This tutorial explains the basic principles of mechanistic ligand-receptor interaction model, which is an operational model of agonism. A growing number of agonist drugs, especially immune oncology drugs, is currently being developed. In this tutorial, time-dependent ordinary differential equation for simple E(max) operational model of agonism was derived step by step. The differential equation could be applied in a pharmacodynamic modeling software, such as NONMEM, for use in non-steady state experiments, in which experimental data are generated while the interaction between ligand and receptor changes over time. Making the most of the non-steady state experimental data would simplify the experimental processes, and furthermore allow us to identify more detailed kinetics of a potential drug. The operational model of agonism could be useful to predict the optimal dose for agonistic drugs from in vitro and in vivo animal pharmacology experiments at the very early phase of drug development.
Animals ; Felodipine ; In Vitro Techniques ; Kinetics ; Pharmacology

The diagnosis of cause of death (COD) or estimation of postmortem interval (PMI) is hard to perform using postmortem blood or other bodily fluids due to various biochemical changes that occur during the agonal phase or after death. To solve these problems, new paradigms and new analytical methods are needed. In this study, postmortem blood was fractionated with specific gravity 1.021, 1.029, 1.038, and 1.045, and the absorbance patterns of each sample of the 131 total cases (12 kinds of COD) were analyzed using a spectrometer. The absorbance was grouped into 9 patterns (ABS pattern 1 to 9) according to the wave length and the signal intensity. These patterns of postmortem blood were found to be distinctly different from the absorbance pattern of fresh blood. The analysis of ABS patterns is useful for the diagnosis of deaths due to acute or rapid bleeding, fire death, drowning and, in some cases, poisoning, but is not useful for the estimation of PMI.
Cause of Death ; Diagnosis ; Drowning ; Felodipine ; Fires ; Hemorrhage ; Poisoning ; Specific Gravity ; Spectrum Analysis

A 21-year-old male was admitted with severe right arm and hand tremors after a thalamic hemorrhage caused by a traffic accident. He was also suffering from agonizing pain in his right shoulder that manifested after the tremor. Neurologic examination revealed a disabling, severe, and irregular kinetic and postural tremor in the right arm during target-directed movements. There was also an irregular ipsilateral rest tremor and dystonic movements in the distal part of the right arm. The amplitude was moderate at rest and extremely high during kinetic and intentional movements. The patient underwent left globus pallidum internus and ventral intermediate thalamic nucleus deep brain stimulation. The patient improved by more than 80% as rated by the Fahn-Tolosa-Marin Tremor Rating Scale and Visual Analog Scale six months after surgery.
Accidents, Traffic ; Arm ; Deep Brain Stimulation* ; Felodipine ; Globus Pallidus* ; Hand ; Hemorrhage ; Humans ; Male ; Neurologic Examination ; Shoulder Pain* ; Shoulder* ; Tremor* ; Visual Analog Scale ; Young Adult

G protein-coupled receptors (GPCRs) are a family of cell-surface proteins that play critical roles in regulating a variety of pathophysiological processes and thus are targeted by almost a third of currently available therapeutics. It was originally thought that GPCRs convert extracellular stimuli into intracellular signals through activating G proteins, whereas β-arrestins have important roles in internalization and desensitization of the receptor. Over the past decade, several novel functional aspects of β-arrestins in regulating GPCR signaling have been discovered. These previously unanticipated roles of β-arrestins to act as signal transducers and mediators of G protein-independent signaling have led to the concept of biased agonism. Biased GPCR ligands are able to engage with their target receptors in a manner that preferentially activates only G protein- or β-arrestin-mediated downstream signaling. This offers the potential for next generation drugs with high selectivity to therapeutically relevant GPCR signaling pathways. In this review, we provide a summary of the recent studies highlighting G protein- or β-arrestin-biased GPCR signaling and the effects of biased ligands on disease pathogenesis and regulation.
Bias (Epidemiology)* ; Felodipine ; GTP-Binding Proteins ; Humans ; Ligands ; Pathology* ; Physiology* ; Transducers

Bile acid has been well known to serve as a hormone in regulating transcriptional activity of Farnesoid X receptor (FXR), an endogenous bile acid nuclear receptor. Moreover, bile acid regulates diverse biological processes, including cholesterol/bile acid metabolism, glucose/lipid metabolism and energy expenditure. Alteration of bile acid metabolism has been revealed in type II diabetic (T2D) patients. FXR-mediated bile acid signaling has been reported to play key roles in improving metabolic parameters in vertical sleeve gastrectomy surgery, implying that FXR is an essential modulator in the metabolic homeostasis. Using a genetic mouse model, intestinal specific FXR-null mice have been reported to be resistant to diet-induced obesity and insulin resistance. Moreover, intestinal specific FXR agonism using gut-specific FXR synthetic agonist has been shown to enhance thermogenesis in brown adipose tissue and browning in white adipose tissue to increase energy expenditure, leading to reduced body weight gain and improved insulin resistance. Altogether, FXR is a potent therapeutic target for the treatment of metabolic diseases.
Adipose Tissue, Brown ; Adipose Tissue, White ; Animals ; Bile Acids and Salts ; Bile* ; Biological Processes ; Body Weight ; Energy Metabolism ; Felodipine ; Gastrectomy ; Homeostasis ; Humans ; Insulin Resistance ; Metabolic Diseases* ; Metabolism ; Mice ; Obesity ; Thermogenesis

Serotonin syndrome, an adverse drug reaction, is a consequence of excess serotonergic agonism of central nervous system receptors and peripheral serotonergic receptors. Serotonin syndrome has been associated with large numbers of drugs and drug combinations, and serotonin-norepinephrine reuptake inhibitor-induced serotonin syndrome is rare. It is often described as a sign of excess serotonin ranging from tremor in mild cases to delirium, neuromuscular rigidity, and hyperthermia in life-threatening cases. Diagnosis is based on the symptoms and patient's history, and several diagnostic criteria have been developed. We experienced a rare case of fibromyalgia accompanied by tremor, hyperreflexia, spontaneous clonus, muscle rigidity, and diaphoresis after 10 days of single use of duloxetine 30 mg. Only one case of serotonin syndrome resulting from administration of duloxetine has been reported in Korea, however that case resulted from co-administration of fluoxetine. We report here on this case along with a review of the relevant literature.
Central Nervous System ; Delirium ; Diagnosis ; Drug Combinations ; Drug-Related Side Effects and Adverse Reactions ; Duloxetine Hydrochloride* ; Felodipine ; Fever ; Fibromyalgia* ; Fluoxetine ; Humans ; Korea ; Muscle Rigidity ; Reflex, Abnormal ; Serotonin Syndrome* ; Serotonin* ; Tremor

Depression is a relatively common agonizing psychiatric disorder that affects the way we feel and think about ourselves and the world around us. Cognitive theories of depression have long posited that various cognitive biases are involved in the development and recurrence of depression. However, the current cognitive theory of depression has been reformulated and expanded from the previous cognitive model of depression based on the results from pharmacological, neuroimaging and neurocognitive studies. This review summarizes the evidence for cognitive dysfunctions in depression and the related pharmacological, neuroanatomical and genetic aspects which aim to integrate our knowledge about the cognitive aspects of depression and its treatment. The newly formulated cognitive theory of depression provides directions for future investigation to identify people at risk, to minimize recurrence, and to maximize long-term beneficial outcomes for those suffering from depression.
Bias (Epidemiology) ; Cognition* ; Depression* ; Felodipine ; Neuroimaging ; Recurrence

Postmortem bacterial culture can be valuable for investigating deaths and determining the cause of death. However, there are many concerns regarding postmortem bacterial culture such as postmortem transmigration and agonal spread of bacteria. The two main methods for identification of the bacteria are biochemical and genetic methods. In Korea, the genetic method has been used for postmortem bacterial culture and identification in forensic medicine. However, there is a lack of consensus on the method to be used for postmortem bacterial culture and identification. Herein, we compared the genetic and biochemical methods of postmortem bacterial culture in autopsy practice. Both analyses were performed on the same samples. Bacteria were identified in 28 of the 34 cases (82.4%). Of the 74 comparable samples, only 28 (37.8%) showed consistent results by both methods. In addition, the biochemical method had a shorter reporting time and was more sensitive. In conclusion, we analyzed the causes of the inconsistency between the two methods and provided appropriate conditions and protocols for postmortem bacterial culture and identification.
Autopsy ; Bacteria ; Biochemical Processes ; Cause of Death ; Consensus ; Felodipine ; Forensic Medicine ; Genetic Processes ; Korea ; Methods*

The selective melatonin receptor agonism effect of ramelteon is useful for insomnia. Here we wanted to present a refractory chronic migraine case, who had significant improvements in migraine after using ramelteon. The possible mechanism for the ramelteon in the migraine relief might be related to melatonin effects.
Felodipine ; Melatonin ; Migraine Disorders* ; Receptors, Melatonin ; Sleep Initiation and Maintenance Disorders ; Sleep Wake Disorders

The Ministry of Health and Welfare in Korea has enforced the oral health promotion program for elderly in Korea. There are the denture delivery program and the fluoride application-scaling program for elderly. Donggu Public Health Center in Daejeon has delivered the fluoride application- scaling program for elderly since the demonstration project in 2009. The official dental hygienists had a prior consultation with Dong-gu branch of Korean Senior Citizens Association in Daejeon. We expanded the program through government office, welfare centers, and nursing homes. The participants were satisfied with the public relations (95.2%), scaling (99.7%), fluoride application (91.5%), toothbrushing education (98.6%), and denture cleaning education (96.6%). After a medial accident with persistent bleeding, the pre-inspection survey about systemic disease and medication was reinforced. The official dental hygienists have agonized over the low participation of the low-income group and the overlap benefit with health insurance benefit of scaling. We suggested it be needed the assessment of the public oral health program to overlap with health insurance benefit.
Aged* ; Dental Hygienists ; Dentures ; Education ; Felodipine ; Fluorides ; Hemorrhage ; Humans ; Insurance, Health ; Korea ; Nursing Homes ; Oral Health* ; Public Health ; Public Relations ; Toothbrushing