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Pediatric Research Jun 2018Pharmacodynamic (PD) endpoints are essential for establishing the benefit-to-risk ratio for therapeutic interventions in children and neonates. This article discusses... (Review)
Review
Pharmacodynamic (PD) endpoints are essential for establishing the benefit-to-risk ratio for therapeutic interventions in children and neonates. This article discusses the selection of an appropriate measure of response, the PD endpoint, which is a critical methodological step in designing pediatric efficacy and safety studies. We provide an overview of existing guidance on the choice of PD endpoints in pediatric clinical research. We identified several considerations relevant to the selection and measurement of PD endpoints in pediatric clinical trials, including the use of biomarkers, modeling, compliance, scoring systems, and validated measurement tools. To be useful, PD endpoints in children need to be clinically relevant, responsive to both treatment and/or disease progression, reproducible, and reliable. In most pediatric disease areas, this requires significant validation efforts. We propose a minimal set of criteria for useful PD endpoint selection and measurement. We conclude that, given the current heterogeneity of pediatric PD endpoint definitions and measurements, both across and within defined disease areas, there is an acute need for internationally agreed, validated, and condition-specific pediatric PD endpoints that consider the needs of all stakeholders, including healthcare providers, policy makers, patients, and families.
Topics: Biomarkers; Child; Child, Preschool; Clinical Trials as Topic; Disease Progression; Dose-Response Relationship, Drug; Drug Evaluation; Drug Therapy; Endpoint Determination; Health Policy; Humans; Infant; Infant, Newborn; Patient Compliance; Pharmaceutical Preparations; Pharmacokinetics; Pharmacology; Practice Guidelines as Topic; Reproducibility of Results; Research Design; Risk; United States; United States Food and Drug Administration
PubMed: 29667952
DOI: 10.1038/pr.2018.38 -
British Journal of Clinical Pharmacology Oct 2022
Topics: Analgesia, Epidural; Child; Humans; Pharmacology; Uterine Contraction
PubMed: 35949148
DOI: 10.1111/bcp.15474 -
Chrono-Pharmaceutical Approaches to Optimize Dosing Regimens Based on the Circadian Clock Machinery.Biological & Pharmaceutical Bulletin 2021Daily rhythmic variations in biological functions affect the efficacy and/or toxicity of drugs: a large number of drugs cannot be expected to exhibit the same potency at... (Review)
Review
Daily rhythmic variations in biological functions affect the efficacy and/or toxicity of drugs: a large number of drugs cannot be expected to exhibit the same potency at different administration times. The "circadian clock" is an endogenous timing system that broadly regulates metabolism, physiology and behavior. In mammals, this clock governs the oscillatory expression of the majority of genes with a period length of approximately 24 h. Genetic studies have revealed that molecular components of the circadian clock regulate the expression of genes responsible for the sensitivity to drugs and their disposition. The circadian control of pharmacodynamics and pharmacokinetics enables 'chrono-pharmaceutical' applications, namely drug administration at appropriate times of day to optimize the therapeutic index (efficacy vs. toxicity). On the other hand, a variety of pathological conditions also exhibit marked day-night changes in symptom intensity. Currently, novel therapeutic approaches are facilitated by the development of chemical compound targeted to key proteins that cause circadian exacerbation of disease events. This review presents an overview of the current understanding of the role of the circadian biological clock in regulating drug efficacy and disease conditions, and also describes the importance of identifying the difference in the circadian machinery between diurnal and nocturnal animals to select the most appropriate times of day to administer drugs in humans.
Topics: Animals; Circadian Clocks; Circadian Rhythm; Humans; Pharmaceutical Preparations; Pharmacokinetics; Pharmacology
PubMed: 34719634
DOI: 10.1248/bpb.b21-00476 -
Clinical Pharmacology and Therapeutics Sep 2021Pharmacogenetics (PGx) seeks to enable selection of the right dose of the right drug for each patient to optimize therapeutic outcomes. Most PGx focuses on... (Review)
Review
Pharmacogenetics (PGx) seeks to enable selection of the right dose of the right drug for each patient to optimize therapeutic outcomes. Most PGx focuses on pharmacokinetics (PKs), due to our relatively advanced understanding of the genes involved in PKs and the causative effects of variants in those genes. Genetic variants can also affect pharmacodynamics (PDs), but relatively few PGx-PD associations have been identified. This is partially due to a more limited understanding of the relevant genes and the consequences of genetic variation, but is also due in part to the potential confounding of PK variability in assessments of clinical outcomes that have a contribution from both PKs and PDs. For example, it is challenging to confirm the effect of mu opioid receptor (OPRM1) genetic variation on opioid response due to the contribution of CYP2D6 genotype to bioactivation of some opioid drugs (i.e., codeine and tramadol). The objectives of this mini-review are to describe several recent efforts to discover and validate PGx-PD that disentangle the influence of PK variability and propose potential approaches that could be used in future PGx-PD analyses. We use the effect of OPRM1 genetics on opioid response to illustrate how these analyses could be conducted and conclude by discussing how PGx-PD could be translated into clinical practice to improve therapeutic outcomes.
Topics: Analgesics, Opioid; Genetic Variation; Genotype; Humans; Pharmacogenetics; Pharmacogenomic Testing; Receptors, Opioid, mu
PubMed: 34043820
DOI: 10.1002/cpt.2312 -
Indian Journal of Pharmacology 2021Hypertension is a leading age-related disease in our society and if left untreated, leads to fatal cardiovascular complications. The prevalence of hypertension has... (Review)
Review
Hypertension is a leading age-related disease in our society and if left untreated, leads to fatal cardiovascular complications. The prevalence of hypertension has increased and becomes a significant global health economic burden, particularly in lower-income societies. Many loci associated with blood pressure and hypertension have been reported by genome-wide association studies that provided potential targets for pharmacotherapy. Pharmacogenetic research had shown interindividual variations in drug efficacy, safety, and tolerability. This could be due to genetic polymorphisms in the pharmacokinetics (genes involved in a transporter, plasma protein binding, and metabolism) or pharmacodynamic pathway (receptors, ion channels, enzymes). Pharmacogenetics promises great hope toward targeted therapy, but challenges remain in implementing pharmacogenetic aided antihypertensive therapy in clinical practice. Using various databases, we analyzed the underlying mechanisms between the candidate gene polymorphisms and antihypertensive drug interactions and the challenges of implementing precision medicine. We review the emergence of pharmacogenetics and its relevance to clinical pharmacological practice.
Topics: Antihypertensive Agents; Essential Hypertension; Genome-Wide Association Study; Humans; Pharmacogenetics; Polymorphism, Genetic
PubMed: 34414909
DOI: 10.4103/ijp.IJP_593_19 -
Neurogastroenterology and Motility Sep 2018Cannabinoid agents and cannabis are frequently used for relief of diverse gastrointestinal symptoms. (Review)
Review
BACKGROUND
Cannabinoid agents and cannabis are frequently used for relief of diverse gastrointestinal symptoms.
PURPOSE
The objective of this article is to increase the awareness of gastroenterologists to the effects of cannabinoids on gastrointestinal motility, as gastroenterologists are likely to encounter patients who are taking cannabinoids, or those with dysmotility that may be associated with cannabinoid mechanisms. The non-selective cannabinoid agonist, dronabinol, retards gastric emptying and inhibits colonic tone and phasic pressure activity. In addition to the well-recognized manifestations of cannabinoid hyperemesis, cannabinoid mechanisms result in human and animal models of gastrointestinal and colonic dysmotility. Decreased enteric FAAH activity is associated with colonic inertia in slow transit constipation and, conversely, the orphan G protein-coupled receptor, GPR55, is overexpressed in streptozotocin-induced gastroparesis, suggesting it is involved in inhibition of antral motility. Experimental therapies in gastrointestinal motility and functional disorders are focused predominantly on pain relief mediated through cannabinoid 2 receptors or inhibition of DAGLα to normalize colonic transit. In summary, cannabinoid mechanisms and pharmacology are relevant to the current and future practice of clinical gastroenterology.
Topics: Animals; Cannabinoids; Gastrointestinal Motility; Humans; Pharmacology, Clinical
PubMed: 29745439
DOI: 10.1111/nmo.13370 -
Molecules (Basel, Switzerland) Apr 2021The review is devoted to modern trends in the chemistry of 2-amino and 2-mercapto substituted benzothiazoles covering the literature since 2015. The reviewed... (Review)
Review
The review is devoted to modern trends in the chemistry of 2-amino and 2-mercapto substituted benzothiazoles covering the literature since 2015. The reviewed heterocycles belong to biologically active and industrially demanded compounds. Newly developed synthesis methods can be divided into conventional multistep processes and one-pot, atom economy procedures, realized using green chemistry principles and simple reagents. The easy functionalization of the 2-NH and 2-SH groups and the benzene ring of the benzothiazole moiety allows considering them as highly reactive building blocks for organic and organoelement synthesis, including the synthesis of pharmacologically active heterocycles. The review provides a summary of findings, which may be useful for developing new drugs and materials and new synthetic approaches and patterns of reactivity.
Topics: Benzothiazoles; Green Chemistry Technology; Humans; Pharmacology
PubMed: 33920281
DOI: 10.3390/molecules26082190 -
The AAPS Journal May 2016Biotherapeutics (BTs), one of the fastest growing classes of drug molecules, offer several advantages over the traditional small molecule pharmaceuticals because of... (Review)
Review
Biotherapeutics (BTs), one of the fastest growing classes of drug molecules, offer several advantages over the traditional small molecule pharmaceuticals because of their relatively high specificity, low off-target effects, and biocompatible metabolism, in addition to legal and logistic advantages. However, their clinical utility is limited, among other things, by their high immunogenic potential and/or variable therapeutic efficacy in different patient populations. Both of these issues, also commonly experienced with small molecule drugs, have been addressed effectively in a number of cases by the successful application of pharmacogenomic tools and approaches. In this introductory article of the special issue, we review the current state of application of pharmacogenomics to BTs and offer suggestions for further expansion of the field.
Topics: Animals; Biological Products; Biological Therapy; Biopharmaceutics; Humans; Pharmacogenetics; Recombinant Proteins
PubMed: 27007601
DOI: 10.1208/s12248-016-9903-4 -
CPT: Pharmacometrics & Systems... Mar 2023Good eyesight belongs to the most-valued attributes of health, and diseases of the eye are a significant healthcare burden. Case numbers are expected to further increase... (Review)
Review
Good eyesight belongs to the most-valued attributes of health, and diseases of the eye are a significant healthcare burden. Case numbers are expected to further increase in the next decades due to an aging society. The development of drugs in ophthalmology, however, is difficult due to limited accessibility of the eye, in terms of drug administration and in terms of sampling of tissues for drug pharmacokinetics (PKs) and pharmacodynamics (PDs). Ocular quantitative systems pharmacology models provide the opportunity to describe the distribution of drugs in the eye as well as the resulting drug-response in specific segments of the eye. In particular, ocular physiologically-based PK (PBPK) models are necessary to describe drug concentration levels in different regions of the eye. Further, ocular effect models using molecular data from specific cellular systems are needed to develop dose-response correlations. We here describe the current status of PK/PBPK as well as PD models for the eyes and discuss cellular systems, data repositories, as well as animal models in ophthalmology. The application of the various concepts is highlighted for the development of new treatments for postoperative fibrosis after glaucoma surgery.
Topics: Animals; Network Pharmacology; Models, Biological; Pharmaceutical Preparations; Pharmacology
PubMed: 36708082
DOI: 10.1002/psp4.12918 -
Biochemical Pharmacology May 2021Geoffrey Burnstock, the founder of the field of purinergic signaling research passed away in Melbourne, Australia on June 3rd, 2020, at the age of 91. With his death,...
Geoffrey Burnstock, the founder of the field of purinergic signaling research passed away in Melbourne, Australia on June 3rd, 2020, at the age of 91. With his death, the world of biomedical research lost one of its most passionate, creative and unconventional thought leaders. He was an inspiration to the many researchers he interacted with for more than 50 years and a frequent irritation to those in the administrative establishment. Geoff never considered himself a pharmacologist having being trained as a zoologist and becoming an autonomic neurophysiologist based on his evolving interests in systems and disease-related research. By the end of his life he had: published some 1550 papers; been cited more than 125,000 times; had an h-index of 156 and had supervised over 100 Ph.D. students. His indelible legacy, based on a holistic, data-based, multidisciplinary, unconventional "outside the box" approach to research was reflected in two of the seminal findings in late 20th century biomedical research: the purinergic neurotransmitter hypothesis and the concept of co-neurotransmission, both of which were initially received by his peers with considerable skepticism that at times verged on disdain. Nonetheless, while raising hackles and threatening the status quo, Geoff persevered and prevailed, becoming a mentor for several generations of biomedical researchers. In this review we provide a joint perspective on Geoff Burnstock's legacy in research.
Topics: Biomedical Research; History, 20th Century; History, 21st Century; Humans; Laboratory Personnel; Male; Pharmacology; Receptors, Purinergic
PubMed: 33203518
DOI: 10.1016/j.bcp.2020.114300