Cancer chemotherapy often triggers peripheral neuropathy in patients, leading to neuropathic pain in the extremities. While previous research has explored various nerve stimulation to alleviate chemotherapy-induced peripheral neuropathy (CIPN), evidence on the effectiveness of noninvasive auricular vagus nerve stimulation (aVNS) remains uncertain. This study aimed to investigate the efficacy of non-invasive aVNS in relieving CIPN pain. To induce CIPN in experimental animals, oxaliplatin was intraperitoneally administered to rats (6 mg/kg). Mechanical and cold allodynia, the representative symptoms of neuropathic pain, were evaluated using the von Frey test and acetone test, respectively. The CIPN animals were randomly assigned to groups and treated with aVNS (5 V, square wave) at different frequencies (2, 20, or 100 Hz) for 20 minutes. Results revealed that 20 Hz aVNS exhibited the most pronounced analgesic effect, while 2 or 100 Hz aVNS exhibited weak effects. Immunohistochemistry analysis demonstrated increased c-Fos expression in the locus coeruleus (LC) in the brain of CIPN rats treated with aVNS compared to sham treatment. To elucidate the analgesic mechanisms involving the adrenergic descending pathway, α 1 -, α 2 -, or β-adrenergic receptor antagonists were administered to the spinal cord before 20 Hz aVNS. Only the β-adrenergic receptor antagonist, propranolol, blocked the analgesic effect of aVNS.These findings suggest that 20 Hz aVNS may effectively alleviate CIPN pain through β-adrenergic receptor activation.

An extended-release (ER) fixed-dose combination (FDC) of tramadol 37.5 mg/acetaminophen 325 mg was developed due to the demand for varying dosages. This study aimed to evaluate the pharmacokinetics (PKs) for two tablets of the new developed tramadol 37.5 mg/acetaminophen 325 mg ER FDC (DW-0920, Wontran Semi ER®) as test formulation compared to one tablet of the tramadol 75 mg/acetaminophen 650 mg ER FDC (DW-0919, Wontran ER®) as reference formulation. A randomized, open-label, 2-way crossover study was conducted in 30 healthy subjects. Subjects were orally administered one of 2 formulations followed by an alternate formulation with a 7-day washout period. Blood samples were collected up to 36 hours post-dose. Plasma concentrations of tramadol and acetaminophen were determined using a validated high-performance liquid chromatography with tandem mass spectrometric method. The geometric mean ratios (GMRs) and their 90% confidence intervals (90% CIs) of test formulation to reference formulation were calculated for the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from zero to the last measurable time point (AUClast). The PK profiles of 2 formulations were comparable. The GMRs (90% CI) of Cmax and AUClast for tramadol were 1.086 (1.047–1.127) and 1.008 (0.975–1.042), respectively. The corresponding values for acetaminophen were 0.956 (0.897–1.019) and 0.986 (0.961–1.011), respectively. All the values were within the bioequivalence range of 0.80–1.25. Two tablets of DW-0920 were comparable to one tablet of DW-0919. The DW-0920 may be used for optimal pharmacotherapy for pain control with a lower dose.

Although wearable electrocardiograms (ECGs) are being increasingly applied in clinical settings, validation methods have not been standardized. As an exploratory evaluation, we performed a multicenter clinical trial implementing an approved wearable patch ECG. Healthy male adults were enrolled in 2 study centers. The approved ECGs were deployed for 6 hours, and pulse rates were measured independently with conventional pulse oximetry at selected time points for correlation analyses. The transmission status of the data was evaluated by heart rates and classified into valid, invalid, and missing. A total of 55 subjects (40 in center 1 and 15 in center 2) completed the study. Overall, 77.40% of heart rates were within the valid range. Invalid and missing data accounted for 1.42% and 21.23%, respectively. There were significant differences in valid and missing data between centers. The proportion of missing data in center 1 (24.77%) was more than twice center 2 (11.77%). Heart rates measured by the wearable ECG and conventional pulse oximetry showed a poor correlation (intraclass correlation coefficient = 0.0454). In conclusion, we evaluated the multicenter feasibility of implementing wearable ECGs. The results suggest that systems to mitigate multicenter discrepancies and remove artifacts should be implemented prior to performing a clinical trial.

Genetic polymorphisms of enzymes and transporters associated with the absorption, distribution, metabolism, and elimination (ADME) of drugs are one of the major factors that contribute to interindividual variations in drug response. In the present study, we aimed to elucidate the pharmacogenetic profiles of the Korean population using the Affymetrix Drug Metabolizing Enzyme and Transporters (DMET™) platform. A total of 1,012 whole blood samples collected from Korean subjects were genotyped using the DMET™ plus microarray. In total, 1,785 single nucleotide polymorphism (SNP) markers for 231 ADME genes were identified. The genotype and phenotype of 13 clinically important ADME genes implemented in the Clinical Pharmacogenetics Implementation Consortium guidelines were compared among different ethnic groups. Overall, the genotype frequencies of the Korean population were similar to those of the East Asian population. Several genes, notably CYP2C19 and VKORC1, showed marked differences in Koreans compared to Europeans (EURs) or Africans (AFRs). The percentage of CYP2C19 poor metabolizers was 15% in Koreans and less than 3% in EURs or AFRs. The frequencies of causative SNPs of the VKORC1 gene for the low warfarin dose phenotype were 90%, 60%, and 10% in Koreans, EURs and AFRs, respectively. Our findings can be utilized for optimal pharmacotherapy in Korean patients.

There are several hurdles to overcome before implementing pharmacogenomics (PGx) in precision medicine. One of the hurdles is unawareness of PGx by clinicians due to insufficient pharmacogenomic information on drug labels. Therefore, it might be important to implement PGx that reflects pharmacogenomic information on drug labels, standard of prescription for clinicians. This study aimed to evaluate the level at which PGx was being used in clinical practice by comparing the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group guidelines and drug labels of the US Food and Drug Administration (FDA) and the Korea Ministry of Food and Drug Safety (MFDS). Two PGx guidelines and drugs labels were scrutinized, and the concordance of the pharmacogenomic information between guidelines and drug labels was confirmed. The concordance of the label between FDA and MFDS was analyzed. In FDA labels, the number of concordant drug with guidelines was 24, while 13 drugs were concordant with MFDS labels. The number of drugs categorized as contraindication, change dose, and biomarker testing required was 7, 12 and 12 for the FDA and 8, 5 and 4 for the MFDS, respectively. The pharmacogenomic information of 9 drugs approved by both FDA and MFDS was identical. In conclusion, pharmacogenomic information on clinical implementation guidelines was limited on both FDA and MFDS labels because of various reasons including the characteristics of the guidelines and the drug labels. Therefore, more effort from pharmaceutical companies, academia and regulatory affairs needs to be made to implement pharmacogenomic information on drug labels.

There are several hurdles to overcome before implementing pharmacogenomics (PGx) in precision medicine. One of the hurdles is unawareness of PGx by clinicians due to insufficient pharmacogenomic information on drug labels. Therefore, it might be important to implement PGx that reflects pharmacogenomic information on drug labels, standard of prescription for clinicians. This study aimed to evaluate the level at which PGx was being used in clinical practice by comparing the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group guidelines and drug labels of the US Food and Drug Administration (FDA) and the Korea Ministry of Food and Drug Safety (MFDS). Two PGx guidelines and drugs labels were scrutinized, and the concordance of the pharmacogenomic information between guidelines and drug labels was confirmed. The concordance of the label between FDA and MFDS was analyzed. In FDA labels, the number of concordant drug with guidelines was 24, while 13 drugs were concordant with MFDS labels. The number of drugs categorized as contraindication, change dose, and biomarker testing required was 7, 12 and 12 for the FDA and 8, 5 and 4 for the MFDS, respectively. The pharmacogenomic information of 9 drugs approved by both FDA and MFDS was identical. In conclusion, pharmacogenomic information on clinical implementation guidelines was limited on both FDA and MFDS labels because of various reasons including the characteristics of the guidelines and the drug labels. Therefore, more effort from pharmaceutical companies, academia and regulatory affairs needs to be made to implement pharmacogenomic information on drug labels.

Vascular endothelial growth factor (VEGF) plays a pivotal role in pathologic ocular neovascularization and vascular leakage via activation of VEGF receptor 2 (VEGFR2). This study was undertaken to evaluate the therapeutic mechanisms and effects of the tetrapeptide Arg-Leu-Tyr-Glu (RLYE), a VEGFR2 inhibitor, in the development of vascular permeability and choroidal neovascularization (CNV). In cultured human retinal microvascular endothelial cells (HRMECs), treatment with RLYE blocked VEGF-A-induced phosphorylation of VEGFR2, Akt, ERK, and endothelial nitric oxide synthase (eNOS), leading to suppression of VEGF-A-mediated hyper-production of NO. Treatment with RLYE also inhibited VEGF-A-stimulated angiogenic processes (migration, proliferation, and tube formation) and the hyperpermeability of HRMECs, in addition to attenuating VEGF-A-induced angiogenesis and vascular permeability in mice. The anti-vascular permeability activity of RLYE was correlated with enhanced stability and positioning of the junction proteins VE-cadherin, β-catenin, claudin-5, and ZO-1, critical components of the cortical actin ring structure and retinal endothelial barrier, at the boundary between HRMECs stimulated with VEGF-A. Furthermore, intravitreally injected RLYE bound to retinal microvascular endothelium and inhibited laser-induced CNV in mice. These findings suggest that RLYE has potential as a therapeutic drug for the treatment of CNV by preventing VEGFR2-mediated vascular leakage and angiogenesis.
Actins ; Animals ; Capillary Permeability ; Choroid ; Choroidal Neovascularization ; Claudin-5 ; Endothelial Cells ; Endothelium ; Humans ; Macular Degeneration ; Mice ; Nitric Oxide Synthase Type III ; Permeability ; Phosphorylation ; Receptors, Vascular Endothelial Growth Factor ; Retinaldehyde ; Vascular Endothelial Growth Factor A

PURPOSE: To describe a patient who presented with central serous chorioretinopathy after 2 months of tadalafil administration without any other underlying disease or medication. CASE SUMMARY: A 49-year-old male patient was transferred from a local clinic with metamorphopsia and decreased visual acuity in the right eye. His visual acuity was 6/20 in the right eye and 18/20 in the left eye. The fundus examination showed a large serous detachment between the superior and inferior blood vessel arcades in the right retina. In his medical history, he used tadalafil three times a week for 2 months. His medication was then stopped, and a follow-up examination was scheduled. After 2 months, a fundus examination showed resolution of the subretinal fluid, and his corrected visual acuity recovered to 20/20. CONCLUSIONS: Tadalafil (Cialis®) is a phosphodiesterase (PDE)-5 inhibitor and predominantly prescribed for the treatment of erectile dysfunction. PDE–5 inhibitors may be potent vasodilators in the retina and choroid, and may induce choroidal vessel engorgement leading to leakage across the retinal pigment epithelium and accumulation of subretinal fluid in selected patients. When making a diagnosis as central serous chorioretinopathy, the physician should confirm the causative drugs that are easy to miss, by performing a thorough review of the patient's medical history and promptly terminating the causative drugs.
Blood Vessels ; Central Serous Chorioretinopathy ; Choroid ; Diagnosis ; Erectile Dysfunction ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Retina ; Retinal Pigment Epithelium ; Subretinal Fluid ; Tadalafil ; Vasodilator Agents ; Vision Disorders ; Visual Acuity

PURPOSE: We report a case of spontaneous recovery of an iris cyst with only tuberculosis medication and conservative eye drops when uveitis and angle closure occurred because of a cyst in a patient with peritoneal tuberculosis. CASE SUMMARY: A 49-year-old female who was diagnosed with iritis and treated with steroid eye drops visited our clinic because of decreased visual acuity 1 month prior. There were anterior chamber inflammation cells and an iris cyst completely obstructing the anterior chamber at 12 o'clock. At the time, the patient had been diagnosed with peritoneal tuberculosis in the Department of Internal Medicine and Gynecology and had been treated with surgery and medication. The patient had no past history of glaucoma, but when the iris cyst developed, the intraocular pressure increased to 29 mmHg and anterior inflammatory cells were seen in the range of +1 to +2. The primary lesion of tuberculosis improved and the iris cyst disappeared with treatments involving medication for tuberculosis, steroid eye drops, and glaucoma eye drops, without invasive treatments such as alcohol curettage, laser treatment, or cyst resection. CONCLUSIONS: If an iris cyst is a new lesion of the eye, it is necessary to identify the pattern and cause of the iris cyst first, and if a secondary benign iris cyst is suspected, the primary treatment of the causative disease is necessary rather than prompt invasive treatment.
Anterior Chamber ; Curettage ; Female ; Glaucoma ; Gynecology ; Humans ; Inflammation ; Internal Medicine ; Intraocular Pressure ; Iris ; Iritis ; Middle Aged ; Ophthalmic Solutions ; Peritonitis, Tuberculous ; Tuberculosis ; Uveitis ; Visual Acuity

BACKGROUND: The renal function of individuals is one of the reasons for the variations in therapeutic response to various drugs. Patients with renal impairment are often exposed to drug toxicity, even with drugs that are usually eliminated by hepatic metabolism. Previous study has reported an increased plasma concentration of indoxyl sulfate and decreased plasma concentration of 4β-hydroxy (OH)-cholesterol in stable kidney transplant recipients, implicating indoxyl sulfate as a cytochrome P450 (CYP) inhibiting factor. In this study, we aimed to evaluate the impact of renal impairment severity-dependent accumulation of indoxyl sulfate on hepatic CYP3A activity using metabolic markers. METHODS: Sixty-six subjects were enrolled in this study; based on estimated glomerular filtration rate (eGFR), they were classified as having mild, moderate, or severe renal impairment. The plasma concentration of indoxyl sulfate was quantified using liquid chromatography-mass spectrometry (LC-MS). Urinary and plasma markers (6β-OH-cortisol/cortisol, 6β-OH-cortisone/cortisone, 4β-OH-cholesterol) for hepatic CYP3A activity were quantified using gas chromatography-mass spectrometry (GC-MS). The total plasma concentration of cholesterol was measured using the enzymatic colorimetric assay to calculate the 4β-OH-cholesterol/cholesterol ratio. The correlation between variables was assessed using Pearson's correlation test. RESULTS: There was a significant negative correlation between MDRD eGFR and indoxyl sulfate levels. The levels of urinary 6β-OH-cortisol/cortisol and 6β-OH-cortisone/cortisone as well as plasma 4β-OH-cholesterol and 4β-OH-cholesterol/cholesterol were not correlated with MDRD eGFR and the plasma concentration of indoxyl sulfate. CONCLUSION: Hepatic CYP3A activity may not be affected by renal impairment-induced accumulation of plasma indoxyl sulfate.
Cholesterol ; Cytochrome P-450 CYP3A* ; Cytochrome P-450 Enzyme System* ; Cytochromes* ; Drug-Related Side Effects and Adverse Reactions ; Gas Chromatography-Mass Spectrometry ; Glomerular Filtration Rate ; Humans ; Indican ; Kidney ; Metabolism ; Plasma ; Spectrum Analysis ; Transplant Recipients