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Han J, Zhang Z, Liu X, Yang H, Liu L. Prediction of Pharmacokinetics for CYP3A4-Metabolized Drugs in Pediatrics and Geriatrics Using Dynamic Age-Dependent Physiologically Based Pharmacokinetic Models. Pharmaceutics 2025; 17:214. [PMID: 40006581 PMCID: PMC11860008 DOI: 10.3390/pharmaceutics17020214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 01/20/2025] [Accepted: 01/30/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: The use of medicines in pediatrics and geriatrics is widespread. However, information on pharmacokinetics of therapeutic drugs mainly comes from healthy adults, and the pharmacokinetic parameters of therapeutic drugs in other age stages, including pediatrics and geriatrics, are limited. The aim of the study was to develop a dynamic age-dependent physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of drugs in humans at different ages. Method: The PBPK models characterizing dynamic age-dependence were developed in adults (20-59 years old) and 1000 virtual individuals were constructed. Four CYP3A substrates, namely midazolam, fentanyl, alfentanil and sufentanil, served as model drugs. Following validation using clinic observations in adult populations, the developed PBPK models were extrapolated to other age populations, such as pediatrics and geriatrics, via replacing their physiological parameters and pharmacokinetic parameters, such as organ volume, organ blood flow, clearance, fu,b and Kt:p. The simulations were compared with clinic observations in corresponding age populations. Midazolam served as an example, the dose transitions between adult pediatrics and adult geriatrics were visualized using the developed PBPK models. Results: Most of observed plasma concentrations fell within the 5th-95th percentile of the predicted values in the 1000 virtual individuals, and the predicted AUC0-t and Cmax were almost within between 0.5 and 2 times of the observations. The optimization of dosages in pediatrics and geriatrics were further documented. Conclusions: The developed PBPK model may be successfully used to predict the pharmacokinetics of CYP3A4-metabolized drugs in different age groups and to optimize their dosage regiments in pediatrics and geriatrics.
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Affiliation(s)
| | | | | | - Hanyu Yang
- Center of Drug Metabolism and Pharmacokinetics, School of pharmacy, China Pharmaceutical University, Nanjing 210009, China; (J.H.); (Z.Z.); (X.L.)
| | - Li Liu
- Center of Drug Metabolism and Pharmacokinetics, School of pharmacy, China Pharmaceutical University, Nanjing 210009, China; (J.H.); (Z.Z.); (X.L.)
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Qian L, Beers JL, Jackson KD, Zhou Z. CBD and THC in Special Populations: Pharmacokinetics and Drug-Drug Interactions. Pharmaceutics 2024; 16:484. [PMID: 38675145 PMCID: PMC11054161 DOI: 10.3390/pharmaceutics16040484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 03/13/2024] [Accepted: 03/25/2024] [Indexed: 04/28/2024] Open
Abstract
Cannabinoid use has surged in the past decade, with a growing interest in expanding cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) applications into special populations. Consequently, the increased use of CBD and THC raises the risk of drug-drug interactions (DDIs). Nevertheless, DDIs for cannabinoids, especially in special populations, remain inadequately investigated. While some clinical trials have explored DDIs between therapeutic drugs like antiepileptic drugs and CBD/THC, more potential interactions remain to be examined. This review summarizes the published studies on CBD and THC-drug interactions, outlines the mechanisms involved, discusses the physiological considerations in pharmacokinetics (PK) and DDI studies in special populations (including pregnant and lactating women, pediatrics, older adults, patients with hepatic or renal impairments, and others), and presents modeling approaches that can describe the DDIs associated with CBD and THC in special populations. The PK of CBD and THC in special populations remain poorly characterized, with limited studies investigating DDIs involving CBD/THC in these populations. Therefore, it is critical to evaluate potential DDIs between CBD/THC and medications that are commonly used in special populations. Modeling approaches can aid in understanding these interactions.
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Affiliation(s)
- Lixuan Qian
- Department of Chemistry, York College, City University of New York, Jamaica, NY 11451, USA;
| | - Jessica L. Beers
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA (K.D.J.)
| | - Klarissa D. Jackson
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA (K.D.J.)
| | - Zhu Zhou
- Department of Chemistry, York College, City University of New York, Jamaica, NY 11451, USA;
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Trinka E. Phenobarbital in Status epilepticus - Rediscovery of an effective drug. Epilepsy Behav 2023; 141:109104. [PMID: 36807987 DOI: 10.1016/j.yebeh.2023.109104] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 01/19/2023] [Indexed: 02/22/2023]
Abstract
Phenobarbital (PB) is one of the oldest Antiseizure Medicines (ASMs), which is in clinical use since 1912. Its value in the treatment of Status epilepticus is currently discussed controversially. Phenobarbital has fallen out of favor in many countries across Europe because of reports of hypotension, arrhythmias, and hypopnea. Phenobarbital has a strong antiseizure effect with remarkably little sedation. It exerts its clinical effects, through the increase of GABE-ergic inhibition and decrease of glutamatergic excitation by inhibition of AMPA receptors. Despite good preclinical evidence, there are remarkably few randomized controlled studies on humans in SE, which suggest, that it is at least as good as lorazepam in first-line treatment in early SE, and significantly better than valproic acid in benzodiazepine-resistant SE. Data from randomized trials and large non-randomized prospective and retrospective studies suggest, that Phenobarbital is well tolerated even if used in very high dose protocols. Thus, despite its decline in its popularity at least in Europe and North America, it should be considered a highly cost-effective treatment for early and established SE, not only in resource-limited settings. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022.
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Affiliation(s)
- Eugen Trinka
- Department of Neurology, Christian-Doppler University Hospital, Paracelsus Medical University, Centre for Cognitive Neuroscience, Member of EpiCARE, Salzburg, Austria; Neuroscience Institute, Christian-Doppler University Hospital, Paracelsus Medical University, Centre for Cognitive Neuroscience, Salzburg, Austria; Institute of Public Health, Medical Decision-Making and HTA, UMIT - Private University for Health Sciences, Medical Informatics and Technology, Hall in Tyrol, Austria.
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Gent L, Schwalbe EC, Procopio N. The impact of maceration on the 'Osteo-ome'; a pilot investigation. J Proteomics 2023; 271:104754. [PMID: 36243311 DOI: 10.1016/j.jprot.2022.104754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 10/03/2022] [Accepted: 10/07/2022] [Indexed: 11/05/2022]
Abstract
The bone proteome, i.e., the 'osteo-ome', is a rich source of information for forensic studies. There have been advances in the study of biomolecule biomarkers for age-at-death (AAD) and post-mortem interval (PMI) estimations, by looking at changes in protein abundance and post-translational modifications (PTMs) at the peptide level. However, the extent to which other post-mortem factors alter the proteome, including 'maceration' procedures adopted in human taphonomy facilities (HTFs) to clean bones for osteological collections, is poorly understood. This pilot study aimed to characterise the impact of these 'cleaning' methods for de-fleshing skeletons on bone biomolecules, and therefore, what further impact this may have on putative biomarkers in future investigations. Three specific maceration procedures, varying in submersion time (one week or two days) and water temperature (55 °C or 87 °C) were conducted on six bovid tibiae from three individual bovines; the proteome of fresh and macerated bones of each individual was compared. The maceration at 87 °C for two days had the greatest proteomic impact, decreasing protein relative abundances and inducing specific PTMs. Overall, these results suggest that routinely-employed maceration procedures are harsh, variable and potentially threaten the viability of discovering new forensic biomarkers in macerated skeletal remains. SIGNIFICANCE: For the first time, the application of bone proteomics in understanding maceration procedures was conducted to help address the risks for experimental confounding associated with this post-mortem cleaning technique. This pilot study demonstrates that recent advances in biomarker discovery for post-mortem interval and age-at-death estimation using bone proteomics has potential for confounding by differing and destructive bone-cleaning methods.
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Affiliation(s)
- Luke Gent
- Forensic Science Research Group, Faculty of Health and Life Sciences, Applied Sciences, Northumbria University, NE1 8ST Newcastle Upon Tyne, UK; School of Natural Sciences, University of Central Lancashire, PR1 2HE Preston, UK
| | - Edward C Schwalbe
- Forensic Science Research Group, Faculty of Health and Life Sciences, Applied Sciences, Northumbria University, NE1 8ST Newcastle Upon Tyne, UK
| | - Noemi Procopio
- Forensic Science Research Group, Faculty of Health and Life Sciences, Applied Sciences, Northumbria University, NE1 8ST Newcastle Upon Tyne, UK; School of Natural Sciences, University of Central Lancashire, PR1 2HE Preston, UK.
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Psoriatic arthritis: review of potential biomarkers predicting response to TNF inhibitors. Inflammopharmacology 2023; 31:77-87. [PMID: 36508130 PMCID: PMC9957889 DOI: 10.1007/s10787-022-01092-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 10/18/2022] [Indexed: 12/14/2022]
Abstract
Psoriatic arthritis (PsA) is a chronic and painful inflammatory immune-mediated disease. It affects up to 40% of people with psoriasis and it is associated with several comorbidities such as obesity, diabetes, metabolic syndrome, and hypertension. PsA is difficult to diagnose because of its diverse symptoms, namely axial and peripheral arthritis, enthesitis, dactylitis, skin changes, and nail dystrophy. Different drugs exist to treat the inflammation and pain. When patients do not respond to conventional drugs, they are treated with biologic drugs. Tumour necrosis factor inhibitors (TNFi's) are commonly given as the first biologic drug; beside being expensive, they also lack efficacy in 50% of patients. A biomarker predicting individual patient's response to TNFi would help treating them earlier with an appropriate biologic drug. This study aimed to review the literature to identify potential biomarkers that should be investigated for their predictive ability. Several such biomarkers were identified, namely transmembrane TNFα (tmTNF), human serum albumin (HSA) and its half-life receptor, the neonatal Fc receptor (FcRn) which is also involved in IgG lifespan; calprotectin, high mobility group protein B1 (HMGB1) and advanced glycation end products (AGEs) whose overexpression lead to excessive production of pro-inflammatory cytokines; lymphotoxin α (LTα) which induces inflammation by binding to TNF receptor (TNFR); and T helper 17 (Th17) cells which induce inflammation by IL-17A secretion.
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Shen C, Liang D, Wang X, Shao W, Geng K, Wang X, Sun H, Xie H. Predictive performance and verification of physiologically based pharmacokinetic model of propylthiouracil. Front Pharmacol 2022; 13:1013432. [PMID: 36278167 PMCID: PMC9579312 DOI: 10.3389/fphar.2022.1013432] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Propylthiouracil (PTU) treats hyperthyroidism and thyroid crisis in all age groups. A variety of serious adverse effects can occur during clinical use and require attention to its pharmacokinetic and pharmacodynamic characteristics in various populations.Objective: To provide information for individualized dosing and clinical evaluation of PTU in the clinical setting by developing a physiologically based pharmacokinetic (PBPK) model, predicting ADME characteristics, and extrapolating to elderly and pediatric populations.Methods: Relevant databases and literature were retrieved to collect PTU’s pharmacochemical properties and ADME parameters, etc. A PBPK model for adults was developed using PK-Sim® software to predict tissue distribution and extrapolated to elderly and pediatric populations. The mean fold error (MFE) method was used to compare the differences between predicted and observed values to assess the accuracy of the PBPK model. The model was validated using PTU pharmacokinetic data in healthy adult populations.Result: The MFE ratios of predicted to observed values of AUC0-t, Cmax, and Tmax were mainly within 0.5 and 2. PTU concentrations in various tissues are lower than venous plasma concentrations. Compared to healthy adults, the pediatric population requires quantitative adjustment to the appropriate dose to achieve the same plasma exposure levels, while the elderly do not require dose adjustments.Conclusion: The PBPK model of PTU was successfully developed, externally validated, and applied to tissue distribution prediction and special population extrapolation, which provides a reference for clinical individualized drug administration and evaluation.
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Affiliation(s)
- Chaozhuang Shen
- Graduate School, Wannan Medical College, Wuhu, Anhui, China
- *Correspondence: Chaozhuang Shen, ; Hua Sun, ; Haitang Xie,
| | - Dahu Liang
- Anhui Provincial Center for Drug Clinical Evaluation, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
| | - Xiaohu Wang
- Graduate School, Wannan Medical College, Wuhu, Anhui, China
| | - Wenxin Shao
- Graduate School, Wannan Medical College, Wuhu, Anhui, China
| | - Kuo Geng
- Graduate School, Wannan Medical College, Wuhu, Anhui, China
| | - Xingwen Wang
- Graduate School, Wannan Medical College, Wuhu, Anhui, China
| | - Hua Sun
- Anhui Provincial Center for Drug Clinical Evaluation, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- *Correspondence: Chaozhuang Shen, ; Hua Sun, ; Haitang Xie,
| | - Haitang Xie
- Anhui Provincial Center for Drug Clinical Evaluation, Yijishan Hospital of Wannan Medical College, Wuhu, Anhui, China
- *Correspondence: Chaozhuang Shen, ; Hua Sun, ; Haitang Xie,
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Pitamberwale A, Mahmood T, Ansari AK, Ansari SA, Limgaokar K, Singh L, Karki G. Biochemical Parameters as Prognostic Markers in Severely Ill COVID-19 Patients. Cureus 2022; 14:e28594. [PMID: 36185918 PMCID: PMC9521622 DOI: 10.7759/cureus.28594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2022] [Indexed: 11/24/2022] Open
Abstract
Background Prognostication plays a pivotal role in critical care medicine. Its importance is indisputable in the management of coronavirus disease 2019 (COVID-19), as the presentation of this disease may vary from docile, self-limiting symptoms to lethal conditions. Amid the COVID-19 pandemic, much emphasis was initially placed on molecular and serological testing. However, it was realized later that routine laboratory tests also provide key information in terms of the severity of the disease and thus could be used to predict the outcome of these patients. Methodology The aim of our study was to evaluate the biochemical parameters as prognostic markers in severely ill COVID-19 patients. We carried out a retrospective, case-control study. The study population was comprised of all severely ill COVID-19 patients admitted between October 2020 and January 2021 at our level 3 COVID hospital. Cases were defined as the patients who expired despite treatment and all resuscitative measures as per the standard operating procedures (SOPs) of our COVID intensive care unit (ICU) while controls were defined as the patients that were transferred out of the COVID ICU for further recovery. The detailed history, findings of physical examination, vitals recorded by point of care testing (POCT) devices at our ICU, clinical diagnosis, and the results of the biochemical analysis were recorded in a specially designed pro forma. The biochemical parameters recorded at the time of admission were compared between the groups of controls and cases in order to evaluate their role as predictors of mortality using appropriate statistical methods. P-values less than 0.05 were considered statistically significant. For all the parameters that showed a statistically significant difference, receiver operating characteristics (ROC) analysis was done to assess the utility of biochemical parameters as predictors of mortality or survival. Areas under the curve (AUCs) of 0.6 to 0.7, 0.7 to 0.8, 0.8 to 0.9, and >0.9 were considered acceptable, fair, good, and excellent for discrimination, respectively. Results Of the 178 severely ill COVID-19 patients enrolled in the study, 86 were controls and 92 were cases (52% mortality). Serum urea (p<0.0001), creatinine (p=0.0019), aspartate transaminase (AST) (p=0.0104), lactate dehydrogenase (LDH) (p=0.0001), procalcitonin (PCT) (p=0.0344), and interleukin 6 (IL-6) (p=0.0311) levels were significantly higher (p<0.05), while total protein (p=0.0086), albumin (p<0.0001), and indirect bilirubin (p=0.0147) levels were significantly lower (p<0.05) in cases as compared to controls. The difference was statistically insignificant (p>0.05) for serum sodium, potassium, total and direct bilirubin, globulin, alanine transaminase (ALT), alkaline phosphatase (ALP), D-dimer, and ferritin. On ROC analysis, urea was fair (AUC=0.721), creatinine (AUC=0.698) and IL-6 (AUC=0.698) were acceptable predictors of mortality, while albumin (AUC=0.698) was an acceptable predictor of survival in severely ill COVID-19 patients during their intensive care stay. Conclusion Understanding the pathophysiological changes associated with the severity of COVID-19 in terms of an alteration of biochemical parameters is a pressing priority. Our study highlights the importance of routine laboratory tests in predicting outcomes in severely ill COVID-19 patients.
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Togioka BM, Schenning KJ. Optimizing Reversal of Neuromuscular Block in Older Adults: Sugammadex or Neostigmine. Drugs Aging 2022; 39:749-761. [PMID: 35934764 DOI: 10.1007/s40266-022-00969-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/18/2022] [Indexed: 11/03/2022]
Abstract
Residual neuromuscular paralysis, the presence of clinically significant weakness after administration of pharmacologic neuromuscular blockade reversal, is associated with postoperative pulmonary complications and is more common in older patients. In contemporary anesthesia practice, reversal of neuromuscular blockade is accomplished with neostigmine or sugammadex. Neostigmine, an acetylcholinesterase inhibitor, increases the concentration of acetylcholine at the neuromuscular junction, providing competitive antagonism of neuromuscular blocking drug and facilitating muscle contraction. Sugammadex, a modified gamma-cyclodextrin, antagonizes neuromuscular blockade by encapsulating rocuronium and vecuronium in a one-to-one ratio for renal clearance, a pharmacokinetic property that led to the recommendation that sugammadex not be administered to those with end-stage renal disease. While data are limited, reports suggest sugammadex is efficacious and well tolerated in individuals with reduced renal function. Sugammadex provides a more rapid and complete reversal of neuromuscular blockade than neostigmine. There is also accumulating evidence that sugammadex may provide a protective effect against the development of postoperative pulmonary complications, nausea, and vomiting, and that it may have beneficial effects on the rate of bowel and bladder recovery after surgery. Accordingly, sugammadex administration is beneficial for most older patients undergoing surgery.
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Affiliation(s)
- Brandon M Togioka
- Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, OR, USA. .,Department of Obstetrics and Gynecology, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Mail Code: UHN-2, Portland, OR, 97239-3098, USA.
| | - Katie J Schenning
- Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, OR, USA
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Berton M, Bettonte S, Stader F, Battegay M, Marzolini C. Repository Describing the Anatomical, Physiological, and Biological Changes in an Obese Population to Inform Physiologically Based Pharmacokinetic Models. Clin Pharmacokinet 2022; 61:1251-1270. [PMID: 35699913 PMCID: PMC9439993 DOI: 10.1007/s40262-022-01132-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/28/2022] [Indexed: 11/24/2022]
Abstract
Background Obesity is associated with physiological changes that can affect drug pharmacokinetics. Obese individuals are underrepresented in clinical trials, leading to a lack of evidence-based dosing recommendations for many drugs. Physiologically based pharmacokinetic (PBPK) modelling can overcome this limitation but necessitates a detailed description of the population characteristics under investigation. Objective The purpose of this study was to develop and verify a repository of the current anatomical, physiological, and biological data of obese individuals, including population variability, to inform a PBPK framework. Methods A systematic literature search was performed to collate anatomical, physiological, and biological parameters for obese individuals. Multiple regression analyses were used to derive mathematical equations describing the continuous effect of body mass index (BMI) within the range 18.5–60 kg/m2 on system parameters. Results In total, 209 studies were included in the database. The literature reported mostly BMI-related changes in organ weight, whereas data on blood flow and biological parameters (i.e. enzyme abundance) were sparse, and hence physiologically plausible assumptions were made when needed. The developed obese population was implemented in Matlab® and the predicted system parameters obtained from 1000 virtual individuals were in agreement with observed data from an independent validation obese population. Our analysis indicates that a threefold increase in BMI, from 20 to 60 kg/m2, leads to an increase in cardiac output (50%), liver weight (100%), kidney weight (60%), both the kidney and liver absolute blood flows (50%), and in total adipose blood flow (160%). Conclusion The developed repository provides an updated description of a population with a BMI from 18.5 to 60 kg/m2 using continuous physiological changes and their variability for each system parameter. It is a tool that can be implemented in PBPK models to simulate drug pharmacokinetics in obese individuals.
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Affiliation(s)
- Mattia Berton
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland. .,University of Basel, Basel, Switzerland.
| | - Sara Bettonte
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.,University of Basel, Basel, Switzerland
| | | | - Manuel Battegay
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.,University of Basel, Basel, Switzerland
| | - Catia Marzolini
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.,University of Basel, Basel, Switzerland
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Clinical pharmacokinetics of quinine and its relationship with treatment outcomes in children, pregnant women, and elderly patients, with uncomplicated and complicated malaria: a systematic review. Malar J 2022; 21:41. [PMID: 35144612 PMCID: PMC8832728 DOI: 10.1186/s12936-022-04065-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 01/30/2022] [Indexed: 11/22/2022] Open
Abstract
Background Standard dosage regimens of quinine formulated for adult patients with uncomplicated and complicated malaria have been applied for clinical uses in children, pregnant women, and elderly. Since these populations have anatomical and physiological differences from adults, dosage regimens formulated for adults may not be appropriate. The study aimed to (i) review existing information on the pharmacokinetics of quinine in children, pregnant women, and elderly populations, (ii) identify factors that influence quinine pharmacokinetics, and (iii) analyse the relationship between the pharmacokinetics and treatment outcomes (therapeutic and safety) of various dosage regimens of quinine. Methods Web of Sciences, Cochrane Library, Scopus, and PubMed were the databases applied in this systematic search for relevant research articles published up to October 2020 using the predefined search terms. The retrieved articles were initially screened by titles and abstracts to exclude any irrelevant articles and were further evaluated based on full-texts, applying the predefined eligibility criteria. Excel spreadsheet (Microsoft, WA, USA) was used for data collection and management. Qualitative data are presented as numbers and percentages, and where appropriate, mean + SD or median (range) or range values. Results Twenty-eight articles fulfilled the eligibility criteria, 19 in children, 7 in pregnant women, and 2 in elderly (14 and 7 articles in complicated and uncomplicated malaria, respectively). Severity of infection, routes of administration, and nutritional status were shown to be the key factors impacting quinine pharmacokinetics in these vulnerable groups. Conclusions The recommended dosages for both uncomplicated and complicated malaria are, in general, adequate for elderly and children with uncomplicated malaria. Dose adjustment may be required in pregnant women with both uncomplicated and complicated malaria, and in children with complicated malaria. Pharmacokinetics studies relevant to clinical efficacy in these vulnerable groups of patients with large sample size and reassessment of MIC (minimum inhibitory concentration) should be considered. Supplementary Information The online version contains supplementary material available at 10.1186/s12936-022-04065-1.
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Wang S, Zhao M, Su Z, Mu R. Annual biological variation and personalized reference intervals of clinical chemistry and hematology analytes. Clin Chem Lab Med 2021; 60:606-617. [PMID: 34773728 DOI: 10.1515/cclm-2021-0479] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 10/28/2021] [Indexed: 11/15/2022]
Abstract
OBJECTIVES A large number of people undergo annual health checkup but accurate laboratory criterion for evaluating their health status is limited. The present study determined annual biological variation (BV) and derived parameters of common laboratory analytes in order to accurately evaluate the test results of the annual healthcare population. METHODS A total of 43 healthy individuals who had regular healthcare once a year for six consecutive years, were enrolled using physical, electrocardiogram, ultrasonography and laboratory. The annual BV data and derived parameters, such as reference change value (RCV) and index of individuality (II) were calculated and compared with weekly data. We used annual BV and homeostatic set point to calculate personalized reference intervals (RIper) which were compared with population-based reference intervals (RIpop). RESULTS We have established the annual within-subject BV (CVI), RCV, II, RIper of 24 commonly used clinical chemistry and hematology analytes for healthy individuals. Among the 18 comparable measurands, CVI estimates of annual data for 11 measurands were significantly higher than the weekly data. Approximately 50% measurands of II were <0.6, the utility of their RIpop were limited. The distribution range of RIper for most measurands only copied small part of RIpop with reference range index for 8 measurands <0.5. CONCLUSIONS Compared with weekly BV, for annual healthcare individuals, annual BV and related parameters can provide more accurate evaluation of laboratory results. RIper based on long-term BV data is very valuable for "personalized" diagnosis on annual health assessments.
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Affiliation(s)
- Shuo Wang
- Department of Laboratory Medicine, The First Hospital of China Medical University, National Clinical Research Center for Laboratory Medicine, Shenyang, Liaoning, P.R. China
| | - Min Zhao
- Department of Laboratory Medicine, The First Hospital of China Medical University, National Clinical Research Center for Laboratory Medicine, Shenyang, Liaoning, P.R. China
| | - Zihan Su
- Department of Laboratory Medicine, The First Hospital of China Medical University, National Clinical Research Center for Laboratory Medicine, Shenyang, Liaoning, P.R. China
| | - Runqing Mu
- Department of Laboratory Medicine, The First Hospital of China Medical University, National Clinical Research Center for Laboratory Medicine, Shenyang, Liaoning, P.R. China
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Age-Related Change in Hepatic Clearance Inferred from Multiple Population Pharmacokinetic Studies: Comparison with Renal Clearance and Their Associations with Organ Weight and Blood Flow. Clin Pharmacokinet 2021; 61:295-305. [PMID: 34514537 DOI: 10.1007/s40262-021-01069-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/10/2021] [Indexed: 01/08/2023]
Abstract
OBJECTIVE This study aimed to examine the magnitude of age-related change in hepatic clearance by integrating the data of multiple drugs and to compare this with renal clearance, considering associations with age-related changes in organ weight and blood flow. METHODS The results of multiple population pharmacokinetic analyses that detected age-related clearance changes in hepatically eliminated drugs were collected. The relationship between hepatic clearance of the unbound drug and age was then analyzed using the nonlinear least-squares method, adjusting for interdrug differences. The obtained change in hepatic clearance was compared with age-related changes in liver weight and hepatic blood flow in Japanese and Westerners. For comparison, the changes in renal clearance were analyzed similarly. RESULTS In total, 18 drugs were analyzed. The hepatic unbound clearance decreased by 32% at age 80 years and by 40% at age 90 years, compared with age 40 years, suggesting that it decreased by 0.80% per year with aging. The rate of the decrease was consistent with decreases in hepatic weight per person or blood flow per person, regardless of ethnicity and sex. Since age-related change in body weight varied somewhat by sex or ethnicity, hepatic weight per body weight was less consistent to account for age-related change in hepatic clearance. As for an index of renal clearance, the changes in inulin clearance with age were similar to those in renal blood flow, with a decrease of 0.97% per year from the age of 40 years. CONCLUSIONS Hepatic clearance consistently decreased by 0.80% per year from the age of 40 years, with aging for multiple drugs analyzed in this study. Changes in organ weight and blood flow are considered to be primarily responsible for the age-related changes in hepatic and renal clearance.
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Mickleburgh HL, Schwalbe EC, Bonicelli A, Mizukami H, Sellitto F, Starace S, Wescott DJ, Carter DO, Procopio N. Human Bone Proteomes before and after Decomposition: Investigating the Effects of Biological Variation and Taphonomic Alteration on Bone Protein Profiles and the Implications for Forensic Proteomics. J Proteome Res 2021; 20:2533-2546. [PMID: 33683123 PMCID: PMC8155572 DOI: 10.1021/acs.jproteome.0c00992] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
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Bone proteomic studies
using animal proxies and skeletonized human
remains have delivered encouraging results in the search for potential
biomarkers for precise and accurate post-mortem interval (PMI) and
the age-at-death (AAD) estimation in medico-legal investigations.
The development of forensic proteomics for PMI and AAD estimation
is in critical need of research on human remains throughout decomposition,
as currently the effects of both inter-individual biological differences
and taphonomic alteration on the survival of human bone protein profiles
are unclear. This study investigated the human bone proteome in four
human body donors studied throughout decomposition outdoors. The effects
of ageing phenomena (in vivo and post-mortem) and
intrinsic and extrinsic variables on the variety and abundancy of
the bone proteome were assessed. Results indicate that taphonomic
and biological variables play a significant role in the survival of
proteins in bone. Our findings suggest that inter-individual and inter-skeletal
differences in bone mineral density (BMD) are important variables
affecting the survival of proteins. Specific proteins survive better
within the mineral matrix due to their mineral-binding properties.
The mineral matrix likely also protects these proteins by restricting
the movement of decomposer microbes. New potential biomarkers for
PMI estimation and AAD estimation were identified. Future development
of forensic bone proteomics should include standard measurement of
BMD and target a combination of different biomarkers.
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Affiliation(s)
- Hayley L Mickleburgh
- Department of Cultural Sciences, Linnaeus University, Kalmar 352 52, Sweden.,Forensic Anthropology Center, Texas State University, San Marcos 78666, Texas, United States
| | - Edward C Schwalbe
- Forensic Science Research Group, Faculty of Health and Life Sciences, Northumbria University, Ellison Building, Northumbria University Newcastle, Newcastle Upon Tyne NE1 8ST, U. K
| | - Andrea Bonicelli
- Forensic Science Research Group, Faculty of Health and Life Sciences, Northumbria University, Ellison Building, Northumbria University Newcastle, Newcastle Upon Tyne NE1 8ST, U. K
| | - Haruka Mizukami
- Forensic Science Research Group, Faculty of Health and Life Sciences, Northumbria University, Ellison Building, Northumbria University Newcastle, Newcastle Upon Tyne NE1 8ST, U. K
| | - Federica Sellitto
- Forensic Science Research Group, Faculty of Health and Life Sciences, Northumbria University, Ellison Building, Northumbria University Newcastle, Newcastle Upon Tyne NE1 8ST, U. K
| | - Sefora Starace
- Dipartimento di Chimica, University of Turin, Via P. Giuria 7, 10125 Turin, Italy
| | - Daniel J Wescott
- Forensic Anthropology Center, Texas State University, San Marcos 78666, Texas, United States
| | - David O Carter
- Forensic Sciences Unit, School of Natural Sciences and Mathematics, Chaminade University of Honolulu, Honolulu 96816, Hawaii, United States
| | - Noemi Procopio
- Forensic Science Research Group, Faculty of Health and Life Sciences, Northumbria University, Ellison Building, Northumbria University Newcastle, Newcastle Upon Tyne NE1 8ST, U. K
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14
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Paliogiannis P, Mangoni AA, Cangemi M, Fois AG, Carru C, Zinellu A. Serum albumin concentrations are associated with disease severity and outcomes in coronavirus 19 disease (COVID-19): a systematic review and meta-analysis. Clin Exp Med 2021; 21:343-354. [PMID: 33511503 PMCID: PMC7842395 DOI: 10.1007/s10238-021-00686-z] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 01/12/2021] [Indexed: 02/08/2023]
Abstract
Coronavirus disease 2019 (COVID-19), an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is responsible for the most threatening pandemic in modern history. The aim of this systematic review and meta-analysis was to investigate the associations between serum albumin concentrations and COVID-19 disease severity and adverse outcomes. A systematic literature search was conducted in PubMed, from inception to October 30, 2020. Sixty-seven studies in 19,760 COVID-19 patients (6141 with severe disease or poor outcome) were selected for analysis. Pooled results showed that serum albumin concentrations were significantly lower in patients with severe disease or poor outcome (standard mean difference, SMD: - 0.99 g/L; 95% CI, - 1.11 to - 0.88, p < 0.001). In multivariate meta-regression analysis, age (t = - 2.13, p = 0.043), publication geographic area (t = 2.16, p = 0.040), white blood cell count (t = - 2.77, p = 0.008) and C-reactive protein (t = - 2.43, p = 0.019) were significant contributors of between-study variance. Therefore, lower serum albumin concentrations are significantly associated with disease severity and adverse outcomes in COVID-19 patients. The assessment of serum albumin concentrations might assist with early risk stratification and selection of appropriate care pathways in this group.
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Affiliation(s)
- Panagiotis Paliogiannis
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, Italy
| | - Arduino Aleksander Mangoni
- Discipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders Medical Centre, Flinders University, Adelaide, Australia
| | - Michela Cangemi
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, Italy
| | - Alessandro Giuseppe Fois
- Department of Medical, Surgical and Experimental Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, Italy
| | - Ciriaco Carru
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, Italy
| | - Angelo Zinellu
- Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43, 07100, Sassari, Italy.
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15
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Feketea GM, Vlacha V. The Diagnostic Significance of Usual Biochemical Parameters in Coronavirus Disease 19 (COVID-19): Albumin to Globulin Ratio and CRP to Albumin Ratio. Front Med (Lausanne) 2020; 7:566591. [PMID: 33224959 PMCID: PMC7670073 DOI: 10.3389/fmed.2020.566591] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 10/19/2020] [Indexed: 01/08/2023] Open
Affiliation(s)
- Gavriela M Feketea
- Department of Hematology, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Department of Pediatrics, Pediatric Allergy Outpatient Clinic, Karamandaneio Children Hospital of Patras, Patras, Greece
| | - Vasiliki Vlacha
- Department of Early Years Learning and Care, University of Ioannina, Ioannina, Greece
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16
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Gotlieb N, Schwartz N, Zelber-Sagi S, Chodick G, Shalev V, Shibolet O. Longitudinal decrease in platelet counts as a surrogate marker of liver fibrosis. World J Gastroenterol 2020; 26:5849-5862. [PMID: 33132639 PMCID: PMC7579756 DOI: 10.3748/wjg.v26.i38.5849] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 06/10/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver cirrhosis is a significant source of morbidity and mortality worldwide. The disease is usually indolent and asymptomatic early in its course while many cirrhotic patients are diagnosed late when severe complications occur. A major challenge is to diagnose advanced fibrosis as early as possible, using simple and non-invasive diagnostics tools. Thrombocytopenia represents advanced fibrosis and portal hypertension (HTN) and most non-invasive scores that predict liver fibrosis incorporate platelets as a strong risk factor. However, little is known about the association between longitudinal changes in platelet counts (PTC), when still within the normal range, and the risk of cirrhosis.
AIM To explore whether platelet counts trajectories over time, can predict advanced liver fibrosis across the different etiologies of liver diseases.
METHODS A nested case-control study utilizing a large computerized database. Cirrhosis cases (n = 5258) were compared to controls (n = 15744) matched for age and sex at a ratio of 1:3. All participants had multiple laboratory measurements prior to enrollment. We calculated the trends of PTC, liver enzymes, bilirubin, international normalized ratio, albumin and fibrosis scores (fibrosis-4 and aspartate transaminase-to-platelet ratio index) throughout the preceding 20 years prior to cirrhosis diagnosis compared to healthy controls. The association between PTC, cirrhosis complications and fibrosis scores prior to cirrhosis diagnosis was investigated.
RESULTS The mean age in both groups was 56 (SD 15.8). Cirrhotic patients were more likely to be smokers, diabetic with chronic kidney disease and had a higher prevalence of HTN. The leading cirrhosis etiologies were viral, alcoholic and fatty liver disease. The mean PTC decreased from 240000/μL to 190000/μL up to 15 years prior to cirrhosis diagnosis compared to controls who’s PTC remained stable around the values of 240000/μL. This trend was consistent regardless of sex, cirrhosis etiology and was more pronounced in patients who developed varices and ascites. Compared to controls whose values remained in the normal range, in the cirrhosis group aspartate aminotransferase and alanine aminotransferase, increased from 40 U/L to 75 U/L and FIB-4 increased gradually from 1.3 to 3 prior to cirrhosis diagnosis. In multivariable regression analysis, a decrease of 50 units in PTC was associated with 1.3 times odds of cirrhosis (95%CI 1.25-1.35).
CONCLUSION In the preceding years before the diagnosis of cirrhosis, there is a progressive decline in PTC, within the normal range, matched to a gradual increase in fibrosis scores.
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Affiliation(s)
- Neta Gotlieb
- Department of Gastroenterology and Hepatology, Tel-Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Naama Schwartz
- School of Public Health, University of Haifa, Haifa 3498838, Israel
| | - Shira Zelber-Sagi
- Department of Gastroenterology and Hepatology, Tel-Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
- School of Public Health, University of Haifa, Haifa 3498838, Israel
| | - Gabriel Chodick
- Institute for Research and Innovation, Maccabi Health Services, Tel Aviv 6812509, Israel
| | - Varda Shalev
- Institute for Research and Innovation, Maccabi Health Services, Tel Aviv 6812509, Israel
| | - Oren Shibolet
- Department of Gastroenterology and Hepatology, Tel-Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
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17
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Stader F, Siccardi M, Battegay M, Kinvig H, Penny MA, Marzolini C. Repository Describing an Aging Population to Inform Physiologically Based Pharmacokinetic Models Considering Anatomical, Physiological, and Biological Age-Dependent Changes. Clin Pharmacokinet 2020; 58:483-501. [PMID: 30128967 DOI: 10.1007/s40262-018-0709-7] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Aging is characterized by anatomical, physiological, and biological changes that can impact drug kinetics. The elderly are often excluded from clinical trials and knowledge about drug kinetics and drug-drug interaction magnitudes is sparse. Physiologically based pharmacokinetic modeling can overcome this clinical limitation but detailed descriptions of the population characteristics are essential to adequately inform models. OBJECTIVE The objective of this study was to develop and verify a population database for aging Caucasians considering anatomical, physiological, and biological system parameters required to inform a physiologically based pharmacokinetic model that included population variability. METHODS A structured literature search was performed to analyze age-dependent changes of system parameters. All collated data were carefully analyzed, and descriptive mathematical equations were derived. RESULTS A total of 362 studies were found of which 318 studies were included in the analysis as they reported rich data for anthropometric parameters and specific organs (e.g., liver). Continuous functions could be derived for most system parameters describing a Caucasian population from 20 to 99 years of age with variability. Areas with sparse data were identified such as tissue composition, but knowledge gaps were filled with plausible qualified assumptions. The developed population was implemented in Matlab® and estimated system parameters from 1000 virtual individuals were in accordance with independent observed data showing the robustness of the developed population. CONCLUSIONS The developed repository for aging subjects provides a singular specific source for key system parameters needed for physiologically based pharmacokinetic modeling and can in turn be used to investigate drug kinetics and drug-drug interaction magnitudes in the elderly.
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Affiliation(s)
- Felix Stader
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland. .,Infectious Disease Modelling Unit, Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland. .,University of Basel, Basel, Switzerland.
| | - Marco Siccardi
- Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Manuel Battegay
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.,University of Basel, Basel, Switzerland
| | - Hannah Kinvig
- Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Melissa A Penny
- Infectious Disease Modelling Unit, Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland.,University of Basel, Basel, Switzerland
| | - Catia Marzolini
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.,University of Basel, Basel, Switzerland
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18
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Bakar KA, Lam SD, Sidek HM, Feroz SR. Characterization of the interaction of diosgenin with human serum albumin and α1-acid glycoprotein using biophysical and bioinformatic tools. J Mol Liq 2020. [DOI: 10.1016/j.molliq.2020.112865] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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19
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Alsmadi MM, Alfarah MQ, Albderat J, Alsalaita G, AlMardini R, Hamadi S, Al‐Ghazawi A, Abu‐Duhair O, Idkaidek N. The development of a population physiologically based pharmacokinetic model for mycophenolic mofetil and mycophenolic acid in humans using data from plasma, saliva, and kidney tissue. Biopharm Drug Dispos 2019; 40:325-340. [DOI: 10.1002/bdd.2206] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 09/22/2019] [Accepted: 10/09/2019] [Indexed: 02/06/2023]
Affiliation(s)
| | | | - Jawaher Albderat
- Queen Rania Abdullah Children Hospital, Royal Medical Services Amman Jordan
| | - Ghazi Alsalaita
- Queen Rania Abdullah Children Hospital, Royal Medical Services Amman Jordan
| | - Reham AlMardini
- Queen Rania Abdullah Children Hospital, Royal Medical Services Amman Jordan
| | - Salim Hamadi
- Deparment of Pharmaceutical Technology, Faculty of PharmacyUniversity of Petra Amman Jordan
| | | | - Omar Abu‐Duhair
- Deparment of Pharmaceutical Technology, Faculty of PharmacyUniversity of Petra Amman Jordan
| | - Nasir Idkaidek
- Deparment of Pharmaceutical Technology, Faculty of PharmacyUniversity of Petra Amman Jordan
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20
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Lee DK, Bang S, Lee S. Anesthetic considerations for surgical treatment of geriatric hip fracture. Anesth Pain Med (Seoul) 2019. [DOI: 10.17085/apm.2019.14.1.8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Affiliation(s)
- Dong Kyu Lee
- Department of Anesthesiology and Pain Medicine, Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Seunguk Bang
- Department of Anesthesiology and Pain Medicine, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Korea
- Department of Anesthesiology and Pain Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sangseok Lee
- Department of Anesthesiology and Pain Medicine, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea
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21
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Swertfeger DK, Rebholz S, Li H, Shah AS, Davidson WS, Lu LJ. Feasibility of a plasma bioassay to assess oxidative protection of low-density lipoproteins by high-density lipoproteins. J Clin Lipidol 2018; 12:1539-1548. [PMID: 30244943 PMCID: PMC6437770 DOI: 10.1016/j.jacl.2018.08.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 07/30/2018] [Accepted: 08/15/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND Traditionally, the impact of lipoproteins on vascular disease has been evaluated in light of their quantity, that is, cholesterol content, in plasma. However, recent studies of high-density lipoproteins (HDLs) have focused on functionality with regard to atheroprotection. For example, bioassays have emerged to assess the ability of HDL, in its near native plasma environment, to promote cholesterol removal (efflux) from cells. As a result, attention has focused on developing plasma-based assays for other putative HDL protective functions including protecting low-density lipoproteins (LDLs) from oxidative damage. OBJECTIVE To determine the feasibility of such an assay in a complex sample such as plasma, we evaluated the contribution of HDL vs other plasma factors in preventing LDL oxidation. METHODS We separated normolipidemic human plasma by gel filtration chromatography and assessed each fraction for its ability to prevent LDL modification by water soluble radical and copper-initiated oxidation mechanisms. RESULTS Using proteomics and selective precipitation methods, we identified major antioxidative contributions for fibrinogen, immunoglobulin G, albumin, and small soluble molecules like uric acid and ascorbate, with albumin being especially dominant in copper-initiated mechanisms. HDL particles were minor contributors (∼1%-2%) to the antioxidant capacity of plasma, irrespective of oxidation mechanism. CONCLUSIONS Given the overwhelming background of antioxidant capacity inherent to highly abundant plasma proteins, specific bioassays of HDL antioxidative function will likely require its complete separation from plasma.
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Affiliation(s)
- Debi K Swertfeger
- Division of Biomedical Informatics, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA
| | - Sandra Rebholz
- Division of Biomedical Informatics, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA; Department of Pathology and Laboratory Medicine, Center for Lipid and Arteriosclerosis Science, University of Cincinnati, Cincinnati, OH, USA
| | - Hailong Li
- Division of Biomedical Informatics, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA
| | - Amy S Shah
- Division of Endocrinology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA
| | - William Sean Davidson
- Department of Pathology and Laboratory Medicine, Center for Lipid and Arteriosclerosis Science, University of Cincinnati, Cincinnati, OH, USA.
| | - Long J Lu
- Division of Biomedical Informatics, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA
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22
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Chetty M, Johnson TN, Polak S, Salem F, Doki K, Rostami-Hodjegan A. Physiologically based pharmacokinetic modelling to guide drug delivery in older people. Adv Drug Deliv Rev 2018; 135:85-96. [PMID: 30189273 DOI: 10.1016/j.addr.2018.08.013] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Revised: 08/20/2018] [Accepted: 08/30/2018] [Indexed: 01/10/2023]
Abstract
Older patients are generally not included in Phase 1 clinical trials despite being the population group who use the largest number of prescription medicines. Physiologically based pharmacokinetic (PBPK) modelling provides an understanding of the absorption and disposition of drugs in older patients. In this review, PBPK models used for the prediction of absorption and exposure of drugs after parenteral, oral and transdermal administration are discussed. Comparisons between predicted drug pharmacokinetics (PK) and observed PK are presented to illustrate the accuracy of the predictions by the PBPK models and their potential use in informing clinical trial design and dosage adjustments in older patients. In addition, a case of PBPK modelling of a bioequivalence study on two controlled release products is described, where PBPK predictions reproduced the study showing bioequivalence in healthy volunteers but not in older subjects with achlorhydria, indicating further utility in prospectively identifying challenges in bioequivalence studies.
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Affiliation(s)
- Manoranjenni Chetty
- Simcyp Ltd (a Certara company), Blades Enterprise Centre, John Street, Sheffield, UK.
| | - Trevor N Johnson
- Simcyp Ltd (a Certara company), Blades Enterprise Centre, John Street, Sheffield, UK
| | - Sebastian Polak
- Simcyp Ltd (a Certara company), Blades Enterprise Centre, John Street, Sheffield, UK; Unit of Pharmacoepidemiology and Pharmacoeconomics, Department of Social Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 Str., 30-688 Cracow, Poland
| | - Farzaneh Salem
- Simcyp Ltd (a Certara company), Blades Enterprise Centre, John Street, Sheffield, UK
| | - Kosuke Doki
- Department of Pharmaceutical Sciences, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan; Centre for Applied Pharmacokinetic Research (CAPKR), University of Manchester, Manchester, UK
| | - Amin Rostami-Hodjegan
- Simcyp Ltd (a Certara company), Blades Enterprise Centre, John Street, Sheffield, UK; Centre for Applied Pharmacokinetic Research (CAPKR), University of Manchester, Manchester, UK
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23
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Khan MS, Roberts MS. Challenges and innovations of drug delivery in older age. Adv Drug Deliv Rev 2018; 135:3-38. [PMID: 30217519 DOI: 10.1016/j.addr.2018.09.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Revised: 08/31/2018] [Accepted: 09/07/2018] [Indexed: 12/12/2022]
Abstract
Both drug delivery performance and various age-related physical, mental and physiological changes can affect drug effectiveness and safety in elderly patients. The many drug delivery systems developed over the years include recent novel transdermal, nasal, pulmonary and orally disintegrating tablets that provide consistent, precise, timely and more targeted drug delivery. Certain drug delivery systems may be associated with suboptimal outcomes in the elderly because of the nature of drug present, a lack of appreciation of the impact of age-related changes in drug absorption, distribution and clearance, the limited availability of pharmacokinetic, safety and clinical data. Polypharmacy, patient morbidity and poor adherence can also contribute to sub-optimal drug delivery systems outcomes in the elderly. The development of drug delivery systems for the elderly is a poorly realised opportunity, with each system having specific advantages and limitations. A key challenge is to provide the innovation that best meets the specific physiological, psychological and multiple drug requirements of individual elderly patients.
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24
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Pharmacokinetic Factors to Consider in the Selection of Antiseizure Drugs for Older Patients with Epilepsy. Drugs Aging 2018; 35:687-698. [DOI: 10.1007/s40266-018-0562-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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25
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Maharaj AR, Gonzalez D, Cohen-Wolkowiez M, Hornik CP, Edginton AN. Improving Pediatric Protein Binding Estimates: An Evaluation of α1-Acid Glycoprotein Maturation in Healthy and Infected Subjects. Clin Pharmacokinet 2018; 57:577-589. [PMID: 28779462 PMCID: PMC5797516 DOI: 10.1007/s40262-017-0576-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
BACKGROUND Differences in plasma protein levels observed between children and adults can alter the extent of xenobiotic binding in plasma, resulting in divergent patterns of exposure. OBJECTIVE This study aims to quantify the ontogeny of α1-acid glycoprotein in both healthy and infected subjects. METHODS Data pertaining to α1-acid glycoprotein from healthy subjects were compiled over 26 different publications. For subjects diagnosed or suspected of infection, α1-acid glycoprotein levels were obtained from 214 individuals acquired over three clinical investigations. The analysis evaluated the use of linear, power, exponential, log-linear, and sigmoid E max models to describe the ontogeny of α1-acid glycoprotein. Utility of the derived ontogeny equation for estimation of pediatric fraction unbound was evaluated using average-fold error and absolute average-fold error as measures of bias and precision, respectively. A comparison to fraction unbound estimates derived using a previously proposed linear equation was also instituted. RESULTS The sigmoid E max model provided the comparatively best depiction of α1-acid glycoprotein ontogeny in both healthy and infected subjects. Despite median α1-acid glycoprotein levels in infected subjects being more than two-fold greater than those observed in healthy subjects, a similar ontogeny pattern was observed when levels were normalized toward adult levels. For estimation of pediatric fraction unbound, the α1-acid glycoprotein ontogeny equation derived from this work (average fold error 0.99; absolute average fold error 1.24) provided a superior predictive performance in comparison to the previous equation (average fold error 0.74; absolute average fold error 1.45). CONCLUSION The current investigation depicts a proficient modality for estimation of protein binding in pediatrics and will, therefore, aid in reducing uncertainty associated with pediatric pharmacokinetic predictions.
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Affiliation(s)
- Anil R Maharaj
- School of Pharmacy, University of Waterloo, 10A Victoria St. S, Kitchener, ON, Canada
| | - Daniel Gonzalez
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Michael Cohen-Wolkowiez
- Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA
- Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA
| | - Christoph P Hornik
- Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA
- Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA
| | - Andrea N Edginton
- School of Pharmacy, University of Waterloo, 10A Victoria St. S, Kitchener, ON, Canada.
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26
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Peck MJ, Sanders EB, Scherer G, Lüdicke F, Weitkunat R. Review of biomarkers to assess the effects of switching from cigarettes to modified risk tobacco products. Biomarkers 2018; 23:213-244. [PMID: 29297706 DOI: 10.1080/1354750x.2017.1419284] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Context: One approach to reducing the harm caused by cigarette smoking, at both individual and population level, is to develop, assess and commercialize modified risk alternatives that adult smokers can switch to. Studies to demonstrate the exposure and risk reduction potential of such products generally involve the measuring of biomarkers, of both exposure and effect, sampled in various biological matrices.Objective: In this review, we detail the pros and cons for using several biomarkers as indicators of effects of changing from conventional cigarettes to modified risk products.Materials and methods: English language publications between 2008 and 2017 were retrieved from PubMed using the same search criteria for each of the 25 assessed biomarkers. Nine exclusion criteria were applied to exclude non-relevant publications.Results: A total of 8876 articles were retrieved (of which 7476 were excluded according to the exclusion criteria). The literature indicates that not all assessed biomarkers return to baseline levels following smoking cessation during the study periods but that nine had potential for use in medium to long-term studies.Discussion and conclusion: In clinical studies, it is important to choose biomarkers that show the biological effect of cessation within the duration of the study.
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Affiliation(s)
| | | | | | - Frank Lüdicke
- Research & Development, Philip Morris International, Neuchâtel, Switzerland
| | - Rolf Weitkunat
- Research & Development, Philip Morris International, Neuchâtel, Switzerland
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27
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Maciążek-Jurczyk M, Szkudlarek A, Chudzik M, Pożycka J, Sułkowska A. Alteration of human serum albumin binding properties induced by modifications: A review. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2018; 188:675-683. [PMID: 28526195 DOI: 10.1016/j.saa.2017.05.023] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 04/23/2017] [Accepted: 05/09/2017] [Indexed: 06/07/2023]
Abstract
Albumin, a major transporting protein in the blood, is the main target of modification that affects the binding of drugs to Sudlow's site I and II. These modification of serum protein moderates its physiological function, and works as a biomarker of some diseases. The main goal of the paper was to explain the possible alteration of human serum albumin binding properties induced by modifications such as glycation, oxidation and ageing, their origin, methods of evaluation and positive and negative meaning described by significant researchers.
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Affiliation(s)
- Małgorzata Maciążek-Jurczyk
- School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Chair and Department of Physical Pharmacy, Jagiellońska 4, 41-200 Sosnowiec, Poland.
| | - Agnieszka Szkudlarek
- School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Chair and Department of Physical Pharmacy, Jagiellońska 4, 41-200 Sosnowiec, Poland
| | - Mariola Chudzik
- School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Chair and Department of Physical Pharmacy, Jagiellońska 4, 41-200 Sosnowiec, Poland
| | - Jadwiga Pożycka
- School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Chair and Department of Physical Pharmacy, Jagiellońska 4, 41-200 Sosnowiec, Poland
| | - Anna Sułkowska
- Silesian Medical College in Katowice, Mickiewicza 29, 40-085 Katowice, Poland
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Wills JW, Summers HD, Hondow N, Sooresh A, Meissner KE, White PA, Rees P, Brown A, Doak SH. Characterizing Nanoparticles in Biological Matrices: Tipping Points in Agglomeration State and Cellular Delivery In Vitro. ACS NANO 2017; 11:11986-12000. [PMID: 29072897 DOI: 10.1021/acsnano.7b03708] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/15/2023]
Abstract
Understanding the delivered cellular dose of nanoparticles is imperative in nanomedicine and nanosafety, yet is known to be extremely complex because of multiple interactions between nanoparticles, their environment, and the cells. Here, we use 3-D reconstruction of agglomerates preserved by cryogenic snapshot sampling and imaged by electron microscopy to quantify the "bioavailable dose" that is presented at the cell surface and formed by the process of individual nanoparticle sequestration into agglomerates in the exposure media. Critically, using 20 and 40 nm carboxylated polystyrene-latex and 16 and 85 nm silicon dioxide nanoparticles, we show that abrupt, dose-dependent "tipping points" in agglomeration state can arise, subsequently affecting cellular delivery and increasing toxicity. These changes are triggered by shifts in the ratio of the total nanoparticle surface area to biomolecule abundance, with the switch to a highly agglomerated state effectively changing the test article midassay, challenging the dose-response paradigm for nanosafety experiments. By characterizing nanoparticle numbers per agglomerate, we show these tipping points can lead to the formation of extreme agglomeration states whereby 90% of an administered dose is contained and delivered to the cells by just the top 2% of the largest agglomerates. We thus demonstrate precise definition, description, and comparison of the nanoparticle dose formed in different experimental environments and show that this description is critical to understanding cellular delivery and toxicity. We further empirically "stress-test" the commonly used dynamic light scattering approach, establishing its limitations to present an analysis strategy that significantly improves the usefulness of this popular nanoparticle characterization technique.
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Affiliation(s)
- John W Wills
- Institute of Life Sciences, Swansea University Medical School , Singleton Park, Swansea, SA2 8PP, U.K
| | - Huw D Summers
- Centre for Nanohealth, Swansea University College of Engineering , Fabian Way, Crymlyn Burrows, Swansea, SA1 8EN, U.K
| | - Nicole Hondow
- School of Chemical and Process Engineering, University of Leeds , Leeds, LS2 9JT, U.K
| | - Aishwarya Sooresh
- Department of Materials Science and Engineering, Texas A&M University , College Station, Texas 77843, United States
| | - Kenith E Meissner
- Department of Biomedical Engineering, Texas A&M University , College Station, Texas 77843, United States
- Department of Physics, Swansea University College of Science , Singleton Park, Swansea, SA2 8PP, U.K
| | - Paul A White
- Department of Biology, University of Ottawa , 30 Marie-Curie Private, Ottawa K1N 9B4, Ontario, Canada
| | - Paul Rees
- Centre for Nanohealth, Swansea University College of Engineering , Fabian Way, Crymlyn Burrows, Swansea, SA1 8EN, U.K
- Broad Institute of MIT and Harvard , 415 Main Street, Cambridge, Massachusetts 02142, United States
| | - Andy Brown
- School of Chemical and Process Engineering, University of Leeds , Leeds, LS2 9JT, U.K
| | - Shareen H Doak
- Institute of Life Sciences, Swansea University Medical School , Singleton Park, Swansea, SA2 8PP, U.K
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Jabir RS, Ho GF, Annuar MABA, Stanslas J. Plasma alpha-1-acid glycoprotein as a potential predictive biomarker for non-haematological adverse events of docetaxel in breast cancer patients. Biomarkers 2017; 23:142-146. [PMID: 28554261 DOI: 10.1080/1354750x.2017.1334152] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
CONTEXT Rash and oral mucositis are major non-haematological adverse events (AEs) of docetaxel, in addition to fatigue, nausea, vomiting and diarrhoea, which restrict the use of the drug in cancer therapy. Alpha-1-acid glycoprotein (AAG) is an acute phase reactant glycoprotein and is a primary carrier of docetaxel in the blood. Docetaxel has extensive binding (>98%) to plasma proteins such as AAG, lipoproteins and albumin. OBJECTIVE To study the association between plasma AAG level and non-haematological AEs of docetaxel in Malaysian breast cancer patients of three major ethnic groups (Malays, Chinese and Indians). MATERIALS AND METHODS One hundred and twenty Malaysian breast cancer patients receiving docetaxel as single agent chemotherapy were investigated for AAG plasma level using enzyme-linked immunosorbent assay technique. Toxicity assessment was determined using Common Terminology Criteria of Adverse Events v4.0. The association between AAG and toxicity were then established. RESULTS There was interethnic variation of plasma AAG level; it was 182 ± 85 mg/dl in Chinese, 237 ± 94 mg/dl in Malays and 240 ± 83 mg/dl in Indians. It was found that low plasma levels of AAG were significantly associated with oral mucositis and rash. CONCLUSIONS This study proposes plasma AAG as a potential predictive biomarker of docetaxel non-haematological AEs namely oral mucositis and rash.
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Affiliation(s)
- Rafid Salim Jabir
- a Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences , Universiti Putra Malaysia , Serdang , Selangor , Malaysia
| | - Gwo Fuang Ho
- b Clinical Oncology Unit , University Malaya Medical Centre , Kuala Lumpur , Malaysia
| | - Muhammad Azrif Bin Ahmad Annuar
- c Radiotherapy & Oncology , Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak , Kuala Lumpur , Malaysia
| | - Johnson Stanslas
- a Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences , Universiti Putra Malaysia , Serdang , Selangor , Malaysia
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Sato M, Iida T, Kikuchi C, Sasakawa T, Kunisawa T. Comparison of caudal ropivacaine-morphine and paravertebral catheter for major upper abdominal surgery in infants. Paediatr Anaesth 2017; 27:524-530. [PMID: 28181346 DOI: 10.1111/pan.13104] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/18/2016] [Indexed: 11/27/2022]
Abstract
BACKGROUND The caudal epidural block is one of the most commonly used regional anesthetic techniques in children. Administration of morphine via caudal injection enables analgesia, even for upper abdominal surgery. The thoracic paravertebral block has also been successfully used to treat perioperative pain during upper abdominal procedures in pediatric patients. AIM In the current study, we compared the two regional techniques for upper abdominal surgery in infants to determine whether one of them was preferable to the other. METHODS Consecutive patients under 12 months of age who underwent upper abdominal surgery were retrospectively divided according to the chosen postoperative analgesia: Group C, caudal ropivacaine-morphine; Group P, paravertebral catheter. We analyzed the following outcomes: requirement for additional analgesics, pain scores, need for mechanical ventilation and oxygen dosage, postoperative blood pressure and heart rate, time to pass first stool, time until first full meal, and complications. RESULTS Twenty-one consecutive patients were included: 10 in Group C and 11 in Group P. Median age at surgery was 80 (47.5-270.0) and 84.5 (34.3-287.5) days, respectively. No difference was found between the two groups in requirement for additional analgesics at 24 h after surgery (median 1 in Group C vs 1 in Group P, P = 0.288, 95% CI: -2 to 1). BOPS pain scores were only lower in Group P when compared to Group C at 24 h after surgery (median 1 vs 2, P = 0.041, 95% CI: -2 to 0). None of the patients had perioperative complications. CONCLUSIONS In this small series, there was no significant difference between caudal ropivacaine-morphine and paravertebral catheter for postoperative care in infants undergoing upper abdominal surgery. Further prospective studies are needed to compare the efficacy and incidence of complications of caudal block and paravertebral catheter for postoperative analgesia.
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Affiliation(s)
- Makoto Sato
- Department of Anesthesiology and Critical Care Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Takafumi Iida
- Department of Anesthesiology and Critical Care Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Chika Kikuchi
- Department of Anesthesiology and Critical Care Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Tomoki Sasakawa
- Department of Anesthesiology and Critical Care Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Takayuki Kunisawa
- Department of Anesthesiology and Critical Care Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
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31
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Ezra A, Rabinovich-Nikitin I, Rabinovich-Toidman P, Solomon B. Multifunctional Effect of Human Serum Albumin Reduces Alzheimer's Disease Related Pathologies in the 3xTg Mouse Model. J Alzheimers Dis 2016; 50:175-88. [PMID: 26682687 DOI: 10.3233/jad-150694] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Alzheimer's disease (AD), the prevalent dementia in the elderly, involves many related and interdependent pathologies that manifests simultaneously, eventually leading to cognitive impairment and death. No treatment is currently available; however, an agent addressing several key pathologies simultaneously has a better therapeutic potential. Human serum albumin (HSA) is a highly versatile protein, harboring multifunctional properties that are relevant to key pathologies underlying AD. This study provides insight into the mechanism for HSA's therapeutic effect. In vivo, a myriad of beneficial effects were observed by pumps infusing HSA intracerebroventricularly, for the first time in an AD 3xTg mice model. A significant effect on amyloid-β (Aβ) pathology was observed. Aβ1-42, soluble oligomers, and total plaque area were reduced. Neuroblastoma SHSY5Y cell line confirmed that the reduction in Aβ1-42 toxicity was due to direct binding rather than other properties of HSA. Total and hyperphosphorylated tau were reduced along with an increase in tubulin, suggesting increased microtubule stability. HSA treatment also reduced brain inflammation, affecting both astrocytes and microglia markers. Finally, evidence for blood-brain barrier and myelin integrity repair was observed. These multidimensional beneficial effects of intracranial administrated HSA, together or individually, contributed to an improvement in cognitive tests, suggesting a non-immune or Aβ efflux dependent means for treating AD.
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32
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Ademowo OS, Hernandez B, Collins E, Rooney C, Fearon U, van Kuijk AW, Tak PP, Gerlag DM, FitzGerald O, Pennington SR. Discovery and confirmation of a protein biomarker panel with potential to predict response to biological therapy in psoriatic arthritis. Ann Rheum Dis 2016; 75:234-41. [PMID: 25187158 DOI: 10.1136/annrheumdis-2014-205417] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2014] [Accepted: 08/14/2014] [Indexed: 11/04/2022]
Abstract
OBJECTIVE Biological therapies, which include antitumour necrosis factor-α and T-cell inhibitors, are potentially effective treatments for psoriatic arthritis (PsA) but are costly and may induce a number of side effects. Response to treatment in PsA is variable and difficult to predict. Here, we sought to identify a panel of protein biomarkers that could be used to predict which patients diagnosed with PsA will respond to biologic treatment. METHODS An integrated discovery to targeted proteomics approach was used to investigate the protein profiles of good and non-responders to biological treatments in patients with PsA. Reverse-phase liquid chromatography coupled to tandem mass spectrometry was used to generate protein profiles of synovial tissue obtained at baseline from 10 patients with PsA. Targeted proteomics using multiple reaction monitoring (MRM) was used to confirm and prevalidate a potential protein biomarker panel in 18 and 7 PsA patient samples, respectively. RESULTS A panel of 107 proteins was selected, and targeted mass spectrometry MRM assays were successfully developed for 57 of the proteins. The 57 proteins include S100-A8, S100-A10, Ig kappa chain C fibrinogen-α and γ, haptoglobin, annexin A1 and A2, collagen alpha-2, vitronectin, and alpha-1 acid glycoprotein. The proteins were measured simultaneously and confirmed to be predictive of response to treatment with an area under the curve of 0.76. In a blinded study using a separate cohort of patients, the panel was able to predict response to treatment. CONCLUSIONS The approach reported here and the initial data provide evidence that a multiplexed protein assay of a panel of biomarkers that predict response to treatment could be developed. TRIAL REGISTRATION NUMBER ISRCTN23328456.
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Affiliation(s)
- Opeyemi S Ademowo
- UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Belinda Hernandez
- UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland UCD School of Mathematical Sciences, University College Dublin, Dublin, Ireland
| | - Emily Collins
- UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland Department of Rheumatology, St. Vincent's University Hospital Dublin, Dublin, Ireland
| | - Cathy Rooney
- UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
| | - Ursula Fearon
- UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland Department of Rheumatology, St. Vincent's University Hospital Dublin, Dublin, Ireland
| | - Arno W van Kuijk
- Department of Clinical Immunology/Rheumatology, Academic Medical Centre/University of Amsterdam, Amsterdam, Netherlands
| | - Paul-P Tak
- Department of Clinical Immunology/Rheumatology, Academic Medical Centre/University of Amsterdam, Amsterdam, Netherlands
| | - Danielle M Gerlag
- Department of Clinical Immunology/Rheumatology, Academic Medical Centre/University of Amsterdam, Amsterdam, Netherlands
| | - Oliver FitzGerald
- UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland Department of Rheumatology, St. Vincent's University Hospital Dublin, Dublin, Ireland
| | - Stephen R Pennington
- UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
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Castro J, Puente P, Martínez R, Hernández A, Martínez L, Pichardo D, Aldana L, Valdés I, Cosme K. Measurement of hematological and serum biochemical normal values of captive housed Chlorocebus aethiops sabaeus monkeys and correlation with the age. J Med Primatol 2015; 45:12-20. [PMID: 26647919 DOI: 10.1111/jmp.12203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/02/2015] [Indexed: 12/01/2022]
Abstract
BACKGROUND Some factors such as sex, age, and captivity conditions have a direct influence on the normal hematological and serum biochemical parameters of African green monkeys. On the other hand, reliability in reported values is in many cases limited by studied animal number (<200) and there is not report on the correlation of these parameters with the age in each sex animal group. Thus, this study sought determining normal hematological (11) and serum biochemical parameters (9) of 400 captive housed African green monkeys and also correlate them with the age of the animals. METHODS A total of 200 females and 200 males were grouped by the sex and age groups (1-2, 3-4, 5-6, and 7-8 years old) for measuring normal values of hematological and serum biochemical parameters and to study the correlation of these parameters with the age of the animals. RESULTS As key outcome, the main hematological and serum biochemical reference values of African green monkeys were determined. Significant differences (P < 0.05) were found among 95% of studied parameters between males and females. About 75% and 95% of the parameters were influenced by the age in the female and male groups, respectively. About 35% of hematological and serum biochemical parameters correlated positively (R(2) > 0.5) with the age in the female monkeys. On the contrary in the male monkeys, only 45% of parameters correlated positively with the age (R(2) > 0.5). CONCLUSIONS Thus, authors believe that results of this study are important for assisting researchers in the assessment of health status of captive housed African green monkeys for preclinical studies.
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Affiliation(s)
- Jorge Castro
- Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
| | - Pedro Puente
- Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
| | - Rafael Martínez
- Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
| | | | - Leticia Martínez
- Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
| | - Dagmara Pichardo
- Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
| | - Lizet Aldana
- Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
| | - Iris Valdés
- Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
| | - Karelia Cosme
- Center for Genetic Engineering and Biotechnology (CIGB), Havana, Cuba
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Hammond TG, Meng X, Jenkins RE, Maggs JL, Castelazo AS, Regan SL, Bennett SNL, Earnshaw CJ, Aithal GP, Pande I, Kenna JG, Stachulski AV, Park BK, Williams DP. Mass spectrometric characterization of circulating covalent protein adducts derived from a drug acyl glucuronide metabolite: multiple albumin adductions in diclofenac patients. J Pharmacol Exp Ther 2014; 350:387-402. [PMID: 24902585 PMCID: PMC4109494 DOI: 10.1124/jpet.114.215079] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Accepted: 05/29/2014] [Indexed: 12/21/2022] Open
Abstract
Covalent protein modifications by electrophilic acyl glucuronide (AG) metabolites are hypothetical causes of hypersensitivity reactions associated with certain carboxylate drugs. The complex rearrangements and reactivities of drug AG have been defined in great detail, and protein adducts of carboxylate drugs, such as diclofenac, have been found in liver and plasma of experimental animals and humans. However, in the absence of definitive molecular characterization, and specifically, identification of signature glycation conjugates retaining the glucuronyl and carboxyl residues, it cannot be assumed any of these adducts is derived uniquely or even fractionally from AG metabolites. We have therefore undertaken targeted mass spectrometric analyses of human serum albumin (HSA) isolated from diclofenac patients to characterize drug-: derived structures and, thereby, for the first time, have deconstructed conclusively the pathways of adduct formation from a drug AG and its isomeric rearrangement products in vivo. These analyses were informed by a thorough understanding of the reactions of HSA with diclofenac AG in vitro. HSA from six patients without drug-: related hypersensitivities had either a single drug-: derived adduct or one of five combinations of 2-8 adducts from among seven diclofenac N-acylations and three AG glycations on seven of the protein's 59 lysines. Only acylations were found in every patient. We present evidence that HSA modifications by diclofenac in vivo are complicated and variable, that at least a fraction of these modifications are derived from the drug's AG metabolite, and that albumin adduction is not inevitably a causation of hypersensitivity to carboxylate drugs or a coincidental association.
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Affiliation(s)
- Thomas G Hammond
- Medical Research Council Centre for Drug Safety Science, Institute of Translational Medicine, (T.G.H., X.M., R.E.J., J.L.M., A.S.C., S.L.R., C.J.E., B.K.P., D.P.W.) and Department of Chemistry (A.V.S.), University of Liverpool, Liverpool, United Kingdom; Nottingham Digestive Diseases Centre, NIHR Nottingham Digestive Diseases-Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham (G.P.A.) and Department of Rheumatology, Nottingham University Hospitals NHS Trust (I.P.), Nottingham, United Kingdom; and AstraZeneca U.K. Ltd (S.N.L.B.) and Safety Assessment, AstraZeneca U.K. Ltd (J.G.K.), Alderley Park, Macclesfield, Cheshire, United Kingdom
| | - Xiaoli Meng
- Medical Research Council Centre for Drug Safety Science, Institute of Translational Medicine, (T.G.H., X.M., R.E.J., J.L.M., A.S.C., S.L.R., C.J.E., B.K.P., D.P.W.) and Department of Chemistry (A.V.S.), University of Liverpool, Liverpool, United Kingdom; Nottingham Digestive Diseases Centre, NIHR Nottingham Digestive Diseases-Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham (G.P.A.) and Department of Rheumatology, Nottingham University Hospitals NHS Trust (I.P.), Nottingham, United Kingdom; and AstraZeneca U.K. Ltd (S.N.L.B.) and Safety Assessment, AstraZeneca U.K. Ltd (J.G.K.), Alderley Park, Macclesfield, Cheshire, United Kingdom
| | - Rosalind E Jenkins
- Medical Research Council Centre for Drug Safety Science, Institute of Translational Medicine, (T.G.H., X.M., R.E.J., J.L.M., A.S.C., S.L.R., C.J.E., B.K.P., D.P.W.) and Department of Chemistry (A.V.S.), University of Liverpool, Liverpool, United Kingdom; Nottingham Digestive Diseases Centre, NIHR Nottingham Digestive Diseases-Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham (G.P.A.) and Department of Rheumatology, Nottingham University Hospitals NHS Trust (I.P.), Nottingham, United Kingdom; and AstraZeneca U.K. Ltd (S.N.L.B.) and Safety Assessment, AstraZeneca U.K. Ltd (J.G.K.), Alderley Park, Macclesfield, Cheshire, United Kingdom
| | - James L Maggs
- Medical Research Council Centre for Drug Safety Science, Institute of Translational Medicine, (T.G.H., X.M., R.E.J., J.L.M., A.S.C., S.L.R., C.J.E., B.K.P., D.P.W.) and Department of Chemistry (A.V.S.), University of Liverpool, Liverpool, United Kingdom; Nottingham Digestive Diseases Centre, NIHR Nottingham Digestive Diseases-Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham (G.P.A.) and Department of Rheumatology, Nottingham University Hospitals NHS Trust (I.P.), Nottingham, United Kingdom; and AstraZeneca U.K. Ltd (S.N.L.B.) and Safety Assessment, AstraZeneca U.K. Ltd (J.G.K.), Alderley Park, Macclesfield, Cheshire, United Kingdom
| | - Anahi Santoyo Castelazo
- Medical Research Council Centre for Drug Safety Science, Institute of Translational Medicine, (T.G.H., X.M., R.E.J., J.L.M., A.S.C., S.L.R., C.J.E., B.K.P., D.P.W.) and Department of Chemistry (A.V.S.), University of Liverpool, Liverpool, United Kingdom; Nottingham Digestive Diseases Centre, NIHR Nottingham Digestive Diseases-Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham (G.P.A.) and Department of Rheumatology, Nottingham University Hospitals NHS Trust (I.P.), Nottingham, United Kingdom; and AstraZeneca U.K. Ltd (S.N.L.B.) and Safety Assessment, AstraZeneca U.K. Ltd (J.G.K.), Alderley Park, Macclesfield, Cheshire, United Kingdom
| | - Sophie L Regan
- Medical Research Council Centre for Drug Safety Science, Institute of Translational Medicine, (T.G.H., X.M., R.E.J., J.L.M., A.S.C., S.L.R., C.J.E., B.K.P., D.P.W.) and Department of Chemistry (A.V.S.), University of Liverpool, Liverpool, United Kingdom; Nottingham Digestive Diseases Centre, NIHR Nottingham Digestive Diseases-Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham (G.P.A.) and Department of Rheumatology, Nottingham University Hospitals NHS Trust (I.P.), Nottingham, United Kingdom; and AstraZeneca U.K. Ltd (S.N.L.B.) and Safety Assessment, AstraZeneca U.K. Ltd (J.G.K.), Alderley Park, Macclesfield, Cheshire, United Kingdom
| | - Stuart N L Bennett
- Medical Research Council Centre for Drug Safety Science, Institute of Translational Medicine, (T.G.H., X.M., R.E.J., J.L.M., A.S.C., S.L.R., C.J.E., B.K.P., D.P.W.) and Department of Chemistry (A.V.S.), University of Liverpool, Liverpool, United Kingdom; Nottingham Digestive Diseases Centre, NIHR Nottingham Digestive Diseases-Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham (G.P.A.) and Department of Rheumatology, Nottingham University Hospitals NHS Trust (I.P.), Nottingham, United Kingdom; and AstraZeneca U.K. Ltd (S.N.L.B.) and Safety Assessment, AstraZeneca U.K. Ltd (J.G.K.), Alderley Park, Macclesfield, Cheshire, United Kingdom
| | - Caroline J Earnshaw
- Medical Research Council Centre for Drug Safety Science, Institute of Translational Medicine, (T.G.H., X.M., R.E.J., J.L.M., A.S.C., S.L.R., C.J.E., B.K.P., D.P.W.) and Department of Chemistry (A.V.S.), University of Liverpool, Liverpool, United Kingdom; Nottingham Digestive Diseases Centre, NIHR Nottingham Digestive Diseases-Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham (G.P.A.) and Department of Rheumatology, Nottingham University Hospitals NHS Trust (I.P.), Nottingham, United Kingdom; and AstraZeneca U.K. Ltd (S.N.L.B.) and Safety Assessment, AstraZeneca U.K. Ltd (J.G.K.), Alderley Park, Macclesfield, Cheshire, United Kingdom
| | - Guruprasad P Aithal
- Medical Research Council Centre for Drug Safety Science, Institute of Translational Medicine, (T.G.H., X.M., R.E.J., J.L.M., A.S.C., S.L.R., C.J.E., B.K.P., D.P.W.) and Department of Chemistry (A.V.S.), University of Liverpool, Liverpool, United Kingdom; Nottingham Digestive Diseases Centre, NIHR Nottingham Digestive Diseases-Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham (G.P.A.) and Department of Rheumatology, Nottingham University Hospitals NHS Trust (I.P.), Nottingham, United Kingdom; and AstraZeneca U.K. Ltd (S.N.L.B.) and Safety Assessment, AstraZeneca U.K. Ltd (J.G.K.), Alderley Park, Macclesfield, Cheshire, United Kingdom
| | - Ira Pande
- Medical Research Council Centre for Drug Safety Science, Institute of Translational Medicine, (T.G.H., X.M., R.E.J., J.L.M., A.S.C., S.L.R., C.J.E., B.K.P., D.P.W.) and Department of Chemistry (A.V.S.), University of Liverpool, Liverpool, United Kingdom; Nottingham Digestive Diseases Centre, NIHR Nottingham Digestive Diseases-Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham (G.P.A.) and Department of Rheumatology, Nottingham University Hospitals NHS Trust (I.P.), Nottingham, United Kingdom; and AstraZeneca U.K. Ltd (S.N.L.B.) and Safety Assessment, AstraZeneca U.K. Ltd (J.G.K.), Alderley Park, Macclesfield, Cheshire, United Kingdom
| | - J Gerry Kenna
- Medical Research Council Centre for Drug Safety Science, Institute of Translational Medicine, (T.G.H., X.M., R.E.J., J.L.M., A.S.C., S.L.R., C.J.E., B.K.P., D.P.W.) and Department of Chemistry (A.V.S.), University of Liverpool, Liverpool, United Kingdom; Nottingham Digestive Diseases Centre, NIHR Nottingham Digestive Diseases-Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham (G.P.A.) and Department of Rheumatology, Nottingham University Hospitals NHS Trust (I.P.), Nottingham, United Kingdom; and AstraZeneca U.K. Ltd (S.N.L.B.) and Safety Assessment, AstraZeneca U.K. Ltd (J.G.K.), Alderley Park, Macclesfield, Cheshire, United Kingdom
| | - Andrew V Stachulski
- Medical Research Council Centre for Drug Safety Science, Institute of Translational Medicine, (T.G.H., X.M., R.E.J., J.L.M., A.S.C., S.L.R., C.J.E., B.K.P., D.P.W.) and Department of Chemistry (A.V.S.), University of Liverpool, Liverpool, United Kingdom; Nottingham Digestive Diseases Centre, NIHR Nottingham Digestive Diseases-Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham (G.P.A.) and Department of Rheumatology, Nottingham University Hospitals NHS Trust (I.P.), Nottingham, United Kingdom; and AstraZeneca U.K. Ltd (S.N.L.B.) and Safety Assessment, AstraZeneca U.K. Ltd (J.G.K.), Alderley Park, Macclesfield, Cheshire, United Kingdom
| | - B Kevin Park
- Medical Research Council Centre for Drug Safety Science, Institute of Translational Medicine, (T.G.H., X.M., R.E.J., J.L.M., A.S.C., S.L.R., C.J.E., B.K.P., D.P.W.) and Department of Chemistry (A.V.S.), University of Liverpool, Liverpool, United Kingdom; Nottingham Digestive Diseases Centre, NIHR Nottingham Digestive Diseases-Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham (G.P.A.) and Department of Rheumatology, Nottingham University Hospitals NHS Trust (I.P.), Nottingham, United Kingdom; and AstraZeneca U.K. Ltd (S.N.L.B.) and Safety Assessment, AstraZeneca U.K. Ltd (J.G.K.), Alderley Park, Macclesfield, Cheshire, United Kingdom
| | - Dominic P Williams
- Medical Research Council Centre for Drug Safety Science, Institute of Translational Medicine, (T.G.H., X.M., R.E.J., J.L.M., A.S.C., S.L.R., C.J.E., B.K.P., D.P.W.) and Department of Chemistry (A.V.S.), University of Liverpool, Liverpool, United Kingdom; Nottingham Digestive Diseases Centre, NIHR Nottingham Digestive Diseases-Biomedical Research Unit, Nottingham University Hospitals NHS Trust and University of Nottingham (G.P.A.) and Department of Rheumatology, Nottingham University Hospitals NHS Trust (I.P.), Nottingham, United Kingdom; and AstraZeneca U.K. Ltd (S.N.L.B.) and Safety Assessment, AstraZeneca U.K. Ltd (J.G.K.), Alderley Park, Macclesfield, Cheshire, United Kingdom
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In vitro drug release and ex vivo percutaneous absorption of resveratrol cream using HPLC with zirconized silica stationary phase. J Chromatogr B Analyt Technol Biomed Life Sci 2013; 947-948:23-31. [PMID: 24381018 DOI: 10.1016/j.jchromb.2013.12.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Revised: 12/02/2013] [Accepted: 12/03/2013] [Indexed: 02/06/2023]
Abstract
Since the designs of optimal formulations for resveratrol permeation via the skin are lacking, the aim of this study was to establish the profile of resveratrol permeability into and across human skin. For that, a laboratory-made chromatographic column was used (Zr-PMODS), with its performance being compared to a traditional C18 column. In vitro drug release was conducted with polysulfone membranes, and the flux (JS) was 30.49 μg cm(-2) h(-1)), with a lag time (LT) of 0.04 h, following a pseudo-first-order kinetics. For ex vivo percutaneous absorption using excised female human skin, the kinetic profile was the same, but JS was 0.87 μg cm(-2) h(-1) and LT was 0.97 h. From the initials 49.30 μg applied to the skin, 9.50 μg were quantified in the receptor medium, 20.48 μg was retained at the stratum corneum (do not account as permeated) and 21.41 μg was retained at the viable epidermis+dermis (account as permeated), totalizing 30.90 μg of resveratrol permeated after 24 h of application (62.6%). From these results, one can conclude that a person using the 1-g emulsion dose released by the pump containing 20mg of resveratrol will have, theoretically, 12.53 mg of it liberated into his bloodstream, gradually and continuously for 24 h.
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Meder F, Kaur S, Treccani L, Rezwan K. Controlling mixed-protein adsorption layers on colloidal alumina particles by tailoring carboxyl and hydroxyl surface group densities. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2013; 29:12502-12510. [PMID: 23875793 DOI: 10.1021/la402093j] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
We show that different ratios of bovine serum albumin (BSA) and lysozyme (LSZ) can be achieved in a mixed protein adsorption layer by tailoring the amounts of carboxyl (-COOH) and aluminum hydroxyl (AlOH) groups on colloidal alumina particles (d50 ≈ 180 nm). The particles are surface-functionalized with -COOH groups, and the resultant surface chemistry, including the remaining AlOH groups, is characterized and quantified using elemental analysis, ζ potential measurements, acid-base titration, IR spectroscopy, electron microscopy, nitrogen adsorption, and dynamic light scattering. BSA and LSZ are subsequently added to the particle suspensions, and protein adsorption is monitored by in situ ζ potential measurements while being quantified by UV spectroscopy and gel electrophoresis. A comparison of single-component and sequential protein adsorption reveals that BSA and LSZ have specific adsorption sites: BSA adsorbs primarily via AlOH groups, whereas LSZ adsorbs only via -COOH groups (1-2 -COOH groups on the particle surface is enough to bind one LSZ molecule). Tailoring such groups on the particle surface allows control of the composition of a mixed BSA and LSZ adsorption layer. The results provide further insight into how particle surface chemistry affects the composition of protein adsorption layers on colloidal particles and is valuable for the design of such particles for biotechnological and biomedical applications.
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Affiliation(s)
- Fabian Meder
- Faculty of Production Engineering, Advanced Ceramics, University of Bremen , D-28359 Bremen, Germany
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Mu R, Chen W, Pan B, Wang L, Hao X, Huang X, Qiao R, Zhao M, Zhang C, Guo W, Huang H, Ma Y, Zhuang J, Zhang J, Shang H. First definition of reference intervals of liver function tests in China: a large-population-based multi-center study about healthy adults. PLoS One 2013; 8:e72916. [PMID: 24058449 PMCID: PMC3772807 DOI: 10.1371/journal.pone.0072916] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Accepted: 07/14/2013] [Indexed: 02/07/2023] Open
Abstract
Background Reference intervals of Liver function tests are very important for the screening, diagnosis, treatment, and monitoring of liver diseases. We aim to establish common reference intervals of liver function tests specifically for the Chinese adult population. Methods A total of 3210 individuals (20–79 years) were enrolled in six representative geographical regions in China. Analytes of ALT, AST, GGT, ALP, total protein, albumin and total bilirubin were measured using three analytical systems mainly used in China. The newly established reference intervals were based on the results of traceability or multiple systems, and then validated in 21 large hospitals located nationwide qualified by the National External Quality Assessment (EQA) of China. Results We had been established reference intervals of the seven liver function tests for the Chinese adult population and found there were apparent variances of reference values for the variables for partitioning analysis such as gender(ALT, GGT, total bilirubin), age(ALP, albumin) and region(total protein). More than 86% of the 21 laboratories passed the validation in all subgroup of reference intervals and overall about 95.3% to 98.8% of the 1220 validation results fell within the range of the new reference interval for all liver function tests. In comparison with the currently recommended reference intervals in China, the single side observed proportions of out of range of reference values from our study for most of the tests deviated significantly from the nominal 2.5% such as total bilirubin (15.2%), ALP (0.2%), albumin (0.0%). Most of reference intervals in our study were obviously different from that of other races. Conclusion These used reference intervals are no longer applicable for the current Chinese population. We have established common reference intervals of liver function tests that are defined specifically for Chinese population and can be universally used among EQA-approved laboratories located all over China.
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Affiliation(s)
- Runqing Mu
- Department of Laboratory Medicine, The First Hospital of China Medical University, Shenyang, China
| | - Wenxiang Chen
- National Center for Clinical Laboratories, Beijing Hospital, Beijing, China
| | - Baishen Pan
- Department of Laboratory Medicine, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Lanlan Wang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Sichuan, China
| | - Xiaoke Hao
- Department of Laboratory Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xianzhang Huang
- Department of Laboratory Science, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong, China
| | - Rui Qiao
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, China
| | - Min Zhao
- Department of Laboratory Medicine, The First Hospital of China Medical University, Shenyang, China
| | - Chuanbao Zhang
- National Center for Clinical Laboratories, Beijing Hospital, Beijing, China
| | - Wei Guo
- Department of Laboratory Medicine, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Hengjian Huang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Sichuan, China
| | - Yueyun Ma
- Department of Laboratory Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Junhua Zhuang
- Department of Laboratory Science, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong, China
| | - Jie Zhang
- Department of Laboratory Medicine, Peking University Third Hospital, Beijing, China
| | - Hong Shang
- Department of Laboratory Medicine, The First Hospital of China Medical University, Shenyang, China
- * E-mail:
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Lavoué R, Geffré A, Braun JP, Peeters D, Trumel C. Breed-specific biochemical reference intervals for the adult Dogue de Bordeaux. Vet Clin Pathol 2013; 42:346-59. [PMID: 23906484 DOI: 10.1111/vcp.12067] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Breed-specific reference intervals are of increasing interest in veterinary medicine. The health monitoring of the Dogue de Bordeaux, a breed predisposed to familial juvenile glomerulonephropathy and hypothyroidism, would benefit from specific reference intervals. OBJECTIVE The purpose of this study was to establish breed-specific biochemical reference intervals for the Dogue de Bordeaux in accordance with the International Federation of Clinical Chemistry and Clinical and Laboratory Standards Institute guidelines. METHODS One hundred and twenty Dogues de Bordeaux from France and Belgium were recruited. Complete urinalysis and chemistry panels, venous blood gas variables, total thyroxin and thyroid stimulating hormone, and fibrinogen and antithrombin were measured for each dog. Reference intervals were determined using the non-parametric method. Confounding variables such as sex, age and color of facial mask were analyzed. RESULTS Due to pre-defined criteria for exclusion, 62 healthy dogs were finally selected for the reference intervals determination. Using the instrument manufacturer's generic canine RI for most analytes did not have a significant impact on potential clinical decisions, except for total proteins, ALT, AST, total cholesterol, lipase and total thyroxin, for which possible clinically relevant differences were noted. CONCLUSION Specific reference intervals for biochemical analytes in the Dogue de Bordeaux were determined under controlled pre-analytical and analytical conditions, and according to international recommendations. The use of these breed-specific reference intervals is recommended when using the specified analytic instruments, especially for the 6 analytes for which the reference intervals differed considerably from those provided by manufacturers.
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Affiliation(s)
- R Lavoué
- Internal Medicine Unit, Toulouse, France
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Grabowsky JA. Drug interactions and the pharmacist: focus on everolimus. Ann Pharmacother 2013; 47:1055-63. [PMID: 23757385 DOI: 10.1345/aph.1r769] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE To evaluate everolimus drug-drug and drug-food interactions, with an emphasis on patients with cancer. DATA SOURCES Literature was accessed through PubMed (1990-March 2013) using Boolean combinations of the terms drug interactions, herb-drug interactions, food-drug interactions, everolimus, antineoplastic agents, hormonal, and breast neoplasms. In addition, reference citations from publications and the prescribing information for everolimus were reviewed. STUDY SELECTION AND DATA EXTRACTION All articles published in English, including human, animal, and in vitro studies, identified from the data sources were included. DATA SYNTHESIS Patients with cancer are at increased risk for drug interactions because of the multiple medications they are prescribed to treat their disease and comorbid conditions. Everolimus, an oral mammalian target of rapamycin (mTOR) inhibitor, is indicated for the treatment in adults with progressive neuroendocrine tumors of pancreatic origin that are unresectable, locally advanced, or metastatic; adults with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib; and, recently, postmenopausal women with advanced hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole. As its use increases among patients with cancer, clinicians must be knowledgeable about potential drug and/or food/nutrient interactions and the mechanisms by which these interactions occur, to mitigate and prevent unwanted reactions and ensure patient safety. CONCLUSIONS Everolimus is a widely used oral mTOR inhibitor that has the potential for drug interactions that may affect therapeutic outcomes, produce toxicities, or both. This article provides a review of evidence-based literature, along with the prescribing information, to educate clinicians on the significance of these drug interactions and their impact on management with everolimus.
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Affiliation(s)
- Jennifer A Grabowsky
- Early Phase Investigational Therapeutics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, USA.
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Cheeti S, Budha NR, Rajan S, Dresser MJ, Jin JY. A physiologically based pharmacokinetic (PBPK) approach to evaluate pharmacokinetics in patients with cancer. Biopharm Drug Dispos 2013; 34:141-54. [PMID: 23225350 DOI: 10.1002/bdd.1830] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Revised: 11/16/2012] [Accepted: 11/29/2012] [Indexed: 12/15/2022]
Abstract
Potential differences in pharmacokinetics (PK) between healthy subjects and patients with cancer were investigated using a physiologically based pharmacokinetic approach integrating demographic and physiological data from patients with cancer. Demographic data such as age, sex and body weight, and clinical laboratory measurements such as albumin, alpha-1 acid glycoprotein (AAG) and hematocrit were collected in ~2500 patients with cancer. A custom oncology population profile was built using the observed relationships among demographic variables and laboratory measurements in Simcyp® software, a population based ADME simulator. Patients with cancer were older compared with the age distribution in a built-in healthy volunteer profile in Simcyp. Hematocrit and albumin levels were lower and AAG levels were higher in patients with cancer. The custom population profile was used to investigate the disease effect on the pharmacokinetics of two probe substrates, saquinavir and midazolam. Higher saquinavir exposure was predicted in patients relative to healthy subjects, which was explained by the altered drug binding due to elevated AAG levels in patients with cancer. Consistent with historical clinical data, similar midazolam exposure was predicted in patients and healthy subjects, supporting the hypothesis that the CYP3A activity is not altered in patients with cancer. These results suggest that the custom oncology population profile is a promising tool for the prediction of PK in patients with cancer. Further evaluation and extension of this population profile with more compounds and more data will be needed.
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Affiliation(s)
- Sravanthi Cheeti
- Department of Clinical Pharmacology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
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Birnbaum AK, Conway JM, Strege MA, Leppik IE. Variability of carbamazepine and valproate concentrations in elderly nursing home residents. Epilepsy Res 2012; 101:22-7. [PMID: 22464175 PMCID: PMC4900894 DOI: 10.1016/j.eplepsyres.2012.02.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2011] [Revised: 02/22/2012] [Accepted: 02/26/2012] [Indexed: 11/29/2022]
Abstract
PURPOSE Measuring antiepileptic drug (AED) concentrations is common practice in nursing homes. Phenytoin (PHT) concentrations fluctuate substantially in many nursing home residents under constant dose conditions; however, the stability of other AED concentrations has not been studied. We investigated the variability of carbamazepine (CBZ) and valproate (VPA) concentrations under constant dose conditions in US nursing home residents. METHODS A database of elderly persons (≥65 years) in 119 nursing homes throughout the US was reviewed for residents with at least one measurement of total PHT, CBZ or VPA. Inclusion criteria for this study were three or more serum concentration measurements while on the same dose of CBZ or VPA, a two-month minimum stay, and no interfering co-medications (inducers or inhibitors). Enrollment occurred over a 2-year period. Data were collected on residents for a minimum of 6 months. KEY FINDINGS Of the 593 residents identified, 245 had CBZ or VPA concentrations measured and 44 (18%) met inclusion criteria (22 on CBZ and 22 VPA). Some subjects had little variability in AED concentrations, others had large fluctuations. Total CBZ concentrations within individuals varied as little as 0mg/L to as much as 6.3mg/L and total VPA concentrations as little as 10.0mg/L to as much as 77.6mg/L. SIGNIFICANCE The variability of PHT, CBZ, and VPA concentrations in many but not all nursing home residents implies that a re-evaluation of the role of AED concentration measurements in the management of patients is needed. Strategies for use and interpretation of AED concentration measurements need to be reevaluated.
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Affiliation(s)
- Angela K Birnbaum
- Department of Experimental & Clinical Pharmacology, College of Pharmacy, 717 Delaware St. SE, Minneapolis, MN 55414, USA.
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Kapur BM, Hutson JR, Chibber T, Luk A, Selby P. Methadone: a review of drug-drug and pathophysiological interactions. Crit Rev Clin Lab Sci 2012; 48:171-95. [PMID: 22035341 DOI: 10.3109/10408363.2011.620601] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Numerous established and potential drug interactions with methadone are clinically important in people treated with methadone either for addiction or for chronic pain. Methadone users often have comorbidities and are prescribed drugs that may interact with methadone. Methadone is extensively metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP 1A2, 2D6, 2D8, 2C9/2C8, 2C19, and 2B6. Eighty-six percent of methadone is protein bound, predominately to α1-acid glycoprotein (AGP). Polymorphisms in or interactions with CYPs that metabolize methadone, changes in protein binding, and other pathophysiological conditions affect the pharmacokinetic properties of methadone. It is critical for health care providers who treat patients on methadone to have adequate information on the interactions of methadone with other drugs of abuse and other medications. We set out to describe drug-drug interactions as well as physiological and pathophysiological factors that may impact the pharmacokinetics of methadone. Using MEDLINE, we conducted a systematic search for papers and related abstracts published between 1966 and June 2010. Keywords that included methadone, drug-drug interactions, CYP P450 and AGP identified a total of 7709 papers. Other databases, including the Cochrane Database of Systematic Reviews and Scopus, were also searched; an additional 929 papers were found. Final selection of 286 publications was based on the relevance of each paper to the topic. Over 50 such interactions were found. Interactions of methadone with other drugs can lead to increased or decreased methadone drug levels in patients and result in potential overdose or withdrawal, respectively. The former can contribute to methadone's fatality. Prescribers of methadone and pharmacists should enquire about any new medications (including natural products and over-the-counter medications) periodically, and especially when an otherwise stable patient suddenly experiences drug craving, withdrawal or intoxication.
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Affiliation(s)
- Bhushan M Kapur
- Department of Clinical Pathology, Sunnybrook Health Sciences Centre, Toronto, Canada.
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Simon MJ, Veering BT. Factors affecting the pharmacokinetics and neural block characteristics after epidural administration of local anaesthetics. ACTA ACUST UNITED AC 2012. [DOI: 10.1016/j.eujps.2010.09.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Jelinek HF, Warner P. Digoxin therapy in the elderly: pharmacokinetic considerations in nursing. Geriatr Nurs 2011; 32:263-9. [PMID: 21600673 DOI: 10.1016/j.gerinurse.2011.03.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2010] [Revised: 03/09/2011] [Accepted: 03/21/2011] [Indexed: 11/29/2022]
Abstract
Digoxin is effective in controlling ventricular rhythm in atrial fibrillation and is used in heart failure when angiotensin converting enzyme inhibitors and diuretics are ineffective. Because use of more than 1 drug is often required with these conditions, pharmacokinetic considerations, including those related to complementary medicine, are important. Increased awareness of drug action in the elderly is important because there is often an increase in body fat and leaner muscle mass as well as changes in organ function, such as that of the kidney, which alters drug activity. Nurses have an important role to play in the safe administration of digoxin.
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Affiliation(s)
- Herbert F Jelinek
- School of Community Health, Charles Sturt University, Albury, Australia
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Werhahn KJ. Epilepsy in the elderly. DEUTSCHES ARZTEBLATT INTERNATIONAL 2009; 106:135-42. [PMID: 19568380 PMCID: PMC2696249 DOI: 10.3238/arztebl.2009.0135] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2008] [Accepted: 11/24/2008] [Indexed: 01/10/2023]
Abstract
BACKGROUND Epilepsy is the third most common disease affecting the brain in the elderly. Current demographic trends will lead to an increased prevalence of epilepsy in the general population. METHOD A selective literature search revealed 102 relevant publications as of September 2008, 50 of which were original articles. RESULTS The level of evidence was found to be very low. No guidelines, systematic reviews or meta-analyses are available, and there have been only three randomized, double-blind trials of treatment for epilepsy in the elderly. The seizures often escape clinical attention, because premonitory symptoms (aura) and secondary generalization into tonic-clonic seizures are both rarer in older patients. On the other hand, sudden loss of consciousness from various causes becomes more common with increasing age, presenting a challenge in differential diagnosis. Treatment is often more complex because of comorbidities and multiple other drugs, and requires a cautious approach. Drug interactions, in particular, require special attention. On the positive side, epileptic seizures in the elderly seem to be more easily controlled by medications than they are in young adults. CONCLUSIONS Epilepsy is often more difficult to recognize in old age. The treatment is hampered by side effects and drug interactions. Thus, certainty about the diagnosis is indispensable, and the treatment often requires the use of newer-generation antiepileptic drugs.
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Affiliation(s)
- Konrad J Werhahn
- Neurologische Klinik, Mainzer Epilepsie Zentrum, Johannes Gutenberg-Universität Mainz.
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Baert B, Annavarapu S, Burvenich C, De Spiegeleer B. Analytical, biopharmaceutical and regulatory evaluation of topical testosterone preparations. Eur J Pharm Biopharm 2008; 72:275-81. [PMID: 19026745 DOI: 10.1016/j.ejpb.2008.10.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2008] [Revised: 08/29/2008] [Accepted: 10/27/2008] [Indexed: 10/21/2022]
Abstract
Testosterone-containing pharmaceutical products for topical use were obtained from the pharmacist or through the internet. The legal status of the different products obtained is discussed: some products through the internet were clearly a medicinal product according to the current definitions, while they are not registered as such. Assay and impurity profiles of each of the marketed samples were obtained using HPLC-UV and ESI-iontrap MS. The analytical results were evaluated relative to the reporting, identification and qualification thresholds as defined by the the International Conference on Harmonisation (ICH) and the European Pharmacopoeia (Ph. Eur.). Preparations with impurities above the qualification threshold were observed. Moreover, in vitro release profiles over an artificial membrane were obtained using a standardised cell in a paddle dissolution bath as well as in a static Franz diffusion cell, using phosphate buffered saline (PBS; pH 7.0) containing 5% bovine serum albumin (BSA) as dissolution or receptor fluid. This biopharmaceutical quality attribute differs significantly between the preparations tested. In conclusion, the equivalency of topical testosterone preparations is not assured, nor on their legal status, nor on their impurity profiling nor on their biopharmaceutical behaviour. This calls for an urgent trans-national product-class harmonisation approach.
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Affiliation(s)
- B Baert
- Drug Quality and Registration (DruQuaR) group, Ghent University, Ghent, Belgium
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Abstract
The number of elderly patients presenting for anaesthesia and surgery has increased exponentially in recent years. Regional anaesthesia is frequently used in elderly patients undergoing surgery. Although the type of anaesthesia (general versus regional anaesthesia) has no substantial effect on perioperative morbidity and mortality in any age group; it intuitively makes sense that elderly patients would benefit from regional anaesthesia because they remain minimally sedated throughout the procedures and awaken with excellent postoperative pain control. However, a multitude of factors influence the outcome, such as the type, duration and invasiveness of the operation, co-existing medical and mental status of the patient and the skill and expertise of the anaesthesiologist and surgeon. These factors make it difficult to decide if and when one technique is equivocally better than another. Thus, it is more important to optimise the overall management of the patient during the perioperative period and, in most cases, it is the quality of the anaesthetic administered rather than the type of anaesthetic which is most important. Sedatives used for regional anaesthesia in the elderly should be short acting, easy to administer, have a low adverse effect profile and high safety margin. Midazolam, lorazepam, ketamine, propofol and low-dose opioids have been successfully used for sedation in the elderly. Aging affects the pharmacokinetics and pharmacodynamics of local anaesthetics, composition and characteristics of tissues and organs within the body, and physiological functions of the body. Changes in the systematic absorption, distribution and clearance of local anaesthetics lead to an increased sensitivity, decreased dose requirement and a change in the onset and duration of action in the elderly. Decreases in neural population, neural conduction velocity and inter-Schwann cell distance can lead to an increased sensitivity to local anaesthetics in the elderly. The addition of an opioid and epinephrine (adrenaline) has been shown to be useful in central neuraxial blockade. Epinephrine also can prolong the duration of peripheral nerve blocks. However, caution must be exercised as epinephrine has the potential for causing ischaemic neurotoxicity in peripheral nerves. Regional anaesthesia appears to be safe and beneficial in elderly patients; however, every anaesthetic administered must be assessed on a case-by-case basis and particular consideration should be given to the health status of the patient, the operation being performed and the expertise of the anaesthesiologist.
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Affiliation(s)
- Ban C H Tsui
- Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, Alberta, Canada.
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Abstract
The physiological changes that occur with increasing age can have significant effects on the pharmacokinetics of neuromuscular-blocking drugs. Changes in cardiac output can affect drug distribution and therefore the speed of onset of neuromuscular block. A decrease in muscle mass and increase in body fat with age can also affect their distribution. The deterioration in renal and hepatic function associated with aging affects the clearance and elimination of many neuromuscular-blocking drugs. The effects of these physiological changes on the pharmacokinetics of neuromuscular-blocking agents may not become apparent clinically in healthy individuals until the age of at least 75 years. There is very little evidence to suggest any alteration in the sensitivity of the neuromuscular junction to neuromuscular-blocking drugs with increasing age. Neuromuscular-blocking drugs that undergo a significant degree of organ-dependent elimination, such as pancuronium bromide, vecuronium bromide, rocuronium bromide and doxacurium chloride, may have a significantly prolonged duration of action in elderly patients. These drugs can be used safely in elderly patients if the anaesthetist is aware of their altered pharmacokinetics in this patient group. Appropriate changes must be made to drug dosage and dose intervals. As the pharmacokinetic changes can be unpredictable, monitoring of neuromuscular block is strongly advised when using these drugs in such patients. The risk of residual block occurring postoperatively after the use of pancuronium bromide increases with age. The duration of action of mivacurium chloride may also be prolonged in the elderly; this change has not been demonstrated to be a result of an alteration in plasma cholinesterase activity. In contrast, there is no evidence of an alteration in the action of suxamethonium chloride (succinylcholine chloride) with increasing age. Atracurium besilate and cisatracurium besilate undergo predominantly organ-independent elimination. Onset of block with these two drugs may be prolonged in the elderly, but their clinical duration of action does not alter significantly with age, making them particularly suitable for use in this patient group. Although atracurium besilate may cause histamine release, there is little evidence of it producing haemodynamic changes in the elderly. Its (1R,1R')-isomer, cisatracurium besilate, has very little direct or indirect cardiovascular effect and is, therefore, the most suitable nondepolarising agent to use in elderly patients.
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49
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Abstract
OBJECTIVE To review the epidemiology and pharmacologic management of epilepsy in elderly patients. DATA SOURCES Controlled trials, case studies, and review articles identified via MEDLINE using the search terms epilepsy, seizures, elderly, phenobarbital, primidone, phenytoin, carbamazepine, valproic acid, felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide. Recently published standard textbooks on epilepsy were also consulted. DATA SYNTHESIS Epilepsy is a common neurologic disorder in the elderly. Cerebrovascular and neurodegenerative diseases are the most common causes of new-onset seizures in these patients. Alterations in protein binding, distribution, elimination, and increased sensitivity to the pharmacodynamic effects of antiepileptic drugs (AEDs) are relatively frequent, and these factors should be assessed at the initiation, and during adjustment, of treatment. Drug-drug interactions are also an important issue in elderly patients, because multiple drug use is common and AEDs are susceptible to many interactions. In addition to understanding age-related changes in the pharmacokinetics and pharmacodynamics of AEDs, clinicians should know the common seizure types in the elderly and the spectrum of AED activity for these seizure types. AEDs with activity against both partial-onset and generalized seizures include felbamate, lamotrigine, levetiracetam, topiramate, valproic acid, and zonisamide. Other AEDs discussed in this review (carbamazepine, gabapentin, phenobarbital, phenytoin, primidone, and tiagabine) are most useful for partial-onset seizures. CONCLUSION The provision of safe and effective drug therapy to elderly patients requires an understanding of the unique age-related changes' in the pharmacokinetics and pharmacodynamics of AEDs as well as an appreciation of common seizure types and the drugs that are effective for the specific types seen in the elderly.
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Affiliation(s)
- S V Bourdet
- University of North Carolina Hospitals, Chapel Hill, USA
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50
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Abstract
For about half a century, the binding of drugs to plasma albumin, the "silent receptor," has been recognized as one of the major determinants of drug action, distribution, and disposition. In the last decade, the binding of drugs, especially but not exclusively basic entities, to another plasma protein, alpha 1-acid glycoprotein (AAG), has increasingly become important in this regard. The present review points out that hundreds of drugs with diverse structures bind to this glycoprotein. Although plasma concentration of AAG is much lower than that of albumin, AAG can become the major drug binding macromolecule in plasma with significant clinical implications. Also, briefly reviewed are the physiological, pathological, and genetic factors that influence binding, the role of AAG in drug-drug interactions, especially the displacement of drugs and endogenous substances from AAG binding sites, and pharmacokinetic and clinical consequences of such interactions. It can be predicted that in the future, rapid automatic methods to measure binding to albumin and/or AAG will routinely be used in drug development and in clinical practice to predict and/or guide therapy.
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Affiliation(s)
- Z H Israili
- Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
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