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Journal of Pharmaceutical and... Jan 2018Nuclear magnetic resonance (NMR) spectroscopy has a unique capability to probe the primary and higher order molecular structure and the structural dynamics of... (Review)
Review
Nuclear magnetic resonance (NMR) spectroscopy has a unique capability to probe the primary and higher order molecular structure and the structural dynamics of biomolecules at an atomic resolution, and this capability has been greatly fortified over the last five decades by an astonishing NMR instrumental and methodological development. Because of these factors, NMR has become a primary tool for the structure investigation of biomolecules, spawning a whole scientific subfield dedicated to the subject. This role of NMR is by now well established and broadly appreciated, especially in the context of academic research dealing with proteins that are purified and isotope-labeled in order to facilitate the necessary sophisticated multidimensional NMR measurements. However, the more recent industrial development, manufacturing, and quality control of biopharmaceuticals provide a different framework for NMR. For example, protein drug substances are not isotope-labeled and are present in a medium of excipients, which make structural NMR measurements much more difficult. On the other hand, biotechnology involves many other analytical requirements that can be efficiently addressed by NMR. In this respect the scope and limitations of NMR are less well understood. Having the non-expert reader in mind, herein we wish to highlight the ways in which modern NMR can effectively support biotechnological developments. Our focus will be on biosimilar proteins, pointing out certain cases where its use is probably essential. Based partly on literature data, and partly on our own hands-on experience, this paper is intended to be a guide for choosing the proper NMR approach for analytical questions concerning the structural comparability of therapeutic proteins, monitoring technology-related impurities, protein quantification, analysis of spent media, identification of extractable and leachable components, etc. Also, we focus on critical considerations, particularly those coming from drug authority guidelines, which limit the use of the well-established NMR tools in everyday practice.
Topics: Animals; Biopharmaceutics; Biosimilar Pharmaceuticals; Drug Industry; Humans; Nuclear Magnetic Resonance, Biomolecular
PubMed: 28760370
DOI: 10.1016/j.jpba.2017.07.004 -
British Journal of Clinical Pharmacology Oct 2008Clinical pharmacology assumes that deductions can be made about the concentrations of drugs from a knowledge of the pharmacokinetic parameters in an individual; and that... (Review)
Review
Clinical pharmacology assumes that deductions can be made about the concentrations of drugs from a knowledge of the pharmacokinetic parameters in an individual; and that the effects are related to the measured concentration. Post-mortem changes render the assumptions of clinical pharmacology largely invalid, and make the interpretation of concentrations measured in post-mortem samples difficult or impossible. Qualitative tests can show the presence of substances that were not present in life, and can fail to detect substances that led to death. Quantitative analysis is subject to error in itself, and because post-mortem concentrations vary in largely unpredictable ways with the site and time of sampling, as a result of the phenomenon of post-mortem redistribution. Consequently, compilations of 'lethal concentrations' are misleading. There is a lack of adequate studies of the true relationship between fatal events and the concentrations that can be measured subsequently, but without such studies, clinical pharmacologists and others should be wary of interpreting post-mortem measurements.
Topics: Drug Overdose; Forensic Toxicology; Humans; Pharmacology, Clinical; Postmortem Changes; Qualitative Research; Substance-Related Disorders
PubMed: 18637886
DOI: 10.1111/j.1365-2125.2008.03231.x -
CMAJ : Canadian Medical Association... Nov 2023Pharmacogenomic testing to identify variations in genes that influence metabolism of antidepressant medications can enhance efficacy and reduce adverse effects of...
BACKGROUND
Pharmacogenomic testing to identify variations in genes that influence metabolism of antidepressant medications can enhance efficacy and reduce adverse effects of pharmacotherapy for major depressive disorder. We sought to establish the cost-effectiveness of implementing pharmacogenomic testing to guide prescription of antidepressants.
METHODS
We developed a discrete-time microsimulation model of care pathways for major depressive disorder in British Columbia, Canada, to evaluate the effectiveness and cost-effectiveness of pharmacogenomic testing from the public payer's perspective over 20 years. The model included unique patient characteristics (e.g., metabolizer phenotypes) and used estimates derived from systematic reviews, analyses of administrative data (2015-2020) and expert judgment. We estimated incremental costs, life-years and quality-adjusted life-years (QALYs) for a representative cohort of patients with major depressive disorder in BC.
RESULTS
Pharmacogenomic testing, if implemented in BC for adult patients with moderate-severe major depressive disorder, was predicted to save the health system $956 million ($4926 per patient) and bring health gains of 0.064 life-years and 0.381 QALYs per patient (12 436 life-years and 74 023 QALYs overall over 20 yr). These savings were mainly driven by slowing or avoiding the transition to refractory (treatment-resistant) depression. Pharmacogenomic-guided care was associated with 37% fewer patients with refractory depression over 20 years. Sensitivity analyses estimated that costs of pharmacogenomic testing would be offset within about 2 years of implementation.
INTERPRETATION
Pharmacogenomic testing to guide antidepressant use was estimated to yield population health gains while substantially reducing health system costs. These findings suggest that pharmacogenomic testing offers health systems an opportunity for a major value-promoting investment.
Topics: Adult; Humans; Depressive Disorder, Major; Pharmacogenetics; Depression; Cost-Benefit Analysis; Antidepressive Agents; Quality-Adjusted Life Years; British Columbia
PubMed: 37963621
DOI: 10.1503/cmaj.221785 -
Acta Poloniae Pharmaceutica 2012Ethylcellulose (EC) based microencapsulated drug delivery systems are being extensively studied throughout the world for achieving extended drug release and protecting... (Review)
Review
Ethylcellulose (EC) based microencapsulated drug delivery systems are being extensively studied throughout the world for achieving extended drug release and protecting the core substance from degradation. The in vitro evaluation of EC microcapsules have elucidated that their particle characteristics are very useful to control drug release behavior, since these enable drugs to be released at a certain controlled release rate based on the characteristics of drug-EC linkage. This review encompasses microencapsulation techniques, core substances and other fundamentals involved in the preparation and characterization of EC microcapsules. EC microcapsules can be considered as mini-osmotic pumps. The release kinetics for EC microcapsules can be fine-tuned by altering osmolality of the dissolution medium or formulations and EC film mechanical characteristics by selecting appropriate EC molecular weights (viscosity), EC substitution grades, coating weights, and pore formers.
Topics: Animals; Capsules; Cellulose; Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug Carriers; Drug Compounding; Humans; Particle Size; Pharmaceutical Preparations; Technology, Pharmaceutical
PubMed: 22574502
DOI: No ID Found -
Translational Psychiatry Jul 2012Addictions are serious and common psychiatric disorders, and are among the leading contributors to preventable death. This selective review outlines and highlights the... (Review)
Review
Addictions are serious and common psychiatric disorders, and are among the leading contributors to preventable death. This selective review outlines and highlights the need for a multi-method translational approach to genetic studies of these important conditions, including both licit (alcohol, nicotine) and illicit (cannabis, cocaine, opiates) drug addictions and the behavioral addiction of disordered gambling. First, we review existing knowledge from twin studies that indicates both the substantial heritability of substance-specific addictions and the genetic overlap across addiction to different substances. Next, we discuss the limited number of candidate genes which have shown consistent replication, and the implications of emerging genomewide association findings for the genetic architecture of addictions. Finally, we review the utility of extensions to existing methods such as novel phenotyping, including the use of endophenotypes, biomarkers and neuroimaging outcomes; emerging methods for identifying alternative sources of genetic variation and accompanying statistical methodologies to interpret them; the role of gene-environment interplay; and importantly, the potential role of genetic variation in suggesting new alternatives for treatment of addictions.
Topics: Biomarkers; Diagnostic and Statistical Manual of Mental Disorders; Endophenotypes; Gene-Environment Interaction; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Humans; Pharmacogenetics; Substance-Related Disorders
PubMed: 22806211
DOI: 10.1038/tp.2012.54 -
Journal of Medicinal Chemistry Nov 2020This Perspective of the published essential medicinal chemistry of cannabidiol (CBD) provides evidence that the popularization of CBD-fortified or CBD-labeled health... (Review)
Review
This Perspective of the published essential medicinal chemistry of cannabidiol (CBD) provides evidence that the popularization of CBD-fortified or CBD-labeled health products and CBD-associated health claims lacks a rigorous scientific foundation. CBD's reputation as a cure-all puts it in the same class as other "natural" panaceas, where valid ethnobotanicals are reduced to single, purportedly active ingredients. Such reductionist approaches oversimplify useful, chemically complex mixtures in an attempt to rationalize the commercial utility of natural compounds and exploit the "natural" label. Literature evidence associates CBD with certain semiubiquitous, broadly screened, primarily plant-based substances of undocumented purity that interfere with bioassays and have a low likelihood of becoming therapeutic agents. Widespread health challenges and pandemic crises such as SARS-CoV-2 create circumstances under which scientists must be particularly vigilant about healing claims that lack solid foundational data. Herein, we offer a critical review of the published medicinal chemistry properties of CBD, as well as precise definitions of CBD-containing substances and products, distilled to reveal the essential factors that impact its development as a therapeutic agent.
Topics: Animals; Cannabidiol; Chemistry, Pharmaceutical; Clinical Trials as Topic; Humans; Placebo Effect
PubMed: 32804502
DOI: 10.1021/acs.jmedchem.0c00724 -
Molecular Pharmaceutics Jul 2022For oral drugs, the formulator and discovery chemist have a tool available to them that can be used to navigate the risks associated with the selection and development... (Review)
Review
For oral drugs, the formulator and discovery chemist have a tool available to them that can be used to navigate the risks associated with the selection and development of immediate release oral drugs and drug products. This tool is the biopharmaceutics classification system (giBCS). Unfortunately, no such classification system exists for inhaled drugs. The perspective outlined in this manuscript provides the foundational principles and framework for a classification system for inhaled drugs. The proposed classification system, an inhalation-based biopharmaceutics classification system (iBCS), is based on fundamental biopharmaceutics principles adapted to an inhalation route of administration framework. It is envisioned that a classification system for orally inhaled drugs will facilitate an understanding of the technical challenges associated with the development of new chemical entities and their associated new drug products (device and drug formulation combinations). Similar to the giBCS, the iBCS will be based on key attributes describing the drug substance (solubility and permeability) and the drug product (dose and dissolution). This manuscript provides the foundational aspects of an iBCS, including the proposed scientific principles and framework upon which such a system can be developed.
Topics: Administration, Inhalation; Administration, Oral; Biopharmaceutics; Permeability; Pharmaceutical Preparations; Solubility
PubMed: 35576168
DOI: 10.1021/acs.molpharmaceut.2c00113 -
Neuropsychopharmacology Reports Mar 2018Opioid analgesics are widely used as effective analgesics for the treatment of moderate-to-severe pain. However, the analgesic efficacy of opioids is well known to vary... (Review)
Review
INTRODUCTION
Opioid analgesics are widely used as effective analgesics for the treatment of moderate-to-severe pain. However, the analgesic efficacy of opioids is well known to vary widely among individuals, and effective pain treatment is hampered by vast individual differences. Although these differences in opioid requirements have been attributed to various factors, genetic factors are becoming increasingly relevant to the development of genome science.
AIM
This review covers the association between opioid analgesic requirements and particularly gene polymorphisms.
FUTURE PERSPECTIVES
Personalized pain treatment has begun using prediction formulas based on associated gene polymorphisms. Improvements in personalized pain treatment are expected as scientific knowledge further expands in the future.
Topics: Genetic Testing; Humans; Pain; Pain Management; Pharmacogenetics; Pharmacogenomic Variants; Precision Medicine
PubMed: 30106264
DOI: 10.1002/npr2.12003 -
British Journal of Pharmacology Jun 2011Patient phenotypes in pharmacological pain treatment varies between individuals, which could be partly assigned to their genotypes regarding the targets of classical... (Review)
Review
Patient phenotypes in pharmacological pain treatment varies between individuals, which could be partly assigned to their genotypes regarding the targets of classical analgesics (OPRM1, PTGS2) or associated signalling pathways (KCNJ6). Translational and genetic research have identified new targets, for which new analgesics are being developed. This addresses voltage-gated sodium, calcium and potassium channels, for which SCN9A, CACNA1B, KCNQ2 and KCNQ3, respectively, are primary gene candidates because they code for the subunits of the respective channels targeted by analgesics currently in clinical development. Mutations in voltage gated transient receptor potential (TRPV) channels are known from genetic pain research and may modulate the effects of analgesics under development targeting TRPV1 or TRPV3. To this add ligand-gated ion channels including nicotinic acetylcholine receptors, ionotropic glutamate-gated receptors and ATP-gated purinergic P2X receptors with most important subunits coded by CHRNA4, GRIN2B and P2RX7. Among G protein coupled receptors, δ-opioid receptors (coded by OPRD1), cannabinoid receptors (CNR1 and CNR2), metabotropic glutamate receptors (mGluR5 coded by GRM5), bradykinin B(1) (BDKRB1) and 5-HT(1A) (HTR1A) receptors are targeted by new analgesic substances. Finally, nerve growth factor (NGFB), its tyrosine kinase receptor (NTRK1) and the fatty acid amide hydrolase (FAAH) have become targets of interest. For most of these genes, functional variants have been associated with neuro-psychiatric disorders and not yet with analgesia. However, research on the genetic modulation of pain has already identified variants in these genes, relative to pain, which may facilitate the pharmacogenetic assessments of new analgesics. The increased number of candidate pharmacogenetic modulators of analgesic actions may open opportunities for the broader clinical implementation of genotyping information.
Topics: Amidohydrolases; Analgesia; Analgesics; Genotype; Humans; Ion Channels; Molecular Targeted Therapy; Pain; Pharmacogenetics; Receptors, G-Protein-Coupled; Signal Transduction
PubMed: 20942817
DOI: 10.1111/j.1476-5381.2010.01074.x -
CNS Neuroscience & Therapeutics Oct 2011Dementia is a major problem of health in developed countries, and a prototypical paradigm of chronic disability, high cost, and social-family burden. Approximately,... (Review)
Review
Dementia is a major problem of health in developed countries, and a prototypical paradigm of chronic disability, high cost, and social-family burden. Approximately, 10-20% of direct costs in this kind of neuropathology are related to pharmacological treatment, with a moderate responder rate below 30% and questionable cost-effectiveness. Over 200 different genes have been associated with the pathogenesis of dementia. Studies on structural and functional genomics, transcriptomics, proteomics and metabolomics have revealed the paramount importance of these novel technologies for the understanding of pathogenic cascades and the prediction of therapeutic outcomes in dementia. About 10-30% of Western populations are defective in genes of the CYP superfamily. The most frequent CYP2D6 variants in the Iberian peninsula are the *1/*1 (57.84%), *1/*4 (22.78%), *1×N/*1 (6.10%), *4/*4 (2.56%), and *1/*3 (2.01%) genotypes, accounting for more than 80% of the population. The frequency of extensive (EMs), intermediate (IMs), poor (PMs), and ultra-rapid metabolizers (UMs) is about 59.51%, 29,78%, 4.46%, and 6.23%, respectively, in the general population, and 57.76, 31.05%, 5.27%, and 5.90%, respectively, in AD cases. The construction of a genetic map integrating the most prevalent CYP2D6+CYP2C19+CYP2C9 polymorphic variants in a trigenic cluster yields 82 different haplotype-like profiles, with *1*1-*1*1-*1*1 (25.70%), *1*1-*1*2-*1*2 (10.66%), *1*1-*1*1-*1*1 (10.45%), *1*4-*1*1-*1*1 (8.09%), *1*4-*1*2-*1*1 (4.91%), *1*4-*1*1-*1*2 (4.65%), and *1*1-*1*3-*1*3 (4.33%), as the most frequent genotypes. Only 26.51% of AD patients show a pure 3EM phenotype, 15.29% are 2EM1IM, 2.04% are pure 3IM, 0% are pure 3PM, and 0% are 1UM2PM. EMs and IMs are the best responders, and PMs and UMs are the worst responders to a combination therapy with cholinesterase inhibitors, neuroprotectants, and vasoactive substances. The pharmacogenetic response in AD appears to be dependent upon the networking activity of genes involved in drug metabolism and genes involved in AD pathogenesis (e.g., APOE). AD patients harboring the APOE-4/4 genotypes are the worst responders to conventional antidementia drugs. To achieve a mature discipline of pharmacogenomics in CNS disorders and dementia it would be convenient to accelerate the following processes: (i) to educate physicians and the public on the use of genetic/genomic screening in daily clinical practice; (ii) to standardize genetic testing for major categories of drugs; (iii) to validate pharmacogenomic information according to drug category and pathology; (iv) to regulate ethical, social, and economic issues; and (v) to incorporate pharmacogenomic procedures both to drugs in development and drugs on the market in order to optimize therapeutics.
Topics: Animals; Apolipoprotein E4; Cytochrome P-450 CYP2D6; Dementia; Genomics; Humans; Pharmacogenetics; Polymorphism, Genetic
PubMed: 20718828
DOI: 10.1111/j.1755-5949.2010.00189.x