Vitamin D and uterine leiomyoma among a sample of US women: Findings from NHANES, 2001–2006

Scientific understanding of the etiology of uterine leiomyomata (UL) remains incomplete, but recent investigations have suggested an association between low Vitamin D and UL risk. In this study, we conducted a cross-sectional analysis of Vitamin D exposure, measured using serum levels of 25(OH)D (a Vitamin D metabolite), and self-reported UL diagnosis among 3590 women aged 20–54 in the National Health and Nutrition Examination Survey (NHANES 2001–2006). Multivariate logistic regression models comparing each quartile of 25(OH)D to the lowest quartile indicated no relationship between 25(OH)D and odds of UL in the whole population (P_trend = 0.37), or in sensitivity analyses. However, a probabilistic analysis correcting outcome misclassification indicated that insufficient 25(OH)D was associated with UL in white (Odds ratio (OR) median estimate: 2.17; 2.5, 97.5 percentiles: (1.26, 23.47)), but not black women (OR median estimate: 1.70; 2.5, 97.5 percentiles: (0.89, 3.51)), suggesting misclassification may have driven some of the null findings.     

Effects of ezetimibe,simvastatin, atorvastatin,and ezetimibe–statin therapies on non-cholesterol sterols in patients with primary hypercholesterolemia

ABSTRACT

Background: Levels of cholesterol are regulated by its synthesis, absorption, and elimination. Plasma levels of phytosterols (e.g., sitosterol, campesterol) and ratios of these sterols to total cholesterol (TC) are reported to correlate with efficiency of intestinal cholesterol absorption, whereas levels of certain cholesterol precursor sterols (e.g., desmosterol, lathosterol) and their ratios to TC correlate with cholesterol biosynthesis. However, there is a paucity of published data concerning the effects of combined treatment using HMG-CoA reductase inhibitors (statins) and a cholesterol absorption inhibitor (ezetimibe) on these parameters.

Objectives: To characterize the effects of ezetimibe co-administered with statins, compared with each treatment alone, on cholesterol precursor sterols and plasma phytosterol levels.

Methods: A post-hoc analysis was performed to determine the effects of treatment with ezetimibe 10?mg, simvastatin (10–80?mg), and atorvastatin (10–80?mg), alone or in combination, on these non-cholesterol sterols using plasma samples from two randomized controlled trials involving patients with primary hypercholesterolemia (low-density lipoprotein [LDL-C]?=?145–250?mg/dL; triglycerides ≤350?mg/dL; N?=?975) but without a recent (≤6-month) history of coronary heart disease (CHD) or either uncontrolled or newly diagnosed diabetes mellitus.

Results: Ezetimibe monotherapy significantly reduced plasma sitosterol and campesterol concentrations from baseline compared with placebo (both p?<?0.001), whereas statins significantly lowered desmosterol and lathosterol levels (p?<?0.001 vs. placebo). Co-administration of ezetimibe and statins significantly decreased plasma levels of all of these sterols (p?<?0.001).

Conclusions: The observed effects of co-administration of ezetimibe and statins on non-cholesterol sterols are consistent with net inhibition of sterol absorption (driven by ezetimibe) in conjunction with net inhibition of cholesterol synthesis (driven by statins). The potential influence of treatment-induced changes in phytosterols on cardiovascular risk warrants further investigation in long-term, prospective, randomized controlled trials. This post-hoc study was by nature exploratory, and, because data from such analyses are not customarily adjusted for multiple comparisons, some associations may have emerged as statistically significant by chance. Future prospective randomized controlled studies may help to confirm our findings and address other research issues, such as the generalizability of our findings to patients with CHD or diabetes mellitus and possible dose:response relationships between escalating statin (or ezetimibe–statin) doses and circulating non-cholesterol levels.     

Human disposition,metabolism and excretion of etamicastat,a reversible,peripherally selective dopamine β-hydroxylase inhibitor

Aims

Etamicastat is a reversible dopamine-β-hydroxylase inhibitor that decreases noradrenaline levels in sympathetically innervated tissues and slows down sympathetic nervous system drive. In this study, the disposition, metabolism and excretion of etamicastat were evaluated following [¹⁴C]-etamicastat dosing.

Methods

Healthy Caucasian males (n = 4) were enrolled in this single-dose, open-label study. Subjects were administered 600 mg of unlabelled etamicastat and 98 µCi weighing 0.623 mg [¹⁴C]-etamicastat. Blood samples, urine and faeces were collected to characterize the disposition, excretion and metabolites of etamicastat.

Results

Eleven days after administration, 94.0% of the administered radioactivity had been excreted; 33.3 and 58.5% of the administered dose was found in the faeces and urine, respectively. Renal excretion of unchanged etamicastat and its N-acetylated metabolite (BIA 5-961) accounted for 20.0 and 10.7% of the dose, respectively. Etamicastat and BIA 5-961 accounted for most of the circulating radioactivity, with a BIA 5-961/etamicastat ratio that was highly variable both for the maximal plasma concentration (19.68–226.28%) and for the area under the plasma concentration–time curve from time zero to the last sampling time at which the concentration was above the limit of quantification (15.82– 281.71%). Alongside N-acetylation, metabolism of etamicastat also occurs through oxidative deamination of the aminoethyl moiety, alkyl oxidation, desulfation and glucuronidation.

Conclusions

Etamicastat is rapidly absorbed, primarily excreted via urine, and its biotransformation occurs mainly via N-acetylation (N-acetyltransferase type 2), although glucuronidation, oxidation, oxidative deamination and desulfation also take place.     

Oxycodone IV?; Eliminate Teaspoonfuls; Avoid Vitamin D Products Dosed and Measured in Drops

These medication errors have occurred in health care facilities at least once. They will happen again—perhaps where you work. Through education and alertness of personnel and procedural safeguards, they can be avoided. You should consider publishing accounts of errors in your newsletters and/or presenting them at your inservice training programs.Your assistance is required to continue this feature. The reports described here were received through the Institute for Safe Medication Practices (ISMP) Medication Errors Reporting Program. Any reports published by ISMP will be anonymous. Comments are also invited; the writers’ names will be published if desired. ISMP may be contacted at the address shown below.Errors, close calls, or hazardous conditions may be reported directly to ISMP through the ISMP Web site (www.ismp.org), by calling 800-FAIL-SAFE, or via e-mail at gro.pmsi@ofnipmsi. ISMP guarantees the confidentiality and security of the information received and respects reporters’ wishes as to the level of detail included in publications.     

Identification and characterization of degradation products of irbesartan using LC–MS/TOF,MS, on-line H/D exchange and LC–NMR

Irbesartan was subjected to hydrolytic, oxidative, photolytic and thermal stress, according to ICH guideline Q1A (R2). The drug showed degradation only in acidic, basic and photoacidic conditions, while it was stable to other stress conditions. A total of three degradation products were formed, which were separated on a C-8 column employing a gradient HPLC method. Initially, a complete mass fragmentation pathway of the drug was established with the help of MS/TOF, MSⁿ and H/D exchange studies. Subsequently, the degradation products were subjected to LC–MS/TOF and on-line H/D exchange mass studies to obtain their accurate mass, fragment pattern and number of labile hydrogens. The MS results helped to assign tentative structures to degradation products, which were verified through ¹H and 2D COSY LC–NMR experiments. The products were identified as (2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methanamine, 1-(1-((2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methylamino)pentylideneamino)cyclopentane carboxylic acid and 2-butyl-3-(tetrazolo[1,5-f]phenanthridin-6-ylmethyl)-1,3-diazaspiro[4.4]non-1-en-4-one. The structures were justified by mechanisms of their formation.     

Chronic inhibition of dipeptidyl peptidase-IV with ASP8497 improved the HbA1c level, glucose intolerance, and lipid parameter level in streptozotocin–nicotinamide-induced diabetic mice

Dipeptidyl peptidase-IV (DPP-IV) is the primary inactivator of glucoregulatory incretin hormones, and DPP-IV inhibitors are expected to become a useful new class of anti-diabetic agent. The aim of the present study is to characterize the chronic in vivo profile of the DPP-IV inhibitor ASP8497. In streptozotocin-nicotinamide-induced diabetic mice, ASP8497 was administered orally for 3 weeks at 1, 3, or 10 mg/kg once daily, which improved the hemoglobin A_1c, non-fasting plasma insulin, fasting blood glucose levels, glucose intolerance, and lipid profiles (plasma triglyceride, non-esterified fatty acid and total cholesterol) with neutral effect on body weight. The pancreatic insulin content and hepatic phosphoenolpyruvate carboxykinase (PEPCK) activity recovered dose-dependently in ASP8497-treated groups. These results revealed that ASP8497 was successful in improving glycemic control and metabolic parameters in streptozotocin-nicotinamide-induced diabetic mice. It is therefore suggested that ASP8497 may be a potential agent for the treatment of type 2 diabetes.     

Identification and characterization of a photolytic degradation product of telmisartan using LC–MS/TOF,LC–MS,LC–NMR and on-line H/D exchange mass studies

Telmisartan, an anti-hypertensive drug, was subjected to stress studies under ICH prescribed conditions of hydrolysis (acidic, neutral and basic), photolysis, oxidation and thermal stress. The drug showed labiality under only photo-acidic condition by forming a single degradation product. HPLC separation of the drug and the degradation product was achieved on C-8 column using gradient method. To characterize the product, a complete mass fragmentation pathway of the drug was initially established. Subsequently, the degradation product peak was subjected to LC–MS/TOF and on-line H/D exchange mass studies. Based on these studies, a tentative structure was assigned to the product as 3-((1,7′-dimethyl-2′-propyl-1H,3′H-2,5′-bibenzo[d]imidazol-3′-yl)methyl)-6H-benzo[c]chromen-6-one, which was verified through ¹H LC–NMR experiments.     

Vitamin D status in relation to age,bone mineral density of the spine and femur in obese Saudi females – A hospital-based study

The aim of the present study was to evaluate the association between Bone mineral density in lumber spine and femoral neck with serum total levels of vitamin D, sun exposure and Consumption of vitamin D Supplement in obese Saudi females aged between 30 and 54?years old. Recent attention to the high prevalence of osteoporosis and its association with low vitamin D levels in adults has raised the importance of vitamin D evaluation. A low level of vitamin D is considered to be one of the most important risk factors for osteoporosis. In this study; 120 obese Saudi females with no diagnosed chronic diseases attending the Outpatient clinic at king Khalid University hospital in Riyadh. Saudi Arabia, recruited randomly in period of 12?months. In this study, Serum levels of total Vitamin D were considered to be severe deficient if it was lower than 25?ng/mL, mild to moderate deficient if it was between 25 and 60?ng/mL and optimum level if it was 61–200?ng/mL. The results showed that; sun exposure was significantly affect and Correlate with serum level of Vitamin D in the subjects. In addition, daily consumption of Vitamin D supplement was significantly affect and Correlate with serum level of Vitamin D in the subjects of this study. Moreover, the results showed that; 50% of the age group (40–49?years old) having severe deficiency of Vitamin D. While, 50% of the age group (50–59?years old) having optimal level of Vitamin D. And these results mean that age is not Correlated with vitamin D deficiency in subjects of this study.     

Design,synthesis and biological evaluation of bivalent ligands against A1–D1 receptor heteromers

Aim:

To design and synthesize bivalent ligands for adenosine A₁–dopamine D₁ receptor heteromers (A₁–D₁R), and evaluate their pharmacological activities.

Methods:

Bivalent ligands and their corresponding A₁R monovalent ligands were designed and synthesized. The affinities of the bivalent ligands for A₁R and D₁R in rat brain membrane preparation were examined using radiolabeled binding assays. To demonstrate the formation of A₁–D₁R, fluorescence resonance energy transfer (FRET) was conducted in HEK293 cells transfected with D₁-CFP and A₁-YFP. Molecular modeling was used to analyze the possible mode of protein-protein and protein-ligand interactions.

Results:

Two bivalent ligands for A₁R and D₁R (20a, 20b), as well as the corresponding A₁R monovalent ligands (21a, 21b) were synthesized. In radiolabeled binding assays, the bivalent ligands showed affinities for A₁R 10–100 times higher than those of the corresponding monovalent ligands. In FRET experiments, the bivalent ligands significantly increased the heterodimerization of A1R and D₁R compared with the corresponding monovalent ligands. A heterodimer model with the interface of helixes 3, 4, 5 of A1R and helixes 1, 6, 7 from D₁R was established with molecular modeling. The distance between the two ligand binding sites in the heterodimer model was approximately 48.4 Å, which was shorter than the length of the bivalent ligands.

Conclusion:

This study demonstrates the existence of A₁–D₁R in situ and a simultaneous interaction of bivalent ligands with both the receptors.     

Safety and efficacy of fibrate–statin combination therapy compared to fibrate monotherapy in patients with dyslipidemia: A meta-analysis

BackgroundDyslipidemia is a major risk factor for the development of cardiovascular disease. Treatment with fibrate, statins, or other lipid-lowering drugs prevents primary or recurrent cardiovascular events. However, all lipid-lowering drugs have side effects, which may become more severe if combination therapy is prescribed.MethodsWe performed a meta-analysis of published data to compare the safety and efficacy of fibrates alone, compared to fibrate–statin combinations, in patients with dyslipidemia. Six articles were assessed in terms of the efficacy of therapy and nine from the viewpoint of therapeutic safety.ResultsIn terms of efficacy, fibrate–statin combinations afforded significantly greater reductions in the levels of total cholesterol (SE = −2.248; 95% CI 1.986–2.510), LDL cholesterol (SE = −2.274; 95% CI 2.015–2.533), and triglycerides (SE = −0.465; 95% CI 0.272–0.658) compared to fibrate alone. In terms of safety, treatment with fibrate alone was associated with a significant decrease in the number of kidney-related adverse events (RR = −0.547; 95% CI 0.368–0.812), compared to treatment with fibrate–statin combinations.ConclusionWe suggest that treatment with a fibrate–statin combination affords clinical benefits that are superior to treatment with fibrate alone, but increases the risk of side effects (particularly renal). Therapy should thus be carefully monitored.     

Vitamin D<Subscript>3</Subscript>–Based Conjugates for Topical Treatment of Psoriasis: Synthesis,Antiproliferative Activity,and Cutaneous Penetration Studies

No HeadingPurpose. The goals of the experiments reported in this paper were to explore skin bioavailability and cell growth inhibitory activity of new vitamin D₃–based conjugates studied as a potential drug complex for psoriasis.Methods. Conjugation was made between polyunsaturated fatty acids (PUFAs), such as linolenic acid or -linolenic acid, and calcipotriol—a vitamin D₃ analogue clinically used for topical treatment of psoriasis. These complexes were prepared by coupling the corresponding fatty acid with calcipotriol in the presence of dicyclohexyl-carbodiimide (DCC) and 4-(dimethylamino)-pyridine (DMAP) to obtain an ester bond.Results. The conjugates were capable of enhancing the penetration of the vitamin into the skin as well as inhibiting proliferation of keratinocytes in cultures. The antiproliferative activity even increased after simulating the full hydrolysis of the conjugates. In vitro skin penetration studies revealed that the conjugates penetrated into the skin at higher levels relative to calcipotriol alone. It was also demonstrated that the conjugate containing n-3 fatty acid penetrated into the skin at higher levels as compared to the conjugate containing n-6 PUFA. High-performance liquid chromatography analysis has shown that after penetration, a major portion of calcipotriol-PUFA conjugate was first converted mainly into another isomer form, presumably by transesterification, and only then it was hydrolyzed to form apparently high local concentrations of both calcipotriol and PUFA.Conclusions. The unique biotransformation that occurred after penetration into the skin indicates that these conjugates are mutual prodrugs that are able to be bioprocessed in the skin and fully converted to the parent therapeutic agents.     

Vascular Calcification,Vitamin K and Warfarin Therapy – Possible or Plausible Connection?

Atherosclerosis is a pathological process underpinning many cardiovascular diseases; it is the main cause of global mortality. Atherosclerosis is characterized by an invasion of inflammatory cells, accumulation of lipids and the formation of fatty streaks (plaques) which subsequently allow accumulation of calcium and other minerals leading to a disturbance in the vascular endothelium and its regulatory role in arterial function. Vascular calcification is a different process, stringently regulated mainly by local factors, in which osteoblast‐like cells accumulate in the muscular layer of arteries ultimately taking on the physiological appearance of bone. The elevated stiffness of the arteries leads to severe vascular complications in brain, heart and kidneys. Recently, evidence from animal experiments as well as clinical and epidemiological results suggests that long‐term treatment with warfarin, but not with the novel direct anticoagulants, can increase the risk or even induce vascular calcification in some individuals. Gamma‐carboxylation is an enzymatic process not only needed for activation of vitamin K but also other proteins which participate in bone formation and vascular calcification. Thus, reduced expression of the vitamin K‐dependent proteins which physiologically inhibit calcification of cellular matrix could be postulated to lead to vascular calcification. Published clinical data, describing at present a few thousand patients, need to be supplemented with controlled studies to confirm this interesting hypothesis.     

Dielectric Study of Equimolar Acetaminophen–Aspirin,Acetaminophen–Quinidine,and Benzoic Acid–Progesterone Molecular Alloys in the Glass and Ultraviscous States and Their Relevance to Solubility and Stability

Equimolar mixtures of acetaminophen–aspirin, acetaminophen–quinidine, and benzoic acid–progesterone have been vitrified and dielectric properties of their glassy and ultraviscous alloys have been studied. For 20 K/min heating rate, their T_gs are 266, 330, and 263 K, respectively. The relaxation has an asymmetric distribution of times, and the distribution parameter increases with increase in temperature. The dielectric relaxation time varies with T according to the Vogel–Fulcher–Tammann equation, log₁₀(τ₀) = A_VFT + [B_VFT/(T ? T₀)], where A_VFT, B_VFT, and T₀ are empirical constants. The equilibrium permittivity is highest for the aspirin–acetaminophen and lowest for the benzoic acid‐progesterone alloy, indicating a substantial interpharmaceutical hydrogen bonding that makes the alloy more stable against crystallization than the pure components. The benzoic acid–progesterone alloy is thermodynamically the most nonideal. It showed cold crystallization on heating, which is attributed to its relatively greater magnitude of the JG relaxation in relation to its α‐relaxation. It is argued that the difference between the free energy of an alloy and the pure components would have an effect on the solubility. Studies of solution thermodynamics of a glassy molecular alloy may be useful for optimizing choice of components and composition to form molecular alloys and to impact drug delivery. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1358–1374, 2010     

Vitamin D Treatment Attenuates Neuroinflammation and Dopaminergic Neurodegeneration in an Animal Model of Parkinson’s Disease,Shifting M1 to M2 Microglia Responses

Microglia-mediated neuroinflammation has been described as a common hallmark of Parkinson’s disease (PD) and is believed to further exacerbate the progressive degeneration of dopaminergic neurons. Current therapies are unable to prevent the disease progression. A significant association has been demonstrated between PD and low levels of vitamin D in patients serum, and vitamin D supplement appears to have a beneficial clinical effect. Herein, we investigated whether vitamin D administered orally in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced preclinical animal model of PD protects against glia-mediated inflammation and nigrostriatal neurodegeneration. Vitamin D significantly attenuated the MPTP-induced loss of tyrosine hydrlase (TH)-positive neuronal cells, microglial cell activation (Iba1-immunoreactive), inducible nitric oxide synthase (iNOS) and TLR-4 expression, typical hallmarks of the pro-inflammatory (M1) activation of microglia. Additionally, Vitamin D was able to decrease pro-inflammatory cytokines mRNA expression in distinct brain areas of the MPTP mouse. Importantly, we also assessed the anti-inflammatory property of vitamin D in the MPTP mouse, in which it upregulated the anti-inflammatory cytokines (IL-10, IL-4 and TGF-β) mRNA expression as well as increasing the expression of CD163, CD206 and CD204, typical hallmarks of alternative activation of microglia for anti-inflammatory signalling (M2). Collectively, these results demonstrate that vitamin D exhibits substantial neuroprotective effects in this PD animal model, by attenuating pro-inflammatory and up-regulating anti-inflammatory processes.     

Potentiating Metronidazole Scaffold against Resistant Trichomonas: Design,Synthesis, Biology and 3D–QSAR Analysis

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