessive fetal loss.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Administration, Oral; Adult; Anticoagulants; Body Weight; Chondrodysplasia Punctata; Female; Fetus; Gestational Age; Humans; Infant, Newborn; Maternal-Fetal Exchange; Optic Atrophy; Pregnancy; Pregnancy Complications, Cardiovascular; Rheumatic Heart Disease; Vitamin K; Warfarin

Topics: Amenorrhea; Atrophy; Body Weight; Contraceptives, Oral; Female; Humans; Intrauterine Devices; Iron; Menopause; Menorrhagia; Menstruation Disturbances; Mucous Membrane; Oligomenorrhea; Vagina; Vitamin K

Topics: Animals; Body Weight; Diet; Female; Hematocrit; Leukocyte Count; Male; Prothrombin Time; Pyrimidines; Swine; Vitamin K; Vitamin K 2

A general saturation equation is derived which is shown to describe a wide variety of nutrient-response relationships in higher organisms. Iterative multiple linear regression analysis is used to obtain least squares estimates of the constants defining theoretical nutrient-response curves. Curves thus generated accurately predict experimentally observed responses. From this treatment, response parameters are developed which are analogous to Vmax and Km of enzyme kinetics. It is proposed that this model be applied in evaluating nutritional requirements and in assessing the relative biological efficiency of nutrient sources.

Topics: Animals; Blood Coagulation; Body Weight; Bone and Bones; Chickens; Dietary Proteins; Isoleucine; Kinetics; Mice; Models, Biological; Nutritional Physiological Phenomena; Rats; Vitamin A; Vitamin D; Vitamin K

Topics: Alkanes; Animals; Arthritis; Body Weight; Corynebacterium; Encephalomyelitis, Autoimmune, Experimental; Fatty Acids; Freund's Adjuvant; Hydrocarbons; Male; Mycobacterium tuberculosis; Nocardia asteroides; Oils; Oxygen; Pharmaceutical Vehicles; Rats; Squalene; Structure-Activity Relationship; Triglycerides; Vaccines, Attenuated; Vitamin A; Vitamin E; Vitamin K

Topics: Adrenal Glands; Animals; Blood Cell Count; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Platelets; Body Weight; Cold Temperature; Factor V; Factor VII; Factor X; Feces; Fibrinogen; Hair; Hemoglobins; Iodine; Male; Organ Size; Prothrombin Time; Rats; Testis; Thyroid Gland; Vitamin K

Topics: Animals; Blood Coagulation; Body Weight; Carotenoids; Chickens; Fibrinogen; Liver; Prothrombin Time; Time Factors; Vitamin A; Vitamin K; Vitamin K Deficiency

This paper deals with the stimulatory effect of the compound 2-methyl-1,4-naphthoquinone, Menadione (vit. K3), in young chicken, during the growing period. That's the case of other products like Bacitracin, Actinomycin D and Terramycin, whose hormetic activity is supplanted by the referred Menadione. Authors present the experimental data with analytical discussion of the results.

Topics: Analysis of Variance; Animals; Bacitracin; Body Weight; Chickens; Dactinomycin; Female; Growth; Male; Oxytetracycline; Stimulation, Chemical; Time Factors; Vitamin K

Topics: Amino Acids; Body Weight; Bronchial Fistula; Enteral Nutrition; Esophageal Atresia; Female; Gastrostomy; Humans; Infant Food; Infant, Newborn; Infant, Newborn, Diseases; Intestinal Obstruction; Lipids; Liver Function Tests; Male; Osmolar Concentration; Postoperative Care; Radiography; Sucrose; Tracheoesophageal Fistula; Vitamin K

Topics: Animals; Body Weight; Choline; Deficiency Diseases; Diet; Drinking Behavior; Fatty Liver; Feces; Feeding Behavior; Female; Hematocrit; Hemoglobins; Hemorrhage; Male; Nitrogen; Nutritional Physiological Phenomena; Organ Size; Rats; Time Factors; Urine; Vitamin K

Topics: Animals; Body Weight; Bone Development; Embryo Implantation; Female; Fetal Death; Fetus; Maternal-Fetal Exchange; Osteogenesis; Pregnancy; Rats; Time Factors; Vitamin K

Topics: Animal Nutritional Physiological Phenomena; Animals; Animals, Newborn; Bilirubin; Body Weight; Diet; Female; Growth; Male; Maternal-Fetal Exchange; Organ Size; Pregnancy; Rats; Time Factors; Vitamin K

Topics: Animals; Avitaminosis; Body Height; Body Weight; Growth; Longevity; Neoplasms; Rats; Vitamin A; Vitamin B Complex; Vitamin D; Vitamin E; Vitamin K; Vitamins

Topics: Acetamides; Animals; Benzopyrenes; Body Weight; Carcinogens; Drug Synergism; Enzyme Induction; Female; Fluorenes; Liver; Mixed Function Oxygenases; Nicotiana; Organ Size; Oxidoreductases; Plants, Toxic; Rats; Sesame Oil; Smoking; Sucrose; Tritium; Vitamin K

Topics: Administration, Oral; Animals; Body Weight; Depression, Chemical; Dicumarol; Hemorrhage; Male; Mice; Vitamin K

Topics: Animals; Bilirubin; Blood Coagulation; Body Weight; Factor Analysis, Statistical; Hemostatics; Male; Prothrombin Time; Rabbits; Thrombelastography; Vitamin K

Topics: Animals; Biological Transport; Body Weight; Cattle; Chromatography, DEAE-Cellulose; Depression, Chemical; Female; Hematocrit; Heparin; Immunodiffusion; Iodine Isotopes; Male; Methods; Models, Biological; Prothrombin; Rabbits; Stimulation, Chemical; Thrombin; Time Factors; Vitamin K; Warfarin

Topics: Animals; Body Weight; Cecal Diseases; Coccidiosis; Poultry Diseases; Vitamin A; Vitamin B Complex; Vitamin K; Vitamins

Topics: Adolescent; Adult; Body Height; Body Weight; Calcium; Celiac Disease; Diet Therapy; Dwarfism; Female; Folic Acid; Humans; Iron; Malabsorption Syndromes; Radiography; Vitamin K

Topics: Anemia, Hypochromic; Avitaminosis; Body Weight; Carbohydrate Metabolism; Diarrhea; Disaccharides; Edema; Feces; Folic Acid; Glucose; Humans; Hypocalcemia; Hypokalemia; Hypoproteinemia; Intestinal Absorption; Intestine, Small; Iron; Malabsorption Syndromes; Vitamin A; Vitamin B 12; Vitamin K; Xylose

Topics: Animals; Body Weight; Cariogenic Agents; Cariostatic Agents; Dental Caries Susceptibility; Dietary Carbohydrates; Dietary Fats; Oils; Rats; Vitamin A; Vitamin D; Vitamin E; Vitamin K; Vitamins

Topics: Acetates; Alcohols; Animals; Bile Acids and Salts; Body Weight; Chickens; Cholestyramine Resin; Intestinal Absorption; Ion Exchange Resins; Liver; Meat; Metabolism; Palmitic Acid; Pharmacology; Poultry; Prothrombin Time; Rats; Research; Toxicology; Vitamin A; Vitamin K; Vitamins

Topics: Anorexia; Anorexia Nervosa; Body Weight; Diet; Diet Therapy; Humans; Psychiatry; Vitamin A; Vitamin K; Vitamins

Topics: Body Weight; Cholesterol; Humans; Infant; Infant, Newborn; Infant, Premature; Nandrolone; Propionates; Testosterone; Vitamin A; Vitamin D; Vitamin K; Vitamins; Weight Gain