The systems involved in vitaminK-dependent carboxylation and vitaminKmetabolism have been extensively studied in rat liver. To determine how clinically applicable this information is, similar in vitro studies were completed using human liver. One major difference exists in the pathways that provide reduced vitamin K1 cofactor for the carboxylation reaction. The coumarin-sensitive DT-diaphorase (EC.188.8.131.52) in human liver appears to play a relatively minor role in the dehydrogenase pathway. However, similar to rat liver, the human liver contains a warfarin-insensitive enzyme in this dehydrogenase pathway. The data suggest that this enzyme is responsible for the antidotic effect of vitamin K1 in cases of coumarin intoxication. Human vitaminK epoxide reductase, which constitutes the other pathway for vitamin K1 reduction, has kinetic and enzymological characteristics that are very similar to the rat enzyme. This enzyme exhibited similar activity in rat and human microsomes. Initial velocities for vitamin K1 epoxide reduction in rat and human microsomes were 20 and 32 pmol/mg X min, respectively. The human enzyme is highly sensitive to warfarin inhibition. The mechanism for this inhibition appears to be similar to what has been proposed for the rat enzyme. Also, a vitaminK-dependent carboxylation system is described that allows both pathways to support the carboxylation reaction with reduced vitamin K1 cofactor. The effect of warfarin on this in vitro […]
endogenous VKD protein substrate (Wallin, Gebhardt, & Prydz, 1978) or into the synthetic peptide substrates (Johan et al., 1987; Wallin & Martin, 1987). Microsomes prepared from animal liver were used to mimic the in vivo vitaminKmetabolism in vitro. Using this coupled in vitro activity assay system, Wallin et al. have confirmed the existence of both the warfarin-sensitive and warfarin-resistant pathways for vitaminK reduction (Wallin & Martin, 1987). In addition, these authors have shown that the reduction of vitaminK is the rate-limiting step in VKD carboxylation (Wallin, Sane, & Hutson, 2002), which has been further confirmed by studying VKD coagulation factor carboxylation in mammalian cells (Hallgren, Qian, Yakubenko, Runge, & Berkner, 2006; Sun, Jin, Camire, & Stafford, 2005; Wajih et al., 2005). Recently, Rishavy et al. reported a similar assay system that coexpressed VKOR and GGCX in insect cells lacking endogenous VKD carboxylation components (Rishavy et al., 2013). VKR function was studied using the coupled activity assay system from intact microsomes. This in vitro coupling-assay approach appears reasonable for studying vitaminKmetabolism and VKD carboxylation; however, the enzymes of the vitaminK cycle have very different lipid and/or detergent requirements for their activities (Carlisle & Suttie, 1980; Hildebrandt, Preusch, Patterson, & Suttie, 1984), which makes it difficult to study the interactions and activities of these enzymes together in vitro.
Benzene is a highly flammable, colorless liquid, and ubiquitous exposures result from its presence in gasoline vapors, cigarette smoke, and industrial processes. After uptake into the body, benzene undergoes a series of metabolic transformations resulting in multiple metabolites that exert toxic effects on the bone marrow. We developed a physiologically based pharmacokinetic model for the uptake and elimination of benzene in mice to relate the concentration of inhaled and orally administered benzene to the tissue doses of benzene and its key metabolites. This model takes into account the zonal distribution of enzymes and metabolisms in the liver, rather than treating the liver as one homogeneous compartment, and considers metabolism in tissues other than the liver. Analysis was done to examine the existence and uniqueness of solutions of the system. We then formulated an inverse problem to obtain estimates for the unknown parameters; data from multiple laboratories and experiments were used. Despite the sources of variability, the model simulations matched the data reasonably well in most cases, showing that the multicompartment metabolism model does improve predictions over the previous model  and that in vitro metabolic constants can be successfully extrapolated to predict in vivo data for benzene metabolism and dosimetry.
Inorganic phosphate (Pi) tended to be lower in CMH supplemented pigs and diﬀ erences between control and CMH + vitamin E supplemented groups were signiﬁ cant (P ≤ 0.05). Opposite tendency were found for phosphocreatine level (PCr) with highest value in pigs supplemented with CMH + vitamin E but diﬀ erences if compare to control group were signiﬁ cant (P ≤ 0.05). Values of ATP (- ATP) were relatively stabile if compare control and experimental groups and diﬀ erences were not signiﬁ cant (P ≥ 0.05). Eﬃ ciency of the metabolism of muscle energetic compounds evaluated by index PCr/Pi was found higher in groups supplemented with CMH and diﬀ erences between group supplemented CMH + vitamin E and control pigs were signiﬁ cant (P ≤ 0.05). Results on P NMR spectroscopy parameters are comparable with earlier results of non mutated genotype (on MH homozygote) of biopsy samples taken of 15 min a er slaughter (Lahucky et al., 2004). Higher eﬃ ciency of energetic muscle metabolism (reduced PCr breakdown, slower PCr decay and higher PCr/ Pi ratio) were found also by others (Moesgaard et al., 1995; Lahucky et al., 2004) in pigs supplemented by magnesium oxide (MgO). It was also shown (Lahucky et al., 2000) that supplementation with vitamin E could improve the eﬃ ciency of the metabolism of energetic compounds in musculus longissimus dorsi. Total water and total protein contents (Tab. IV) were not inﬂ uenced and signiﬁ cant diﬀ erences were not found (P ≥ 0.05). Intramuscular fat content was higher in group CMH compared to CMH + E and the control group. Berg and Allee (2001) reported 5 days CMH
Vitamin D is a steroid hormone that can be synthesized in the skin after exposure to ultraviolet light and can also be obtained through exogenous supplementation or dietary intake. 1 Epidemiological studies have shown that vitamin D de ﬁ ciency affects nearly one billion people worldwide. 2 Vitamin D de ﬁ ciency is more severe in adults, especially in the Middle East and Asia. 3 The prevalence of vitamin D de ﬁ ciency varies by geographical location, duration of sunlight, use of sunscreen, and dietary habits. 4 A recent multi-centric study in ﬁ ve major cities in China 5 found that the prevalence of vitamin D de ﬁ ciency in mainland urban population was 55.9%, and the serum level of 25-hydroxyvitamin D [25(OH)D] was <50 nmol/L. Other studies have shown that the prevalence of vitamin D de ﬁ ciency in adult men and women in the United States ranged from 40% to 100%. 6
The fate of an intravenous dose of tritiated vitamin D 3 was studied in seven normal subjects, four children with vitamin D-resistant rickets, and four adults with a familial history of vitamin D-resistant rickets and persistent hypophosphatemia. An abnormal metabolism of vitamin D in vitamin D-resistant rickets was defined and characterized by a decrease in the plasma fractional turnover rate, a marked increase in plasma water-soluble metabolites, and a relative decrease in the conversion of vitamin D to a polar, biologically active metabolite. Alterations in vitamin D metabolism in the adults with persistent hypophosphatemia were similar but less severe than those of affected children with vitamin D-resistant rickets. It is tentatively concluded that the abnormalities in vitamin D metabolism documented in
Recent evidence suggests that non-vitaminK oral anticoagulants (NOACs) are as effective as vitaminK antagonists (VKAs) such as warfarin in the prevention of stroke and systemic embolism in patients with AF with a lower risk of intracranial hemorrhage. As com- pared to warfarin, dabigatran was associated with reduced risk of ischemic stroke and systemic embo- lism as well as intracranial hemorrhage, but with a higher rate of gastrointestinal hemorrhage. 10 Apixa-
16. Tremey B, Tazarourte K, Ract C, Gabteni M, Lavagna L, Dépret-Vassal J, Segalin V, Saintonge S, Vigué B: Teaching improves adherence to clinical guidelines in the treatment of oral anticoagulation-related severe bleeding in the emergency department. Intensive Care Med 2009, 35:1444 – 1448. 17. Menzin J, Hoesche J, Friedman M, Nichols C, Bergman GE, Crowther M, Garcia D, Jones C: Failure to correct International Normalized Ratio and mortality among patients with warfarin-related major bleeding: an analysis of electronic health records. J Thromb Haemost 2012, 10:596 – 605. 18. Tanaka KA, Szlam F, Dickneite G, Levy JH: Effects of prothrombin complex
In this thesis, we have developed a physiologically based pharmacokinetic model for the uptake and metabolism of benzene in mice. This compartmental model was found by applying mass balance techniques to a series of compartments that represent the concentration or amount of various metabolites of benzene in different tissues. The original single compartment liver model only included metabolism in the liver, which was assumed to be one homogeneous compartment. The existence and uniqueness of solutions of this system of differential equations were examined. An inverse prob- lem was formulated using a modified maximum likelihood cost function to find the values of unknown parameters; here, our model results were compared to published experimental data obtained from multiple independent laboratories. The sensitivity coefficients for various estimated parameters were investigated and confidence inter- vals for chi-squared distributions with one degree of freedom were also computed. Although the model produced reasonable predictions for much of the urinary data and gave very accurate qualitative results for the amount of benzene exhaled, there were still large discrepancies in the model predictions of the tissue data.
Anticoagulant therapy is the mainstay treatment for the primary and secondary prevention of thromboembolic complications in patients with atrial ﬁ brillation (AF), venous thromboembolism (VTE) and mechanical heart valve replacement. 1 However, since it is a chronic treatment for most clinical indications, it can affect the health-related quality of life. 2,3 For instance, vitaminK antagonists (VKA), such as warfarin, have several food and drug interactions and require dose adjustment, therefore mandating periodic blood testing of the international normalized ratio (INR). 1
The metabolic fate of intravenously injected vitamin D 3 -1,2- 3 H (D 3 - 3 H) was studied in two normal individuals on chronic phenobarbital therapy. Silicic acid column chromatography of lipid-soluble plasma extracts obtained serially for 96 hr after D 3 - 3 H injection demonstrated a decreased plasma D 3 - 3 H half-life and increased conversion to more polar metabolites. The polar metabolites formed included several with chromatographic mobility similar to known biologically inactive vitamin D metabolites and one with chromatographic mobility identical to 25-hydroxycholecalciferol. Disappearance of this latter material was also accelerated. A child with rickets and a normal volunteer studied before and after a 2 wk course of
ultraviolet A and B, and demonstrated that systolic and diastolic blood pressure significantly decreased after 6 weeks of therapy in the ultraviolet B group, suggesting that vitamin D synthesis in the skin lowered blood pres- sure . A randomized controlled trial conducted in el- derly German women demonstrated that modest doses of vitamin D (400 IU) plus calcium given orally over an 8-week period significantly reduced their systolic blood pressure by 9% . However, studies conducted on el- derly subjects in Denmark , in Taiwan , and in the UK  demonstrated no effect of vitamin D sup- plementation on blood pressure. At the end of 7 years of follow-up, the Women’s Health Initiative Study (WHI) conducted in the United States demonstrated no signifi- cant difference in systolic or diastolic blood pressure in women randomized to calcium and vitamin D (400 IU) . Thus, studies on vitamin D supplementation have not consistently demonstrated a positive therapeutic effect on hypertension.
2. Wright, N.C.; Looker, A.; Saag, K.; Curtis, J.R.; Dalzell, E.S.; Randall, S.; Dawson- Hughes, B. The recent prevalence of osteoporosis and low bone mass based on bone mineral density at the femoral neck or lumbar spine in the United States. J Bone Miner Res., 2014; 29(11): 2520-6.
Table 4 shows the nonimmunization rates for children receiving and not receiving vitaminK prophylaxis. For DTaP-IPV-Hib, meningococcal conjugate and pneumococcal conjugate, which are scheduled to have 3 doses by 12 months of age, the nonimmunization rates as of 15 months were consis- tently ∼ 5% in those who received the vitaminK prophylaxis (either injection or oral), but 74% to 75% in those who did not receive vitaminK prophylaxis. For MMR and varicella vaccines, which are scheduled to have 1 dose at 12 months, 18.7% and 20.4%, respectively, of those who received vitaminK pro- phylaxis were not immunized as of 15 months; in comparison, 82.1% and 85.0%, respectively, were not immu- nized in those refusing the prophylaxis. Overall, the risk of being completely unimmunized with any of these sched- uled childhood immunizations (DTaP-IPV- Hib, meningococcal and pneumococ- cal conjugates, MMR, and varicella) at 15 months was 14.6 (95% CI 13.9 – 15.3) times higher in those who declined vitaminK, compared with those re- ceiving the prophylaxis.
A recent RCT investigated the effects of high dose Vitamin D supplementation compared with low dose supplementation in Long Term Care (LTC) residents in relation to rates of Acute Respiratory Infections (ARIs) (Ginde et al., 2017). Residents aged >60 years from 25 different facilities were eligible for inclusion. Those with a history of sarcoidosis, hypercalcaemia, renal failure, renal stones, active cancer, Vitamin D supplementation >1,000IU/day and immunosuppression use were excluded. A total of 107 residents were randomised, 55 to receive high dose Vitamin D (3,00-4,000IU/day) and 52 to receive standard dose Vitamin D (400-1,000IU/day). The mean age of participants in the high dose group was 80 years compared with 82 years in the standard group was with a mean serum 25(OOH)D level of 57.4nmol/L in both groups initially. Over the twelve-month follow-up period, there was a lower incidence of overall ARI rates in the high dose group compared with the low dose group, RR 0.60 (0.38-0.94, 95% CI). In subgroup analysis, the high dose group had lower rates of upper ARI, but there was no difference between groups in relation to lower ARI rates. Also, there was no difference between mortality and all cause hospitalisation between the groups. There was of note higher incidence of falls in the higher dose Vitamin D group, the reasons for which are unclear.
fracture, as there is a lack of evidence. The USPSTF also states that “ Daily supplementation with ≤ 400 IU of vitamin D3 and ≤ 1000 mg of calcium has no net bene ﬁ t for the primary prevention of fractures ” and that “ Evidence is lacking regarding the bene ﬁ t of daily sup- plementation with >400 IU of vitamin D3 and >1000 mg of calcium for the primary prevention of fractures in postmenopausal women, and the balance of bene ﬁ ts and harms cannot be determined. ” 17 Thus, what else can a clinician prescribe to help to prevent osteoporosis and its consequences? A broad amount of data seems to indicate substantial potential for supplementary vitaminK. However, currently few guidelines recommend vitaminK therapy for prevention or treatment of osteoporosis.