Patient safety incident reports related to traditional Japanese Kampo medicines: medication errors and adverse drug events in a university hospital for a ten-year period.

BACKGROUND: Kampo medicine is traditional Japanese medicine, which originated in ancient traditional Chinese medicine, but was introduced and developed uniquely in Japan. Today, Kampo medicines are integrated into the Japanese national health care system. Incident reporting systems are currently being widely used to collect information about patient safety incidents that occur in hospitals. However, no investigations have been conducted regarding patient safety incident reports related to Kampo medicines. The aim of this study was to survey and analyse incident reports related to Kampo medicines in a Japanese university hospital to improve future patient safety. METHODS: We selected incident reports related to Kampo medicines filed in Toyama University Hospital from May 2007 to April 2017, and investigated them in terms of medication errors and adverse drug events. RESULTS: Out of 21,324 total incident reports filed in the 10-year survey period, we discovered 108 Kampo medicine-related incident reports. However, five cases were redundantly reported; thus, the number of actual incidents was 103. Of those, 99 incidents were classified as medication errors (77 administration errors, 15 dispensing errors, and 7 prescribing errors), and four were adverse drug events, namely Kampo medicine-induced interstitial pneumonia. The Kampo medicine (crude drug) that was thought to induce interstitial pneumonia in all four cases was Scutellariae Radix, which is consistent with past reports. According to the incident severity classification system recommended by the National University Hospital Council of Japan, of the 99 medication errors, 10 incidents were classified as level 0 (an error occurred, but the patient was not affected) and 89 incidents were level 1 (an error occurred that affected the patient, but did not cause harm). Of the four adverse drug events, two incidents were classified as level 2 (patient was transiently harmed, but required no treatment), and two incidents were level 3b (patient was transiently harmed and required substantial treatment). CONCLUSIONS: There are many patient safety issues related to Kampo medicines. Patient safety awareness should be raised to prevent medication errors, especially administration errors, and adverse drug events in Kampo medicine.

[A case of elderly-onset type 1 diabetes mellitus: negative for antiglutamic acid dehydrogenase antibody and positive insulinoma-associated tyrosine phosphatase-like protein-2 antibody].

An 83-year-old Japanese woman given a diagnosis of type 2 diabetes mellitus 3 years previously was hospitalized for markedly elevated plasma glucose (386 mg/dl) and glycated hemoglobin (9.3%) levels. Laboratory study results showed urinary connecting peptide immunoreactivity (CPR) concentrations of 8.9 µg/day and serum CPR levels <0.2 ng/ml before and 0.3 ng/ml 6 min after glucagon administration, indicating decreased insulin secretion. Although antiglutamic acid dehydrogenase (GAD) antibody levels were negative, insulinoma-associated tryrosine phosphatase-like protein-2 (IA-2) antibody levels were positive (50 U/ml), leading to a diagnosis of type 1 diabetes mellitus. Furthermore, human leukocyte antigen (HLA) typing revealed DRB1*0901, a diabetes-susceptibility gene. Intensive insulin therapy was initiated. This was a rare case of elderly-onset type 1 diabetes.

Cooperative effect of serum 25-hydroxyvitamin D concentration and a polymorphism of transforming growth factor-beta1 gene on the prevalence of vertebral fractures in postmenopausal osteoporosis.

A T869-->C polymorphism of the transforming growth factor-beta1 (TGF-beta1) gene is reported to be associated with genetic susceptibility to both osteoporosis and vertebral fractures. A low serum 25-hydroxyvitamin D [25(OH)D] level is known to be associated with a higher risk for hip fracture. This study aimed to assess a possible cooperative effect of the gene polymorphism and vitamin D status on vertebral fracture risk. The prevalence of vertebral fracture in 168 postmenopausal female patients with osteoporosis was analyzed, and its association with the TGF-beta1 gene polymorphism and serum 25(OH)D concentration was assessed cross-sectionally. The fracture prevalence increased according to the rank order of the TGF-beta1 genotypes CC < CT < TT, as expected. A significant difference was found not only between the CC and TT genotypes (P = 0.005) but also between the CC and CT genotypes (P < 0.05) when the patients with serum 25(OH)D of more than the median value [22 ng/ml (55 nmol/l)] were analyzed. On the other hand, when those with serum 25(OH)D of less than the median value were analyzed, the protective effect of the C allele against the fracture was blunted; statistical significance in the difference of the fracture prevalence was lost between the CC genotype and the other genotypes. These data suggest that vitamin D fulfillment is prerequisite for the TGF-beta1 genotype in exerting its full effect on the fracture prevalence.

Hypoglycemia due to ectopic secretion of insulin-like growth factor-I in a patient with an isolated sarcoidosis of the spleen.

Hypoglycemia is reported to be one of the manifestations of a patient with hypothalamic sarcoid infiltrates due to impaired counter-regulation of glucose. But, without hypothalamic lesion, patients with sarcoidosis would not be expected to have hypoglycemia. We recently identified a patient with an isolated sarcoidosis of the spleen who had experienced frequent fasting hypoglycemia which completely disappeared after splenectomy. During hypoglycemia, serum insulin was undetectable. Endocrinological examination revealed no abnormality. The objective was to investigate whether the patient's hypoglycemia was due to ectopic secretion of an insulin-mimetic factor by the splenic sarcoidosis. Serum insulin-like growth factor-I (IGF-I) and IGF-II were measured by RIA. Serum visfatin and free IGF-I were by ELISA. A high molecular weight form of IGF-II, termed "big" IGF-II, was identified by Western blotting. Tissue IGF-I was quantified by real time RT-PCR after RNA extraction. Before operation, total and free serum IGF-I, serum IGF-II and serum visfatin were within reference range. Big IGF-II was not detected in patient's serum extract. After operation, hypoglycemia did not recur and serum insulin returned to normal, while serum IGF-I decreased by half the preoperative level. RT-PCR revealed that mRNA level of IGF-I in the sarcoidosis tissue was about 1.8-fold greater than that in the normal spleen tissue. These data suggest that ectopic secretion of IGF-I by the splenic sarcoidosis and its direct access to the liver via the portal vein might cause fasting hypoglycemia mainly by suppressing hepatic gluconeogenesis.

[Community participation is associated with life satisfaction in elderly people with diabetes mellitus].

METHODS: Comprehensive questionnaires encompassing physical, psychological, and social aspects were administered by interview to 56 elderly outpatients with diabetes mellitus. Life satisfaction was assessed using the Life Satisfaction Index K (LSIK) . We also assessed the emotional and instrumental social support provided by the families living along with the participants or living separately from the participants. The Index of Social Interaction (18 items) was used to assess the social relationships and the environmental social resources, which were classified into 5 domains: 1) independence, 2) social curiosity, 3) relationships with other people, 4) participation in the community, and 5) feelings of safety. RESULTS: In a univariate analysis, the presence of diabetic neuropathy and pain in the lower back or knee joints were associated with low LSIK scores. Community participation, social curiosity, relationships with other people, and instrumental support from families living together with the participants positively correlated with high LSIK scores. The LSIK scores of the leaders of the diabetes patient group were higher than the scores of those who only participated in the diabetes patient group. In a multiple linear regression analysis, community participation, instrumental support from families living along with the participants, and the absence of neuropathy were independently associated with high LSIK scores. CONCLUSION: Community participation is an important factor associated with life satisfaction in elderly people with diabetes mellitus.

Combined Treatment with Two Water Extracts of Eleutherococcus senticosus Leaf and Rhizome of Drynaria fortunei Enhances Cognitive Function: A Placebo-Controlled, Randomized, Double-Blind Study in Healthy Adults.

We previously found that the water extract of Eleutherococcus senticosus leaves (ES extract) enhanced cognitive function in normal mice. Our study also revealed that the water extract of rhizomes of Drynaria fortunei (DR extract) enhanced memory function in Alzheimer's disease model mice. In addition, our previous experiments suggested that a combined treatment of ES and DR extracts synergistically improved memory and anti-stress response in mice. Although those two botanical extracts are expected to be beneficial for neuropsychological function, no clinical data has ever been reported. Therefore, we performed a placebo-controlled, randomized, double-blind study to evaluate cognitive enhancement and anti-stress effects by the intake of a combined extract in healthy volunteers. The intake period was 12 weeks. The Japanese version of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) test was used for neurocognitive assessment. The combined treatment of ES and DR extracts significantly increased the figure recall subscore of RBANS (p = 0.045) in an intergroup comparison. Potentiation of language domain ((p = 0.040), semantic fluency (p = 0.021) and figure recall (p = 0.052) was shown by the extracts (in intragroup comparison). In anti-stress response, the anxiety/uncertainly score was improved by the extract in an intragroup comparison (p = 0.022). No adverse effects were observed. The combined treatment of ES and DR extracts appear to safely enhance a part of cognitive function in healthy adults.

Cistanche tubulosa (Schenk) Wight Extract Enhances Hindlimb Performance and Attenuates Myosin Heavy Chain IId/IIx Expression in Cast-Immobilized Mice.

Skeletal muscle atrophy is encountered in many clinical conditions, but a pharmacological treatment has not yet been established. Cistanche tubulosa (Schenk) Wight is an herbal medicine used in traditional Japanese and Chinese medicine. In the current study, we investigated the effect of C. tubulosa extract (CTE) on atrophied muscle in vivo. We also investigated hindlimb cast immobilization in mice and devised a novel type of hindlimb-immobilizing cast, consisting of sponge-like tape and a thin plastic tube. Using this method, 3 out of 4 groups of mice (n = 11 for each group) were cast-immobilized in the hindlimbs and administered CTE or vehicle for 13 days. A sham procedure was performed in the mice of the fourth group to which the vehicle was administered. Next, the triceps surae muscles (TS) were excised. To analyze the effect of the novel cast system and CTE administration on muscle atrophy, we evaluated TS wet weight and myofiber cross-sectional area (CSA). We also determined MyHC IId/IIx expression levels by western blotting, since their increase is a hallmark of disuse muscle atrophy, suggesting slow-to-fast myofiber type shift. Moreover, we performed two tests of hindlimb performance. The novel cast immobilization method significantly reduced TS wet weight and myofiber CSA. This was accompanied by deterioration of hindlimb function and an increase in MyHC IId/IIx expression. CTE administration did not alter TS wet weight or myofiber CSA; however, it showed a trend of amelioration of the loss of hindlimb function and of suppression of the increased MyHC IId/IIx expression in cast-immobilized mice. Our novel hindlimb cast immobilization method effectively induced muscle atrophy. CTE did not affect muscle mass, but suppressed the shift from slow to fast myofiber type in cast-immobilized mice, ameliorating hindlimb function deterioration.

Recurrent Drug-induced Liver Injury Caused by the Incidental Readministration of a Kampo Formula Containing Scutellariae Radix.

A 67-year-old woman experiencing coughing visited a clinic and was prescribed drugs, including shosaikoto extract, for 4 days. She subsequently suffered from liver injury, but her condition improved after the discontinuation of all medications. Approximately 1 year later, she experienced fatigue, consulted another clinic, and received saikokeishikankyoto extract for 21 days. She subsequently suffered liver injury again. Both shosaikoto and saikokeishikankyoto contain Scutellariae Radix. This case is thought to be one of recurrent drug-induced liver injury caused by the incidental readministration of a Kampo formula containing Scutellariae Radix. An awareness of adverse drug events caused by Kampo formulas, especially those containing Scutellariae Radix, is essential.

White Matter Hyperintensity in Elderly Patients with Diabetes Mellitus Is Associated with Cognitive Impairment, Functional Disability, and a High Glycoalbumin/Glycohemoglobin Ratio.

Aims: Although evidence has accumulated that white matter hyperintensity (WMH) is associated with the deterioration of cognitive function and impairment of activities of daily living (ADL), the clinical relevance of WMH in elderly patients with diabetes mellitus (DM) is not still clear. The aim of this study was to examine whether WMH volume is associated with ADL and cognitive function and whether glucose control and glucose variability can affect WMH volume in these patients. Methods: This cross-sectional study investigated the associations of WMH with cognitive function and instrumental ADL (IADL), as well as metabolic and vascular risk factors in a total of 178 elderly patients with diabetes. The study assessed WMH volumes and the functional status of cognition and IADL. WMH volumes were evaluated by obtaining axial T2-weighted and fluid-attenuated inversion recovery sequence images on brain magnetic resonance imaging and assessing the images using Software for Neuro-Image Processing in Experimental Research. Results: We found a significant association between WMH volumes and Mini-Mental State Examination (MMSE) scores (p = 0.039) and between WMH and IADL status (p = 0.006). Furthermore, we found significant relations of large WMH volumes with a high glycoalbumin/glycohemoglobin ratio (GA/HbA1c) (p < 0.001). Large WMH volumes were also found to be associated with a low body mass index (p = 0.014) and a low diastolic blood pressure (p = 0.024), but not with HbA1c. Multiple regression analysis showed that high GA/HbA1c, which reflects high glucose variability, was a significant determining factor for large WMH volumes. We also found that GA/HbA1c was negatively associated with both MMSE (p = 0.036) and IADL (p < 0.001). Conclusion: GA/HbA1c, which is a marker of glucose variability, was independently associated with WMH volumes, which could lead to the decline of cognition and IADL in elderly patients with DM.

Telomere attrition in beta and alpha cells with age.

We have reported telomere attrition in ß and α cells of the pancreas in elderly patients with type 2 diabetes, but it has not been explored how the telomere lengths of these islet cells change according to age in normal subjects. To examine the telomere lengths of ß and α cells in individuals without diabetes across a wide range of ages, we conducted measurement of the telomere lengths of human pancreatic ß and α cells obtained from 104 autopsied subjects without diabetes ranging in age from 0 to 100 years. As an index of telomere lengths, the normalized telomere-centromere ratio (NTCR) was determined for ß (NTCRß) and α (NTCRα) cells by quantitative fluorescence in situ hybridization (Q-FISH). We found NTCRß and NTCRα showed almost the same levels and both decreased according to age (p < 0.001 for both). NTCRs decreased more rapidly with age and were more widely distributed (p = 0.036 for NTCRß, p < 0.001 for NTCRα) in subjects under 18 years of age than in subjects over 18 years. There was a positive correlation between NTCRß and NTCRα only among adult subjects (p < 0.001). In conclusion, the telomeres of ß and α cells become shortened with normal aging process.

Risk factors associated with falls in elderly patients with type 2 diabetes.

AIMS: This study investigated risk factors of falls in elderly patients with type 2 diabetes mellitus. METHODS: A total of 211 patients aged ≧60years (168 diabetic patients and 43 non-diabetic control subjects) were studied. Factors associated with falls in the past year were retrospectively examined using multiple logistic regression analysis. RESULTS: The prevalence of patients who had a history of falls in the past year was twice as high as in diabetic patients compared in control subjects (36.9% vs. 18.6%, P<0.05). When diabetic patients were exclusively analyzed, the presence of any level of hypoglycemia and the Timed Up and Go test (TUG) scores correlated with patients' falls. The presence of hypoglycemia (OR 3.62, 95% CI: 1.242-10.534, P=0.018), cognitive impairment (OR 3.63, 95% CI: 1.227-10.727, P=0.020), and high Fall Risk Index scores (OR 1.2, 95% CI: 1.010-1.425, P=0.039) was independently correlated with the presence of multiple falls. When the diabetic patients were divided into three groups according to the frequency of hypoglycemia episodes, the prevalence of falls increased as the frequency of hypoglycemia increased. CONCLUSION: Hypoglycemia was a risk factor of falls in elderly type 2 diabetic patients.

ß-cell telomere attrition in diabetes: inverse correlation between HbA1c and telomere length.

CONTEXT: Although accelerated ß-cell telomere shortening may be associated with diabetes that shows a dramatically increased incidence with aging, ß-cell telomere length in diabetes has never been explored. OBJECTIVE: The objective of the present study was to examine telomere length in the ß-cells of patients with diabetes. DESIGN AND PATIENTS: We determined telomere length in ß- and α-cells of pancreases obtained at autopsy from 47 patients with type 2 diabetes and 51 controls, all older than 60 years. MAIN OUTCOME MEASURE: The normalized telomere to centromere ratio (NTCR), an index of telomere length, was determined for ß- (NTCRß) and α- (NTCRα) cells by quantitative fluorescence in situ hybridization. RESULTS: The NTCRß was reduced by 27% ± 25% and NTCRα by 15% ± 27% in the patients with diabetes relative to the controls (P < .01 for both). Importantly, the degree of shortening was significantly (P < .01) greater in ß-cells than in α-cells. The histogram of NTCR distribution was significantly skewed to the left in the patients with diabetes relative to the controls for both ß- and α-cells, indicating preferential depletion of longer-telomere islet cells. Glycated hemoglobin was negatively correlated with ß-cell telomere length, and the telomeres were significantly shorter in patients who had used hypoglycemic agents than in those who had not. CONCLUSION: The telomeres of ß-cells are shortened in patients with type 2 diabetes. There may be a vicious cycle involving ß-cell telomere attrition and sustained hyperglycemia.

Severe hyponatremia due to inappropriate secretion of antidiuretic hormone following pleurodesis.

A 69-year-old man was diagnosed as having syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (serum sodium: 113 mEq/L) 13 days after a right upper lobectomy due to squamous cell carcinoma of the lung (pT1N0M0, stage IA) whereas the preoperative serum sodium level was nearly normal. He had undergone pleurodesis by instillation of OK432 at 2 and 5 days after surgery for prolonged air leakage. Since other possible causes of SIADH, such as residue of lung cancer, pulmonary infections, brain disorders, or known causative drugs were ruled out, the SIADH in this patient was likely associated with pleurodesis by the use of OK-432. A review of similar cases reported suggests that it is important to be aware of the possibility of severe hyponatremia due to SIADH after chemical pleurodesis.