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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
13.  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
14.  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
15.  Overview of the Alberta Kidney Disease Network 
BMC Nephrology  2009;10:30.
Background
The Alberta Kidney Disease Network is a collaborative nephrology research organization based on a central repository of laboratory and administrative data from the Canadian province of Alberta.
Description
The laboratory data within the Alberta Kidney Disease Network can be used to define patient populations, such as individuals with chronic kidney disease (using serum creatinine measurements to estimate kidney function) or anemia (using hemoglobin measurements). The administrative data within the Alberta Kidney Disease Network can also be used to define cohorts with common medical conditions such as hypertension and diabetes. Linkage of data sources permits assessment of socio-demographic information, clinical variables including comorbidity, as well as ascertainment of relevant outcomes such as health service encounters and events, the occurrence of new specified clinical outcomes and mortality.
Conclusion
The unique ability to combine laboratory and administrative data for a large geographically defined population provides a rich data source not only for research purposes but for policy development and to guide the delivery of health care. This research model based on computerized laboratory data could serve as a prototype for the study of other chronic conditions.
doi:10.1186/1471-2369-10-30
PMCID: PMC2770500  PMID: 19840369
16.  The epidemiology of intensive care unit-acquired hyponatraemia and hypernatraemia in medical-surgical intensive care units 
Critical Care  2008;12(6):R162.
Introduction
Although sodium disturbances are common in hospitalised patients, few studies have specifically investigated the epidemiology of sodium disturbances in the intensive care unit (ICU). The objectives of this study were to describe the incidence of ICU-acquired hyponatraemia and hypernatraemia and assess their effects on outcome in the ICU.
Methods
We identified 8142 consecutive adults (18 years of age or older) admitted to three medical-surgical ICUs between 1 January 2000 and 31 December 2006 who were documented to have normal serum sodium levels (133 to 145 mmol/L) during the first day of ICU admission. ICU acquired hyponatraemia and hypernatraemia were respectively defined as a change in serum sodium concentration to below 133 mmol/L or above 145 mmol/L following day one in the ICU.
Results
A first episode of ICU-acquired hyponatraemia developed in 917 (11%) patients and hypernatraemia in 2157 (26%) patients with an incidence density of 3.1 and 7.4 per 100 days of ICU admission, respectively, during 29,142 ICU admission days. The incidence of both ICU-acquired hyponatraemia (age, admission diagnosis, Acute Physiology and Chronic Health Evaluation (APACHE) II score, length of ICU stay, level of consciousness, serum glucose level, body temperature, serum potassium level) and ICU-acquired hypernatraemia (baseline creatinine, APACHE II score, mechanical ventilation, length of ICU stay, body temperature, serum potassium level, level of care) varied according to patients' characteristics. Compared with patients with normal serum sodium levels, hospital mortality was increased in patients with ICU-acquired hyponatraemia (16% versus 28%, p < 0.001) and ICU-acquired hypernatraemia (16% versus 34%, p < 0.001).
Conclusions
ICU-acquired hyponatraemia and hypernatraemia are common in critically ill patients and are associated with increased risk of hospital mortality.
doi:10.1186/cc7162
PMCID: PMC2646327  PMID: 19094227
17.  Access to health care among status Aboriginal people with chronic kidney disease 
Background
Ethnic disparities in access to health care and health outcomes are well documented. It is unclear whether similar differences exist between Aboriginal and non-Aboriginal people with chronic kidney disease in Canada. We determined whether access to care differed between status Aboriginal people (Aboriginal people registered under the federal Indian Act) and non-Aboriginal people with chronic kidney disease.
Methods
We identified 106 511 non-Aboriginal and 1182 Aboriginal patients with chronic kidney disease (estimated glomerular filtration rate less than 60 mL/min/1.73 m2). We compared outcomes, including hospital admissions, that may have been preventable with appropriate outpatient care (ambulatory-care–sensitive conditions) as well as use of specialist services, including visits to nephrologists and general internists.
Results
Aboriginal people were almost twice as likely as non-Aboriginal people to be admitted to hospital for an ambulatory-care–sensitive condition (rate ratio 1.77, 95% confidence interval [CI] 1.46–2.13). Aboriginal people with severe chronic kidney disease (estimated glomerular filtration rate < 30 mL/min/1.73 m2) were 43% less likely than non-Aboriginal people with severe chronic kidney disease to visit a nephrologist (hazard ratio 0.57, 95% CI 0.39–0.83). There was no difference in the likelihood of visiting a general internist (hazard ratio 1.00, 95% CI 0.83–1.21).
Interpretation
Increased rates of hospital admissions for ambulatory-care–sensitive conditions and a reduced likelihood of nephrology visits suggest potential inequities in care among status Aboriginal people with chronic kidney disease. The extent to which this may contribute to the higher rate of kidney failure in this population requires further exploration.
doi:10.1503/cmaj.080063
PMCID: PMC2572655  PMID: 18981441

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