Impact of Polypharmacy and Risk Factors for Exacerbation of Lower Urinary Tract Symptoms in Patients with Urological Conditions: A Retrospective Study in a Japanese Municipal Hospital.

Polypharmacy exacerbates lower urinary tract symptoms (LUTS). Japan exhibits a higher prevalence of concomitant medication use in drug therapy than other countries. Previous age- and sex-specific reports exist; however, none include patients of all ages. Therefore, this retrospective study determined the impact of polypharmacy and its associated risk factors on LUTS exacerbation in outpatients with urological conditions. We included patients receiving medication who visited the Department of Urology at the Gifu Municipal Hospital (Gifu, Japan) between January, 2018 and December, 2018. The association between LUTS and polypharmacy and the risk factors for LUTS exacerbation were investigated. Patients were categorized into two groups according to their polypharmacy status. We performed propensity score matching and compared the International Prostate Symptom Score (IPSS) between the groups using the unpaired t-test. Multiple logistic regression analysis was performed to examine the risk factors, including "polypharmacy" and "taking multiple anticholinergic medications" for LUTS exacerbation. When comparing the IPSS between the groups, the polypharmacy group was found to have significantly higher scores than the non-polypharmacy group in six items, including "total score" and "storage score." Multiple logistic regression analysis results showed high significance in three items, including "polypharmacy" (odds ratio (OR) = 1.67, 95% confidence interval (CI): 1.03-2.71) and "taking multiple anticholinergic medications" (OR = 8.68, 95% CI: 1.05-71.7). In conclusion, this study revealed that "polypharmacy" and "taking multiple anticholinergic medications" were risk factors for LUTS. Particularly, "polypharmacy" is associated with storage symptom exacerbation. Therefore, eliminating "polypharmacy" and "taking multiple anticholinergic medications" is expected to improve LUTS.

Probable effects of polypharmacy and equivalent doses of psychotropic drugs on prevalence of adverse drug events among psychiatric inpatients in a general hospital in Japan.

OBJECTIVE: In psychiatry, polypharmacy or high psychotropic drug doses increase adverse drug event (ADE) prevalence. However, the full relationship between polypharmacy and ADEs is unclear, and few studies have evaluated dose equivalents for psychotropic drugs for ADEs. Thus, we conducted a retrospective analysis to clarify the effects of polypharmacy and chlorpromazine (CP)-, diazepam (DAP)-, and imipramine- equivalent doses on all ADEs in inpatients. METHODS: Psychiatric inpatients in a Japanese hospital from April 1, 2016 to March 31, 2018, were enrolled. ADE severity and causality were assessed. Multiple logistic regression analyses were performed to evaluate ADE risk factors. RESULTS: Among 462 patients analyzed, out of 471 patients enrolled, 145 (31.4%) experienced ADEs. The causality assessment determined that "possible" was 96.5%. The most common ADEs were nervous system disorders (35%). Multiple logistic regression analyses indicated an increase in ADE prevalence with the number of drugs used (≥5; p = 0.026); CP-equivalent dose (p = 0.048); and endocrine, nutritional, and metabolic disorders (p = 0.045). DAP-equivalent dose; infectious and parasitic diseases; and injury, poisoning, and consequences of other external causes decreased ADE prevalence (p = 0.047, 0.022, and 0.021, respectively). CONCLUSIONS: Avoiding polypharmacy in psychiatric inpatients and adjusting drug regimens to safe equivalent doses could reduce ADEs during hospitalization.

[Establishment of Blinatumomab Home Administration Transition Program Using CADD-Legacy® Pump].

We established a transition program from hospital to home administration of blinatumomab using the CADD-Legacy® pump and evaluated its safety and feasibility in 2 pediatric patients. The program recommended that repeated overnight stays with continued hospitalization would help patients safely transition to home administration of blinatumomab. Pediatric patients who do not attend school, such as preschoolers, or who return to their original school, can be transited to an outpatient setting if people caring for pediatric patients, including teachers in the school, are educated.

[Effectiveness of Pharmaceutical Intervention While Administering 5-Aminolevulinic Acid Hydrochloride through a Collaboration of Physicians and Pharmacists].

5-aminolevulinic acid hydrochloride is a highly effective drug in reducing tumor residuals in transurethral resection of the bladder tumors; however, hypotension is a serious side effect that causes clinical problems. To avoid serious side effects, a pharmacist, in consultation with a physician, decided to discontinue the antihypertensive medication, and the effect of this pharmaceutical intervention was examined retrospectively. This study included patients who received 5-aminolevulinic acid hydrochloride at Gifu Municipal Hospital and were instructed to continue receiving their usual antihypertensive medication on the day of surgery. The control group comprised 17 patients before the pharmaceutical intervention, and the intervention group comprised 18 patients after the pharmaceutical intervention. The difference in systolic blood pressure before and after 5-aminolevulinic acid hydrochloride administration was -19.4±22.5 mmHg in the control group and -2.8±16.0 mmHg in the intervention group. The intervention group showed a significantly lower decrease in blood pressure(p=0.019). Intervention to avoid hypotension through the collaboration between physicians and pharmacists may be effective in improving the safety of 5-aminolevulinic acid hydrochloride.

Melphalan Febrile Neutropenia Risk Factors.

This study aimed to identify the risk factors of febrile neutropenia(FN)onset associated with melphalan(L-PAM)therapy. Thirty-nine patients(21 men, 18 women)were administered L-PAM intravenously for multiple myeloma(MM)from April 2011 to February 2022 at the Department of Hematology of Gifu Municipal Hospital. Patients were classified into those with and without FN(Grade 3 or higher), complete blood count and liver function tests were performed immediately before starting therapy. Univariate analysis with Fisher's exact probability test was performed. Factors with p<0.2 were considered as independent variables for multivariate analysis in the multiple logistic regression analysis. A multivariate analysis with 2 independent variables, lactate dehydrogenase(LD)level>222 U/L(upper limit of the facility reference value)and white <3.3×103/µL(lower limit of the facility reference value)from the univariate analysis, and FN onset(Grade 3 or higher)as the dependent variable showed that LD level>222 U/L(odds ratio: 6.33, 95% confidence interval: 1.12-35.8, p=0.037)was a significant factor. In conclusion, patients with LD levels >222 U/L immediately before starting therapy require adequate monitoring for FN onset following L-PAM administration.

The association between polypharmacy and the efficiency of the functional independence measure in an acute-stage hospital: a retrospective cohort study.

BACKGROUND: The Functional Independence Measure (FIM) evaluates the activities of daily living (ADL), and FIM efficiency represents daily improvement in FIM. Polypharmacy affects both ADL and FIM; however, few studies have evaluated its relationship with FIM efficiency. AIM: This retrospective study investigated the effect of polypharmacy on FIM efficiency in patients undergoing rehabilitation at our acute care hospital in 2014. METHODS: We collected data on the patients' age, sex, diagnosis, length of hospital stay, type and duration of rehabilitation, indications for rehabilitation, FIM score before and after rehabilitation, and number of pharmaceuticals being used. Polypharmacy was defined as the administration of five or more pharmaceuticals. Using propensity score matching, we compared the FIM efficiency between the polypharmacy and non-polypharmacy groups (sub-scales and totals). RESULTS: A total of 2455 patients were included. The analytical population included 2168 patients. The analytical population used for propensity score matching included 727 patients in each group (total: 1454 patients). The following FIM sub-scale items were found to be associated with significantly low FIM efficiency in the polypharmacy group: self-care (polypharmacy group FIM efficiency: 0.43 points/day, non-polypharmacy group FIM efficiency: 0.54 points/day) and sphincter control (0.11 points/day and 0.18 points/day, respectively). No significant differences in the FIM efficiency were observed either for any other sub-scales or for totals. DISCUSSION: In the polypharmacy group, self-care and sphincter control, in particular, were associated with inhibited improvement in ADL and FIM. CONCLUSIONS: Reducing polypharmacy among acute-phase patients would allow an earlier return to their normal daily lives.

What activities of daily living at discharge affect the discharge destination of patients in an acute-care hospital in Japan: A retrospective factor analysis.

It is important to clarify the influence of activities of daily living (ADL) at discharge on the discharge destination of hospitalised patients. The Functional Independence Measure (FIM) is a widely used ADL assessment scale. In this retrospective study, we aimed to identify what ADL based on FIM at discharge affect the discharge destination of hospitalised patients in an acute-care hospital, in addition to how nutritional status and the number of drugs used, as well as types of disease, affect discharge-to-home. We surveyed age, sex, disease type, length of hospital stay, discharge destination, FIM score at discharge, serum albumin level, and the number of continued drugs in hospitalised patients who underwent rehabilitation in Gifu Municipal Hospital (Gifu, Japan) between January 2014 and December 2014. Multiple logistic regression analysis was performed with discharge to home as a dependent variable and age, sex, disease, FIM score and polypharmacy as independent variables. Multiple logistic regression analysis indicated that a significantly high percentage of discharged-to-home patients were associated with 'self-care' (≥33 points; OR: 2.03), 'sphincter control' (≥14 points; OR: 1.49), 'transfers' (≥13 points; OR: 1.94), and 'locomotion' (≥7 points; OR: 3.55), among others. High FIM sub-scale scores at discharge for self-care, sphincter control, transfers, and locomotion were clarified as factors associated with discharge-to-home. These findings of the association of ADL based on FIM and discharge destination would be useful in deciding discharge destinations for patients in an acute-phase hospital.

[Risk Factors for Anti-PD1 Antibody-Induced Skin Eruptions].

Skin complication caused by anti-programmed cell death-1(PD1)antibody is a typical immune-related adverse event. We designed this study to clarify the correlation between risk factors(patient's background and laboratory data)and skin toxicity( rash and eruption, excluding itch)after administration of either nivolumab or pembrolizumab. From February 2016 to January 2018, we evaluated the clinical outcomes of 54 patients who were administered anti-PD1 antibody. The patients were divided into 2 groups: 9 patients with skin eruption caused by anti-PD1 antibody(skin eruption group)and 45 patients without skin eruption caused by anti-PD1 antibody(non-skin eruption group). Univariate analysis revealed a significant difference in eosinophil counts in both the groups before anti-PD1 antibody administration(>300/µL)(p=0.020). Factors with p<0.2 in the univariate analysis and 4 factors, age(<65 years of age), sex(male), allergy(+), and pembrolizumab, likely to be related to the appearance of skin eruption, were examined by multivariate analysis. Consequently, eosinophil count before anti-PD1 antibody administration(>300/µL)was identified as a risk factor (odds ratio: 9.530, 95% confidence interval: 1.260-71.80). In conclusion, we suggest that cases with an increased eosinophil count before anti-PD1 antibody administration(>300/µL)may be associated with the appearance of skin eruption.

Analysis of Adverse Reactions Caused by Potentially Inappropriate Prescriptions and Related Medical Costs That Are Avoidable Using the Beers Criteria: The Japanese Version and Guidelines for Medical Treatment and Its Safety in the Elderly 2015.

We conducted a retrospective study to investigate adverse drug reactions and associated medical costs among elderly individuals that could be avoided if pharmacotherapy was performed in accordance with the Beers Criteria: the Japanese Version (BCJV) and Guidelines for Medical Treatment and Its Safety in the Elderly 2015 (GL2015). Patients aged at least 65 years who were either hospitalized at Gifu Municipal Hospital between October 1 and November 30, 2014 (n = 1236) or had outpatient examinations at Gifu Municipal Hospital on October 1-2, 2014 (n = 980) were included in the study. The outcomes measured were usage rates of drugs listed in the BCJV and GL2015, incidence rates of adverse drug reactions, and additional costs incurred per patient due to adverse reactions. Among the inpatients, usage rates of drugs listed in the BCJV and GL2015 were 24.0 and 72.4%, respectively, and adverse reactions to these drugs occurred at rates of 3.0 and 8.2%, respectively. Among the outpatients, while the usage rates were 26.2% (BCJV) and 59.9% (GL2015), the incidence rates of adverse reactions were 4.7% (BCJV) and 3.9% (GL2015). The additional costs incurred due to adverse drug reactions ranged from 12713-163925 yen per patient. Our results demonstrate that appropriate use of drugs based on the BCJV and GL2015 can help prevent adverse reactions; this would reduce the overall medical costs.

[Construction and Evaluation of a New Support System for Prescription Inspection of Anticancer Drug Injection Preparation via Quality Control].

Using electronic medical charts at the department of pharmacy of Gifu Municipal Hospital, we constructed a new support system for the prescription inspection of anticancer drug injection preparation via quality control. The system comprises: (1)a "regimen inspection sheet" that can be easily used to check the regimen and clinical laboratory data of patients before the administration of anticancer drugs and(2)an "instruction sheet confirming implementation" that can conveniently confirm the latest clinical laboratory data used to decide the administration of anticancer drugs. Using this system, the safety of anticancer drug administration and work efficiency may be improved.

Medical and economic factors influencing generic drug use in the Japanese public health system: Influencing factors in different populations.

Factors influencing generic drug use must be considered when new drug policies are established and initiatives are implemented to promote generic drug use. This study was conducted to elucidate medical and economic factors that influence generic drug use in the Japanese public health system by evaluating the degree of generic drug use via a multivariate analysis. We conducted a retrospective study of medications administered to inpatients at Gifu Municipal Hospital (Japan) from November 1 to 14, 2014. Details of inpatients (age, sex, and type of medical insurance) and the drugs administered (prescribing institution, dispensing pharmacy, price, and class) were assessed. A total of 1409 drugs (original, 639; generic, 770) were analyzed. Multivariate analysis showed significant differences in out-of-pocket medical fees [odds ratio (OR), 0.595], drugs prescribed at Gifu Municipal Hospital (OR, 1.811), drugs prepared at a health insurance pharmacy (OR, 1.541), drugs containing the same active substances as in the generic drugs used at Gifu Municipal Hospital (OR, 3.712), and drugs costing ≥30 yen and containing the same active substance/having the same specifications (OR, 0.516). Drugs prescribed at a large key hospital in the community with high adoption rates of generic drugs, drugs containing the same active substances as the generic drugs adopted by the hospital, and drugs prepared at health insurance pharmacies contributed to a more frequent use of generic drugs. By contrast, out-of-pocket medical fees and being prescribed expensive drugs contributed to the less frequent use of generic drugs.

[Predictors of Nivolumab-Induced Skin Reactions].

Skin reactions to nivolumab are typical immune-related adverse events. We investigated the relation between patient background and test values before nivolumab administration and skin reactions. From February 2016 to February 2017, we evaluated the clinical outcomes of 21 patients who were administered nivolumab. Patients were divided into 2 groups: 3 cases of skin reactions to nivolumab(skin reaction group)and 18 cases without skin reactions to nivolumab(non-skin reaction group). In the skin reaction group, the numbers of eosinophils and basophils before nivolumab administration were significantly higher than those in the non-skin reaction group(p=0.0015 and p=0.0075, respectively). It was suggested that the numbers of eosinophils or basophils before nivolumab administration might be associated with the appearance of skin reactions.

Establishing an Indicator of Hypokalemia in Patients Receiving Anti-Epidermal Growth Factor Receptor Antibodies.

Risk factors for hypokalemia were analyzed in patients who received anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR MoAbs) at Gifu Municipal Hospital between February 2010 and March 2013. Subjects were 51 patients (27 men and 24 women) with the median age (interquartile range) of 66 (63-72) years. The study period started from the initiation of anti-EGFR MoAbs administration and ended 4 weeks after administration was completed. Patients were categorized into the side effect group if both minimum serum potassium (Min S-K) grade and b grade (pre-treatment S-K grade-Min S-K grade) were B1; otherwise, they were placed into the no side effect group. Univariate analysis for factors to prevent the side effect identified the "concomitant use of hyperkalemia-inducing drugs" to be statistically significant (p=0.010). Multivariate analysis was conducted on factors with a p value of <0.25 in the univariate analysis and on "concomitant use of hyperkalemia-inducing drugs," which was likely to clinically affect S-K decrease, although its p value was >0.25. It showed that "concomitant use of hyperkalemia-inducing drugs" was a significant risk-prevention factor (odds ratio: 0.138, 95% confidence interval[CI]: 0.033-0.581, p=0.007). In conclusion, "concomitant use of hyperkalemia-inducing drugs" is a factor associated with preventing hypokalemia accompanying anti-EGFR MoAbs administration.

Kinetics of hematopoietic stem cells and supportive activities of stromal cells in a three-dimensional bone marrow culture system.

In the bone marrow, hematopoietic cells proliferate and differentiate in close association with a three-dimensional (3D) hematopoietic microenvironment. Previously, we established a 3D bone marrow culture system. In this study, we analyzed the kinetics of hematopoietic cells, and more than 50% of hematopoietic progenitor cells, including CFU-Mix, CFU-GM and BFU-E in 3D culture were in a resting (non-S) phase. Furthermore, we examined the hematopoietic supportive ability of stromal cells by measuring the expression of various mRNAs relevant to hematopoietic regulation. Over the 4 weeks of culture, the stromal cells in the 3D culture are not needlessly activated and "quietly" regulate hematopoietic cell proliferation and differentiation during the culture, resulting in the presence of resting hematopoietic stem cells in the 3D culture for a long time. Thus, the 3D culture system may be a new tool for investigating hematopoietic stem cell-stromal cell interactions in vitro.

Guanylin-Guanylyl cyclase-C signaling in macrophages regulates mesenteric fat inflammation induced by high-fat diet.

Guanylin (Gn), a bioactive peptide, and its receptor, guanylyl cyclase-C (GC-C), are primarily present in the intestine and maintain homeostasis in body fluids. Recently, rats whose macrophages overexpress Gn and GC-C were found to be resistant to diet-induced obesity. Considering that obesity is strongly related to a chronic inflammatory state in white adipose tissues, it is possible that Gn-GC-C macrophages contribute to the regulation of inflammation. In the present study, we investigated the inflammatory state of mesenteric fat in rats transgenic for both Gn and GC-C (double-transgenic [dTg] rats) by evaluating the levels of cyclic guanosine monophosphate (cGMP), a second messenger of Gn-GC-C, cGMP-dependent protein kinase (PKG), and phosphorylated vasodilator-stimulated phosphoprotein (VASP), a target protein of PKG. The levels of cGMP in dTg rats was higher than in WT rats fed the same diet. Although there were no significant differences in levels of PKG and phosphorylated VASP between WT and dTg rats fed a standard diet (STD), these levels in dTg rats fed a high fat diet (HFD) were markedly increased compared with levels in HFD WT rats. Furthermore, mRNA levels of proinflammatory factors in mesenteric fat were lower in HFD dTg rats than in HFD WT rats and were similar to levels in STD WT and dTg rats. These results indicate that the Gn-GC-C system in macrophages regulates the cGMP-PKG-VASP pathway and controls obesity through the downregulation of proinflammatory factors.

Immunomodulatory and antiparasitic effects of garlic extract on Eimeria vermiformis-infected mice.

We investigated the immunomodulatory and parasiticidal effects of garlic extract on coccidiosis caused by Eimeria vermiformis infection in male ICR mice. One group received garlic extract daily until the end of the experiment by the oral route from 10 days prior to oral infection with 300 sporulated E. vermiformis oocysts (infected-garlic(+)). The other group served as a control positive with E. vermiformis infection alone (infected-garlic(-)). In the infected-garlic(+) group, garlic extract treatment induced a significant reduction in fecal oocyst output when compared with the infected-garlic(-) group. Histopathological, immunohistochemical, and gene expression analysis for inflammatory cytokines in ileal tissues showed that the garlic extract treatment impaired intracellular development of E. vermiformis during the early stages by increasing the number of intraepithelial CD8(+) T cells and decreasing IL-10 expression. This induced cell cytotoxicity which was reflected by a decrease in oocyst numbers in the intestinal villi and the feces, indicating anticoccidial effects of the garlic extract. However, further studies to explore the precise mechanism of the observed effects of garlic treatment during Eimeria infection are needed to verify our results.

The Establishment of Indicators of Thrombocytopenia in Patients Receiving Lenalidomide Therapy.

The onset of thrombocytopenia and related factors was analyzed in patients with multiple myeloma (MM) who were receiving lenalidomide (Len) therapy at the Department of Hematology, Gifu Municipal Hospital between July 2010 and March 2014. We included 28 MM patients (18 males and 10 females) with a median age of 70.5 (range: 55-84) years. The patients were examined from the start of Len therapy until treatment discontinuation, prolongation, or dose reduction. A significant correlation was observed between platelet (Plt) count prior to the start of Len therapy (pre-treatment Plt) and the difference between pre-treatment Plt and the minimum Plt up to the point in time of treatment discontinuation, prolongation, or dosage reduction (min-Plt) (r=0.674, p<0.001). Univariate analysis revealed that factors causing thrombocytopenia of grade 2or above as a side-effect showed a significant difference when the Plt count was below the lower limit of the normal value (<14.0×10(4)/µL)(p=0.011). Factors with p<0.25 in the univariate analysis and daily dosage of Len were examined by multivariate analysis; thus, a Plt count below the lower limit of the normal value was identified as a factor (odds ratio: 15.12, 95% confidence interval [CI]: 1.712-133.5, p=0.015). In conclusion, we suggest that a Plt count below the lower limit of the normal value prior to the start of Len therapy is a prognostic factor for thrombocytopenia as a side-effect of Len therapy.

[A female chronic myeloid leukemia patient who gave birth after stopping imatinib intentionally but who maintained a major molecular response with interferon].

Imatinib was administrated to a 38-year-old woman with chronic myeloid leukemia(CML). A major molecular response (MMR)(≤5 copies/0.5 µgRNA in Amp-CML detected using the transcription mediated amplification/hybridization protection assay(TMA/HPA)method)was achieved in 18 months. She maintained MMR for 10 months, and wished to become pregnant. Imatinib was stopped intentionally because she wished to plan a pregnancy, but we prescribed interferon alpha (IFN-a)due to the likelihood of the CML recurring after pregnancy. The nausea caused by IFN-a was improved by administrating it during the night, and she gave birth to a healthy baby by a normal delivery, whilst maintaining MMR. In this case, IFN-a treatment gave good clinical results, the patient's prognosis was improved, and she could maintain a good quality of life. We consider this to be an informative example of IFN-a therapy for CML during pregnancy.

[Analysis of factors influencing the occurrence of infusion reaction after initial treatment with rituximab].

We investigated factors influencing the occurrence of infusion reactions after initial treatment with rituximab. We included patients who were administered rituximab for the treatment of B-cell non-Hodgkin's lymphoma at the Gifu Municipal Hospital Hematology from February 2010 to March 2013. Fifty-one patients were included; their median age was 72(44-87)years, and 31 were men and 20 were women. We defined the index of infusion reaction as the maximal change in body temperature within 24 hours from the administration of rituximab and evaluated the correlation with change in body temperature and each factor, and differences of change in body temperature between the upper and lower groups divided by standard value of each factor by using the t test without correspondence. The "2,000 U/mL or less group"of soluble interleukin-2 receptor(sIL- 2R)levels and the "over 2,000 U/mL group"showed significant different(p=0.014). The "double value or less group"of a standard value(211 IU/L)and "over double value group"showed significantly different lactate dehydrogenase(LDH)levels (p=0.017). The "lower limit or less group"of the standard value(men: 13 g/dL, women: 12 g/dL)and the "over lower limit group"showed significantly different hemoglobin(Hb)levels(p=0.020). In conclusion, the levels of sIL-2R, LDH, and Hb may predict the occurrence of infusion reaction after the initial administration of rituximab in patients with B-cell non-Hodgkin's lymphoma.

Anatomical View of the Internal Carotid Artery Occlusion in Japanese Black Cattle.

The internal carotid artery (ICA) is a branch of the common carotid artery (CCA), along with the external carotid artery (ECA), which together provide the blood supply for the brain. The description of the ICA in cattle is vague, including denial of its existence or degeneration at an early stage after birth. This anatomical study investigated the internal carotid artery in Japanese black cattle. Sixty-five heads of Japanese black cattle aged from newborn to 13 years were dissected and injected with colored latex from the CCA after separating the head and body. Diameter measurements of the artery branches from the CCA on its bifurcation were conducted. Furthermore, a histological examination of the ICA wall's structures, which consist of the tunica intima, tunica media, and tunica externa, was performed. The ICA of Japanese black cattle is closed on the left side after age 3 years, except for a small lumen at 13 years, whereas the right ICA remains open at all ages. The location of occlusion of the left internal carotid artery (LICA) shows thickness of the tunica intima and an increased connective tissue layer area. The diameter of the ICA does not differ between the left and right sides, and there is no correlation with age. Therefore, further studies are needed, especially of ICA occlusion related to Japanese black cattle's physiology or cerebrospinal disease.