Small Airway Absorption and Microdosimetry of Inhaled Corticosteroid Particles after Deposition

Purpose

To predict the cellular-level epithelial absorbed dose from deposited inhaled corticosteroid (ICS) particles in a model of an expanding and contracting small airway segment for different particle forms.

Methods

A computational fluid dynamics (CFD)-based model of drug dissolution, absorption and clearance occurring in the surface liquid of a representative small airway generation (G13) was developed and used to evaluate epithelial dose for the same deposited drug mass of conventional microparticles, nanoaggregates and a true nanoaerosol. The ICS medications considered were budesonide (BD) and fluticasone propionate (FP). Within G13, total epithelial absorption efficiency (AE) and dose uniformity (microdosimetry) were evaluated.

Results

Conventional microparticles resulted in very poor AE of FP (0.37%) and highly nonuniform epithelial absorption, such that <5% of cells received drug. Nanoaggregates improved AE of FP by a factor of 57-fold and improved dose delivery to reach approximately 40% of epithelial cells. True nanoaerosol resulted in near 100% AE for both drugs and more uniform drug delivery to all cells.

Conclusions

Current ICS therapies are absorbed by respiratory epithelial cells in a highly nonuniform manner that may partially explain poor clinical performance in the small airways. Both nanoaggregates and nanoaerosols can significantly improve ICS absorption efficiency and uniformity.

     

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.

     

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.

     

<Emphasis Type="Italic">In Vitro</Emphasis> Assessment of Spray Deposition Patterns in a Pediatric (12 Year-Old) Nasal Cavity Model

Purpose

Nasal sprays available for the treatment of cold and allergy symptoms currently use identical formulations and devices for adults as well as for children. Due to the obvious differences between the nasal airway dimensions of a child and those of an adult, the performance of nasal sprays in children was evaluated.

Methods

Deposition patterns of nasal sprays administered to children were tested using a nasal cast based on MRI images obtained from a 12 year old child’s nasal cavity. Test formulations emitting a range of spray patterns were investigated by actuating the device into the pediatric nasal cast under controlled conditions.

Results

The results showed that the nasal sprays impacted in the anterior region of the 12 year old child’s nasal cavity, and only limited spray entered the turbinate region – the effect site for most topical drugs and the primary absorptive region for systemically absorbed drugs.

Conclusion

Differences in deposition patterns following the administration of nasal sprays to adults and children may lead to differences in efficacy between these populations. Greater anterior deposition in children may result in decreased effectiveness, greater anterior dosage form loss, and the increased potential for patient non-compliance.

     

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.

     

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.

     

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.

     

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

     

Blood Urea Nitrogen/Creatinine Ratio and Response to Tolvaptan in Patients with Decompensated Heart Failure: A Retrospective Analysis

Introduction

Arginine vasopressin-stimulated reabsorption of urea occurs in the collecting duct via increased expression of the urea transporter.

Objective

The aim of this study was to evaluate whether the blood urea nitrogen/creatinine (BUN/Cr) ratio is useful for predicting tolvaptan response in patients with decompensated heart failure (HF).

Methods

Among 71 consecutive patients with HF who received oral tolvaptan between 2010 and 2014, we retrospectively studied 33 patients with decompensated HF without any mechanical circulatory assistance or inotropic support who had already been treated with loop diuretics. A responder to tolvaptan was defined as an individual who experienced a ≥30 % increase in their respective 24-h urine volume.

Results

Among the 33 patients, 21 met the criteria of a responder. The area under the receiver operating characteristic curves of BUN/Cr and BUN were 0.790 and 0.714, respectively, and the respective cut-off values for responders to tolvaptan were 23.8 and 49.0. BUN/Cr and BUN retained their significant relationships with the responder status (odds ratio for BUN/Cr >23.8: 20.9; 95 % confidence interval [CI] 2.7–531.1; p = 0.002; odds ratio for BUN ≥49: 7.7; 95 % CI 1.4–65.8; p = 0.02).

Conclusion

Our results suggest that high BUN/Cr may be a predictor of response to tolvaptan in decompensated HF patients. A prospective study with a large sample size is required to confirm this preliminary finding.

     

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.

     

Fabrication of 3-O-sn-Phosphatidyl-L-serine Anchored PLGA Nanoparticle Bearing Amphotericin B for Macrophage Targeting

Purpose

To fabricate, characterize and evaluate 3-O-sn-Phosphatidyl-L-serine (PhoS) anchored PLGA nanoparticles for macrophage targeted therapeutic intervention of VL.

Materials and Methods

PLGA-AmpB NPs were prepared by well-established nanoprecipitation method and decorated with Phos by thin film hydration method. Physico-chemical characterization of the formulation was done by Zetasizer nano ZS and atomic force microscopy.

Results

The optimized formulation (particle size, 157.3?±?4.64 nm; zeta potential, ? 42.51?±?2.11 mV; encapsulation efficiency, ～98%) showed initial rapid release up to 8 h followed by sustained release until 72 h. PhoS generated ‘eat-me’ signal driven augmented macrophage uptake, significant increase in in-vitro (with ～82% parasite inhibition) and in-vivo antileishmanial activity with preferential accumulation in macrophage rich organs liver and spleen were found. Excellent hemo-compatibility justified safety profile of developed formulation in comparison to commercial formulations.

Conclusion

The developed PhoS-PLGA-AmpB NPs have improved efficacy, and necessary stability which promisingly put itself as a better alternative to available commercial formulations for optimized treatment of VL.

     

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.

     

Effects of cocaine self-administration history under limited and extended access conditions on in vivo striatal dopamine neurochemistry and acoustic startle in rhesus monkeys

Rationale

The transition from infrequent and controlled cocaine use to dependence may involve enduring changes in neurobiology as a consequence of persistent drug use.

Objective

The present study utilized an intravenous drug self-administration protocol of increasing cocaine access to evaluate potential changes in dopamine function in vivo, including changes in sensitivity to psychostimulants.

Materials and methods

Drug-naïve rhesus monkeys were provided limited access (1 h) to cocaine self-administration for 60 days followed by 60 days under an extended access condition (4 h). Basal levels of striatal extracellular dopamine and its metabolites, as well as the effectiveness of cocaine and amphetamine to elevate dopamine, were determined with in vivo microdialysis before the initiation of cocaine self-administration and during limited and extended access. The effect of cocaine and amphetamine on the acoustic startle response was also examined to assess complementary behavioral changes as a function of drug history.

Results

Extended access to cocaine self-administration lead to increased daily intake compared to limited access conditions but did not result in escalated intake over time. However, cocaine- and amphetamine-induced increases in striatal dopamine were diminished as a function of cocaine self-administration history. Surprisingly, there was no effect of drug-taking history on sensitivity to psychostimulant-induced enhancement of startle amplitude.

Conclusions

The present experiments provide evidence of a hypofunctional dopamine system that is not associated with an escalation in drug intake or reflected in measures of acoustic startle.

     

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.

     

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.

     

Adherence to HAART therapy measured by electronic monitoring in newly diagnosed HIV patients in Botswana

Aims

This pilot study was designed to evaluate the feasibility and benefits of electronic adherence monitoring of antiretroviral medications in HIV patients who recently started Highly Active Anti Retroviral Therapy (HAART) in Francistown, Botswana and to compare this with self-reporting.

Methods

Dosing histories were compiled electronically using Micro Electro Mechanical Systems (MEMS) monitors to evaluate adherence to prescribed therapies. Thirty patients enrolled in the antiretroviral treatment program were monitored over 6 weeks. These patients were all antiretroviral (ARV) naïve. After each visit (mean three times) to the pharmacy, the data compiled by the monitors were downloaded. Electronic monitoring of adherence was compared to patient self-reports of adherence.

Results

The mean individual medication adherence level measured with the electronic device was 85% (range 21–100%). The mean adherence level measured by means of self-reporting was 98% (range 70–100%). Medication prescribed on a once-a-day dose base was associated with a higher adherence level (97.9% for efavirenz) compared with a twice-a-day regimen (88.4% for Lamivudine/Zidovudine).

Conclusions

It is feasible to assess treatment adherence of patients living in a low resource setting on HAART by using electronic monitors. Adherence, even in the early stages of treatment, appears to be insufficient in some patients and may be below the level required for continuous inhibition of viral replication. This approach may lead to improved targeting of counselling about their medication intake of such patients in order to prevent occurrence of resistant viral strains due to inadequate inhibition of viral replication. In this pilot study a significant difference between the data recorded through the electronic monitors and those provided by self-reporting was observed.

     

Investigation Into the Effects of Tenilsetam on Markers of Neuroinflammation in GFAP-IL6 Mice

Purpose

To test the short- and long-term effects of Tenilsetam on chronic neuroinflammation in the GFAP-IL6 mouse.

Methods

From 3 months of age, GFAP-IL6 mice were divided into 2 groups and fed with Tenilsetam enriched food pellets or control food pellets, respectively, for either 5 or 15 months. Total numbers of Iba-1⁺ microglia, TSPO⁺ cells were determined using an unbiased stereological method. Levels of methylglyoxal and TNF-α in the cerebellar homogenate were tested using HPLC and ELISA, respectively.

Results

Tenilsetam decreased the total number of Iba-1⁺ microglia in both the cerebellum and the hippocampus of GFAP-IL6 mice at 8 months and in the cerebellum at 18 months. In the cerebellum, it decreased the density of microglia in GFAP-IL6 mice to a similar level after 5 and 15 months’ feeding. Tenilsetam prevented the volume loss of the cerebellum at 8 months. It also significantly decreased TNF-α in the cerebellum of GFAP-IL6 mice to a similar level of WT mice after 15 months of feeding.

Conclusion

Tenilsetam has anti-inflammatory effects evidenced by the decreased number of microglia in both the cerebellum and hippocampus, and decreased TNF-α levels in the GFAP-IL6 Tenilsetam fed animals.

     

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.

     

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.