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1.  Patients with chronic kidney disease and their intent to use electronic personal health records 
Background
Electronic personal health records (ePHRs) provide patients with access to their personal health information, aiming to inform them about their health, enhance self-management, and improve outcomes. Although they have been associated with improved health outcomes in several chronic diseases, the potential impact of ePHR use in chronic kidney disease (CKD) is unknown.
Objectives
We sought to understand perceptions of CKD patients about ePHRs, and describe characteristics associated with their expressed intent to use an ePHR.
Design
Self-administered paper based survey.
Setting
The study was conducted in Calgary, Alberta, Canada at a multidisciplinary CKD clinic from November 2013 to January 2014.
Participants
Patients with non-dialysis-dependent CKD.
Measurements
Demographics, perceived benefits, and drawbacks of ePHRs were obtained. A univariate analysis was used to assess for an association with the expressed intention to use an ePHR.
Methods
A patient survey was used to determine perceptions of ePHRs, and to identify factors that were associated with intention to use an ePHR.
Results
Overall 63 patients with CKD (76.2 % male, 55.6 % ≥65 years old) completed the survey. The majority (69.8 %) expressed their intent to use an ePHR. CKD patients over the age of 65 were less likely to intend to use an ePHR as compared to those aged <65 years (OR 0.22, 95 % CI: [0.06, 0.78]). Those with post-secondary education (OR 3.31, 95 % CI: [1.06, 10.41]) and Internet access (OR 5.70, 95 % CI: [1.64, 19.81]) were more likely to express their intent to use an ePHR. Perceived benefits of ePHR use included greater involvement in their own care (50.0 % indicated this), better access to lab results (75.8 %), and access to health information (56.5 %). Although 41.9 % reported concerns about privacy of health information, there was no association between these concerns and the intent to use an ePHR.
Limitations
Our results are limited by small study size and single centre location.
Conclusions
We found that patients with CKD expressed their intention to use ePHRs, and perceive benefits such as personal involvement in their health care and better access to lab results. Studies of CKD patients using ePHRs are needed to determine whether ePHR use improves patient outcomes.
doi:10.1186/s40697-015-0058-5
PMCID: PMC4465011  PMID: 26075082
Personal health record; Electronic personal health record; PHR; ePHR; Chronic kidney disease; Patient-centered care
2.  Role of vascular function in predicting arteriovenous fistula outcomes: an observational pilot study 
Background
Many arteriovenous fistula (AVF) fail prior to use due to lack of maturation or thrombosis. Determining vascular function prior to surgery may be helpful to predict subsequent AVF success. This is a feasibility study to describe the vascular function in a cohort of chronic kidney disease (CKD) patients who are awaiting AVF creation.
Methods
A prospective cohort of 28 CKD patients expected to progress to HD underwent arterial stiffness (pulse wave velocity, PWV) and endothelial function testing (flow mediated dilation FMD, and peripheral arterial tonometry, PAT) one week prior to AVF creation. AVF success was defined as maintaining patency and achieving maturation. Post operative fistula assessment at 8 weeks evaluated maturation (clinical assessment of adequate fistula flowand ultrasound diameter ≥ 0.5 cm).
Results
The median age 72 years (62 - 78), 75% males, eGFR 15 ml/min/1.73 m2 (12 – 18). 20 (71%) patients had successful AVF surgery with a mature AVF at 8 weeks. Patients with AVF success had higher mean PAT values 1.87 ± 0.52 than those with failed AVF 1.41 ± 0.24 p = 0.03.
Conclusions
Microvascular endothelial function as measured using PAT may be useful as a predictor of AVF maturation and function. This simple non invasive marker of vascular function may be a useful tool to predict AVF outcomes.
doi:10.1186/s40697-015-0055-8
PMCID: PMC4422532  PMID: 25949818
Arteriovenous fistula; Endothelial function; Vascular reactivity; Peripheral arterial tonometry
4.  The effect of hormone therapy on all-cause and cardiovascular mortality in women with chronic kidney disease: protocol for a systematic review and meta-analysis 
Systematic Reviews  2015;4:44.
Background
Chronic kidney disease affects approximately one in ten North Americans and is associated with a high risk of cardiovascular disease. Chronic kidney disease in women is characterized by an abnormal sex hormone profile and low estradiol levels. Since low estradiol levels are associated with an increased cardiovascular risk in healthy women, our objective is to determine the effect of hormone therapy on all-cause mortality, cardiovascular mortality, and cardiovascular morbidity in women with chronic kidney disease.
Methods/design
Studies examining hormone therapy for adult women with chronic kidney disease will be included. The primary outcome is all-cause or cardiovascular mortality and morbidity. We will search electronic bibliographic databases (MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL)) along with relevant conference proceedings, table of contents of journals, and review articles. Two investigators will independently screen identified abstracts and select observational cohort studies, case–control studies, and randomized controlled trials examining hormone therapy in women with chronic kidney disease. These investigators will also independently abstract data from relevant full-text journal articles and assess risk of bias. Where possible, these data will be summarized using pooled or combined estimates for the risk ratio or hazard ratio of all-cause mortality, cardiovascular mortality, and cardiovascular morbidity in women with chronic kidney disease with and without hormone therapy. A random effects model will be used, and meta-regression and subgroup analyses will be used to explore potential source of heterogeneity.
Discussion
Given the high burden of cardiovascular disease in women with chronic kidney disease, this study will help guide clinical practice by summarizing current evidence on the use of hormone therapy for prevention of all-cause mortality, cardiovascular mortality, and cardiovascular morbidity in this population.
Systematic review registration
The final protocol was registered with PROSPERO (CRD42014014566).
doi:10.1186/s13643-015-0020-8
PMCID: PMC4414431  PMID: 25874808
Hormone therapy; Chronic kidney disease; Cardiovascular mortality; All-cause mortality; Cardiovascular morbidity
5.  Kidney function, albuminuria and life expectancy 
Background
Lower estimated glomerular filtration rate is associated with reduced life expectancy. Whether this association is modified by the presence or absence of albuminuria, another cardinal finding of chronic kidney disease, is unknown.
Objective
Our objective was to estimate the life expectancy of middle-aged men and women with varying levels of eGFR and concomitant albuminuria.
Design
A retrospective cohort study.
Setting
A large population-based cohort identified from the provincial laboratory registry in Alberta, Canada.
Participants
Adults aged ≥30 years who had outpatient measures of serum creatinine and albuminuria between May 1, 2002 and March 31, 2008.
Measurements
Predictor: Baseline levels of kidney function identified from serum creatinine and albuminuria measurements. Outcomes: all cause mortality during the follow-up.
Methods
Patients were categorized based on their estimated glomerular filtration rate (eGFR) (≥60, 45–59, 30–44, and 15–29 mL/min/1 · 73 m2) as well as albuminuria (normal, mild, and heavy) measured by albumin-to-creatinine ratio or urine dipstick. The abridged life table method was applied to calculate the life expectancies of men and women from age 40 to 80 years across combined eGFR and albuminuria categories. We also categorized participants by severity of kidney disease (low risk, moderately increased risk, high risk, and very high risk) using the combination of eGFR and albuminuria levels.
Results
Among men aged 50 years and with eGFR ≥60 mL/min/1.73 m2, estimated life expectancy was 24.8 (95% CI: 24.6-25.0), 17.5 (95% CI: 17.1-17.9), and 13.5 (95% CI: 12.6-14.3) years for participants with normal, mild and heavy albuminuria respectively. Life expectancy for men with mild and heavy albuminuria was 7.3 (95% CI: 6.9-7.8) and 11.3 (95% CI: 10.5-12.2) years shorter than men with normal proteinuria, respectively. A reduction in life expectancy was associated with an increasing severity of kidney disease; 24.8 years for low risk (95% CI: 24.6-25.0), 19.1 years for moderately increased risk (95% CI: 18.7-19.5), 14.2 years for high risk (95% CI: 13.5-15.0), and 9.6 years for very high risk (95% CI: 8.4-10.8). Among women of similar age and kidney function, estimated life expectancy was 28.9 (95% CI: 28.7-29.1), 19.8 (95% CI: 19.2-20.3), and 14.8 (95% CI: 13.5-16.0) years for participants with normal, mild and heavy albuminuria respectively. Life expectancy for women with mild and heavy albuminuria was 9.1 (95% CI: 8.5-9.7) and 14.2 (95% CI: 12.9-15.4) years shorter than the women with normal proteinuria, respectively. For women also a graded reduction in life expectancy was observed across the increasing severity of kidney disease; 28.9 years for low risk (95% CI: 28.7-29.1), 22.5 years for moderately increased risk (95% CI: 22.0-22.9), 16.5 years for high risk (95% CI: 15.4-17.5), and 9.2 years for very high risk (95% CI: 7.8-10.7).
Limitations
Possible misclassification of long-term kidney function categories cannot be eliminated. Possibility of confounding due to concomitant comorbidities cannot be ruled out.
Conclusion
The presence and degree of albuminuria was associated with lower estimated life expectancy for both gender and was especially notable in those with eGFR ≥30 mL/min/1.73 m2. Life expectancy associated with a given level of eGFR differs substantially based on the presence and severity of albuminuria.
Electronic supplementary material
The online version of this article (doi:10.1186/s40697-014-0033-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s40697-014-0033-6
PMCID: PMC4349777  PMID: 25780622
6.  Serum uric acid level, blood pressure, and vascular angiotensin II responsiveness in healthy men and women 
Physiological Reports  2014;2(12):e12235.
Abstract
Uric acid is associated with hypertension and increased renin–angiotensin system activity, although this relationship diminishes after chronic exposure to high levels. Uric acid is more strongly associated with poor outcomes in women compared to men, although whether this is due to a sex‐specific uric acid‐mediated pathophysiology or reflects sex differences in baseline uric acid levels remains unknown. We examined the association between uric acid and vascular measures at baseline and in response to angiotensin‐II challenge in young healthy humans. Fifty‐two subjects (17 men, 35 premenopausal women) were studied in high‐salt balance. Serum uric acid levels were significantly higher in men compared to women (328 ± 14 μmol/L vs. 248 ± 10 μmol/L, P < 0.001), although all values were within normal sex‐specific range. Men demonstrated no association between uric acid and blood pressure, either at baseline or in response to angiotensin‐II. In stark contrast, a significant association was observed between uric acid and blood pressure at baseline (systolic blood pressure, P = 0.005; diastolic blood pressure, P = 0.02) and in response to angiotensin‐II (systolic blood pressure, P = 0.035; diastolic blood pressure, P = 0.056) in women. However, this sex difference lost significance after adjustment for baseline uric acid. When all subjects were stratified according to high (>300 μmol/L) or low (≤300 μmol/L) uric acid levels, only the low uric acid group showed a positive association between uric acid and measures of vascular tone at baseline and in response to angiotensin‐II. Differences in uric acid‐mediated outcomes between men and women likely reflect differences in exposure to increased uric acid levels, rather than a sex‐specific uric acid‐mediated pathophysiology.
The lower baseline uric acid levels in women compared to men may account for differences in uric acid‐associated vascular outcomes rather than sex‐mediated differences in pathophysiology.
doi:10.14814/phy2.12235
PMCID: PMC4332213  PMID: 25501427
Blood pressure; hypertension; renin–angiotensin system; sex; uric acid
7.  Effect of oral vitamin D analogs on mortality and cardiovascular outcomes among adults with chronic kidney disease: a meta-analysis 
Clinical Kidney Journal  2014;8(1):41-48.
Background
Vitamin D deficiency is highly prevalent in patients with chronic kidney disease (CKD) and has been associated with all-cause and cardiovascular mortality in observational studies. However, evidence from randomized controlled trials (RCTs) supporting vitamin D supplementation is lacking. We sought to assess whether vitamin D supplementation alters the relative risk (RR) of all-cause and cardiovascular mortality, as well as serious adverse cardiovascular events, in patients with CKD, compared with placebo.
Methods
PubMed/MEDLINE, EMBASE, Cochrane Library, and selected nephrology journals and conference proceedings were searched in October 2013. RCTs considered for inclusion were those that assessed oral vitamin D supplementation versus placebo in adults with CKD (≤60 mL/min/1.73 m2), including end-stage CKD requiring dialysis. We calculated pooled RR of mortality (all-cause and cardiovascular) and that of cardiovascular events and stratified by CKD stage, vitamin D analog and diabetes prevalence.
Results
The search identified 4246 articles, of which 13 were included. No significant treatment effect of oral vitamin D on all-cause mortality (RR: 0.84; 95% CI: 0.47, 1.52), cardiovascular mortality (RR: 0.79; 95% CI: 0.26, 2.28) or serious adverse cardiovascular events (RR: 1.20; 95% CI: 0.49, 2.99) was observed. The pooled analysis demonstrated large variation in trials with respect to dosing (0.5 ug–200 000 IU/week) and duration (3–104 weeks).
Conclusions
Current RCTs do not provide sufficient or precise evidence that vitamin D supplementation affects mortality or cardiovascular risk in CKD. While its effect on biochemical endpoints is well documented, the results demonstrate a lack of appropriate patient-level data within the CKD literature, which warrants larger trials with clinical primary outcomes related to vitamin D supplementation.
doi:10.1093/ckj/sfu122
PMCID: PMC4310425  PMID: 25713709
cardiovascular outcomes; clinical trials; meta-analysis; mortality; vitamin D
8.  The VITAH Trial Vitamin D supplementation and cardiac autonomic tone in hemodialysis: a blinded, randomized controlled trial 
BMC Nephrology  2014;15:129.
Background
Patients with end-stage kidney disease (ESKD) have a high rate of mortality and specifically an increased risk of sudden cardiac death (SCD). Impaired cardiac autonomic tone is associated with elevated risk of SCD. Moreover, patients with ESKD are often vitamin D deficient, which we have shown may be linked to autonomic dysfunction in humans. To date, it is not known whether vitamin D supplementation normalizes cardiac autonomic function in the high-risk ESKD population. The VITamin D supplementation and cardiac Autonomic tone in Hemodialysis (VITAH) randomized trial will determine whether intensive vitamin D supplementation therapies improve cardiac autonomic tone to a greater extent than conventional vitamin D supplementation regimens in ESKD patients requiring chronic hemodialysis.
Methods/Design
A total of 60 subjects with ESKD requiring thrice weekly chronic hemodialysis will be enrolled in this 2x2 crossover, blinded, randomized controlled trial. Following a 4-week washout period from any prior vitamin D therapy, subjects are randomized 1:1 to intensive versus standard vitamin D therapy for 6 weeks, followed by a 12-week washout period, and finally the remaining treatment arm for 6 weeks. Intensive vitamin D treatment includes alfacalcidiol (activated vitamin D) 0.25mcg orally with each dialysis session combined with ergocalciferol (nutritional vitamin D) 50 000 IU orally once per week and placebo the remaining two dialysis days for 6 weeks. The standard vitamin D treatment includes alfacalcidiol 0.25mcg orally combined with placebo each dialysis session per week for 6 weeks. Cardiac autonomic tone is measured via 24 h Holter monitor assessments on the first dialysis day of the week every 6 weeks throughout the study period. The primary outcome is change in the low frequency: high frequency heart rate variability (HRV) ratio during the first 12 h of the Holter recording at 6 weeks versus baseline. Secondary outcomes include additional measures of HRV. The safety of intensive versus conventional vitamin D supplementation is also assessed.
Discussion
VITAH will determine whether an intensive vitamin D supplementation regimen will improve cardiac autonomic tone compared to conventional vitamin D supplementation and will assess the safety of these two supplementation regimens in ESKD patients receiving chronic hemodialysis.
Trial registration
ClinicalTrials.gov, NCT01774812
doi:10.1186/1471-2369-15-129
PMCID: PMC4130113  PMID: 25098377
Chronic kidney disease; Vitamin D; Ergocalciferol; Alfacalcidiol; Autonomic nervous system; Cardiovascular risk; Clinical trial
9.  Likelihood of coronary angiography among First Nations patients with acute myocardial infarction 
Background:
Morbidity due to cardiovascular disease is high among First Nations people. The extent to which this may be related to the likelihood of coronary angiography is unclear. We examined the likelihood of coronary angiography after acute myocardial infarction (MI) among First Nations and non–First Nations patients.
Methods:
Our study included adults with incident acute MI between 1997 and 2008 in Alberta. We determined the likelihood of angiography among First Nations and non–First Nations patients, adjusted for important confounders, using the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) database.
Results:
Of the 46 764 people with acute MI, 1043 (2.2%) were First Nations. First Nations patients were less likely to receive angiography within 1 day after acute MI (adjusted odds ratio [OR] 0.73, 95% confidence interval [CI] 0.62–0.87). Among First Nations and non–First Nations patients who underwent angiography (64.9%), there was no difference in the likelihood of percutaneous coronary intervention (PCI) (adjusted hazard ratio [HR] 0.92, 95% CI 0.83–1.02) or coronary artery bypass grafting (CABG) (adjusted HR 1.03, 95% CI 0.85–1.25). First Nations people had worse survival if they received medical management alone (adjusted HR 1.38, 95% CI 1.07–1.77) or if they underwent PCI (adjusted HR 1.38, 95% CI 1.06–1.80), whereas survival was similar among First Nations and non–First Nations patients who received CABG.
Interpretation:
First Nations people were less likely to undergo angiography after acute MI and experienced worse long-term survival compared with non–First Nations people. Efforts to improve access to angiography for First Nations people may improve outcomes.
doi:10.1503/cmaj.131667
PMCID: PMC4081235  PMID: 24847149
10.  Correction for Irrelevant Absorption in Multicomponent Spectrophotometric Assay of Riboflavin, Formylmethylflavin, and Degradation Products: Kinetic Applications 
AAPS PharmSciTech  2013;14(3):1101-1107.
In the spectrophotometric assay of multicomponent systems involved in drug degradation studies, some minor or unknown degradation products may be present. These products may interfere in the assay and thus invalidate the results due to their absorption in the range of analytical wavelengths. This interference may be eliminated by the application of an appropriate correction procedure to obtain reliable data for kinetic treatment. The present study is based on the application of linear and non-linear irrelevant absorption corrections in the multicomponent spectrophotometric assay of riboflavin and formylmethylflavin during the photolysis and hydrolysis studies. The correction procedures take into account the interference caused by minor or unknown products and have shown considerable improvement in the assay data in terms of the molar balance. The treatment of the corrected data has led to more accurate kinetic results in degradation studies.
doi:10.1208/s12249-013-9998-1
PMCID: PMC3755170  PMID: 23821430
degradation kinetics; formylmethylflavin; irrelevant absorption; riboflavin; spectrophotometric assay
11.  Cyclooxygenases 1 and 2 Differentially Regulate Blood Pressure and Cerebrovascular Responses to Acute and Chronic Intermittent Hypoxia: Implications for Sleep Apnea 
Background
Obstructive sleep apnea (OSA) is associated with increased risk of cardiovascular and cerebrovascular disease resulting from intermittent hypoxia (IH)‐induced inflammation. Cyclooxygenase (COX)‐formed prostanoids mediate the inflammatory response, and regulate blood pressure and cerebral blood flow (CBF), but their role in blood pressure and CBF responses to IH is unknown. Therefore, this study's objective was to determine the role of prostanoids in cardiovascular and cerebrovascular responses to IH.
Methods and Results
Twelve healthy, male participants underwent three, 6‐hour IH exposures. For 4 days before each IH exposure, participants ingested a placebo, indomethacin (nonselective COX inhibitor), or Celebrex® (selective COX‐2 inhibitor) in a double‐blind, randomized, crossover study design. Pre‐ and post‐IH blood pressure, CBF, and urinary prostanoids were assessed. Additionally, blood pressure and urinary prostanoids were assessed in newly diagnosed, untreated OSA patients (n=33). Nonselective COX inhibition increased pre‐IH blood pressure (P≤0.04) and decreased pre‐IH CBF (P=0.04) while neither physiological variable was affected by COX‐2 inhibition (P≥0.90). Post‐IH, MAP was elevated (P≤0.05) and CBF was unchanged with placebo and nonselective COX inhibition. Selective COX‐2 inhibition abrogated the IH‐induced MAP increase (P=0.19), but resulted in lower post‐IH CBF (P=0.01). Prostanoids were unaffected by IH, except prostaglandin E2 was elevated with the placebo (P=0.02). Finally, OSA patients had elevated blood pressure (P≤0.4) and COX‐1 formed thromboxane A2 concentrations (P=0.02).
Conclusions
COX‐2 and COX‐1 have divergent roles in modulating vascular responses to acute and chronic IH. Moreover, COX‐1 inhibition may mitigate cardiovascular and cerebrovascular morbidity in OSA.
Clinical Trial Registration
URL: www.clinicaltrials.gov. Unique identifier: NCT01280006
doi:10.1161/JAHA.114.000875
PMCID: PMC4309085  PMID: 24815497
blood pressure; cerebrovascular circulation; intermittent hypoxia; obstructive sleep apnea; prostaglandins
12.  Studies on Tolfenamic Acid–Chitosan Intermolecular Interactions: Effect of pH, Polymer Concentration and Molecular Weight 
AAPS PharmSciTech  2013;14(2):870-879.
Solid-state properties of tolfenamic acid (TA) and its complexes with chitosan (CT) have been studied. Effect of medium pH, molecular weight of polymer and its different concentrations on these TA–CT complexes were studied in detail. Low and medium molecular weight CT have been used in different ratios at pH ranging from 4 to 6 and freeze-drying technique has been employed to modify the appearance of crystalline TA. Physical properties of the formed complexes have been studied by employing X-ray diffraction, differential scanning calorimetry and scanning electron microscopy; chemical structure has been studied using Fourier transform infrared spectroscopy. The results showed that both forms of the polymer exhibited complete conversion in 1:8 ratio at pH 4, 1:4 at pH 5 and 1:1 at pH 6 indicating a marked effect of pH on drug–polymer complexation. The percent crystallinity calculations indicated low molecular weight CT slightly more effective than the other form. No changes in the complexes have been observed during the 12 week storage under controlled conditions. Both forms of CT at different pH values indicated retardation of recrystallization in TA during cooling of the melt from 1:1 ratios exhibiting formation of strong intermolecular hydrogen bonding between the drug and the polymer.
doi:10.1208/s12249-013-9974-9
PMCID: PMC3665981  PMID: 23620261
amorphous; chitosan; effect of pH and molecular weight; freeze-drying; recrystallization; tolfenamic acid
13.  Association between First Nations ethnicity and progression to kidney failure by presence and severity of albuminuria 
Background:
Despite a low prevalence of chronic kidney disease (estimated glomerular filtration rate [GFR] < 60 mL/min per 1.73 m2), First Nations people have high rates of kidney failure requiring chronic dialysis or kidney transplantation. We sought to examine whether the presence and severity of albuminuria contributes to the progression of chronic kidney disease to kidney failure among First Nations people.
Methods:
We identified all adult residents of Alberta (age ≥ 18 yr) for whom an outpatient serum creatinine measurement was available from May 1, 2002, to Mar. 31, 2008. We determined albuminuria using urine dipsticks and categorized results as normal (i.e., no albuminuria), mild, heavy or unmeasured. Our primary outcome was progression to kidney failure (defined as the need for chronic dialysis or kidney transplantation, or a sustained doubling of serum creatinine levels). We calculated rates of progression to kidney failure by First Nations status, by estimated GFR and by albuminuria category. We determined the relative hazard of progression to kidney failure for First Nations compared with non–First Nations participants by level of albuminuria and estimated GFR.
Results:
Of the 1 816 824 participants we identified, 48 669 (2.7%) were First Nations. First Nations people were less likely to have normal albuminuria compared with non–First Nations people (38.7% v. 56.4%). Rates of progression to kidney failure were consistently 2- to 3-fold higher among First Nations people than among non–First Nations people, across all levels of albuminuria and estimated GFRs. Compared with non–First Nations people, First Nations people with an estimated GFR of 15.0–29.9 mL/min per 1.73 m2 had the highest risk of progression to kidney failure, with similar hazard ratios for those with normal and heavy albuminuria.
Interpretation:
Albuminuria confers a similar risk of progression to kidney failure for First Nations and non–First Nations people.
doi:10.1503/cmaj.130776
PMCID: PMC3903763  PMID: 24295865
14.  Photodegradation and Stabilization of Betamethasone-17 Valerate in Aqueous/Organic Solvents and Topical Formulations 
AAPS PharmSciTech  2012;14(1):177-182.
The effects of solvent [acetonitrile, methanol, and acetonitrile/water mixture (20:80, v/v)], buffer concentration (phosphate buffer, pH 7.5), ionic strength and commonly employed adjuvants on the photodegradation of betamethasone-17 valerate in cream and gel formulations have been studied on exposure to UV light (300–400 nm). A validated high-performance liquid chromatography method has been used to determine the parent compound and its photodegraded products. The photodegradation data in the studied solvents showed greater decomposition of the drug in solvents with a lower dielectric constant. A comparatively higher rate of photodegradation was observed in the cream formulation compared to that for the gel formulation. The kinetic treatment of the photodegradation data revealed that the degradation of the drug follows first-order kinetics and the apparent first-order rate constants for the photodegradation reactions, in the media studied, range from 1.62 to 11.30 × 10−3 min−1. The values of the rate constants decrease with increasing phosphate concentration and ionic strength which could be due to the deactivation of the excited state and radical quenching. The second-order rate constant (k′) for the phosphate ion-inhibited reactions at pH 7.5 has been found to be 5.22 × 10−2 M−1 s−1. An effective photostabilization of the drug has been achieved in cream and gel formulations with titanium dioxide (33.5–42.5%), vanillin (21.6–28.7%), and butyl hydroxytoluene (18.2–21.6%).
doi:10.1208/s12249-012-9902-4
PMCID: PMC3581653  PMID: 23250710
betamethasone-17 valerate; creams and gels; kinetics; photodegradation; photostabilization
15.  A Comparison of Prediction Equations for Estimating Glomerular Filtration Rate in Pregnancy 
Objective
To compare existing glomerular filtration rate (GFR) prediction equations with the gold standard, inulin clearance, in pregnancy.
Methods
Five equations were assessed for precision, bias, and accuracy in prediction of true GFR, measured by inulin clearance in 12 healthy, pregnant women during the second (T2) and third (T3) trimesters and in postpartum (PP).
Results
Precision was greatest with 24-hour creatinine clearance estimation of GFR (R2 = 13% (T2), R2 = 26% (T3)). Other than 100/SCr, all equations underestimated true GFR. 30% accuracy was greatest in 100/SCr (83% (T2), 92% (T3)).
Conclusions
Current GFR prediction formulae do not appear to be sufficient for estimating GFR in the gravid state.
doi:10.1080/10641950801986720
PMCID: PMC3811128  PMID: 19440935
Pregnancy; Glomerular filtration rate; Prediction equation; Inulin clearance; Kidney
16.  Photoinitiated Polymerization of 2-Hydroxyethyl Methacrylate by Riboflavin/Triethanolamine in Aqueous Solution: A Kinetic Study 
ISRN Pharmaceutics  2013;2013:958712.
The polymerization of 1–3 M 2-hydroxyethyl methacrylate (HEMA) initiated by riboflavin/triethanolamine system has been studied in the pH range 6.0–9.0. An approximate measure of the kinetics of the reaction during the initial stages (~5% HEMA conversion) has been made to avoid the effect of any variations in the volume of the medium. The concentration of HEMA in polymerized solutions has been determined by a UV spectrophotometric method at 208 nm with a precision of ±3%. The initial rate of polymerization of HEMA follows apparent first-order kinetics and the rates increase with pH. This may be due to the presence of a labile proton on the hydroxyl group of HEMA. The second-order rate constants for the interaction of triethanolamine and HEMA lie in the range of 2.36 to 8.67 × 10−2 M−1 s−1 at pH 6.0–9.0 suggesting an increased activity with pH. An increase in the viscosity of HEMA solutions from 1 M to 3 M leads to a decrease in the rate of polymerization probably as a result of the decrease in the reactivity of the flavin triplet state. The effect of pH and viscosity of the medium on the rate of reaction has been evaluated.
doi:10.1155/2013/958712
PMCID: PMC3794564  PMID: 24175102
17.  Development and Characterization of Novel Polyurethane Films Impregnated with Tolfenamic Acid for Therapeutic Applications 
BioMed Research International  2013;2013:178973.
The present study deals with the preparation of polyurethane (PU) films impregnated with a nonsteroidal anti-inflammatory drug, tolfenamic acid (TA). Solvent evaporation technique has been employed for the preparation of TA-PU films in two different ratios of 1 : 2 and 1 : 5 in Tetrahydrofuran (THF) or THF-ethanol mixtures. The prepared films were characterized using X-Ray Diffraction (XRD), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FTIR), Scanning Electron Microscopy (SEM), and release studies. The results indicate transformation of crystalline TA to its amorphous form. The degree of crystallinity changes both by increasing the polymer concentration and solvent used for the film preparations. The release profiles of TA were also found to be affected, showing a decrease from approximately 50% to 25% from 1 : 2 to 1 : 5 ratios, respectively.
doi:10.1155/2013/178973
PMCID: PMC3773997  PMID: 24073394
18.  Oral contraceptive progestins and angiotensin-dependent control of the renal circulation in humans 
Journal of human hypertension  2009;23(6):407-414.
Oral contraceptive (OC) use is associated with increased intra-renal renin-angiotensin-aldosterone system (RAA System) activity and risk of nephropathy, though the contribution of progestins contained in the OC in the regulation of angiotensin-dependent control of the renal circulation has not been elucidated. Eighteen OC users (8 non-diabetic, 10 Type 1 diabetic) were studied in high salt balance, a state of maximal RAA System suppression. Progestational and androgenic activity of the progestin in each OC was standardized to that of the reference progestin norethindrone. Renal plasma flow (RPF) was measured by paraaminohippurate clearance at baseline and in response to angiotensin converting enzyme (ACE)-inhibition. There was a positive correlation between OC progestational activity and the RPF response to ACE-inhibition (r=0.52, p=0.03). Similar results were noted with OC androgenic activity (r=0.54, p=0.02). On subgroup analysis, only non-diabetic subjects showed an association between progestational activity and angiotensin-dependent control of the renal circulation (r=0.71, p=0.05 non-diabetic; r=0.14, p=0.7 diabetic; p=0.07 between groups). Similar results were noted with respect to androgenic activity (r=0.88, p=0.005 non-diabetic; r=−0.33, p=0.3 diabetic; p=0.002 between groups). Our results suggest that the OC progestin component is a significant influence on the degree of angiotensin-dependent control of the renal circulation, though these findings may not apply to women with diabetes.
doi:10.1038/jhh.2008.148
PMCID: PMC3712637  PMID: 19158821
Progestational activity; Androgenic activity; Renal plasma flow; Female Oral contraceptive
19.  Vitamin D Levels Are Associated with Cardiac Autonomic Activity in Healthy Humans 
Nutrients  2013;5(6):2114-2127.
Vitamin D deficiency (≤50nmol/L 25-hydroxy vitamin D) is a cardiovascular (CV) risk factor that affects approximately one billion people worldwide, particularly those affected by chronic kidney disease (CKD). Individuals with CKD demonstrate abnormal cardiac autonomic nervous system activity, which has been linked to the significant rates of CV-related mortality in this population. Whether vitamin D deficiency has a direct association with regulation of cardiac autonomic activity has never been explored in humans. Methods: Thirty-four (34) healthy, normotensive subjects were studied and categorized based on 25-hydroxy vitamin D deficiency (deficient vs. non-deficient, n = 7 vs. 27), as well as 1,25-dihydroxy vitamin D levels (above vs. below 25th percentile, n = 8 vs. 26). Power spectral analysis of electrocardiogram recordings provided measures of cardiac autonomic activity across low frequency (LF) and high frequency (HF, representative of vagal contribution) bands, representative of the sympathetic and vagal limbs of the autonomic nervous system when transformed to normalized units (nu), respectively, as well as overall cardiosympathovagal balance (LF:HF) during graded angiotensin II (AngII) challenge (3 ng/kg/min × 30 min, 6 ng/kg/min × 30 min). Results: At baseline, significant suppression of sympathovagal balance was observed in the 25-hydroxy vitamin D-deficient participants (LF:HF, p = 0.02 vs. non-deficient), although no other differences were observed throughout AngII challenge. Participants in the lowest 1,25-dihydroxy VD quartile experienced significant withdrawal of inhibitory vagal control, as well as altered overall sympathovagal balance throughout AngII challenge (HF, mean difference = −6.98 ± 3 nu, p = 0.05; LF:HF, mean difference = 0.34 ± 0.1, p = 0.043 vs. above 25th percentile). Conclusions: Vitamin D deficiency is associated with suppression of resting cardiac autonomic activity, while low 1,25-dihydroxy vitamin D levels are associated with unfavourable cardiac autonomic activity during an acute AngII stressor, offering a potential pathophysiological mechanism that may be acting to elevate CV risk in in populations with low vitamin D status.
doi:10.3390/nu5062114
PMCID: PMC3725496  PMID: 23752493
vitamin D and cardiovascular disease; vitamin D deficiency; cholecalciferol; cardiac autonomic nervous system; heart rate variability; angiotensin II
20.  The impact of nocturnal hemodialysis on sexual function 
BMC Nephrology  2012;13:67.
Background
Sexual dysfunction is common in patients with end stage renal disease (ESRD) and treatment options are limited. Observational studies suggest that nocturnal hemodialysis may improve sexual function. We compared sexual activity and responses to sexual related questions in the Kidney Disease Quality of Life Short Form questionnaire among patients randomized to frequent nocturnal or thrice weekly conventional hemodialysis.
Methods
We performed a secondary analysis of data from an RCT which enrolled 51 patients comparing frequent nocturnal and conventional thrice weekly hemodialysis. Sexual activity and responses to sexual related questions were assessed at baseline and six months using relevant questions from the Kidney Disease Quality of Life Short Form questionnaire.
Results
Overall, there was no difference in sexual activity, or the extent to which people were bothered by the impact of kidney disease on their sex life between the two groups between randomization and 6 months. However, women and patients age < 60 who were randomized to frequent nocturnal hemodialysis were less bothered by the impact of kidney disease on their sex life at 6 months, compared with patients allocated to conventional hemodialysis (p = 0.005 and p = 0.024 respectively).
Conclusions
Our results suggest that frequent nocturnal hemodialysis is not associated with an improvement in sexual activity in all patients but might have an effect on the burden of kidney disease on sex life in women and patients less than 60 years of age. The validity of these subgroup findings require confirmation in future RCTs.
doi:10.1186/1471-2369-13-67
PMCID: PMC3457870  PMID: 22834992
Nocturnal hemodialysis; Sex; Sexual function; Frequent hemodialysis
21.  Photostability and Interaction of Ascorbic Acid in Cream Formulations 
AAPS PharmSciTech  2011;12(3):917-923.
The kinetics of photolysis of ascorbic acid in cream formulations on UV irradiation has been studied using a specific spectrophotometric method with a reproducibility of ±5%. The apparent first-order rate constants (kobs) for the photolysis of ascorbic acid in creams have been determined. The photoproducts formed in the cream formulations include dehydroascorbic acid and 2,3-diketogulonic acid. The photolysis of ascorbic acid appears to be affected by the concentration of active ingredient, pH, and viscosity of the medium and formulation characteristics. The study indicates that the ionized state and redox potentials of ascorbic acid are important factors in the photostability of the vitamin in cream formulations. The viscosity of the humectant present in the creams appears to influence the photostability of ascorbic acid. The results show that the physical stability of the creams is an important factor in the stabilization of the vitamin. In the cream formulations stored in the dark, ascorbic acid undergoes aerobic oxidation and the degradation is affected by similar factors as indicated in the photolysis reactions. The rate of oxidative degradation in the dark is about seventy times slower than that observed in the presence of light.
doi:10.1208/s12249-011-9659-1
PMCID: PMC3167265  PMID: 21735345
ascorbic acid; cream formulations; kinetics; photostability; spectrophotometric method
23.  Stabilizing effect of citrate buffer on the photolysis of riboflavin in aqueous solution 
Results in Pharma Sciences  2011;1(1):11-15.
In the present investigation the photolysis of riboflavin (RF) in the presence of citrate species at pH 4.0–7.0 has been studied. A specific multicomponent spectrophotometric method has been used to assay RF in the presence of photoproducts during the reactions. The overall first-order rate constants (kobs) for the photolysis of RF range from 0.42 to 1.08×10–2 min−1 in the region. The values of kobs have been found to decrease with an increase in citrate concentration indicating an inhibitory effect of these species on the rate of reaction. The second-order rate constants for the interaction of RF with total citrate species causing inhibition range from 1.79 to 5.65×10–3 M−1 min−1 at pH 4.0–7.0. The log k–pH profiles for the reactions at 0.2–1.0 M citrate concentration show a gradual decrease in kobs and the value at 1.0 M is more than half compared to that of k0, i.e., in the absence of buffer, at pH 5.0. Divalent citrate ions cause a decrease in RF fluorescence due to the quenching of the excited singlet state resulting in a decrease in the rate of reaction and consequently leading to the stabilization of RF solutions. The greater quenching of fluorescence at pH 4.0 compared to that of 7.0 is in accordance with the greater concentration of divalent citrate ions (99.6%) at that pH. The trivalent citrate ions exert a greater inhibitory effect on the rate of RF photolysis compared to that of the divalent citrate ions probably as a result of excited triplet state quenching. The values of second-order rate constants for the interaction of divalent and trivalent citrate ions are 0.44×10–2 and 1.06×10–3 M–1 min–1, respectively, indicating that the trivalent ions exert a greater stabilizing effect, compared to the divalent ions, on RF solutions.
Highlights
► Stabilizing effect of divalent and trivalent citrate ions on riboflavin photolysis has been demonstrated. ► Trivalent citrate ions exert a greater stabilizing effect as observed with a change in pH. ► Role of excited singlet and triplet states (quenching) in causing stabilization has been emphasized.
doi:10.1016/j.rinphs.2011.06.002
PMCID: PMC4150622  PMID: 25755977
Riboflavin; Citrate buffer; Photolysis; Kinetics; Spectrophotometric assay; Fluorescence
24.  Nocturnal Hypoxia and Loss of Kidney Function 
PLoS ONE  2011;6(4):e19029.
Background
Although obstructive sleep apnea (OSA) is more common in patients with kidney disease, whether nocturnal hypoxia affects kidney function is unknown.
Methods
We studied all adult subjects referred for diagnostic testing of sleep apnea between July 2005 and December 31 2007 who had serial measurement of their kidney function. Nocturnal hypoxia was defined as oxygen saturation (SaO2) below 90% for ≥12% of the nocturnal monitoring time. The primary outcome, accelerated loss of kidney function, was defined as a decline in estimated glomerular filtration rate (eGFR) ≥4 ml/min/1.73 m2 per year.
Results
858 participants were included and followed for a mean study period of 2.1 years. Overall 374 (44%) had nocturnal hypoxia, and 49 (5.7%) had accelerated loss of kidney function. Compared to controls without hypoxia, patients with nocturnal hypoxia had a significant increase in the adjusted risk of accelerated kidney function loss (odds ratio (OR) 2.89, 95% confidence interval [CI] 1.25, 6.67).
Conclusion
Nocturnal hypoxia was independently associated with an increased risk of accelerated kidney function loss. Further studies are required to determine whether treatment and correction of nocturnal hypoxia reduces loss of kidney function.
doi:10.1371/journal.pone.0019029
PMCID: PMC3084745  PMID: 21559506
25.  Fluorescent labeling of human albumin using the new aromatic dialdehyde labels and the study of innerfilter effect 
The labels naphthalene-2,3-dicarboxaldehyde (NDA), 1-phenylnaphthalene-2,3-dialdehyde (ΦNDA), and anthracene-2,3-dialdehyde (ADA) have been used as fluorigenic reagents. They formed fluorescent derivatives with proteins. The derivatives formed are in fact isoindoles. The fluorescence decay of the labels-antibody was found to extend over a period of 4, 8, and 10 h for ΦNDA, ADA, and NDA-derivative, respectively. Protein formed is comparatively less stable as compared to simple amino acids. In relation to innerfilter effect, the addition of cytochrome C, myoglobin, and ATP as absorbers to label-human albumin fluorophores appeared to have quenched the fluorescence. In the case of using NDA as label, the fluorescence was quenched roughly 70%, 24%, and 58% for addition of cytochrome C, myoglobin, and ATP, respectively. The labels used were found to give rapid, reproducible, and reliable results.
doi:10.4103/0975-7406.72143
PMCID: PMC2996066  PMID: 21180475
Fluorescent labeling; fluorophores; innerfilter effect; quenching

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