Objective: The Japanese risk management plan (RMP) contains the risk minimization action plans for important potential risks of drugs.  One of the basic risk minimization action plans is reminding on package insert; however, we found that some potential risks were not described in package inserts.  In this study, we investigated the description of potential risks on package inserts.
Design: Document analysis.
Methods: We collected all posted RMP documents and the package inserts of corresponding products from the Pharmaceutical and Medical Devices Agency website on January 31, 2015 and investigated the risk minimization action plans of important potential risk items and whether the items had been described in each package insert.
Results: Of 268 important potential risk items in 81 products, 56 items were not described on package insert.  The major reason for not including the risk items on the package insert was “causality was not indicated sufficiently” and some items had no written reason.
Conclusion: About 20% of important potential risks are not described in package inserts.  Because most post-marketing pharmacovigilance plans depend on spontaneous reporting by healthcare personnel, description on package insert, the most frequently referred drug information resource, should be considered.

The effects of voluntary exercise on resting systolic blood pressure and vascular lesions of stroke-prone spontaneously hypertensive rats (stroke-prone SHR) were investigated with and without 1 % saline loading. Forty male stroke-prone SHR aged 7 weeks were assigned to one of 4 experimental groups. Each consisted 10 animals ; sedentary control (S), sedentary with 1 % saline loading (SS), exercised control (E), and exercised with 1 % saline loading (ES) . Animals were sacrificed at the 5 th week. In the prehypertensive phase, resting caudal arterial systolic blood pressure was significantly lower in the E group than in the S group. However, after being loaded with 1 % saline, the ES group showed higher resting systolic blood pressure than those of the SS group. In addition, the ES group revealed severer renal, myocardial, and cerebrovascular lesions than those of the rest of the groups.

Noxious stimuli in the esophagus activate nociceptive receptors on esophageal mucosa, such as transient receptor potential, acid-sensing ion channel and the P2X family, a family of ligand-gated ion channels responsive to ATP, and this generates signals that are transmitted to the central nervous system via either spinal nerves or vagal nerves, resulting in esophageal sensation. Among the noxious stimuli, gastric acid and other gastric contents are clinically most important, causing typical reflux symptoms such as heartburn and regurgitation. A conventional acid penetration theory has been used to explain the mechanism of heartburn, but much recent evidence does not support this theory. Therefore, it may be necessary to approach the causes of heartburn symptoms from a new conceptual framework. Hypersensitivity of the esophagus, like that of other visceral organs, includes peripheral, central and probably psychosocial factor-mediated hypersensitivity, and is known to play crucial roles in the pathoegenesis of nonerosive reflux disease, functional heartburn and non-cardiac chest pain. There also are esophagitis patients who do not perceive typical symptoms. This condition is known as silent gastroesophageal reflux disease. Although the pathogenesis of silent gastroesophageal reflux disease is still not known, hyposensitivity to reflux of acid may possibly explain the condition.
Adenosine Triphosphate ; Central Nervous System ; Chest Pain ; Esophagitis ; Esophagus ; Gastric Acid ; Gastroesophageal Reflux ; Heartburn ; Humans ; Hypersensitivity ; Ion Channels ; Ligand-Gated Ion Channels ; Mucous Membrane ; Nociceptors ; Sensation ; Spinal Nerves

The median time of brain metastasis from the diagnosis of breast cancer is approximately 3 years. In this case report, a 69-year-old woman demonstrated cerebellar ataxia. Brain magnetic resonance imaging revealed enhanced lesions in bilateral cerebellar hemispheres. She had undergone surgery, radiation, and chemotherapy for uterine and breast cancer 24 years prior and 16 years prior, respectively. Although she had not received any anticancer treatment for 10 years, no recurrences were identified using whole body scans. A partial tumor resection was performed and the histological diagnosis was an adenocarcinoma from breast cancer. As no extracranial lesions were found, gamma-knife irradiation was performed, without additional systemic chemotherapy. One month posttreatment, the tumors dramatically reduced in size and the patient completely recovered from cerebellar ataxia. Systemic chemotherapy is not always required for brain metastasis from breast cancer with a long interval period, as long as no evidence of extracranial recurrence is detected.
Adenocarcinoma ; Aged ; Brain* ; Breast Neoplasms* ; Breast* ; Cerebellar Ataxia ; Diagnosis ; Drug Therapy ; Female ; Humans ; Magnetic Resonance Imaging ; Neoplasm Metastasis* ; Neoplasm Recurrence, Local ; Prognosis ; Recurrence* ; Whole Body Imaging

Because adenine is effective for managing cases of radiation-induced and drug-induced leukopenia, it may be effective in cases of antipsychotic-induced leukopenia and neutropenia. Here, we report our experience with patients with leukopenia and neutropenia caused by an antipsychotic overdose or discontinuation of lithium carbonate, in whom adenine administration ameliorated the white blood cell and neutrophil counts. The progress of patients suggests that adenine is effective in cases of leukopenia and neutropenia associated with lithium carbonate discontinuation and an antipsychotic overdose.
Adenine* ; Antipsychotic Agents* ; Humans ; Leukocytes ; Leukopenia* ; Lithium Carbonate* ; Lithium* ; Neutropenia* ; Neutrophils

BACKGROUND/AIMS: When a person is experiencing stress, corticotropin-releasing hormone (CRH) can modulate gut physiologies, such as visceral sensation or gastrointestinal motility, and its intravenous administration mimics stress-induced physiological changes. However, the influence of CRH on the esophagus is yet unknown. Accordingly, we investigated whether intravenous CRH administration increases esophageal sensitivity to electrical stimulation in healthy Japanese subjects. METHODS: Twenty healthy subjects were recruited. We quantified the initial perception threshold (IPT) every 15 minutes after CRH injection. Venous blood was collected with a cannula, and both plasma adrenocorticotropic hormone (ACTH) and cortisol were measured at pre-stimulation, 0, 30, 60, 90, and 120 minutes. The results from each time point were compared against a baseline IPT obtained before electrical stimulation was initiated. RESULTS: When compared to the baseline IPT value (16.9 ± 4.5), CRH significantly decreased electrical threshold of the esophagus at 30, 45, 60, 75 minutes (14.1 ± 4.2, 13.1 ± 5.0, 12.1 ± 5.7, 14.0 ± 5.8 minutes, P < 0.01, respectively) after CRH injection, suggesting that CRH increased esophageal sensitivity to the electrical stimulus. CRH also significantly increased plasma ACTH levels at 30 minutes (50.3 ± 17.7, P < 0.01), and cortisol levels at 30 minutes (22.0 ± 6.7 minutes, P < 0.01) and 60 minutes (20.3 ± 6.7 minutes, P < 0.01) after CRH injection, when compared to the pre-stimulation ACTH and cortisol values. CONCLUSION: Intravenous CRH administration increased esophageal electrical sensitivity in normal subjects, emphasizing the important role of stress in esophageal sensitivity.
Administration, Intravenous ; Adrenocorticotropic Hormone ; Asian Continental Ancestry Group ; Catheters ; Corticotropin-Releasing Hormone* ; Electric Stimulation ; Esophagus ; Gastrointestinal Motility ; Healthy Volunteers ; Humans ; Hydrocortisone ; Plasma ; Sensation

BACKGROUND/AIMS: Although chronic constipation is a common symptom, to date no international consensus has been reached regarding its definition. The aims of this study were (1) to investigate defecation habits and (2) to examine the prevalence of constipation using the Japanese Society of Internal Medicine (JSIM) and the Rome III criteria using an online survey. METHODS: An online questionnaire composed of items on the frequency, interval, form of defecation, the management, and self-recognition of constipation (reference standard of constipation) was created. A total of 5155 valid responses were received. In addition, constipation symptoms were evaluated through a survey using the JSIM and the Rome III criteria. RESULTS: In the internet survey, 28.4% of the respondents considered themselves to be constipated. Stratified by sex, significantly more females (37.5%) than males (19.1%) considered themselves to be constipated (P < 0.001). The prevalence of constipation among the respondents was 28.0% using the Rome III, but only 10.1% using the JSIM. The diagnostic accuracy was 73.2% for the Rome III and 78.1% for the JSIM, while the diagnostic specificity was 81.1% for the Rome III and 97.5% for the JSIM. However, the diagnostic sensitivities for both measures were low, at 52.2% and 29.2% for the Rome III and the JSIM, respectively. CONCLUSIONS: The online survey developed for this study was able to provide clarification regarding defecation patterns. The results also suggest a discrepancy between the self-recognized prevalence of constipation in Japan and prevalence of constipation based on the JSIM criteria.
Asian Continental Ancestry Group ; Consensus ; Constipation* ; Defecation ; Female ; Humans ; Internal Medicine ; Internet* ; Japan ; Male ; Prevalence* ; Sensitivity and Specificity ; Surveys and Questionnaires

BACKGROUND/AIMS: Few studies are available that have investigated the risk factors for overlapping irritable bowel syndrome (IBS)-like symptoms in patients with inactive inflammatory bowel disease (IBD). The present study has 3 objectives: (1) to assess the prevalence of IBS-like symptoms in Japanese patients with inactive IBD using Rome III criteria, (2) to examine the relationship of IBS-like symptoms to health related quality of life (HR-QOL), and (3) to investigate associations for developing IBS-like symptoms in patients with inactive IBD. METHODS: IBS-like symptoms were evaluated using the Rome III questionnaire for functional gastrointestinal disorders. HR-QOL and hospital anxiety and depression scale were evaluated. RESULTS: IBS-like symptoms were found in 17.5% (7/40) of patients with inactive ulcerative colitis, 27.1% (29/107) of patients with inactive Crohn’s disease (CD), and 5.3% (23/438) of healthy control subjects. The QOL level was significantly lower and anxiety score was significantly higher in inactive CD patients with IBS-like symptoms than in those without such symptoms (P = 0.003, P = 0.009). Use of anti-anxiety drugs was associated with the presence of IBS symptoms (P = 0.045). HR-QOL score was lower and anxiety score was higher in patients with inactive ulcerative colitis, but the difference was not statistically significant. CONCLUSIONS: The prevalence of IBS-like symptoms in inactive IBD patients was significantly higher than in healthy controls. Inactive CD patients with IBS-like symptoms has low QOL and anxiety; suggesting that anxiety may be associated with symptom development in such patients.
Anti-Anxiety Agents ; Anxiety ; Asian Continental Ancestry Group* ; Colitis, Ulcerative ; Depression ; Gastrointestinal Diseases ; Humans ; Inflammatory Bowel Diseases* ; Irritable Bowel Syndrome ; Prevalence* ; Quality of Life ; Risk Factors

BACKGROUND/AIMS: Gastric motility abnormalities have been considered to be pathophysiological features of functional dyspepsia (FD) that are closely related to dyspepsia symptoms, especially postprandial distress syndrome (PDS). The aims of this study are to (1) investigate the prevalence of gastric motility disorders and (2) evaluate the association between gastric motility abnormalities and dyspeptic symptoms using gastric scintigraphy in the PDS type of FD. METHODS: Forty healthy subjects and 94 PDS type FD patients were enrolled in the study. The volunteers and patients ingested a radiolabeled (technetium-99m) solid test meal, and scintigraphic images were recorded. Gastric accommodation and emptying were assessed by scintigraphic imaging. The patients’ dyspeptic symptoms were also explored using self-completed symptom questionnaires with 10 variables (4 scales, 0–3 points) at the same time. RESULTS: In 94 Japanese FD patients, the prevalence of impaired gastric accommodation and delayed emptying were 14.9% (14/94) and 10.6% (10/94), respectively. Gastric motility abnormalities were seen in 25.5% (24/94) of FD patients. There was no association between gastric motility abnormalities and dyspeptic symptoms. CONCLUSIONS: Gastric motility abnormalities were seen in 25.5% of Japanese PDS type FD patients. However, there was no association between gastric motility abnormalities and dyspeptic symptoms on gastric scintigraphy.
Asian Continental Ancestry Group ; Dyspepsia* ; Healthy Volunteers ; Humans ; Meals ; Prevalence* ; Radionuclide Imaging ; Stomach ; Volunteers ; Weights and Measures