Risk factors for thrombocytopenia and analysis of time to platelet transfusion after azacitidine treatment.

The use of azacitidine (AZA) has been known to lead to a high incidence of hematotoxic adverse events. The aims of this study were to identify the risk factors for thrombocytopenia after the administration of AZA and to analyze time to the initial platelet transfusion. Sixty-two patients with myelodysplastic syndrome (MDS), who were treated with AZA in Gifu Municipal Hospital between March 2012 and June 2020, were included in this study. The risk factors for thrombocytopenia were identified using univariate analysis of patient characteristics, disease type, and laboratory values immediately before the start of treatment. Variables with p<0.2 identified in the univariate analysis were used as independent variables in the multivariate analysis. This analysis identified "creatinine clearance (CCr) <60 mL/min" as a significant factor (odds ratio, 4.790; 95% confidence interval [CI], 1.380-16.70; p=0.014). Subsequently, time in days to the initial platelet transfusion after the initial administration of AZA was analyzed using the log-rank test. The overall median time in days to platelet transfusion was 370 days. The log-rank test was used to determine the influence of patient characteristics, disease type, and laboratory values immediately before the start of treatment. The subsequent Cox proportional hazard regression analysis using variables with p<0.2 as independent variables identified "hemoglobin (Hb) <8.0 g/dL" as a significant factor (hazard ratio, 2.143; 95% CI, 1.001-4.573; p=0.048). The results of this study led to the following clinical implications: first, patients with CCr of <60 mL/min at the start of treatment should be treated with caution due to the risk of thrombocytopenia. Second, patients with Hb of <8.0 g/dL at the start of treatment may require platelet transfusion in the early stage of treatment.

Effects of polypharmacy on the prevalence of adverse drug events resulting in outpatient visits and hospitalization.

A high proportion of hospitalizations is attributable to the prevalence of adverse drug events. This retrospective study included outpatients and inpatients to determine the prevalence of adverse drug events and if polypharmacy increases it. The prevalence, classification, and causality of adverse drug events were assessed based on medical records, laboratory values, and other data. Multivariate analysis (multiple logistic regression analysis) was performed with the presence or absence of adverse drug events at the time of the visit as the dependent variable and items for which the P-value was <0.25 in the univariate analysis as independent variables. The prevalence of adverse drug events was 13.0%, 10.9%, and 16.0% among all patients, the outpatient group, and the inpatient group, respectively. Multivariate analysis showed that polypharmacy (≥5 drugs) significantly increased the risk of adverse drug events in all patients. The prevalence of adverse drug events significantly increased with each additional drug used. We expect that minimizing the number of medications through moderation of the number of prescription drugs and elimination of polypharmacy will reduce the number of outpatient visits and hospitalizations due to adverse drug events.

Cost utility analysis of pharmacist counseling care for breast cancer chemotherapy outpatients.

Chemotherapy for cancer is increasingly implemented in the outpatient setting. Pharmacists contribute to cancer treatment by conducting counseling during outpatient chemotherapy visits. They provide guidance on drug treatment, side effects, and side effect countermeasures on every visit. However, there have been few economic evaluations of pharmacist involvement in outpatient chemotherapy. Therefore, we performed a cost utility analysis. We assigned usual care (control) and pharmacist counseling to two groups of 19 patients receiving outpatient chemotherapy for breast cancer at Gifu Municipal hospital. Quality of life was measured at three timepoints before and during chemotherapy treatment using the EuroQol 5 dimension instrument (EQ-5D). EQ-5D values across the timepoints were 0.831, 0.757, and 0.791 for the control group, and 0.882, 0.883, and 0.921 for the pharmacist counseling group. The additional cost in the pharmacist counseling group was 2,227 yen per counseling session. The change in quality-adjusted life years (QALY) was a maximum of -0.021±0.186 in the control group and 0.007±0.199 in the pharmacist counseling group. The maximum cost for one QALY was 1,360,558 yen (≈12,460 US dollars). Pharmacists' counseling in outpatient cancer chemotherapy for breast cancer patients had an acceptable incremental cost-effect ratio, contributing to improved patient quality of life without significant additional expenditure to healthcare.

Factors influencing the use of over-the-counter drugs and health foods/supplements.

Over-the-counter (OTC) drugs and health foods/supplements are used as means of self-medication with the aim of preventing diseases and maintaining health. No reports have yet addressed the relationship between healthcare systems and self-medication. Here, we carried out a retrospective survey to identify healthcare system factors affecting OTC drug and health food/supplement usage. Patients hospitalized at Gifu Municipal Hospital between October 1, 2014 and March 31, 2015 were given a survey. The items surveyed were age, gender, disease, alcohol intake/smoking status, insurance classification, and medical pharmaceuticals, OTC drugs, and health foods/supplements used immediately before hospitalization. We performed multiple logistic regression analysis using OTC drugs and health foods/supplements as dependent variables with patient attributes, medical insurance, etc. as independent variables. A total of 5,965 patients were analyzed. OTC users comprised 2.6 % (156 people) of the total. The use of OTC drugs was significantly higher for females and alcohol consumers than in other categories. In contrast, the use of OTC drugs was significantly lower for participants in public expense/medical subsidy programs. Health foods/supplements were used by 4.0 % of all subjects (240 people); their use was significantly higher among females and users of medical pharmaceuticals. On the other hand, the use of health foods/supplements was significantly lower for smokers, users of the latter-stage elderly healthcare system, and users of public expense/medical subsidy programs.

Effects of a single arthrocentesis and a COX-2 inhibitor on disorders of temporomandibular joints. A preliminary clinical study.

Our aim was to examine the short-term effect of combined treatment with single arthrocentesis and a COX-2 inhibitor on 26 patients with severe symptoms of temporomandibular joint (TMJ) disorders. The severity of the disorders was graded according to the degree of restriction of mouth opening and pain score on a visual analogue scale. Synovial fluid was collected from the superior joint space of the affected TMJ, and arthrocentesis was done with isotonic saline, 200ml. Subsequently, etodolac, 400mg/day, was given for 2 weeks. At 14 days, patients were re-examined and further specimens of synovial fluid were collected. Patients generally lost their symptoms and the severity of the disorders improved significantly (P<0.01). The concentrations of total protein and albumin in synovial fluid decreased with no statistical significance. However, the concentration of matrix metalloproteinase-3 and its ratios to total protein and albumin did decrease significantly (P<0.05). Our results suggest that a larger controlled study is necessary to clarify the contributory effect of arthrocentesis and etodolac for patients with severe symptoms of TMJ disorders.

Matrix metalloproteinase-2 in synovial lavage fluid of patients with disorders of the temporomandibular joint.

We examined the matrix metalloproteinase-2 (MMP-2) activity in synovial lavage fluid of patients with disorders of the temporomandibular joint (TMJ) and explored the possible correlationship between MMP-2 activity and radiological changes. We studied 86 patients and 10 healthy volunteers. An arthrogram and a double contrast arthrotomogram were taken to evaluate intra-articular morphological changes. The patients were divided into three groups: no abnormality (n = 36), internal derangement (n = 39), and osteoarthritis (n = 11). Samples of synovial fluid were studied by gelatin zymography, and we sought a correlation between the band detected and radiological findings. ProMMP-2 was detected in all samples and active MMP-2 was detected in 9/36 with no abnormality, 14/39 with internal derangement and 5/11 with osteoarthritis. No active form of MMP-2 was detected in the control group. The incidence of active MMP-2 was high in the internal derangement group and highest in the osteoarthritis group, which suggests that active MMP-2 plays an important part in the development of conditions of the TMJ.

Osteosarcoma metastatic to the mandible: a case report.

A case of osteosarcoma that metastasized to the mandibular ramus from the femur in a 36-year-old man is presented. The patient was referred to us for the diagnosis and treatment of swelling of the left cheek. Radiologic examination showed a radiolucent lesion containing radiopaque areas within the left mandibular ramus. The patient previously suffered from a femoral small cell osteosarcoma, which was resected 71 months before our first examination. After induction of general anesthesia, a unilateral mandibulectomy and a simultaneous reconstruction using a titanium plate and an artificial condyle were performed. The postoperative course was uneventful, with satisfactory facial appearance and jaw function. The histopathologic features of the mandibular tumor were identical to those of the femoral tumor. Thus the mandibular lesion was diagnosed as a metastatic small cell osteosarcoma. At 27 months after the operation there had been no recurrence.

Lysophosphatidylcholine promotes cholesterol efflux from mouse macrophage foam cells.

We examined the effects of lysophosphatidylcholine (lyso-PC) on promoting cholesterol efflux from macrophage foam cells. Mouse peritoneal macrophages were converted to foam cells by incubation with [3H]cholesteryl linoleate-labeled or unlabeled acetyl-LDL. When these cells were incubated with lyso-PC, [3H]cholesterol release was promoted in relation to both dose and time, and cellular cholesterol mass was decreased, while medium cholesterol mass was increased. These cholesterol efflux-promotive effects of lyso-PC were confirmed by the fact that the lyso-PC-treated cells showed less oil red O staining than the control cells. ApoE secretion, estimated by Western blotting of the medium, was also augmented by lyso-PC. Both the cholesterol and apoE released by lyso-PC treatment were floated by ultracentrifugation of the medium after its density had been adjusted to 1.210 g/mL. By electron microscopic analysis, vesicular lipoproteins were observed in ultracentrifugally concentrated conditioned medium of lyso-PC. Monensin, a protein secretion inhibitor, effectively inhibited [3H]cholesterol release induced by lyso-PC but not by apoA-I. These results suggest that lyso-PC may inhibit the development of atherosclerosis or enhance its regression by stimulating cholesterol efflux from macrophage foam cells.

Depletion of brain glutathione by buthionine sulfoximine enhances cerebral ischemic injury in rats.

Oxygen free radicals have been implicated in the pathogenesis of brain injury induced by ischemia/reperfusion. We studied the role of endogenous reduced glutathione (GSH) in brain infarction associated with focal cerebral ischemia caused by permanent ligation of the right middle cerebral artery (MCA) and the right common carotid artery (CCA) plus temporary occlusion of the left CCA. GSH levels in the ischemic side of cortex decreased with time after ischemia and preceded cortical infarction estimated by the staining of mitochondrial respiratory enzymes with 2,3,5-triphenyltetrazolium chloride. GSH levels in the contralateral cortex were unchanged through the experimental periods. The extent of decrease of GSH levels and the severity of infarction in the ischemic cortex at 24 h after ischemia depended on the duration of occlusion of the left CCA. Depletion of brain GSH with buthionine sulfoximine, a selective inhibitor for gamma-glutamylcysteine synthetase, exacerbated cortical infarction and edema after ischemia. These results suggest that the endogenous brain GSH is an important determinant in the defense mechanisms against lesion formation after ischemia and support the possible role of oxygen radicals in the pathogenesis of ischemic brain injury.

Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn superoxide dismutase.

Oxygen-derived free radicals have been implicated in the pathogenesis of vasogenic edema and infarction caused by ischemia and reperfusion injury. In earlier studies, exogenously supplied liposome-entrapped CuZn superoxide dismutase (CuZn-SOD) ameliorated ischemic brain edema and infarction in rats following focal cerebral ischemia. To ascertain directly the role of SOD in the protection against superoxide radical-induced injury, we measured infarct size and water content 24 hr following focal cerebral ischemia in nontransgenic mice and in transgenic mice bearing the human SOD1 gene. These transgenic mice have 3.1-fold higher cellular CuZn-SOD activity in the brain than do their nontransgenic littermates. We also measured antioxidant levels (reduced glutathione and reduced ascorbate) of contralateral cortex, infarct cortex, surrounding cortex, and striatum. Infarct size and brain edema were significantly decreased in transgenic mice compared with nontransgenic mice. Reduced glutathione and reduced ascorbate levels decreased in the ischemic hemisphere, but levels in surrounding cortex and striatum were significantly higher in transgenic mice than in nontransgenic mice. These results indicate that increased endogenous SOD activity in brain reduces the level of ischemic damage and support the concept that superoxide radicals play an important role in the pathogenesis of infarction and edema following focal cerebral ischemia.

Effect of antiperoxidative drugs on gastric damage induced by ethanol in rats.

Lesion formation due to oral administration of absolute ethanol could be prevented by parenteral pretreatment with antiperoxidative drugs such as butylated hydroxytoluene (BHT), quercetin and quinacrine. Also effective were allopurinol and oxypurinol, inhibitors of xanthine oxidase, but not superoxide dismutase (SOD) and hydroxyl radical scavengers, such as sodium benzoate and dimethyl sulfoxide (DMSO). BHT, quercetin, quinacrine and sulfhydryl compounds such as reduced glutathione and cysteamine which offer gastroprotection in vivo against ethanol inhibited lipid peroxidation induced in vitro by ferrous ion in porcine gastric mucosal homogenate, but SOD, sodium benzoate, DMSO, allopurinol and oxypurinol did not. These results suggest the possibility that an active species, probably derived from free iron mobilized by the xanthine oxidase system, other than oxygen radicals such as hydroxyl radicals, contributes to lipid peroxidation and lesion formation in the gastric mucosa after absolute ethanol administration.

Effect of polyamines on acidified ethanol-induced gastric lesions in rats.

The participation of polyamines and nonprotein sulfhydryls in the gastric cytoprotective mechanisms was studied using gastric mucosal lesions produced by acidified ethanol in rats as an experimental model. Treatment with prostaglandin E2 (PGE2), but not cimetidine, prevented the formation of gastric mucosal lesions. Oral administration of cadaverine, spermidine and spermine prevented the lesion formation by acidified ethanol in a dose-dependent manner. Indomethacin or acetazolamide had no influence on the cytoprotective effect of spermine, whereas sulfhydryl blockers such as iodoacetamide and N-ethylmaleimide partially blocked it. Sulfhydryl compounds such as cysteine, reduced glutathione (GSH), and cysteamine prevented the lesion formation induced by acidified ethanol. The concentration of nonprotein sulfhydryls in the gastric mucosa was significantly decreased at 1 hr after administration of acidified ethanol, and this decrease was partially prevented by spermine or PGE2. These results suggest that the cytoprotective effect of spermine may not be mediated by endogenous prostaglandins or alkaline secretion in the gastric mucosa, but may be partially related to endogenous sulfhydryl compounds.

On RNA-polymerases of leukemia L 1210 origin and an enzymatic method to screen antitumor antibiotics.

Four DNA-dependent RNA-polymerases were separated from the cell homogenate of moust leukemia L1210 cell by DEAE-cellulose column chromatography and tentatively designated as Peaks I, II, III and IV in the elution order. Peak II was inactivated by the addition of alpha-amanitin and effects of antibiotics and enzymes on the RNA-polymerase activity using Peaks, I, II and a mixture of Peaks I and II were examined. The RNA-polymerases were used to screen for enzyme inhibitors produced by microbes. This enzymatic method was successfully proved to select antitumor antibiotics.