PURPOSE: To report a case of corneal and lenticular pigmentation after prolonged clozapine therapy. CASE SUMMARY: A 56-year-old male visited our hospital with a progressive decline in vision that affected both eyes. He had a history of schizophrenia. He was being treated with 200 mg clozapine and 1 mg lorazepam daily, and had been treated with clozapine for 5 years. At the first visit, his best-corrected-visual acuity was 20/32 in both eyes. Slit lamp examination of the corneas showed bright, fine, grayish-brown deposits on the endothelium, and on dilation, bilateral central stellate opacity of the anterior portion of the lens capsule was revealed. CONCLUSIONS: Clozapine may induce corneal and lenticular pigmentation and thus may lead to a decline in vision. Patients on long-term clozapine therapy should be considered for regular ophthalmic review.
Clozapine ; Cornea ; Endothelium ; Humans ; Lorazepam ; Male ; Middle Aged ; Pigmentation ; Schizophrenia ; Slit Lamp

Luteolin, a widespread flavonoid, has been known to have neuroprotective activity against various neurologic diseases such as epilepsy, and Alzheimer’s disease. However, little information is available regarding the hypnotic effect of luteolin. In this study, we evaluated the hypnotic effect of luteolin and its underlying mechanism. In pentobarbital-induced sleeping mice model, luteolin (1, and 3 mg/kg, p.o.) decreased sleep latency and increased the total sleep time. Through electroencephalogram (EEG) and electromyogram (EMG) recording, we demonstrated that luteolin increased non-rapid eye movement (NREM) sleep time and decreased wake time. To evaluate the underlying mechanism, we examined the effects of various pharmacological antagonists on the hypnotic effect of luteolin. The hypnotic effect of 3 mg/kg of luteolin was not affected by flumazenil, a GABAA receptor-benzodiazepine (GABAAR-BDZ) binding site antagonist, and bicuculine, a GABAAR-GABA binding site antagonist. On the other hand, the hypnotic effect of 3 mg/kg of luteolin was almost completely blocked by caffeine, an antagonist for both adenosine A1 and A2A receptor (A1R and A2AR), 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), an A1R antagonist, and SCH-58261, an A2AR antagonist. From the binding affinity assay, we have found that luteolin significantly binds to not only A1R but also A2AR with IC₅₀ of 1.19, 0.84 μg/kg, respectively. However, luteolin did not bind to either BDZ-receptor or GABAAR. From these results, it has been suggested that luteolin has hypnotic efficacy through A1R and A2AR binding.
Adenosine ; Animals ; Binding Sites ; Caffeine ; Electroencephalography ; Epilepsy ; Eye Movements ; Flumazenil ; Hand ; Hypnotics and Sedatives ; Luteolin ; Mice ; Receptor, Adenosine A1 ; Receptor, Adenosine A2A ; Sleep Initiation and Maintenance Disorders

Hemangioblastoma (HBL) in the suprasellar region is very rare and a few cases have been reported. Suprasellar HBL without von Hippel-Lindau disease is much rarer. A 76-year old male patient presented progressively deteriorating visual disturbance. MRI demonstrated solid suprasellar mass of 20 mm in diameter, broadly based to planum sphenoidale and diaphragm sella and dural tail sign after the administration of gadolinium diethylene triamine penta-acetic acid (Gd-DTPA). Preoperative diagnosis was meningioma. Total resection of the tumor was not accomplished because of massive hemorrhage, and the histopathologic examination revealed the tumor to be HBL. The visual disturbance of the patient was not improved. The authors reviewed the literature and considered a differential diagnosis of suprasellar tumors and treatment of suprasellar HBL.
Diagnosis ; Diagnosis, Differential ; Diaphragm ; Gadolinium ; Hemangioblastoma ; Hemorrhage ; Humans ; Magnetic Resonance Imaging ; Male ; Meningioma ; Tail ; Temazepam ; von Hippel-Lindau Disease

3-Carene, a bicyclic monoterpene, is one of the major components of the pine tree essential oils. It has been reported that, in addition to its known properties as a phytoncide, 3-carene has anti-inflammatory, antimicrobial, and anxiolytic effects. We have previously demonstrated that α-pinene, the major component of pine tree, has a hypnotic effect through GABA(A)-benzodiazepine (BZD) receptors. However, a hypnotic effect of 3-carene has not been studied yet. Here, we report that oral administration of 3-carene increases the sleep duration and reduces sleep latency in pentobarbital-induced sleep test. 3-Carene potentiates the GABA(A) receptor-mediated synaptic responses by prolonging the decay time constant of inhibitory synaptic responses. These enhancing effects of 3-carene are reproduced by zolpidem, a modulator for GABA(A)-BZD receptor, and fully inhibited by flumazenil, an antagonist for GABA(A)-BZD receptor. The molecular docking of 3-carene to the BZD site of GABA(A) protein structure, suggests that 3-carene binds to the BZD site of α1 and ϒ2 subunits of GABA(A)-BZD receptor. These results indicate that, similar to α-pinene, 3-carene shows a sleep-enhancing effect by acting as a positive modulator for GABA(A)-BZD receptor.
Administration, Oral ; Anti-Anxiety Agents ; Flumazenil ; Hypnotics and Sedatives ; Oils, Volatile ; Pinus

BACKGROUND: Terminally ill cancer patients suffer from refractory symptoms, and the last option of treatment is to consider sedatives. However, due to concerns that sedation may shorten survival time, some people prefer not to take sedatives. The purpose of this study was to investigate the effects of sedative administration on survival time among terminally ill cancer patients.METHODS: Two hundreds and thirty-seven patients who were hospitalized to the hospice care unit of public hospitals in Seoul from January, 2015 to March, 2016 were analyzed retrospectively. The univariate and multivariate Cox's proportional hazard regression model was used to determine independent factors related to survival time.RESULTS: The usage of sedation was necessary because the incidence of insomnia was 61.4% in the lorazepam only group, and the incidence of delirium was highest in the haloperidol group and the haloperidol with lorazepam group. Interestingly, multivariate analysis showed that male (HR, 1.766; P < 0.001), decreased consciousness (HR, 1.803; P=0.003), anorexia (HR, 1.506; P=0.012), resting dyspnea (HR, 1.757; P < 0.001), elevated serum bilirubin (HR, 1.657; P=0.001), and the haloperidol with lorazepam group (HR, 0.535, P < 0.001) were each significantly associated with survival time. Furthermore, patients in the haloperidol with lorazepam group survived longer than patients with no such medications.CONCLUSION: There is no evidence that treatment with sedative medication shortens the survival time of patients with terminally ill cancer with refractory symptoms.
Anorexia ; Bilirubin ; Consciousness ; Delirium ; Dyspnea ; Haloperidol ; Hospice Care ; Hospices ; Hospitals, Public ; Humans ; Hypnotics and Sedatives ; Incidence ; Lorazepam ; Male ; Multivariate Analysis ; Palliative Care ; Retrospective Studies ; Seoul ; Sleep Initiation and Maintenance Disorders ; Terminally Ill

OBJECTIVE: Cellular, animal, and human epidemiological studies suggested that benzodiazepines increase the risk of cancer and cancer mortality. Obesity is also clearly linked to carcinogenesis. However, no human studies have examined benzodiazepine-associated carcinogenesis as assessed by changes in cancer biomarkers. METHODS: A total of 19 patients were recruited, and received a 6-week treatment of 0.5 mg lorazepam. The measured cancer biomarkers were angiopoietin-2 (ANG-2), soluble CD40 ligand, epidermal growth factor, endoglin, soluble Fas ligand (sFASL), heparin-binding EGF-like growth factor (HB-EGF), insulin-like growth factor binding protein, interleukin (IL)-6, IL-8, IL-18, plasminogen activator inhibitor (PLGF), placental growth factor, transforming growth factor (TGF)-α, tumor necrosis factor (TNF)-α, urokinase-type plasminogen (uPA), vascular endothelial growth factor (VEGF)-A, VEGF-C, and VEGF-D. RESULTS: Six cancer biomarkers were significantly increased in all patients as a whole. The subgroup analysis revealed a distinct pattern of change. Overweight patients showed a significant increase in 11 cancer biomarkers, including ANG-2, sFASL, HB-EGF, IL-8, PLGF, TGF-α, TNF-α, uPA, VEGF-A, VEGF-C, and VEGF-D. However, normal-weight patients did not show any changes in cancer biomarkers. CONCLUSION: Adiposity may have primed the carcinogenic potential, leading to lorazepam-associated carcinogenesis in overweight patients. Epidemiological studies addressing this issue should consider the potential modulator contributing to benzodiazepine-associated carcinogenesis.
Adiposity ; Angiopoietin-2 ; Animals ; Benzodiazepines ; Biomarkers, Tumor ; Carcinogenesis* ; Carrier Proteins ; CD40 Ligand ; Epidemiologic Studies ; Epidermal Growth Factor ; Fas Ligand Protein ; Heparin-binding EGF-like Growth Factor ; Humans ; Interleukin-18 ; Interleukin-8 ; Interleukins ; Lorazepam ; Mortality ; Obesity ; Overweight* ; Plasminogen ; Plasminogen Activators ; Transforming Growth Factors ; Tumor Necrosis Factor-alpha ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factor C ; Vascular Endothelial Growth Factor D

Negative myoclonus (NM) is a jerky, shock-like involuntary movement caused by a sudden, brief interruption of muscle contraction. An 80-year-old man presented with multifocal NM and confusion. Two days before the onset of NM, he commenced the intake of pregabalin at a dose of 150 mg/day for neuropathic pain. His NM resolved completely and mental status improved gradually after the administration of lorazepam intravenously and the discontinuation of pregabalin. Our study suggests that pregabalin can cause NM even in patients without a history of seizures.
Aged, 80 and over ; Dyskinesias ; Humans ; Lorazepam ; Muscle Contraction ; Myoclonus ; Neuralgia ; Pregabalin ; Seizures

The autonomic nervous system contributes to prostate cancer proliferation and metastasis. However, the exact molecular mechanism remains unclear. In this study, muscarinic acetylcholine receptor M1 (CHRM1) expression was measured via immunohistochemical analysis in human prostate cancer tissue array slides. PC-3, LNCaP, and A549 cells were treated with pirenzepine or carbachol, and the cell migration and invasion abilities were evaluated. Western blotting and quantitative real-time PCR were performed to measure GLI family zinc finger 1 (GLI1), patched 1 (PTCH1), and sonic hedgehog (SHH) expression levels. High expression of CHRM1 was found in early-stage human prostate cancer tissues. In addition, the selective CHRM1 antagonist pirenzepine inhibited PC-3, LNCaP, and A549 cell migration and invasion, but the agonist carbachol promoted the migration and invasion of these three cell lines. Muscarinic signaling can be relayed by hedgehog signaling. These data show that CHRM1 is involved in the regulation of prostate cancer migration and invasion through the hedgehog signaling pathway.
Carbachol/pharmacology* ; Cell Movement/genetics* ; Cell Proliferation ; Hedgehog Proteins/genetics* ; Humans ; Male ; Muscarinic Agonists/pharmacology* ; Muscarinic Antagonists/pharmacology* ; Patched-1 Receptor/genetics* ; Pirenzepine/pharmacology* ; Prostatic Neoplasms/pathology* ; Receptor, Muscarinic M1/genetics* ; Zinc Finger Protein GLI1/genetics*

OBJECTIVES: To identify the new designer drugs which are totally unknown and not in the routine testing list by the technologies such as high-resolution mass spectrometry in drug facilitated sexual assault, in order to solve the problem in actual cases. METHODS: The milky fluid from an actual case was extracted and analyzed using LC-QE, ¹H-NMR and GC-MS, respectively. The accurate masses and cluster ions isotope patterns of unknown compound were obtained by LC-QE. The molecular formula was confirmed as C₁₆H₁₂C₂N₂O based on the protons number of ¹H-NMR. The isomers diclazepam and 4-chlorodiazepam were separated and detected with GC-MS. RESULTS: The new designer benzodiazepine as diclazepam in the milky fluid was identified. The results provided direct evidence for the investigation and qualitative analysis of such cases. CONCLUSIONS The combined application of various methods, including LC-QE, ¹H-NMR and GC-MS, can be used to detect unknown new psychoactive substances.
Benzodiazepines/chemistry* ; Benzodiazepinones ; Chromatography, Liquid/methods* ; Designer Drugs/chemistry* ; Female ; Gas Chromatography-Mass Spectrometry/methods* ; Humans ; Male ; Mass Spectrometry/methods* ; Sex Offenses ; Substance Abuse Detection/methods* ; Toxicology/methods*

BACKGROUND/AIMS: Appropriate sedation during endoscopy can significantly reduce the discomfort experienced by a patient when the procedure is performed; however, it is associated with several potential risks. Very few reports describe sedation-related adverse events occurring during endoscopy. Our study evaluated the current status of sedation-related adverse events during a diagnostic upper endoscopy. MATERIALS AND METHODS: We reviewed medical records of 5,564 cases of diagnostic upper endoscopy performed using midazolam for sedation at the Ewha Womans University, Mokdong Hospital, between January 2015 and March 2016. RESULTS: Among the 5,564 cases, sedation-related adverse events were reported in 56 cases (1.0%). Among these 56 patients, 30 patients (53.6.%) were men and 26 patients (46.4%) were women. Mean age of the patients was 63.7±15.4 years. The most common adverse event reported was hypoxia, which was observed in 37 patients (0.7%). Other adverse events included sedation failure (18 patients, 0.3%) and delayed discharge from the recovery room due to delayed recovery of consciousness (one patient, 0.02%). Among patients presenting with hypoxia, 35 patients recovered after administration of intravenous flumazenil and oxygen via nasal prongs. Administration of oxygen alone helped recovery in 2 patients. All patients recovered uneventfully with no mortalities registered. CONCLUSIONS: Our study showed that the use of sedative midazolam is relatively safe during an upper endoscopy. The rate of occurrence of adverse events was very low, and no fatal adverse events were observed. However, close observation and continuous monitoring is an essential component of safe sedation during endoscopy.
Anoxia ; Conscious Sedation ; Consciousness ; Endoscopy* ; Female ; Flumazenil ; Humans ; Male ; Medical Records ; Midazolam ; Mortality ; Oxygen ; Recovery Room