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1.
Liang Li Lizhi Zhang Philip F. Binkley Wolfgang Sadee Danxin Wang 《Pharmaceutical research》2017,34(8):1648-1657
Purpose
Protein kinase C α (PRKCA) is involved in multiple functions and has been implicated in heart failure risks and treatment outcomes. This study aims to identify regulatory variants affecting PRKCA expression in human heart, and evaluate attributable risk of heart disease.Methods
mRNA expression quantitative trait loci (eQTLs) were extracted from the Genotype and Tissue Expression Project (GTEx). Allelic mRNA ratios were measured in 51 human heart tissues to identify cis-acting regulatory variants. Potential regulatory regions were tested with luciferase reporter gene assays and further evaluated in GTEx and genome-wide association studies.Results
Located in a region with robust enhancer activity in luciferase reporter assays, rs9909004 (T?>?C, minor allele frequency =0.47) resides in a haplotype displaying strong eQTLs for PRKCA in heart (p?=?1.2?×?10?23). The minor C allele is associated with both decreased PRKCA mRNA expression and decreased risk of phenotypes characteristic of heart failure in GWAS analyses (QT interval p?=?3.0?×?10?14). While rs9909004 is the likely regulatory variant, other variants in high linkage disequilibrium cannot be excluded. Distinct regulatory variants appear to affect expression in other tissues.Conclusions
The haplotype carrying rs9909004 influences PRKCA expression in the heart and is associated with traits linked to heart failure, potentially affecting therapy of heart failure.2.
Lim-Kyu Lee Seung-Min Yang Jaehong Park Junghwan Kim 《Toxicology and Environmental Health Sciences》2018,10(1):42-48
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.3.
Objective
Although the organic compounds, 2-propylaniline and 4-propylaniline are frequently used in many industrial sectors, and have little information about the potential genetic toxicity, and it is covered by the Occupational Safety & Health Act (OSHAct) in Korea.Methods
The mutation test of 2-propylaniline and 4-propylaniline was evaluated in five different doses for each chemical through a well-known Ames bacterial mutation test. This test was performed regardless of metabolic activation.Results
In this assay, we obtained positive results under all tested conditions, indicating that these two chemicals have mutagenic and potentially carcinogenic properties.Conclusion
Both 2-propylaniline and 4-propylaniline were mutagenic under the conditions of these tests. This result means that all of these chemicals exhibit mutations and potential carcinogenicity.4.
Shannon Ruzycki Mark Yarema Hossein Sadrzadeh Alain Tremblay 《Journal of medical toxicology》2016,12(2):185-188
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.5.
Naoki Itoh Eiichi Yamamoto Tomofumi Santa Takashi Funatsu Masaru Kato 《Pharmaceutical research》2016,33(6):1440-1446
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.6.
Faessel HM Burstein AH Troutman MD Willavize SA Rohrbacher KD Clark DJ 《European journal of clinical pharmacology》2008,64(11):1101-1109
Objective
This study investigated the effect of varenicline on the multiple-dose pharmacokinetics of digoxin.Methods
Eighteen smokers were randomized to receive digoxin (Lanoxicaps® 0.2 mg QD) with varenicline 1 mg BID or placebo for 14 days.Results
Varenicline had no clinically relevant effect on the digoxin steady-state exposure, as evidenced by the 90% confidence intervals for the ratios of AUC0–24 (87.5–108%) and Cmin (83.8–116%) wholly contained within 80–125%. Digoxin Cmax and Tmax remained unchanged in the presence of varenicline, consistent with no apparent alteration in digoxin bioavailability. A minimal 11.3% increase in digoxin renal clearance was noted during varenicline treatment while having no impact on its systemic exposure. Results are supported by mechanistic evidence in Caco-2 cell monolayers that varenicline is neither a P-gp substrate nor an inhibitor of P-gp-mediated efflux of digoxin. Co-administration of varenicline and digoxin was well tolerated.Conclusion
The results suggest that digoxin can be safely administered with varenicline without the need for dose adjustment.7.
Background
Poison hemlock (Conium maculatum) is a common plant with a significant toxicity. Data on this toxicity is sparse as there have been few case reports and never a documented poisoning after intravenous injection.Objectives
We present a case of intravenous poison hemlock injection encountered in the emergency department.Case Report
We describe a 30-year-old male who presented to the emergency department after a brief cardiac arrest after injecting poison hemlock. The patient had return of spontaneous circulation in the emergency department but had prolonged muscular weakness and encephalopathy later requiring tracheostomy.Conclusion
Intravenous injection of poison hemlock alkaloids can result in significant toxicity, including cardiopulmonary arrest, prolonged weakness, and encephalopathy.8.
Rationale
The attentional bias for drug cues is believed to be a causal cognitive process mediating human drug seeking and relapse.Objectives, methods and results
To test this claim, we trained smokers on a tobacco conditioning procedure in which the conditioned stimulus (or S+) acquired parallel control of an attentional bias (measured with an eye tracker), tobacco expectancy and instrumental tobacco-seeking behaviour. Although this correlation between measures may be regarded as consistent with the claim that the attentional bias for the S+ mediated tobacco seeking, when a secondary task was added in the test phase, the attentional bias for the S+ was abolished, yet the control of tobacco expectancy and tobacco seeking remained intact.Conclusions
This dissociation suggests that the attentional bias for drug cues is not necessary for the control that drug cues exert over drug-seeking behaviour. The question raised by these data is what function does the attentional bias serve if it does not mediate drug seeking?9.
Background
Gold nanoparticles now command a great deal of attention for medical applications. Despite the importance of nano-bio interfaces, interaction between peptides and proteins with gold surfaces is not still fully understood, especially in a molecular level.Methods
In the present study computational simulation of adsorption of 20 amino acids, in three forms of mono-amino acid, homo di-peptide and homo tri-peptide, on the gold nanoparticles was performed by Gromacs using OPLSAA force field. The flexibility, stability, and size effect of the peptides on the gold nanoparticles were studied as well as the molecular structure of them.Results
According to our results, adsorbed homo tri-peptides on the gold surface had more flexibility, more gyration, and the farthest distance from the GNP in comparison with homo di-peptides and mono-amino acids.Conclusion
Our findings provide new insights into the precise control of interactions between amino acids anchored on the GNPs.10.
Antony V. Samrot Ujjala Burman Padmanaban S P. Yamini Arul Maximus Rabel 《Toxicology and Environmental Health Sciences》2018,10(3):162-167
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.11.
Julie Babyar 《Journal of pharmaceutical innovation》2017,12(2):185-187
Purpose
The purpose of this perspective piece is to address the potential for drug and medical product innovation through sound regulation and strengthened international harmonization.Methods
Current literature, recommendations and guidelines in regulatory agencies assisted in this perspective review.Results
Multiple guidelines and recommendations provide for strategic planning and process improvement capabilities at local, national and international levels.Conclusions
Seeking best practice starts with identifying and improving individual nation drug regulatory bodies, including the US Food and Drug Administration (FDA). Inefficiency causes and process improvement solutions have been suggested and outlined in strategic plans at the FDA as well as with multiple stakeholder organizations and public-private partnerships. Cohesively, these groups should be tasked with formal, consistent updates on improvement as well as ongoing supportive research and evaluation of the changes implemented. Simultaneously, the international community has a tremendous opportunity to act on best practice for drug and medical product innovation by aligning sound and consistent approach to regulation.12.
Rizzo M Lamers CT Sauer CG Ramaekers JG Bechara A Andersen GJ 《Psychopharmacology》2005,179(3):559-566
Rationale
Illicit drug use can increase driver crash risk due to loss of control over vehicle trajectory. This study asks, does recreational use of ±3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) and tetrahydrocannabinol (THC; marijuana) impair cognitive processes that help direct our safe movement through the world?Objective
This study assesses the residual effects of combined MDMA/THC use, and of THC use alone, upon perceived trajectory of travel.Methods
Perception of self-motion, or heading, from optical flow patterns was assessed using stimuli comprising random dot ground planes presented at three different densities and eight heading angles (1, 2, 4 and 8° to the left or right). On each trial, subjects reported if direction of travel was to the left or the right.Results
Results showed impairments in both drug groups, with the MDMA/THC group performing the worst.Conclusions
The finding that these psychoactive agents adversely affect heading perception, even in recently abstinent users, raises potential concerns about MDMA use and driving ability.13.
Rationale
Methylphenidate (Ritalin®) is commonly prescribed for behavioral problems associated with attention deficit/hyperactivity disorder (ADHD). The results of previous studies suggest that methylphenidate increases cigarette smoking in participants without psychiatric diagnoses. Whether methylphenidate increases cigarette smoking in participants diagnosed with ADHD is unknown.Objective
In this within-subjects, repeated measures experiment, the acute effects of a range of doses of methylphenidate (10, 20, and 40 mg) and placebo were assessed in nine cigarette smokers who were not attempting to quit and met diagnostic criteria for ADHD but no other Axis I psychiatric disorders other than nicotine dependence.Methods
Each dose of methylphenidate was tested once while placebo was tested twice. One hour after ingesting drug, participants were allowed to smoke ad libitum for 4 h. Measures of smoking included total cigarettes smoked, total puffs, and carbon monoxide levels. Snacks and decaffeinated drinks were available ad libitum; caloric intake during the 4-h smoking session was calculated.Results
Methylphenidate increased the total number of cigarettes smoked, total number of puffs, and carbon monoxide levels. Methylphenidate decreased the number of food items consumed and caloric intake.Conclusions
The results of this experiment suggest that acutely administered methylphenidate increases cigarette smoking in participants with ADHD, which is concordant with findings from previous studies that tested healthy young adults. These data indicate that clinicians may need to consider non-stimulant options or counsel their patients before starting methylphenidate when managing ADHD-diagnosed individuals who smoke.14.
Rationale
The view of smoking as an addiction to nicotine implies that nicotine is an addictive drug and a primary reinforcer. However, nicotine other than in tobacco does not appear to be very rewarding for smokers. This potential anomaly to the nicotine addiction thesis is resolved by the proposition that the reward associated with smoking depends on “high-nicotine boli.” According to the nicotine delivery kinetics hypothesis, smoked nicotine reaches the brain in 5–10 s in high concentrations, which provide reinforcing “hits” of nicotine to the brain.Objectives
Because of its essential role in the nicotine addiction thesis, this review set out to examine the current empirical basis of the nicotine delivery kinetics hypothesis.Materials and methods
We reviewed studies that bear on two questions: First, does nicotine from cigarettes reach the brain significantly faster than from other nicotine delivery devices? Second, is there a relationship between delivery kinetics and any rewarding effects of nicotine?Results
There is little empirical support for the nicotine delivery kinetics hypothesis. Several studies found that arterial nicotine levels associated with smoking are much lower than predicted by the nicotine delivery kinetics thesis and not higher than with other nicotine delivery devices. More importantly, comparisons of nicotine delivery devices with varying speeds of delivery do not suggest any correlation between nicotine delivery profile and subjective reward.Conclusions
This review indicates that the wide endorsement of the nicotine delivery kinetics hypothesis is unjustified. Critical research is required to resolve the anomalies within the nicotine addiction theory of smoking.15.
Michael T. Jones Hanns-Christian Mahler Sandeep Yadav Dilbir Bindra Vincent Corvari R. Matthew Fesinmeyer Kapil Gupta Alexander M. Harmon Kenneth D. Hinds Atanas Koulov Wei Liu Kevin Maloney John Wang Ping Y. Yeh Satish K. Singh 《Pharmaceutical research》2018,35(8):148
Purpose
Polysorbates are commonly added to protein formulations and serve an important function as stabilizers. This paper reviews recent literature detailing some of the issues seen with the use of polysorbate 80 and polysorbate 20 in protein formulations. Based on this knowledge, a development strategy is proposed that leads to a control strategy for polysorbates in protein formulations.Methods
A consortium of Biopharmaceutical scientists working in the area of protein formulations, shared experiences with polysorbates as stabilizers in their formulations.Results
Based on the authors experiences and recent published literature, a recommendation is put forth for a development strategy which will lead into the appropriate control strategy for these excipients.Conclusions
An appropriate control strategy may comprise one or more elements of raw material, in-process and manufacturing controls. Additionally, understanding the role, if any, polysorbates play during stability will require knowledge of the criticality of the excipient, based upon its impact on CQAs due to variations in concentration and degradation level.16.
Dong-Min Seon Yuri Park Gwan-Tae Yu Myoung-Hwan Park Jongwan Choi 《Toxicology and Environmental Health Sciences》2018,10(1):72-78
Objective
Use of transparent organosilane hybrid films to protect substrates such as glasses and plastics is of great importance for electronic applications. In this study, graphene oxides (GOs) were chemically conjugated with organosilane oligomers to improve the dispersibility and hardness of organosilane coatings.Methods
The GO-conjugation with organosilane oligomers (GO-oSi) was prepared through a two-step route featuring amine-carboxyl coupling reaction and oligomerization with silica precursors. The structural properties of GO-oSi were characterized using Fourier transform infrared spectroscopy, Raman spectroscopy, and X-ray photoelectron spectroscopy.Results
The stability of the GO-organosilane coating dispersion was confirmed after storage in ethanol for 10 days via Tyndall effect analysis. After photopolymerization with organosilane coating agent, the transparencies of the GO-organosilane films were 94% or more, the enhanced hardness was characterized from 3H to 5H through pencil hardness testing.Conclusion
The simple strategy of pre-conjugation of GOs with organosilane oligomers has the potential to enhance dispersion and hardness of a wide variety of coating materials.17.
Susan M. Patterson Carmel M. Hughes Kate L. Lapane 《International journal of clinical pharmacy》2007,29(5):517-525
Objective
To assess the suitability of an American model of pharmaceutical care for nursing home residents (The Fleetwood model) for application in nursing homes in the United Kingdom.Method
Pharmacists (those from a hospital setting or involved in prescribing support), general practitioners, nursing home managers and advocates for older people were invited to participate in semi-structured interviews or focus groups. The American Fleetwood model was explained to all participants who were asked for their views and opinions on how such a model could be adapted for use in the UK setting. All interviews and focus groups were tape-recorded, transcribed verbatim and analysed using the framework method.Main outcome measure
An adapted model of pharmaceutical care for use in UK nursing homes.Results
There was general concern about prescribing in nursing homes, particularly in relation to psychoactive drugs. All participants were supportive of the proposed model of care and endorsed the greater involvement of pharmacists. However, participants also recognised that unlike pharmacists in the US nursing home setting for which the Fleetwood model had been developed, pharmacists implementing this approach in the UK would face major challenges in relation to access to records (medical and medication), prescribers and residents.Conclusion
The findings highlighted the key elements of access which will need to be considered if this model of pharmaceutical care is to be applied to nursing home residents in the UK.Impact of findings on practice
The model has been revised to take account of the challenges relating to access and will be tested in a randomised controlled trial.18.
Kathryn T Kopec Caroline Freiermuth Susan Maynard Michael Beuhler 《Journal of medical toxicology》2018,14(4):323-326
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.19.
Purpose
Multifractal geometry has become a powerful tool to describe complex structures in many fields. Our first aim was to combine imaging and multifractal analysis to better understand the microstructure of pharmaceutical extrudates. A second objective was to study erosion/dispersion behavior of the formulations because it would condition release of any drug.Methods
Different formulations containing a lipid, a polymer and different silica based inorganic carriers were produced by hot-melt extrusion at various screw speeds. Multifractal analysis was based on scanning electron microscopy/energy dispersive X-Ray spectroscopy images. This microstructural analysis was complemented with dynamic optical imaging of formulation erosion/dispersion behavior.Results
Multifractal analysis indicated that inorganic carrier type and concentration as well as the screw speed affected the microstructure of the extrudates. The aqueous erosion/dispersion study showed that only the type and concentration of inorganic carrier were important.Conclusions
The use of microstructural and dispersion analysis appeared to be complementary to better characterize and understand complex formulations obtained by hot-melt extrusion.20.