Intranasal Fentanyl Intoxication Leading to Diffuse Alveolar Hemorrhage

Context

Increasing rates of opioid abuse, particularly fentanyl, may lead to more presentations of unusual effects of opioid toxicity. Diffuse alveolar hemorrhage is a rare complication of fentanyl overdose.

Case Details

A 45-year-old male presented in hypoxic respiratory failure secondary to diffuse alveolar hemorrhage requiring intubation. Comprehensive drug screening detected fentanyl without exposure to cocaine. Further history upon the patient’s recovery revealed exposure to snorted fentanyl powder immediately prior to presentation.

Discussion

Diffuse alveolar hemorrhage is a potential, though rare, presentation of opioid intoxication.

Conclusions

Recognition of less common complications of opioid abuse such as diffuse alveolar hemorrhage is important in proper management of overdoses.

     

Patient satisfaction with a chronic kidney disease risk assessment service in community pharmacies

Background

Patient satisfaction is an important determinant of the feasibility and sustainability of community pharmacy screening services. However, few studies have evaluated this, with no such study performed for a chronic kidney disease risk assessment service.

Objective

The aim was to determine patient satisfaction with a chronic kidney disease risk assessment service performed in community pharmacies.

Setting

Community pharmacies in the state of Tasmania, Australia.

Method

An anonymous nine-item satisfaction survey, with Likert-type scales, was developed following a literature review of existing surveys. Reliability of the nine-item scale was determined using Cronbach’s alpha. Patients were asked an additional question on willingness to pay, with choices of amount from $5 to $25. The satisfaction survey was mailed to 389 patients who participated in the chronic kidney disease risk assessment study.

Main outcome measure

Patient level of satisfaction with and willingness to pay for the chronic kidney disease service.

Results

Responses from 143 participants were included in the final analysis. Cronbach’s alpha for the nine-item satisfaction scale was 0.87. The majority of participants agreed that the time required to undergo the risk assessment process was justified (90.2%); overall, they were satisfied with the chronic kidney disease risk assessment service (90.0%) and they felt comfortable with the pharmacist referring their results to their doctor (88.9%). Of 136 participants who answered the question on willingness to pay, 62.9% indicated that they would pay for the chronic kidney disease service. Of these, 29.2, 25.8 and 19.1% were willing to pay $20, $10 and $5, respectively.

Conclusion

Patient satisfaction with the community pharmacy-based chronic kidney disease risk assessment was high. These findings provide support for the implementation of the service within community pharmacy practice.

     

Increased breakpoints on a progressive ratio schedule reinforced by IV cocaine are associated with reduced locomotor activation and reduced dopamine efflux in nucleus accumbens shell in rats

Rationale

It has been hypothesized that sensitization of the neurochemical effects within the mesolimbic dopamine (DA) system might account for specific aspects of the addiction process. We have recently developed a self-administration procedure which produces increases in responding reinforced by cocaine on a progressive ratio (PR) schedule. This may reflect an increased motivation to self-administer cocaine, one hallmark of addiction.

Objectives

The goal of this experiment was to investigate behavioral and neurochemical changes associated with increased cocaine self-administration on a PR schedule.

Materials and methods

Rats self-administered cocaine over 14 days under a PR schedule. Cocaine-stimulated locomotor activity was evaluated before as well as 1 or 14 days after self-administration training. Cocaine-induced DA changes in the core and shell of the nucleus accumbens in the same animals were also examined.

Results

Subjects showed increased responding over time, to about 200% of baseline. Cocaine-induced locomotor activation was decreased at both withdrawal times compared to naïve animals. Microdialysis showed no differences after self-administration in the nucleus accumbens core dopamine response at either time point. There was, however, a significant decrease in the dopamine response to cocaine in the shell of the nucleus accumbens.

Conclusion

The present results demonstrate that a progressive increase in breakpoints on a PR schedule can be established in rats at a time when the ability of cocaine to increase extracellular DA levels and stimulate locomotor activity is reduced. Therefore, sensitization of the mesolimbic DA system does not account for the observed change in drug-taking behavior.

     

Absorption and Clearance of Pharmaceutical Aerosols in the Human Nose: Effects of Nasal Spray Suspension Particle Size and Properties

Purpose

The objective of this study was to use a recently developed nasal dissolution, absorption, and clearance (DAC) model to evaluate the extent to which suspended drug particle size influences nasal epithelial drug absorption for a spray product.

Methods

Computational fluid dynamics (CFD) simulations of mucociliary clearance and drug dissolution were used to calculate total and microscale epithelial absorption of drug delivered with a nasal spray pump. Ranges of suspended particle sizes, drug solubilities, and partition coefficients were evaluated.

Results

Considering mometasone furoate as an example, suspended drug particle sizes in the range of 1-5 μm did not affect the total nasal epithelial uptake. However, the microscale absorption of suspended drug particles with low solubilities was affected by particle size and this controlled the extent to which the drug penetrated into the distal nasal regions.

Conclusions

The nasal-DAC model was demonstrated to be a useful tool in determining the nasal exposure of spray formulations with different drug particle sizes and solubilities. Furthermore, the model illustrated a new strategy for topical nasal drug delivery in which drug particle size is selected to increase the region of epithelial surface exposure using mucociliary clearance while minimizing the drug dose exiting the nasopharynx.

     

Intranasal Delivery of Topically-Acting Levofloxacin to Rats: a Proof-of-Concept Pharmacokinetic Study

Purpose

To evaluate the potential of levofloxacin intranasal administration as a promising alternative approach to treat local infections such as chronic rhinosinusitis, by delivering drug concentrations directly to the site of infection.

Methods

Drug concentrations were measured in plasma, olfactory bulb and nasal mucosa of anterior (ANM) and posterior regions after intranasal (0.24 mg/kg) and intravenous (10 mg/kg) administration to rats, and pharmacokinetic parameters were compared between routes. For intranasal administration a thermoreversible in-situ gel was used.

Results

Plasma and olfactory bulb exposure to levofloxacin was minimal following intranasal dose, preventing systemic and central nervous system adverse effects. Levofloxacin concentration-time profile in ANM revealed higher concentrations during the first 60 min of the study following intranasal administration than the corresponding ones obtained after intravenous administration. A rapid and continuous decay of levofloxacin concentration in this nasal region was observed after intranasal delivery, resulting in much lower values at the last sampling time-points.

Conclusion

The higher dose-normalized concentrations and pharmacokinetic exposure parameters of levofloxacin in ANM after intranasal administration, demonstrates that intranasal delivery of the formulated gel is, by itself, advantageous for delivering levofloxacin to biophase and thus an attractive approach in management of chronic rhinosinusitis.

     

Effect of cocaine self-administration on striatal PKA-regulated signaling in male and female rats

Rationale

Chronic cocaine produces changes in the dopamine (DA)/D1/cAMP/protein kinase A (PKA)-regulated signaling pathway that may underlie the development of addiction.

Objective

Given sex differences in the progression to cocaine addiction, we examined the possibility that the PKA pathway is differentially activated by cocaine in male and female rats.

Materials and methods

Rats were given 24-h access to cocaine (1.5 mg/kg) or saline for 7 days under a discrete trial procedure (four trials per hour). Rats were then retested on responding for cocaine under a progressive-ratio schedule after either 0 (no-delay retest) or 10 (10-day-delay retest) days of abstinence. Markers of PKA-regulated signaling in the striatum and nucleus accumbens were evaluated by Western blotting, including phosphorylation of DA and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr 34 and glutamate receptor 1 (GluR1) at Ser 845.

Results

Compared to males, females had higher levels of DARPP-32 phosphorylated at the PKA site in the striatum. Increased phosphorylation of DARPP-32 at the PKA site was also seen in the nucleus accumbens of females compared to males, particularly among controls and rats tested after a 10-day abstinence period. DARPP-32 phosphorylation was also increased as a consequence of cocaine when tested after a 0-day abstinence period in male rats but not female rats.

Conclusion

These findings indicate sex differences in PKA-regulated signaling in drug-naïve controls. Furthermore, these data suggest that regulation of PKA signaling by cocaine is differentially influenced in male and female rats as a consequence of cocaine exposure and cocaine abstinence period.

     

Influence of Ethanol on Darunavir Hepatic Clearance and Intracellular PK/PD in HIV-Infected Monocytes,and CYP3A4-Darunavir Interactions Using Inhibition and in Silico Binding Studies

Purpose

Although the prevalence of alcohol consumption is higher in HIV+ people than general public, limited information is available on how alcohol affects the metabolism and bioavailability of darunavir (DRV).

Methods

DRV was quantified by using LC-MS/MS method. All in vitro experiments were performed using human liver microsomes and HIV-infected monocytic cells. CYP3A4 and DRV/Ritonavir (RTV) docking was performed using GOLD suite 5.8.

Results

Ethanol (20 mM) significantly decreased apparent half-life and increased degradation rate constant of RTV-boosted DRV but not for DRV alone. Similarly, ethanol exposure increased hepatic intrinsic clearance for RTV-boosted DRV with no significant influence on DRV alone. Ethanol showed a limited influence on intracellular total DRV exposure in the presence of RTV without altering maximum concentration (C_max) values in HIV-infected monocytic cells. Ethanol alone elevated HIV replication but this effect was nullified with the addition of DRV or DRV + RTV. Additionally, inhibitory potency of DRV was significantly reduced in the presence of ethanol. Our docking results projected that ethanol increases the average distance between DRV and CYP3A4 heme, and alter the orientation of DRV-CYP3A4 binding.

Conclusions

Collectively these findings suggest that DRV metabolism is primarily influenced by ethanol in the liver, but has minor effect in HIV-residing monocytes.

     

Stressful life experiences,alcohol consumption,and alcohol use disorders: the epidemiologic evidence for four main types of stressors

Background

Exposure to stress is potentially important in the pathway to alcohol use and alcohol use disorders. Stressors occur at multiple time points across the life course, with varying degrees of chronicity and severity.

Method

We review evidence from epidemiologic studies on the relationship between four different stressors (fateful/catastrophic events, child maltreatment, common adult stressful life events in interpersonal, occupational, financial, and legal domains, and minority stress) and alcohol consumption and alcohol use disorders.

Results

Studies generally demonstrate an increase in alcohol consumption in response to exposure to terrorism or other disasters. Research has demonstrated little increase in incident alcohol use disorders, but individuals with a history of alcohol use disorders are more likely to report drinking to cope with the traumatic event. Childhood maltreatment is a consistent risk factor for early onset of drinking in adolescence and adult alcohol use disorders, and accumulating evidence suggests that specific polymorphisms may interact with child maltreatment to increase risk for alcohol consumption and disorder. Stressful life events such as divorce and job loss increase the risk of alcohol disorders, but epidemiologic consensus on the specificity of these associations across gender has not been reached. Finally, both perceptions of discrimination and objective indicators of discrimination are associated with alcohol use and alcohol use disorders among racial/ethnic and sexual minorities.

Conclusion

Taken together, these literatures demonstrate that exposure to stress is an important component in individual differences in risk for alcohol consumption and alcohol use disorders. However, many areas of this research remain to be studied, including greater attention to the role of various stressors in the course of alcohol use disorders and potential risk moderators when individuals are exposed to stressors.

     

A Study on Toxicity of Chemically Synthesised Silver Nanoparticle on <Emphasis Type="Italic">Eudrilus eugeniae</Emphasis>

Objective

To evaluate the toxicity of the silver nanoparticle against earthworms - Eudrilus eugeniae, a model for soil organism.

Methods

Silver nanoparticles were synthesised by chemical reduction and further characterised by UV Visible Spectroscopy and FeSEM. Earthworms were allowed to interact with different concentrations of the synthesized silver nanoparticles. After exposure period, histology and inductively coupled plasma optical emission spectrometry (ICP-OES) were done to determine the accumulation and toxic effects exhibited by the nanoparticle on earthworms.

Results

The synthesized nanoparticle was found to be between the size of 180 and 200 nm. Histology studies revealed that silver nanoparticles to cause fibrosis, lipofuscin-like deposits and also gut disruption in earthworms.

Conclusion

Silver nanoparticles were found to be toxic to Eudrilus eugeniae, which was evidenced by histology.

     

Elucidation of the Mechanism of Increased Activity of Immunostimulatory DNA by the Formation of Polypod-like Structure

Purpose

We previously demonstrated that the immunostimulatory activity of CpG DNA is increased by the formation of polypod-like structures. The present study was designed to elucidate the mechanism underlying this increase.

Methods

Tripodna (three pods) and hexapodna (six pods) were prepared. The cellular uptake of Alexa Fluor 488-labeled DNA samples was examined in several cell lines by measuring the MFI of cells. TNF-α release from RAW264.7 cells was measured after addition of polypodna containing CpG motifs. Dissociation of double stranded DNA was evaluated using FRET.

Results

Tripodna and hexapodna were efficiently taken up by macrophage-like RAW264.7 cells and dendritic DC2.4 cells, but not by fibroblast or endothelial cell lines. The uptake by RAW264.7 cells was highest for hexapodna, followed by tripodna, dsDNA, and ssDNA. The release of TNF-α from RAW264.7 cells was also highest for hexapodna. The ratio of TNF-α release to cellular uptake was highest for ssDNA, and lowest for dsDNA. Tripodna and hexapodna were more easily dissociated into single strands after cellular uptake than was dsDNA.

Conclusions

The efficient cellular uptake and prompt dissociation into single strands can be directly related to the high immunostimulatory activity of polypod-like structured DNAs containing CpG motifs.

     

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.

     

Adderall<Superscript>®</Superscript> produces increased striatal dopamine release and a prolonged time course compared to amphetamine isomers

Rationale

Adderall^® is currently used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD) and is composed of a novel mixture of approximately 24% l-amphetamine and 76% d-amphetamine salts. There are, however, no investigations of the pharmacological effects of this combination in vivo.

Objectives

The technique of high-speed chronoamperometry using Nafion^®-coated single carbon-fiber microelectrodes was used to study amphetamine-evoked dopamine (DA) release produced by Adderall^®, d-amphetamine, or d,l-amphetamine in the striatum of anesthetized male Fischer 344 (F344) rats. The amphetamine solutions were locally applied from micropipettes by pressure ejection.

Results

Local applications of Adderall^® resulted in significantly greater DA release signal amplitudes with prolonged time course of dopamine release and re-uptake as compared to d-amphetamine and d,l-amphetamine.

Conclusions

These data support the hypothesis that the combination of amphetamine enantiomers and salts in Adderall^® has effects on DA release, which result in increased and prolonged DA release, compared to d- and d,l-amphetamine.

     

Dermal Drug Delivery for Cutaneous Malignancies: Literature at a Glance

Purpose

Cutaneous malignancies are the most common human cancers, and despite growing public awareness of the harmful effects of sun exposure, incidence and morbidity continue to rise which has generated great interest in unravelling of their aetiology and in the search for new non-invasive treatment strategies.

Methods

A yearly increase in incidence of cutaneous malignancies has been reported since a long time worldwide, suggesting that prevalence of this cancer will soon equal that of all other cancers combined. Grouping of various skin lesions and malignancies under a common umbrella term poses challenges because clear differences exist in their aetiopathogenesis, clinical course and management strategies, suggesting the need of the novel and future therapeutic perspectives for the treatment from nanotechnology to immunotherapy.

Results

Moreover, treatment modalities should comprised of gold standards of the current recommended therapies worldwide and the actual needs of these patients.

Conclusion

The overall goal of this review was to explore the approaches for cutaneous malignancies’ new technological methods instead of new molecules.

     

Notch-1 siRNA and Methotrexate towards a Multifunctional Approach in Rhematoid Arthritis Management: a Nanomedicine Approach

Purpose

Rheumatoid arthritis (RA) is a chronic inflammatory disease and Notch pathway plays a pivotal role in synoviocytes involved in progression of RA.

Methods

Herein, we have designed a self-assembled polymeric micelles based on polycaprolactone-polyethylene glycol (PCL-PEG) and polyethylenimine-polyethylene glycol (PEI-PEG) was prepared and loaded with methotrexate and Notch-1 siRNA for the effective treatment of rheumatoid arthritis.

Results

The MTX/siRNA-loaded polymeric micelles (siM-PM) showed appreciable cellular uptake in Raw264.7 cells which were activated with LPS and did not exhibit any toxicity to Raw264.7 and HUVEC cells. The AUC of siM-PM was 4-fold higher compared to that of free MTX while t1/2 was 6 fold for siM-PM compared to that of free drug indicating the superior pharmacokinetic parameters. Importantly, siM-PM significantly reduced the paw thickness and slowed the disease progression remarkably, indicating that siM-PM is very effective in recovering the edema in arthritic animals. Importantly, 2-fold decrease in arthritic score was observed in siM-PM treated group at the end of day 24. The data clearly reveals anti-inflammatory effect of combinational nanoparticle due to the sequence specific downregulation of Notch-1 expression in the RA clinical models.

Conclusions

Overall, nanomedicine-based delivery of MTX and siRNA could overcome the side effects of small molecules and could improve the therapeutic effect of siRNA in rheumatoid arthritis.

     

Endocytic Uptake,Transport and Macromolecular Interactions of Anionic PAMAM Dendrimers within Lung Tissue

Purpose

Polyamidoamine (PAMAM) dendrimers are a promising class of nanocarrier with applications in both small and large molecule drug delivery. Here we report a comprehensive evaluation of the uptake and transport pathways that contribute to the lung disposition of dendrimers.

Methods

Anionic PAMAM dendrimers and control dextran probes were applied to an isolated perfused rat lung (IPRL) model and lung epithelial monolayers. Endocytosis pathways were examined in primary alveolar epithelial cultures by confocal microscopy. Molecular interactions of dendrimers with protein and lipid lung fluid components were studied using small angle neutron scattering (SANS).

Results

Dendrimers were absorbed across the intact lung via a passive, size-dependent transport pathway at rates slower than dextrans of similar molecular sizes. SANS investigations of concentration-dependent PAMAM transport in the IPRL confirmed no aggregation of PAMAMs with either albumin or dipalmitoylphosphatidylcholine lung lining fluid components. Distinct endocytic compartments were identified within primary alveolar epithelial cells and their functionality in the rapid uptake of fluorescent dendrimers and model macromolecular probes was confirmed by co-localisation studies.

Conclusions

PAMAM dendrimers display favourable lung biocompatibility but modest lung to blood absorption kinetics. These data support the investigation of dendrimer-based carriers for controlled-release drug delivery to the deep lung.

     

Photochemically Controlled Drug Dosing from a Polymeric Scaffold

Purpose

To develop the first photoactive biomaterial coating capable of controlled drug dosing via inclusion of synthesised drug-3,5-dimethoxybenzoin (DMB) conjugates in a poly(2-methyoxyethyl acrylate) (pMEA) scaffold.

Methods

Flurbiprofen- and naproxen-DMB conjugates were prepared via esterification and characterised via NMR spectroscopy and mass spectrometry following chromatographic purification. Conjugate photolysis was investigated in acetonitrile solution and within the pMEA matrix following exposure to low-power 365 nm irradiation. Photo-liberation of drug from pMEA into phosphate buffered saline was monitored using UV-vis spectroscopy.

Results

The synthetic procedures yielded the desired drug conjugates with full supporting characterisation. Drug regeneration through photolysis of the synthesised conjugates was successful in both acetonitrile solution and within the pMEA scaffold upon UV irradiation. Conjugates were retained within the pMEA scaffold with exclusive drug liberation following irradiation and increased drug dose with increasing exposure. Multi-dosing capacity was demonstrated though the ability of successive irradiation periods to generate further bursts of drug.

Conclusion

This study demonstrates the first application of photochemically controlled drug release from a biomaterial coating and the feasibility of using pMEA as a scaffold for housing the photoactive drug-DMB conjugates.

     

The Effort of Health Management for Workers in Y Combined Cycle Power Plant in Korea

Objective

This study promotes health management activities in Y combined cycle power plants in Korea, focusing on occupational health activities, such as preventing cardiovascular disease and musculoskeletal disorders and managing work environment measurements.

Methods

The results of the present study were collected from the company’s internal documents and reports in Y combined cycle power plant.

Results

Diverse results for workplace activities are summarized. Furthermore, this study discusses attempts to reduce potential safety risks and to improve workers’ health conditions at the Y combined cycle power plants in Korea.

Conclusion

The Y combined cycle plant discussed seeks to prevent accidents to improve workers’ health; thus, specific efforts related to onsite health and expected results for workers are evaluated.

     

Adjunctive Use of Ketamine for Benzodiazepine-Resistant Severe Alcohol Withdrawal: a Retrospective Evaluation

Introduction

Benzodiazepine (BZD)-resistant alcohol withdrawal remains a challenge for most institutions due to limited evidence with available agents. One published study currently exists utilizing the N-methyl-d-aspartate antagonist, ketamine, for alcohol withdrawal.

Objective

The purpose of our study was to evaluate the effect of adjunctive ketamine continuous infusion on symptom control and lorazepam infusion requirements for BZD-resistant alcohol withdrawal patients in the intensive care unit.

Methods

A retrospective review was conducted of patients receiving ketamine adjunctively with a lorazepam infusion for severe alcohol withdrawal between August 2012 and August 2014. Outcomes included time to symptom control, lorazepam infusion requirements, ketamine initial and maximum daily infusion rates, and adverse effects of ketamine.

Results

Thirty patients were included in the analysis. Mean time to initiation of ketamine after the initiation of a lorazepam infusion was 41.4 h. All patients achieved initial symptom control within 1 h of ketamine initiation. Median initial ketamine infusion rate was 0.75 mg/kg/h and the average maximum daily rate was 1.6 mg/kg/h. Significant decreases in lorazepam infusion rates from baseline were observed at 24 h (??4 mg/h; p?=?0.01) after ketamine initiation. No patients experienced documented CNS adverse effects. Two patients experienced hypertension and no patients experienced tachycardia related to ketamine.

Conclusion

Adjunctive ketamine could provide symptom control for BZD-refractory patients and may potentially reduce lorazepam infusion requirements. Future studies to determine optimal dosing, timing of initiation, and place in therapy for BZD-resistant alcohol withdrawal are needed. The mechanism of action via the NMDA receptor with ketamine may provide benefit for BZD-resistant alcohol withdrawal.