Cost Effectiveness of Eplerenone for the Treatment of Systolic Heart Failure with Mild Symptoms in Alberta,Canada

Background

Eplerenone has been demonstrated as being cost effective for the treatment of patients with systolic heart failure (HF) and mild symptoms in several jurisdictions; however, its cost effectiveness is unknown in the context of Alberta, Canada.

Methods

We used a discrete-event simulation model to compare costs and outcomes between standard care and standard care plus eplerenone for the treatment of HF with mild symptoms. We used Alberta data (whenever possible) together with a healthcare perspective, a lifetime horizon, and 3 % annual discount rate for analyses.

Results

Clinically, eplerenone prevented HF hospitalizations, atrial fibrillations, and cardiovascular (CV) deaths, but incurred more adverse events and device implantations than standard care. The remaining life of patients receiving eplerenone was 7.08 versus 5.83 years for those receiving standard care. Eplerenone gained 1.25 life-years and 1.18 quality-adjusted life-years (QALYs), with an incremental cost of $Can7200. Therefore, the incremental cost-effectiveness ratio (ICER) was $Can5700 per life-year gained and $Can6100 per QALY gained.

Conclusions

Given the most cited ICER threshold is $Can50,000, the use of eplerenone as an adjunct to standard care for treating patients with systolic HF and mild symptoms is cost effective in the context of Alberta. Eplerenone would cost the Alberta health system about $Can4.6 million a year in drug costs. Incorporating reductions in health services utilization associated with eplerenone, the budget impact is smaller. For the first year, the use of eplerenone is cost saving and for 5 years the cost is approximately $Can6 million.

     

Dinitrophenol (DNP) Fatality Associated with a Falsely Elevated Salicylate Level: a Case Report with Verification of Laboratory Cross Reactivity

Introduction

2,4-Dinitrophenol (DNP) is a known uncoupler of oxidative phosphorylation that clinically leads to hyperthermia, tachycardia, tachypnea, and metabolic acidosis. Intentional overdoses of DNP are often fatal. We present an analytically confirmed fatal case of DNP overdose with a falsely positive elevated salicylate concentration. We further explored this cross reactivity of DNP with two salicylate assays.

Methods

Clinically relevant serial dilutions of DNP were prepared in drug-free serum and analyzed using two different colorimetric NADH/NAD-based analytical methodologies.

Results

The enzymatic salicylate assay demonstrated a reproducible false elevation of salicylate starting at a DNP level of 100 mg/L while the EMIT-based methodology was without any such interference at the maximum concentration tested (150 mg/L).

Conclusions

DNP cross reacts with some salicylate assays. This knowledge is important for providers, as there are significant variations in the management of DNP versus salicylate toxicity.

     

Drug Interaction Between Clopidogrel and Ranitidine or Omeprazole in Stable Coronary Artery Disease: A Double-Blind,Double Dummy,Randomized Study

Background

Proton-pump inhibitors (PPIs) are often prescribed to patients receiving dual antiplatelet therapy (DAPT). However, this class of medication, especially omeprazole, has been associated with a reduction in clopidogrel efficacy, leading many clinicians to substitute omeprazole with ranitidine.

Objectives

Our objective was to compare the antiplatelet effect of clopidogrel before and after the addition of omeprazole or ranitidine.

Methods

We measured platelet aggregability at baseline and after 1 week of clopidogrel 75 mg daily. Subjects were then randomized in a double-blinded, double-dummy fashion to omeprazole 20 mg twice daily (bid) or ranitidine 150 mg bid. We repeated aggregability tests after 1 additional week, using VerifyNow P2Y12? (Accumetrics; San Diego, CA, USA), depicting aggregability as percent inhibition of platelet aggregation (IPA).

Results

We enrolled 41 patients in the omeprazole group and 44 in the ranitidine group. IPA was significantly decreased after the addition of omeprazole to clopidogrel (from 26.3 ± 32.9 to 17.4 ± 33.1 %; p = 0.025), with no statistical significant changes observed in the ranitidine group (from 32.6 ± 28.9 to 30.1 ± 31.3 %; p = 0.310). The comparison of IPA in both groups at the end of the follow-up showed a trend toward significance (p = 0.07, 95 % confidence interval [CI] ?1.19 to 26.59); after excluding homozygous patients for 2C19*2 genotype, the comparison of IPA between the groups reached statistical significance (32.7 ± 30.8 vs. 17.7 ± 33.4 %, respectively, for ranitidine and omeprazole groups; p = 0.04).

Conclusions

Unlike omeprazole, ranitidine did not influence platelet aggregability response to clopidogrel.

Clinical Trial Registration

NCT01896557.

     

Topiramate increases the rewarding properties of cocaine in young-adult mice limiting its clinical usefulness

Rationale

Topiramate is an anticonvulsant drug which has been evaluated as a therapeutic option for the treatment of cocaine addiction during the last decade.

Objectives

The purpose of this study was to evaluate the effects of topiramate on the reinforcing actions of cocaine. To this aim, the topiramate-mediated regulation of acquisition and extinction phases of the cocaine conditioned place preference (CPP) was assessed in young-adult mice using three experimental designs.

Methods

Topiramate (50 mg/kg, p.o.) was given as follows: (1) during cocaine (1 and 25 mg/kg, i.p.) conditioning sessions (4 days) and cocaine (25 mg/kg) post-conditioning session; (2) 2 weeks before and during cocaine conditioning (25 mg/kg); and (3) during extinction of CPP induced by cocaine (25 mg/kg). In the first experimental design, changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) gene expressions were measured in the ventral tegmental area (VTA).

Results

Topiramate significantly increased cocaine-induced CPP and delayed or failed to produce extinction after the first cocaine reinstatement extinction in the first and second experiments. Furthermore, treatment with topiramate after place conditioning blocked the extinction of cocaine-induced CPP. TH and DAT gene expression in the VTA was significantly lower both with topiramate alone and in combination with cocaine compared with animals receiving only cocaine.

Conclusions

These findings suggest that topiramate increases the rewarding properties of cocaine, at least in part, by regulating dopaminergic signaling in the mesolimbic circuit. Consequently, the results of this study do not support the use of topiramate for the treatment of problems related to cocaine dependence.

Highlights

? Topiramate increases the rewarding properties of cocaine in CPP? Topiramate alters dopaminergic signaling in the mesolimbic circuit? Topiramate delays the extinction of cocaine-induced CPP? TH and DAT gene expression in the VTA decreases with topiramate and/or with cocaine? Results show that it should limit the use of topiramate in cocaine-dependent subjects

     

A Retrospective Study of Clinical Effects of Powdered Caffeine Exposures Reported to Three US Poison Control Centers

Introduction

Anhydrous caffeine, often sold on the Internet as a powdered caffeine product, is sold as “pure caffeine” to be used as an additive to beverages and has also been used as an ingredient in energy supplement products.

Methods

This is a retrospective multiple-poison center chart review of calls regarding powdered caffeine to poison centers covering Oregon, Alaska, Guam, Washington, and Utah between January 1, 2013 and June 30, 2015.

Results

There were 40 calls to three poison centers over 30 months for powdered caffeine exposure. The majority of patients were over age 19 (52.5 %; 21/40) and male (70 %; 28/40). Sixty percent (24/40) of the patients were symptomatic but only 10 % (4/40) required admission; 52.5 % (21/40) of the patient calls were for inadvertent overdose of powdered caffeine; one patient overdosed in a self-harm attempt.

Discussion

Powdered caffeine calls to three poison centers during a 30-month study period were rare, and severe caffeine toxicity due to exposure was found in few patients. The majority of symptoms were reported after an inadvertent powdered caffeine overdose.

Conclusions

An analysis of calls to three poison centers for powdered caffeine found that exposures were uncommon, but did result in toxicity, and highlighted that the lack of clear dosing instructions on product packaging may place patients at risk of inadvertent overdose.

     

Effect of Nanoparticle Surface on the HPLC Elution Profile of Liposomal Nanoparticles

Purpose

Nanoparticles have been used in diverse areas, and even broader applications are expected in the future. Since surface modification can influence the configuration and toxicity of nanoparticles, a rapid screening method is important to ensure nanoparticle quality.

Methods

We examined the effect of the nanoparticle surface morphology on the HPLC elution profile using two types of 100-nm liposomal nanoparticles (AmBisome^? and DOXIL^?).

Results

These 100-nm-sized nanoparticles eluted before the holdup time (about 4 min), even when a column packed with particles with a relatively large pore size (30 nm) was used. The elution time of the nanoparticles increased with pegylation of the nanoparticles and protein adsorption to the nanoparticles; however, the nanoparticles still eluted before the holdup time.

Conclusions

The results of this study indicate that HPLC is a suitable tool for rapid evaluation of the surface of liposomal nanoparticles.

     

Electronic data capture using the Womac<Superscript>®</Superscript> NRS 3.1 Index (m-Womac<Superscript>®</Superscript>): a pilot study of repeated independent remote data capture in OA

Aim

A preliminary evaluation of mobile phone technology for repeated independent remote data capture using the mobile phone-based m-WOMAC^® NRS 3.1 Index.

Methods

Following orientation to the m-WOMAC^® Index, and initial completion in the office, patients took the phones home and independently completed the Index on four subsequent occasions over 12 days, sending their data each time to a server in USA.

Results

Three men and nine women with hip (n = 2) and knee (n = 10) OA successfully completed the m-WOMAC^® Index on each occasion. Average time to completing the Index at termination was 4.8 min. The majority of patients rated logging on/opening the application, completing the m-WOMAC^® Index on the phone, and sending data as very easy (10–11/12), and were very confident (11/12) in continuing to use the phone to report their symptoms.

Conclusions

These data support the feasibility of repeated independent remote data capture using the m-WOMAC^® NRS3.1 Index.

     

Modern Intermittent Haemodialysis (IHD) is an Effective Method of Removing Salicylate in Chronic Topical Salicylate Toxicity

Introduction

There are limited data on modern intermittent hemodialysis (IHD) efficacy on salicylate elimination from topical poisoning.

Case report

A 54-year-old male sought treatment for dyspnea but was then diagnosed with salicylate toxicity from topical application of Dencorub Extra Strength Heat Gel® for 1 week. Each tube contained 100 g with 26 % methylsalicylate (26 g). Laboratory workup was remarkable for an elevated anion gap of 30 and salicylate concentration of 78.7 mg/dL [5.7 mmol/L (N?<?0.4 mmol/L)]. Treatment with urinary alkalinization was followed by hemodialysis for 5 h. Extraction ratios were 0.44 with clearance rates of 78.5 mL/min. Salicylate concentrations fell rapidly following initiation of hemodialysis with no rebound observed.

Discussion

Modern high flux IHD is an effective method of removing salicylates in the treatment of chronic topical poisoning.

     

The effects of chronic versus acute desipramine on nicotine withdrawal and nicotine self-administration in the rat

Rationale

Nicotine withdrawal is characterized by depression-like symptomatology that may be mediated by dysregulations in norepinephrine transmission. These aversive aspects of nicotine withdrawal and the rewarding effects of nicotine play major roles in maintaining nicotine dependence.

Objectives

The aim of this work was to evaluate the effects of desipramine (DMI), a preferential norepinephrine reuptake inhibitor and antidepressant, on preclinical models of nicotine dependence in rats.

Materials and methods

A rate-independent current-intensity discrete-trial threshold intracranial self-stimulation procedure was used to assess brain reward function during nicotine withdrawal induced by cessation of nicotine infusion via subcutaneous osmotic mini pumps (3.16 mg/kg/day, base). Nicotine withdrawal was also measured by somatic signs of withdrawal. DMI was administered acutely (2 or 5 mg/kg, salt) during nicotine/saline withdrawal. In other naïve rats, chronic DMI treatment via mini pump (15 mg/kg/day, salt) began after 7 days of nicotine/saline exposure and continued during administration of nicotine/saline for 14 days and during nicotine/saline withdrawal. Additional rats acquired intravenous nicotine- or food-maintained responding, were prepared with DMI/vehicle-containing mini pumps, and self-administered nicotine or food during 12 days of DMI/vehicle exposure.

Results

Acute DMI administration had no effect on threshold elevations observed in nicotine-withdrawing rats. Chronic DMI administration prevented the reward threshold elevations and the increased somatic signs of nicotine withdrawal. Although chronic DMI significantly decreased nicotine self-administration, it also decreased food-maintained responding.

Conclusions

The results suggest that norepinephrine reuptake inhibitors may be effective anti-smoking treatments that reduce the anhedonic depression-like and somatic components of nicotine withdrawal and may alter the rewarding effects of nicotine and food.

     

Efficacious Cefazolin Prophylactic Dose for Morbidly Obese Women Undergoing Bariatric Surgery Based on Evidence from Subcutaneous Microdialysis and Populational Pharmacokinetic Modeling

Purpose

To determine the efficacious cefazolin prophylactic dose for bariatric surgery using free subcutaneous concentrations accessed by microdialysis after 2 g or 3 g i.v. bolus dosing to morbidly obese women and POPPK modeling.

Methods

A POPPK model with variable plasma and subcutaneous tissue protein binding was developed to simultaneously describe plasma and tissue data sets. The outcomes was predicted for common surgical site infection (SSI) bacteria over 3, 4, 5 and 6 h periods postdose, as probability of target attainment (PTA) using Monte Carlo simulation.

Results

CFZ 2 g warrant up to 5 h SSI prophylaxis for bacteria with MICs ≤1 mg/L such as Escherichia coli and Staphylococcus aureus. For species such as Klebsiella pneumoniae, which present MIC distribution frequency of 2 mg/L, the maintenance of PTA?≥?90% occurs with a 3 g dose for surgeries lasting up to 5 h, and 2 g dose provide an adequate response up to 4 h (PTA of 89%).

Conclusions

Effectiveness of CFZ 2 g is similar to 3 g against bacteria with a MIC up to 2 mg/L, especially if the surgery does not last for more than 4 h.

     

Effect of efavirenz on the pharmacokinetics of ketoconazole in HIV-infected patients

Objective

To investigate the effect of efavirenz on the ketoconazole pharmacokinetics in HIV-infected patients.

Methods

Twelve HIV-infected patients were assigned into a one-sequence, two-period pharmacokinetic interaction study. In phase one, the patients received 400 mg of ketoconazole as a single oral dose on day 1; in phase two, they received 600 mg of efavirenz once daily in combination with 150 mg of lamivudine and 30 or 40 mg of stavudine twice daily on days 2 to 16. On day 16, 400 mg of ketoconazole was added to the regimen as a single oral dose. Ketoconazole pharmacokinetics were studied on days 1 and 16.

Results

Pretreatment with efavirenz significantly increased the clearance of ketoconazole by 201%. C_max and AUC_0?24 were significantly decreased by 44 and 72%, respectively. The T _½ was significantly shorter by 58%.

Conclusion

Efavirenz has a strong inducing effect on the metabolism of ketoconazole.

     

Real-Time UV Imaging of Nicotine Release from Transdermal Patch

Purpose

This study was conducted to characterize UV imaging as a platform for performing in vitro release studies using Nicorette® nicotine patches as a model drug delivery system.

Methods

The rate of nicotine release from 2 mm diameter patch samples (Nicorette®) into 0.067 M phosphate buffer, pH 7.40, was studied by UV imaging (Actipix SDI300 dissolution imaging system) at 254 nm. The release rates were compared to those obtained using the paddle-over-disk method.

Results

Calibration curves were successfully established which allowed temporally and spatially resolved quantification of nicotine. Release profiles obtained from UV imaging were in qualitative agreement with results from the paddle-over-disk release method.

Conclusion

Visualization as well as quantification of nicotine concentration gradients was achieved by UV imaging in real time. UV imaging has the potential to become an important technology platform for conducting in vitro drug release studies.

     

Antinociceptive interaction of gabapentin with minocycline in murine diabetic neuropathy

Objective

Diabetic neuropathy (DN) is the most common complication of diabetes and pain is one of the main symptoms of diabetic neuropathy, however, currently available drugs are often ineffective and complicated by adverse events. The purpose of this research was to evaluate the antinociceptive interaction between gabapentin and minocycline in a mice experimental model of DN by streptozocin (STZ).

Methods

The interaction of gabapentin with minocycline was evaluated by the writhing and hot plate tests at 3 and 7 days after STZ injection or vehicle in male CF1 mice.

Results

STZ (150 mg/kg, i.p.) produced a marked increase in plasma glucose levels on day 7 (397.46 ± 29.65 mg/dL) than on day 3 (341.12 ± 35.50 mg/dL) and also developed neuropathic pain measured by algesiometric assays. Gabapentin produced similar antinociceptive activity in both writhing and hot plate tests in mice pretreated with STZ. However, minocycline was more potent in the writhing than in the hot plate test in the same type of mice. The combination of gabapentin with minocycline produced synergistic interaction in both test.

Conclusion

The combination of gabapentin with minocycline in a 1:1 proportion fulfills all the criteria of multimodal analgesia and this finding suggests that the combination provide a therapeutic alternative that could be used for human neuropathic pain management.

     

Population Pharmacokinetic Modeling to Describe the Total Plasma and Free Brain Levels of Fluconazole in Healthy and <Emphasis Type="BoldItalic">Cryptococcus neoformans</Emphasis> Infected Rats: How Does the Infection Impact the Drug’s Levels on Biophase?

Purpose

The present work aimed to evaluate the influence of experimental meningitis caused by C. neoformans on total plasma and free brain concentrations of fluconazole (FLC) in Wistar rats.

Method

The infection was induced by the administration of 100 μL of inoculum (1.10⁵ CFU) through the tail vein. Free drug in the brain was assessed by microdialisys (μD). Blood and μD samples were collected at pre-determined time points up to 12 h after intravenous administration of FLC (20 mg/kg) to healthy and infected rats. The concentration-time profiles were analyzed by non-compartmental and population pharmacokinetics approaches.

Results

A two-compartmental popPK model was able to simultaneously describe plasma and free drug concentrations in the brain for both groups investigated. Analysis of plasma and μD samples showed a better FLC distribution on the brain of infected than healthy animals (1.04?±?0.31 vs 0.69?±?0.14, respectively). The probability of target attainment was calculated by Monte Carlo simulations based on the developed popPK model for 125 mg/kg dose for rats and 400–2000 mg for humans.

Conclusions

FLC showed a limited use in monotherapy to the treatment of criptoccocosis in rats and humans to value of MIC >8 μg/mL.

     

Pharmacokinetic-Pharmacodynamic Relationship of Erenumab (AMG 334) and Capsaicin-Induced Dermal Blood Flow in Healthy and Migraine Subjects

Purpose

Capsaicin-induced dermal blood flow (CIDBF) is a validated biomarker used to evaluate the target engagement of potential calcitonin gene-related peptide-blocking therapeutics for migraine. To characterize the pharmacokinetics (PK) and quantify the inhibitory effects of erenumab (AMG 334) on CIDBF, CIDBF data were pooled from a single- and a multiple-dose study in healthy and migraine subjects.

Methods

Repeated capsaicin challenges and DBF measurements were performed and serum erenumab concentrations determined. A population analysis was conducted using a nonlinear mixed-effects modeling approach. Effects of body weight, gender, and age on model parameters were evaluated.

Results

Two-compartment target-mediated drug disposition (TMDD) model assuming binding of erenumab in the central compartment best described the nonlinear PK of erenumab. Subcutaneous absorption half-life was 1.6 days and bioavailability was 74%. Erenumab produced a maximum inhibition of 89% (95% confidence interval: 87–91%). Erenumab concentrations required for 50% and 99% of maximum inhibition were 255 ng/mL and 1134 ng/mL, respectively. Increased body weight was associated with increased erenumab clearance but had no effect on the inhibitory effect on CIDBF.

Conclusions

Our results show that erenumab pharmacokinetics was best characterized by a TMDD model and resulted in potent inhibition of CIDBF.

     

Scanning Electron Microscope Observations of Powder Sticking on Punches during a Limited Number (<Emphasis Type="BoldItalic">N</Emphasis> &lt; 5) of Compactions of Acetylsalicylic Acid

Purpose

To obtain quantitative information and mechanistic insight into the problem of sticking of acetylsalicylic acid tablets on a metallic punch.

Methods

Low voltage scanning electron microscopy was used to observe punch area coverage and morphology of adhered powder on a flat punch used for a limited number of compactions.

Results

Material accumulation in terms of area coverage of the punch per compaction cycle was determined at two pressures over five compactions. The distribution of the adhered material on the punch was non-uniform with more material left on the center of the punch. The sizes of the adhered particles range from 1 to 100 μm, with 50% of the punch surface coverage from particles of an equivalent diameter > 30 μm. Three types of adhered particles were identified after the first compaction: (a) fragments of initial particles with very high aspect ratio, (b) nearly equiaxed fragments with multiple cracks, (c) heavily deformed islands of low profile. Some preliminary ideas that explain these observations are presented and discussed.

Conclusions

The ability of SEM to provide quantitative information on sticking from few compactions presents an interesting possibility for a material sparing technique that provides insight on the propensity of sticking.

     

Differences between serum polar lipid profiles of male and female rheumatoid arthritis patients in response to glucocorticoid treatment

Objective

As there are pharmacological differences between males and females, and glucocorticoid (GC) treatment is associated with increased cardiovascular mortality rate in rheumatoid arthritis (RA) patients, it is important to study serum polar lipid profiles of male and female patients in response to GC therapy. Gender differences may require an adjustment to the treatment strategy for a selection of patients.

Methods

Serum samples from 281 RA patients were analysed using a targeted lipidomics platform. The differences in GC use and gender on polar lipid profiles were cross sectionally examined by multiple linear regressions, while correcting for confounding factors.

Results

Differences in polar lipids between GC users and non-GC users in females and males were merely restricted to lysophospholipids (lysophosphatidylcholines and lysophosphatidylethanolamines). Lysophospholipids in female patients treated with GCs were significantly higher than female patients not treated with GCs (p = 6.0 E?6), whereas no significant difference was observed in male GC users versus non-users (p = 0.397).

Conclusion

The lysophospholipid profiles in response to GCs were significantly different between male and female RA patients, which may have implications for the cardiovascular risk of GC treatment.

     

Maturation of Oxycodone Pharmacokinetics in Neonates and Infants: a Population Pharmacokinetic Model of Three Clinical Trials

Purpose

The aim of the current population pharmacokinetic study was to quantify oxycodone pharmacokinetics in children ranging from preterm neonates to children up to 7 years of age.

Methods

Data on intravenous or intramuscular oxycodone administration were obtained from three previously published studies (n?=?119). The median [range] postmenstrual age of the subjects was 299 days [170 days-7.8 years]. A population pharmacokinetic model was built using 781 measurements of oxycodone plasma concentration. The model was used to simulate repeated intravenous oxycodone administration in four representative infants covering the age range from an extremely preterm neonate to 1-year old infant.

Results

The rapid maturation of oxycodone clearance was best described with combined allometric scaling and maturation function. Central and peripheral volumes of distribution were nonlinearly related to bodyweight. The simulations on repeated intravenous administration in virtual patients indicated that oxycodone plasma concentration can be kept between 10 and 50 ng/ml with a high probability when the maintenance dose is calculated using the typical clearance and the dose interval is 4 h.

Conclusions

Oxycodone clearance matures rapidly after birth, and between-subject variability is pronounced in neonates. The pharmacokinetic model developed may be used to evaluate different multiple dosing regimens, but the safety of repeated doses should be ensured.

     

Identification of D-Amino Acids in Light Exposed mAb Formulations

Purpose

We previously demonstrated that D-amino acids can form as a result of photo-irradiation of a monoclonal antibody (mAb) at both λ?=?254 nm and λ?>?295 nm (λ_max?=?305 nm), likely via reversible hydrogen transfer reactions of intermediary thiyl radicals. Here, we investigate the role of various excipients (sucrose, glucose, L-Arg, L-Met and L-Leu) on D-amino acid formation, and specifically the distribution of D-amino acids in mAb monomers and aggregates present after light exposure.

Methods

The mAb-containing formulations were photo-irradiated at λ?=?254 nm and λ_max?=?305 nm, followed by fractionation of aggregate and monomer fractions using size exclusion chromatography. These aggregate and monomer fractions were subjected to hydrolysis and subsequent amino acid analysis.

Results

Both aggregate and monomer fractions collected from all formulations showed the formation of D-Glu and D-Val, whereas the formation of D-Ala was limited to the aggregate fraction collected from an L-Arg-containing formulation. Interestingly, quantitative analysis revealed higher yields of D-amino acids in the L-Arg-containing formulation.

Conclusions

Generally, D-amino acids accumulated to similar extents in monomers and aggregates.