Age-related differences in ophthalmic drug disposition II: Drug-protein interactions of pilocarpine and chloramphenicol

1982 ◽  
Vol 3 (2) ◽  
pp. 115-128 ◽  
Author(s):  
Susan C. Miller ◽  
Thomas F. Patton
Keyword(s):  
Protein Interactions ◽  
Drug Disposition ◽  
Age Related ◽  
Ophthalmic Drug

Age-related differences in ophthalmic drug disposition III. Corneal permeability of pilocarpine in rabbits

1983 ◽  
Vol 16 (2) ◽  
pp. 203-213 ◽  
Author(s):  
Michael Francoeur ◽  
Imran Ahmed ◽  
Steve Sitek ◽  
Thomas F. Patton
Keyword(s):  
Drug Disposition ◽  
Corneal Permeability ◽  
Age Related ◽  
Ophthalmic Drug

scholarly journals Polyphenol Supplementation Reverses Age-Related Changes in Microglial Signaling Cascades

2021 ◽  
Vol 22 (12) ◽  
pp. 6373
Author(s):  
Ahmad Jalloh ◽  
Antwoine Flowers ◽  
Charles Hudson ◽  
Dale Chaput ◽  
Jennifer Guergues ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Control Diet ◽  
Bioinformatic Analysis ◽  
Diet Group ◽  
Differentially Expressed ◽  
Signaling Cascades ◽  
Complex Nature ◽  
Differentially Expressed Proteins ◽  
Ms Analysis ◽  
Age Related

Microglial activity in the aging neuroimmune system is a central player in aging-related dysfunction. Aging alters microglial function via shifts in protein signaling cascades. These shifts can propagate neurodegenerative pathology. Therapeutics require a multifaceted approach to understand and address the stochastic nature of this process. Polyphenols offer one such means of rectifying age-related decline. Our group used mass spectrometry (MS) analysis to explicate the complex nature of these aging microglial pathways. In our first experiment, we compared primary microglia isolated from young and aged rats and identified 197 significantly differentially expressed proteins between these groups. Then, we performed bioinformatic analysis to explore differences in canonical signaling cascades related to microglial homeostasis and function with age. In a second experiment, we investigated changes to these pathways in aged animals after 30-day dietary supplementation with NT-020, which is a blend of polyphenols. We identified 144 differentially expressed proteins between the NT-020 group and the control diet group via MS analysis. Bioinformatic analysis predicted an NT-020 driven reversal in the upregulation of age-related canonical pathways that control inflammation, cellular metabolism, and proteostasis. Our results highlight salient aspects of microglial aging at the level of protein interactions and demonstrate a potential role of polyphenols as therapeutics for age-associated dysfunction.

scholarly journals O20 Dose-linearity of the pharmacokinetics of an intravenous [14C]midazolam microdose in children

2019 ◽  
Vol 104 (6) ◽  
pp. e9.1-e9
Author(s):  
BD van Groen ◽  
WHJ Vaes ◽  
BK Park ◽  
EHJ Krekels ◽  
E van Duijn ◽  
...  
Keyword(s):  
Drug Disposition ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Developmental Changes ◽  
Developmentally Regulated ◽  
Age Related ◽  
Dose Linearity ◽  
Significant Difference ◽  
Therapeutic Doses ◽  
Cyp3a Enzyme

BackgroundDrug disposition in children may vary from adults due to age-related variation in drug metabolism, but paediatric pharmacokinetic (PK) studies are challenging. Microdose studies present an innovation to study PK in paediatrics, and can only be used when the PK of a microdose are dose-linear to a therapeutic dose. We aimed to assess dose-linearity of [14C]midazolam (MDZ), a marker for the activity of the developmentally regulated CYP3A enzyme, by comparing the PK of an intravenous (IV) [14C]MDZ microtracer given simultaneously with therapeutic MDZ, with the PK of a single IV [14C]MDZ microdose.MethodsPreterm to 2-year-old infants admitted to the intensive care unit received [14C]MDZ IV either as a microtracer during therapeutic MDZ infusion or as an isolated microdose. Dense blood sampling was done up to 36 hours after dosing. Plasma concentrations of [14C]MDZ and [14C]1-OH-MDZ were determined by accelerator mass spectrometry. A population PK model was developed with NONMEM 7.4 to study whether there was a difference in the PK of the microtracer versus those of a microdose [14C]MDZ.ResultsOf fifteen children (median gestational age 39.4 [range 23.9–41.4] weeks, postnatal age 11.4 [0.6–49.1] weeks), nine received a microdose and six a microtracer [14C]MDZ (111 Bq/kg; 37.6 ng/kg). In a two-compartment PK model, bodyweight was the most significant covariate for volume of distribution. There was no statistically significant difference in any PK parameter between the [14C]MDZ microdose or microtracer, suggesting the PK of MDZ to be linear within the range of the therapeutic doses and microdoses.ConclusionOur data supports the dose-linearity of an IV [14C]MDZ microdose in children, thus a [14C]MDZ microdosing approach can be used to study developmental changes in hepatic CYP3A activity.Disclosure(s)This project was funded by the ZonMw ERA-NET PRIOMEDCHILD programme (projectnumber 113205022). * both authors contributed equally

scholarly journals Effects of pharmacologically induced Leydig cell testosterone production on intratesticular testosterone and spermatogenesis†

2019 ◽  
Vol 102 (2) ◽  
pp. 489-498 ◽  
Author(s):  
Jin-Yong Chung ◽  
Sean Brown ◽  
Haolin Chen ◽  
June Liu ◽  
Vassilios Papadopoulos ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Leydig Cell ◽  
Mitochondrial Membrane ◽  
Leydig Cells ◽  
Translocator Protein ◽  
Brown Norway ◽  
Inner Mitochondrial Membrane ◽  
Negative Effects ◽  
Rate Determining Step ◽  
Age Related

Abstract The Leydig cells of the mammalian testis produce testosterone (T) in response to luteinizing hormone (LH). In rats and men with reduced serum T levels, T replacement therapy (TRT) will raise T levels, but typically with suppressive effects on sperm formation. The rate-determining step in T formation is the translocation of cholesterol to the inner mitochondrial membrane, mediated by protein–protein interactions of cytosolic and outer mitochondrial membrane proteins. Among the involved proteins is cholesterol-binding translocator protein (TSPO) (18 kDa TSPO). We hypothesized that in contrast to TRT, the administration of the TSPO agonist N,N-dihexyl-2-(4-fluorophenyl)indole-3-acetamide (FGIN-1-27), by stimulating the ability of the Leydig cells to produce T, would result in the elevation of serum T levels while maintaining intratesticular T concentration and therefore without suppression of spermatogenesis. Age-related reductions in both serum and intratesticular T levels were seen in old Brown Norway rats. Both exogenous T and FGIN-1-27 increased serum T levels. With exogenous T, serum LH and Leydig cell T formation were suppressed, and intratesticular T was reduced to below the concentration required to maintain spermatogenesis quantitatively. In contrast, FGIN-1-27 stimulated Leydig cell T formation, resulting in increased serum T without reductions in intratesticular T concentrations or in testicular sperm numbers. FGIN-1-27 also significantly increased serum and intratesticular T levels in rats made LH-deficient by treatment with the gonadotropin-releasing hormone antagonist cetrorelix. These results point to a possible approach to increasing serum T without negative effects on spermatogenesis, based upon stimulating T production by the Leydig cells themselves rather than administering T exogenously.

scholarly journals Using the drug-protein interactome to identify anti-ageing compounds for humans

2018 ◽  
Author(s):  
Matías Fuentealba Valenzuela ◽  
Handan Melike Dönertaş ◽  
Rhianna Williams ◽  
Johnathan Labbadia ◽  
Janet Thornton ◽  
...  
Keyword(s):  
Risk Factor ◽  
Animal Models ◽  
Protein Interactions ◽  
Human Life ◽  
Drug Repurposing ◽  
Developed Countries ◽  
Animal Testing ◽  
Age Related ◽  
Human Ageing ◽  
Hsp 90

AbstractAdvancing age is the dominant risk factor for most of the major killer diseases in developed countries. Hence, ameliorating the effects of ageing may prevent multiple diseases simultaneously. Drugs licensed for human use against specific diseases have proved to be effective in extending lifespan and healthspan in animal models, suggesting that there is scope for drug repurposing in humans. New bioinformatic methods to identify and prioritise potential anti-ageing compounds for humans are therefore of interest. In this study, we first used drug-protein interaction information, to rank 1,147 drugs by their likelihood of targeting ageing-related gene products in humans. Among 19 statistically significant drugs, 6 have already been shown to have pro-longevity properties in animal models (p < 0.001). Using the targets of each drug, we established its association with ageing at multiple levels of biological actions including pathways, functions and protein interactions. Finally, combining all the data, we calculated a comprehensive ranked list of drugs that predicted tanespimycin, an inhibitor of HSP-90, as the top-ranked novel anti-ageing candidate. We experimentally validated the pro-longevity effect of tanespimycin through its HSP-90 target in Caenorhabditis elegans.Author SummaryHuman life expectancy is continuing to increase worldwide, as a result of successive improvements in living conditions and medical care. Although this trend is to be celebrated, advancing age is the major risk factor for multiple impairments and chronic diseases. As a result, the later years of life are often spent in poor health and lowered quality of life. However, these effects of ageing are not inevitable, because very long-lived people often suffer rather little ill-health at the end of their lives. Furthermore, laboratory experiments have shown that animals fed with specific drugs can live longer and with fewer age-related diseases than their untreated companions. We therefore need to identify drugs with anti-ageing properties for humans. We have therefore used computers to search for drugs that affect components and processes known to be important in human ageing. This approach worked, because it was able to re-discover several drugs known to increase lifespan in animal models, plus some new ones, including one that we tested experimentally and validated in this study. These drugs are now a high priority for animal testing and for exploring effects on human ageing.

scholarly journals Age-related Immune-Stromal Networks Inhibit Response to Regenerative Immunotherapies

2021 ◽  
Author(s):  
Jin Han ◽  
Christopher Cherry ◽  
Anna Ruta ◽  
David R. Maestas ◽  
Joscelyn C. Mejias ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Neutralizing Antibodies ◽  
Tissue Repair ◽  
Therapeutic Response ◽  
Tissue Injury ◽  
Inflammatory Diseases ◽  
Communication Analysis ◽  
Age Related ◽  
Immunological Changes ◽  
Immune Changes

Aging is associated with immunological changes that compromise response to infections and vaccines, exacerbate inflammatory diseases and could potentially mitigate tissue repair. Indeed, regenerative medicine strategies designed to promote tissue repair are now focusing on the immune system as a therapeutic target due to its role in response to tissue damage and regulation of tissue repair. However, age-related immune changes to the response to damage and the resulting impact on repair remains unknown. Here, we characterized age-related immunological changes that inhibit tissue repair and therapeutic response to a clinical regenerative biological scaffold derived from extracellular matrix (ECM). We found that aging reduced the response of interleukin (IL)4 producing eosinophils and CD4 T cells in a volumetric muscle injury treated with ECM leading to reduced repair and increased fibrosis. Single cell RNA sequencing and cell-cell communication analysis via transcription factor (TF) activation revealed diminished interactions between immune and stromal modules in aging animals. Validation of the age-specific TFs and predicated protein interactions in the tissue and draining lymph nodes found multiple genes activated in old animals only after injury that were primarily related to IL17 signaling. Local inhibition of age-related type 3 immune activation using IL17-neutralizing antibodies restored therapeutic response to ECM and promoted muscle repair in older animals through increased recruitment of IL4 producing immune cells and regenerating muscle fibers. Altogether, innate and adaptive immune changes that occur with aging, in combination with dysregulated stromal communication, contribute to an impaired response to tissue injury which can be overcome with combination immunotherapy.

scholarly journals Classical complement cascade initiating C1q protein within neurons in the aged rhesus macaque dorsolateral prefrontal cortex

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Dibyadeep Datta ◽  
Shannon N. Leslie ◽  
Yury M. Morozov ◽  
Alvaro Duque ◽  
Pasko Rakic ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Rhesus Macaque ◽  
Protein Interactions ◽  
Dorsolateral Prefrontal Cortex ◽  
Rhesus Macaques ◽  
Inhibitory Synapses ◽  
Complement Cascade ◽  
Age Related ◽  
Dorsolateral Prefrontal ◽  
Age Related Changes

Abstract Background Cognitive impairment in schizophrenia, aging, and Alzheimer’s disease is associated with spine and synapse loss from the dorsolateral prefrontal cortex (dlPFC) layer III. Complement cascade signaling is critical in driving spine loss and disease pathogenesis. Complement signaling is initiated by C1q, which tags synapses for elimination. C1q is thought to be expressed predominately by microglia, but its expression in primate dlPFC has never been examined. The current study assayed C1q levels in aging primate dlPFC and rat medial PFC (mPFC) and used immunoelectron microscopy (immunoEM), immunoblotting, and co-immunoprecipitation (co-IP) to reveal the precise anatomical distribution and interactions of C1q. Methods Age-related changes in C1q levels in rhesus macaque dlPFC and rat mPFC were examined using immunoblotting. High-spatial resolution immunoEM was used to interrogate the subcellular localization of C1q in aged macaque layer III dlPFC and aged rat layer III mPFC. co-IP techniques quantified protein-protein interactions for C1q and proteins associated with excitatory and inhibitory synapses in macaque dlPFC. Results C1q levels were markedly increased in the aged macaque dlPFC. Ultrastructural localization found the expected C1q localization in glia, including those ensheathing synapses, but also revealed extensive localization within neurons. C1q was found near synapses, within terminals and in spines, but was also observed in dendrites, often near abnormal mitochondria. Similar analyses in aging rat mPFC corroborated the findings in rhesus macaques. C1q protein increasingly associated with PSD95 with age in macaque, consistent with its synaptic localization as evidenced by EM. Conclusions These findings reveal novel, intra-neuronal distribution patterns for C1q in the aging primate cortex, including evidence of C1q in dendrites. They suggest that age-related changes in the dlPFC may increase C1q expression and synaptic tagging for glial phagocytosis, a possible mechanism for age-related degeneration.

scholarly journals Physiologically based pharmacokinetic/pharmacodynamic model for the prediction of morphine brain disposition and analgesia in adults and children

2021 ◽  
Vol 17 (3) ◽  
pp. e1008786
Author(s):  
Laurens F. M. Verscheijden ◽  
Carlijn H. C. Litjens ◽  
Jan B. Koenderink ◽  
Ron H. J. Mathijssen ◽  
Marcel M. Verbeek ◽  
...  
Keyword(s):  
Analgesic Effect ◽  
Drug Disposition ◽  
Opioid Analgesic ◽  
Extracellular Fluid ◽  
Older Children ◽  
Time Profiles ◽  
Physiologically Based Pharmacokinetic ◽  
Age Related ◽  
Drug Concentrations ◽  
Physiologically Based

Morphine is a widely used opioid analgesic, which shows large differences in clinical response in children, even when aiming for equivalent plasma drug concentrations. Age-dependent brain disposition of morphine could contribute to this variability, as developmental increase in blood-brain barrier (BBB) P-glycoprotein (Pgp) expression has been reported. In addition, age-related pharmacodynamics might also explain the variability in effect. To assess the influence of these processes on morphine effectiveness, a multi-compartment brain physiologically based pharmacokinetic/pharmacodynamic (PB-PK/PD) model was developed in R (Version 3.6.2). Active Pgp-mediated morphine transport was measured in MDCKII-Pgp cells grown on transwell filters and translated by an in vitro-in vivo extrapolation approach, which included developmental Pgp expression. Passive BBB permeability of morphine and its active metabolite morphine-6-glucuronide (M6G) and their pharmacodynamic parameters were derived from experiments reported in literature. Model simulations after single dose morphine were compared with measured and published concentrations of morphine and M6G in plasma, brain extracellular fluid (ECF) and cerebrospinal fluid (CSF), as well as published drug responses in children (1 day– 16 years) and adults. Visual predictive checks indicated acceptable overlays between simulated and measured morphine and M6G concentration-time profiles and prediction errors were between 1 and -1. Incorporation of active Pgp-mediated BBB transport into the PB-PK/PD model resulted in a 1.3-fold reduced brain exposure in adults, indicating only a modest contribution on brain disposition. Analgesic effect-time profiles could be described reasonably well for older children and adults, but were largely underpredicted for neonates. In summary, an age-appropriate morphine PB-PK/PD model was developed for the prediction of brain pharmacokinetics and analgesic effects. In the neonatal population, pharmacodynamic characteristics, but not brain drug disposition, appear to be altered compared to adults and older children, which may explain the reported differences in analgesic effect.

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