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1.
Shaoning?Wang Shihui?Yu Yuwei?Lin Peizhi?Zou Guihong?Chai Heidi?H.?Yu Hasini?Wickremasinghe Nivedita?Shetty Junhong?Ling Jian?Li Qi??Zhou 《Pharmaceutical research》2018,35(10):187
Purpose
This study aims to develop liposomal formulations containing synergistic antibiotics of colistin and ciprofloxacin for the treatment of infections caused by multidrug-resistant Pseudomonas aeruginosa.Methods
Colistin (Col) and ciprofloxacin (Cip) were co-encapsulated in anionic liposomes by ammonium sulfate gradient. Particle size, encapsulation efficiency, in vitro drug release and in vitro antibiotic activities were evaluated.Results
The optimized liposomal formulation has uniform sizes of approximately 100 nm, with encapsulation efficiency of 67.0% (for colistin) and 85.2% (for ciprofloxacin). Incorporation of anionic lipid (DMPG) markedly increased encapsulation efficiency of colistin (from 5.4 to 67.0%); however, the encapsulation efficiency of ciprofloxacin was independent of DMPG ratio. Incorporation of colistin significantly accelerated the release of ciprofloxacin from the DMPG anionic liposomes. In vitro release of ciprofloxacin and colistin in the bovine serum for 2 h were above 70 and 50%. The cytotoxicity study using A549 cells showed the liposomal formulation is as non-toxic as the drug solutions. Liposomal formulations of combinations had enhanced in vitro antimicrobial activities against multidrug resistant P. aeruginosa than the monotherapies.Conclusions
Liposomal formulations of two synergistic antibiotics was promising against multidrug resistant P. aeruginosa infections.2.
Marko Lamminsalo Ella Taskinen Timo Karvinen Astrid Subrizi Lasse Murtomäki Arto Urtti Veli-Pekka Ranta 《Pharmaceutical research》2018,35(8):153
Purpose
To extend the physiological features of the anatomically accurate model of the rabbit eye for intravitreal (IVT) and intracameral (IC) injections of macromolecules.Methods
The computational fluid dynamic model of the rabbit eye by Missel (2012) was extended by enhancing the mixing in the anterior chamber with thermal gradient, heat transfer and gravity, and studying its effect on IC injections of hyaluronic acids. In IVT injections of FITC-dextrans (MW 10–157 kDa) the diffusion though retina was defined based on published in vitro data. Systematic changes in retinal permeability and convective transport were made, and the percentages of anterior and posterior elimination pathways were quantified. Simulations were compared with published in vivo data.Results
With the enhanced mixing the elimination half-lives of hyaluronic acids after IC injection were 62–100 min that are similar to in vivo data and close to the theoretical value for the well-stirred anterior chamber (57 min). In IVT injections of FITC-dextrans a good match between simulations and in vivo data was obtained when the percentage of anterior elimination pathway was over 80%.Conclusions
The simulations with the extended model closely resemble in vivo pharmacokinetics, and the model is a valuable tool for data interpretation and predictions.3.
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.4.
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.5.
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.6.
Mitchell C. Brenner Wojciech Krzyzanski James Z. Chou Pierre E. Signore Cyra K. Fung David Guzman Dongxia Li Weihua Zhang David R. Olsen Viet-Tam L. Nguyen Carolyn W. Koo Mark D. Sternlicht Kenneth E. Lipson 《Pharmaceutical research》2016,33(8):1833-1849
Purpose
To evaluate and model the pharmacokinetic and pharmacodynamic behavior in rats of FG-3019, a human monoclonal antibody targeting connective tissue growth factor (CTGF).Methods
FG-3019, human CTGF (rhCTGF), or the N-terminal domain of rhCTGF were administered intravenously to rats and concentrations of these proteins as well as endogenous CTGF were determined by immunoassays. FG-3019, or 125I-labeled FG-3019, and human CTGF (rhCTGF) were co-administered to assess the impact of CTGF on the elimination rate and tissue localization of FG-3019, which was further characterized by immunohistochemical analysis. A PK/PD model for target-mediated elimination of FG-3019 was developed to fit the kinetic data.Results
FG-3019 exhibited non-linear pharmacokinetics in rats. Circulating concentrations of the N-terminal half of CTGF increased after dosing with FG-3019, reached maximal levels after 1–5 days, and returned toward baseline levels as FG-3019 cleared from the circulation, whereas the concentration of intact CTGF was unaffected by administration of FG-3019. Co-administration of rhCTGF dramatically enhanced the rate of FG-3019 elimination, redistributing the majority of 125I-labeled FG-3019 from the blood to the liver, kidney, spleen and adrenal gland. FG-3019 co-administered with CTGF was found along the sinusoids of the liver and adrenal glands, the capillaries of the kidney glomeruli and in the spleen. A pharmacokinetic model for target-mediated elimination of FG-3019 was used to fit the time courses of FG-3019 and endogenous CTGF plasma concentrations, as well as time courses of rhCTGF and rhCTGF N-fragment after intravenous administration of these species.Conclusions
FG-3019 is subject to target mediated elimination in rats.7.
8.
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.9.
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.10.
Purpose
To understand hydrolysis and alcoholysis of polyvinylpyrrolidone-co-vinylacetate (PVPVA) during formulation and storage, elucidate the reaction mechanism, establish an intrinsic kinetic model, and apply this model coupled with GastroPlus? modeling to predict the amount of PVPVA degradation in vivo.Methods
The experimental approach includes the detection of the polymer reaction by solution nuclear magnetic resonance (NMR) and the measurement of reaction product concentration via gas chromatography (GC). The theoretical approach includes the establishment of the intrinsic kinetic model and the application of GastroPlus? to predict the degree of PVPVA degradation.Results
The kinetic model established is a first order reaction between PVPVA and 2-propanol (IPA) or water under an acidic condition. The application of this kinetic model shows that between 1.7 and 6.8 mg of degradant is formed in the GI tract for a 850 mg dose of PVPVA.Conclusions
The results from this application provide valuable input for process development and the risk analysis of the degradation of PVPVA.11.
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.12.
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.13.
14.
Purpose
To evaluate a random forest model that counts silicone oil droplets and non-silicone oil particles in protein formulations with large class imbalance.Methods
In this work, we present a novel approach for automated image analysis of flow microscopy data based on random forest classification enabling rapid analysis of large data sets. The random forest approach overcomes many of the limitations of traditional classification schemes derived from simple filters or regression models. In particular, the approach does not require a priori selection of important morphology parameters.Results
We analyzed silicone oil droplets and non-silicone oil particles observed in four model systems with protein concentrations of 20, 50 and 125 mg/mL. Filters based on random forests achieve higher classification accuracies when compared to regression based filters. Additionally, we showcase a procedure that allows for accurate counting of particles ≥1 μm.Conclusions
Our method is generally applicable for classification and counting of different classes of particles as long as class morphologies are differentially expressed.15.
Bilyana M. Dicheva Ann L. B. Seynhaeve Thomas Soulie Alexander M. M. Eggermont Timo L. M. ten Hagen Gerben A. Koning 《Pharmaceutical research》2016,33(3):627-638
Purpose
To evaluate pharmacokinetic profile, biodistribution and therapeutic effect of cationic thermosensitive liposomes (CTSL) encapsulating doxorubicin (Dox) upon mild hyperthermia (HT).Methods
Non-targeted thermosensitive liposomes (TSL) and CTSL were developed, loaded with Dox and characterized. Blood kinetics and biodistribution of Dox-TSL and Dox-CTSL were followed in B16BL6 tumor bearing mice upon normothermia (NT) or initial hyperthermia conditions. Efficacy study in B16BL6 tumor bearing mice was followed with Dox-TSL or Dox-CTSL upon NT or HT. Efficacy study in LLC tumor bearing mice was performed upon two HT conditions. Intravital microscopy was performed on B16BL6 tumors implanted in dorsal-skin fold window-bearing mice.Results
Targeting did not cause faster blood clearance of CTSL compared to TSL. Highest uptake of liposomes was observed in spleen, kidneys and liver. Applying HT prior to CTSL administration increased drug delivery to the tumor and CTSL delivered ~1.7 fold higher Dox concentration compared to TSL. Efficacy in B16BL6 murine melanoma showed that HT had a significant effect on CTSL in tumor suppression and prolonged survival. Efficacy in LLC Lewis lung carcinoma tumor model demonstrates that two HT treatments hold promises for a successful treatment option.Conclusion
CTSL have potency to increase drug efficacy in tumors due to their targeted and drug release functions.16.
Purpose
To examine the combination of bortezomib and vorinostat in multiple myeloma cells (U266) and xenografts, and to assess the nature of their potential interactions with semi-mechanistic pharmacodynamic models and biomarkers.Methods
U266 proliferation was examined for a range of bortezomib and vorinostat exposure times and concentrations (alone and in combination). A non-competitive interaction model was used with interaction parameters that reflect the nature of drug interactions after simultaneous and sequential exposures. p21 and cleaved PARP were measured using immunoblotting to assess critical biomarker dynamics. For xenografts, data were extracted from literature and modeled with a PK/PD model with an interaction parameter.Results
Estimated model parameters for simultaneous in vitro and xenograft treatments suggested additive drug effects. The sequence of bortezomib preincubation for 24 hours, followed by vorinostat for 24 hours, resulted in an estimated interaction term significantly less than 1, suggesting synergistic effects. p21 and cleaved PARP were also up-regulated the greatest in this sequence.Conclusions
Semi-mechanistic pharmacodynamic modeling suggests synergistic pharmacodynamic interactions for the sequential administration of bortezomib followed by vorinostat. Increased p21 and cleaved PARP expression can potentially explain mechanisms of their enhanced effects, which require further PK/PD systems analysis to suggest an optimal dosing regimen.17.
Tommaso Iannitti Julio César Morales-Medina Alessandro Coacci Beniamino Palmieri 《Pharmaceutical research》2016,33(12):2879-2890
Background
In the field of aesthetic medicine there is an increasing demand for safe and effective hyaluronic acid (HA) fillers to counteract the aging process.Methods and Aims
We designed a study to evaluate the safety and histological biocompatibility of Aliaxin® Global Performance, a cross-linked HA filler and Viscoderm® Skinkò E, a product composed of non-cross-linked HA and a complex including vitamins, antioxidants, amino acids and minerals injected into the skin of guinea pigs. Then, we translated our findings into the clinical setting, administering a combination of these compounds to patients seeking a facial rejuvenation procedure targeting moderate-to-severe wrinkles affecting the nasolabial folds.Results
The animal study showed that the two compounds did not induce any significant inflammatory reactions and increased collagen and elastic fibers in the skin. In the clinical setting, injection of Aliaxin® Global Performance, followed by Viscoderm® Skinkò E, resulted in a higher improvement in nasolabial fold hydration, trans-epidermal water loss and wrinkle aesthetic appearance, if compared with a protocol based on Aliaxin® Global Performance alone.Conclusion
In summary, we show evidence on the safety and mechanism underlying two new HA-based compounds of different cross-linkage and composition, proposing that they can be safely used in combination in patients seeking facial rejuvenation procedures with long-lasting efficacy.18.
Peter W. Crane Timothy J. Wiegand Michael Kamali Marilynn Reif Rose Wratni Ronald Montante Tracey Loveland 《Journal of medical toxicology》2018,14(3):242-247
Introduction
Telemedicine and its use in medical toxicology have existed for some time. There are varied definitions, but existing ones center on using currently available forms of audio, video, and internet communications to provide “real-time” patient care. Definitions have historically limited reimbursement but recently expanded CMS guidelines have improved this. Here we describe our experience with telemedicine and reimbursement.Methods
A retrospective study was conducted of all toxicology and billing reimbursement for fiscal year 2016 for a solo Medical Toxicology service. Clinical identifiers were used to match telemedicine consults to hospital financial databases and then removed. Telemedicine consults were isolated, quantified, and described.Results
A total of 16 telemedicine consults were conducted. Average age was 37.2 (range 2 months–82 years). Gender was evenly split at 8:8. Twenty-five percent were pediatric consultations. The main purposes of consultation were as follows: diagnosis and disease management in drug ingestion, triage assistance, clearance consults, antidote administration, and buprenorphine induction. At the time of the work, $1896.00 for 9.3 h of teletoxicology services was reimbursed equating to an hourly reimbursement rate of $203.90/h.Limitations
Our data was obtained from a toxicology practice with a surrounding infrastructure dedicated to telemedicine. All sites may not have this robust ancillary support. Furthermore, not all states have reimbursement mandates such as New York State.Conclusion
To our knowledge, this is the first published work describing pilot data in the successful reimbursement for Medical Toxicology services delivered via telemedicine. Toxicology via telemedicine represents a great opportunity for advancing the practice of toxicology in an economically feasible way, particularly in rural or underserved areas.19.
Qing-Hui Zhou Chao Wu Devika Soundara Manickam David Oupický 《Pharmaceutical research》2009,26(7):1581-1589
Purpose
To investigate pharmacokinetics of reversibly stabilized DNA nanoparticles (rSDN) using a single-step lysis RT-PCR.Methods
rSDN were prepared by coating bioreducible polycation/DNA polyplexes with multivalent N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers. Targeted polyplexes were formulated by linking cyclic RGD ligand (c(RGDyK)) to the HPMA surface layer of rSDN. The pharmacokinetic parameters in tumor-bearing mice were analyzed by PKAnalyst®.Results
The pharmacokinetics of naked plasmid DNA, simple DNA polyplexes, rSDN, and RGD-targeted rSDN exhibited two-compartment model characteristics with area under the blood concentration–time curve (AUC) increasing from 1,102 ng?ml?1?min?1 for DNA to 3,501 ng?ml?1?min?1 for rSDN. Non-compartment model analysis revealed increase in mean retention time (MRT) from 4.5 min for naked DNA to 22.9 min for rSDN.Conclusions
RT-PCR is a sensitive and convenient method suitable for analyzing pharmacokinetics and biodistribution of DNA polyplexes. Surface stabilization of DNA polyplexes can significantly extend their MRT and AUC compared to naked DNA. DNA degradation in rSDN in blood circulation, due to a combined effect of disulfide reduction and competitive reactions with charged molecules in the blood, contributes to DNA elimination.20.
Thuy Vu Peiming Ma Jiyun Sunny Chen Jan de Hoon Anne Van Hecken Lucy Yan Liviawati Sutjandra Wu Lisa Hamilton Gabriel Vargas 《Pharmaceutical research》2017,34(9):1784-1795