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Pharmacopsychiatry Jan 2018Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual... (Review)
Review
Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.
Topics: Drug Monitoring; Guidelines as Topic; Humans; Mental Disorders; Neuropharmacology; Psychopharmacology; Psychotropic Drugs
PubMed: 28910830
DOI: 10.1055/s-0043-116492 -
The AAPS Journal Jul 2014This review further clarifies the concept of pharmaceutical quality by design (QbD) and describes its objectives. QbD elements include the following: (1) a quality... (Review)
Review
This review further clarifies the concept of pharmaceutical quality by design (QbD) and describes its objectives. QbD elements include the following: (1) a quality target product profile (QTPP) that identifies the critical quality attributes (CQAs) of the drug product; (2) product design and understanding including identification of critical material attributes (CMAs); (3) process design and understanding including identification of critical process parameters (CPPs), linking CMAs and CPPs to CQAs; (4) a control strategy that includes specifications for the drug substance(s), excipient(s), and drug product as well as controls for each step of the manufacturing process; and (5) process capability and continual improvement. QbD tools and studies include prior knowledge, risk assessment, mechanistic models, design of experiments (DoE) and data analysis, and process analytical technology (PAT). As the pharmaceutical industry moves toward the implementation of pharmaceutical QbD, a common terminology, understanding of concepts and expectations are necessary. This understanding will facilitate better communication between those involved in risk-based drug development and drug application review.
Topics: Chemistry, Pharmaceutical; Drug Design; Drug Industry; Humans; Pharmaceutical Preparations; Quality Improvement; Technology, Pharmaceutical
PubMed: 24854893
DOI: 10.1208/s12248-014-9598-3 -
Asian Pacific Journal of Cancer... Aug 2018Cytochromes P450s (CYPs) constitute a superfamily of enzymes that catalyze the metabolism of drugs and other substances. Endogenous substrates of CYPs include... (Review)
Review
Cytochromes P450s (CYPs) constitute a superfamily of enzymes that catalyze the metabolism of drugs and other substances. Endogenous substrates of CYPs include eicosanoids, estradiol, arachidonic acids, cholesterol, vitamin D and neurotransmitters. Exogenous substrates of CYPs include the polycyclic aromatic hydrocarbons and about 80% of currently used drugs. Some isoforms can activate procarcinogens to ultimate carcinogens. Genetic polymorphisms of CYPs may affect the enzyme catalytic activity and have been reported among different populations to be associated with various diseases and adverse drug reactions. With regard of drug metabolism, phenotypes for CYP polymorphism range from ultrarapid to poor metabolizers. In this review, we discuss some of the most clinically important CYPs isoforms (CYP2D6, CYP2A6, CYP2C19, CYP2C9, CYP1B1 and CYP1A2) with respect to gene polymorphisms and drug metabolism. Moreover, we review the role of CYPs in renal, lung, breast and prostate cancers and also discuss their significance for atherosclerosis and type 2 diabetes mellitus.
Topics: Atherosclerosis; Cytochrome P-450 Enzyme System; Diabetes Mellitus; Genetic Predisposition to Disease; Humans; Neoplasms; Pharmaceutical Preparations; Pharmacogenetics; Polymorphism, Genetic
PubMed: 30139042
DOI: 10.22034/APJCP.2018.19.8.2057 -
JAMA Jul 2022Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial... (Comparative Study)
Comparative Study Randomized Controlled Trial
Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial.
IMPORTANCE
Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment.
OBJECTIVE
To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes.
DESIGN, SETTING, AND PARTICIPANTS
A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications.
INTERVENTIONS
Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978).
MAIN OUTCOMES AND MEASURES
The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters.
RESULTS
Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = .02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = .45).
CONCLUSIONS AND RELEVANCE
Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03170362.
Topics: Antidepressive Agents; Clinical Decision-Making; Depressive Disorder, Major; Drug Interactions; Female; Humans; Inappropriate Prescribing; Male; Middle Aged; Pharmacogenetics; Pharmacogenomic Testing; Remission Induction; Treatment Outcome; United States; United States Department of Veterans Affairs
PubMed: 35819423
DOI: 10.1001/jama.2022.9805 -
Journal of Pharmaceutical Sciences Jun 2023N-Nitrosamine risk assessment and control have become an integral part of pharmaceutical drug product development and quality evaluation. Initial reports of nitrosamine...
N-Nitrosamine risk assessment and control have become an integral part of pharmaceutical drug product development and quality evaluation. Initial reports of nitrosamine contamination were linked with the drug substance and its manufacturing process. Subsequently, the drug product and aspects of the formulation process have shown to be relevant. Regarding specific formulation contributions to nitrosamine content in a product, one risk lies in possible interactions between nitrosating agents, derived from nitrite in excipients, and vulnerable amines, either present as moieties of the active molecule or as impurities / degradants. However, the limited validated information on nitrite levels in excipients available until now, has been an obstacle for scientists to assess the risk of nitrosamine formation in pharmaceutical products. This has driven the creation of a database to store and share such validated information. The database, maintained by Lhasa Limited, constitutes a central platform to hold the data donated by the pharmaceutical company members on the nitrite concentrations in common excipients measured with validated analytical procedures. The goal of this data sharing initiative is to provide a common framework to contextualize and estimate the risk posed by presence of nitrites to contribute to the formation of nitrosamines in drug products. The major findings from the database analyses are: (1) average nitrite content and batch to batch variance differ among excipients, (2) for solid dosage forms, the nitrite contribution is dominated by the highest formula % excipients, e.g., the fillers (diluents), which are typically used in larger proportion, and are characterized by low nitrite levels and low variability, leading to an average value of 1 µg/g nitrite in a typical formulation, (3) substantial differences in average nitrite content in batches from different excipient vendors potentially reflecting differences in source materials or processing methods for excipient manufacturing. That final point suggests that future selection of raw materials or processing by excipient manufacturers may help reduce nitrite levels in finished drug product formulations, and thus the overall risk of nitrosamine formation in cases where the product contains vulnerable amines.
Topics: Nitrites; Nitrosamines; Excipients; Chemistry, Pharmaceutical; Amines; Risk Assessment
PubMed: 35500671
DOI: 10.1016/j.xphs.2022.04.016 -
Medical Science Monitor : International... Jul 2002Pharmacogenomics, a revolutionary chapter in the history of pharmacology, has received new impetus from the development and accessibility of molecular biotechnologies,... (Review)
Review
Pharmacogenomics, a revolutionary chapter in the history of pharmacology, has received new impetus from the development and accessibility of molecular biotechnologies, notably DNA chips. The longstanding notion of responders/non-responders has given way to a more organic approach, where idiosyncrasy becomes an obsolete concept. This is a major step towards predictive, individualized medicine. In this review, several applications of pharmacogenomics are considered. Genetic polymorphisms of metabolization reactions, mainly with cytochrome P450, explain most of the cases described today. More fundamental and innovative studies have tried to link the structure of receptors or transporters and drug response. A leading topic in neuropsychopharmacology is the relation between the polymorphism of dopaminergic receptors and the efficacy of, or adverse reaction to, neuroleptics. In asthma, the structure of the beta2-adrenergic receptor has been associated with response to treatment. Intrinsic genetic predisposition also plays an important role in cardiovascular diseases, and the role of ion channel mutations will be discussed. Research in oncological molecular epidemiology has explored the connection between the predisposition to certain cancers and specific enzymatic equipment hindering the detoxification of potentially carcinogenic exogenous compounds, or, on the contrary, promoting metabolic activation implicated in the formation of reactive compounds. The search for determinants of addictive behavior is another vast field of pharmacogenomics. Finally, we consider the impact of pharmacogenomics on the methodology of drug development in preclinical and clinical trials. Progress in methods of phenotyping/genotyping should promote diagnosis, guide the choice of drug for an individual (benefit/risk ratio), and determine dosage and regimen.
Topics: Cardiovascular Physiological Phenomena; Central Nervous System; Clinical Trials as Topic; Cytochrome P-450 Enzyme System; Drug Design; Genotype; Humans; Methyltransferases; Neoplasms; Pharmacogenetics; Phenotype; Polymorphism, Genetic; Respiratory Physiological Phenomena; Substance-Related Disorders
PubMed: 12119546
DOI: No ID Found -
Biomolecules Jan 2021Propolis, a product of the honey bee, has been used in traditional medicine for many years. A hydrophobic bioactive polyphenolic ester, caffeic acid phenethyl ester... (Review)
Review
Propolis, a product of the honey bee, has been used in traditional medicine for many years. A hydrophobic bioactive polyphenolic ester, caffeic acid phenethyl ester (CAPE), is one of the most extensively investigated active components of propolis. Several studies have indicated that CAPE has a broad spectrum of pharmacological activities as anti-oxidant, anti-inflammatory, anti-viral, anti-fungal, anti-proliferative, and anti-neoplastic properties. This review largely describes CAPE neuroprotective effects in many different conditions and summarizes its molecular mechanisms of action. CAPE was found to have a neuroprotective effect on different neurodegenerative disorders. At the basis of these effects, CAPE has the ability to protect neurons from several underlying causes of various human neurologic diseases, such as oxidative stress, apoptosis dysregulation, and brain inflammation. CAPE can also protect the nervous system from some diseases which negatively affect it, such as diabetes, septic shock, and hepatic encephalopathy, while numerous studies have demonstrated the neuroprotective effects of CAPE against adverse reactions induced by different neurotoxic substances. The potential role of CAPE in protecting the central nervous system (CNS) from secondary injury following various CNS ischemic conditions and CAPE anti-cancer activity in CNS is also reviewed. The structure-activity relationship of CAPE synthetic derivatives is discussed as well.
Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents; Antifungal Agents; Antioxidants; Antiviral Agents; Apoptosis; Brain; Caffeic Acids; Humans; Inflammation; Ischemia; Neurodegenerative Diseases; Parkinson Disease; Phenylethyl Alcohol; Propolis; Psychotic Disorders; Seizures
PubMed: 33525407
DOI: 10.3390/biom11020176 -
Postepy Higieny I Medycyny... Feb 2017Nowadays, dynamic development in nanotechnological sciences is observed. Nanoparticles are frequently used in medicine and pharmacy as delivery systems for different... (Review)
Review
Nowadays, dynamic development in nanotechnological sciences is observed. Nanoparticles are frequently used in medicine and pharmacy as delivery systems for different kinds of active substances. One of the latest developed substances, with an unusually wide scope of utility, is graphene. The ways of its use in different fields of industry, not only pharmaceutical and medical, have been a subject of study for many research groups since the moment of its development in 2004. Graphene in pure form is highly hydrophobic. However, the presence of defects on its surface allows chemical modifications to be made, e.g. introduction of oxygen groups by covalent bonding. Also, non-covalent modifications are extensively used, including van der Waals forces, hydrogen bonding, coordination bonds, electrostatic and π-π stacking interactions. Due to the large surface area, graphene can be used in combination therapy, consisting in simultaneous administration of two or more pharmacologically active agents. Another interesting approach is gene therapy. Application of the PEI-graphene oxide system increased the efficacy of transfection. Possibilities of graphene and graphene oxide are not limited to their use as active substance delivery systems. These compounds by themselves were also found to be bacteriostatic and antibacterial agents.
Topics: Graphite; Humans; Hydrogen Bonding; Nanotechnology; Oxides
PubMed: 28258673
DOI: 10.5604/01.3001.0010.3797 -
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 -
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