Pharmacological Investigation of Hypoalbuminemia on the Prolonged and Potentiated Action of Midazolam in Rats.

Midazolam (MDZ) is clinically used for its sedative and anticonvulsant properties. However, its prolonged or potentiated effects are sometimes concerning. The main binding protein of MDZ is albumin, and reduced serum albumin levels could lead to MDZ accumulation, thereby potentiating or prolonging its effects. Previous investigations have not thoroughly examined these phenomena from a behavioral pharmacology standpoint. Consequently, this study aimed to evaluate both the prolonged and potentiated effects of MDZ, as well as the effects of serum albumin levels on the action of MDZ in low-albumin rats. Male Wistar rats were classified into control (20% protein diet), low-protein (5% protein), and non-protein groups (0% protein diet) and were fed the protein-controlled diets for 30 d to obtain low-albumin rats. The locomotor activity and muscle relaxant effects of MDZ were evaluated using the rotarod, grip strength, and open-field tests conducted 10, 60, and 120 min after MDZ administration. Serum albumin levels decreased significantly in the low-protein and non-protein diet groups compared with those in the control group. Compared with the control rats, low-albumin rats demonstrated a significantly shorter time to fall, decreased muscle strength, and a significant decrease in the distance traveled after MDZ administration in the rotarod, grip strength, and open-field tests, respectively. Decreased serum albumin levels potentiated and prolonged the effects of MDZ. Hence, serum albumin level is a critical parameter associated with MDZ administration, which should be monitored, and any side effects related to decreased albumin levels should be investigated.

Medical Economic Effect of Pharmaceutical Interventions by Board-Certified Pharmacists in Palliative Pharmacy for Patients with Cancer Using Medical Narcotics in Japan: A Multicenter, Retrospective Study.

BACKGROUND: The Japanese Society for Pharmaceutical Palliative Care and Sciences specializes in pharmacology in the field of palliative medicine. More than 700 board-certified pharmacists in palliative pharmacy (BCPPP) are actively involved in palliative pharmacotherapy at various hospitals and pharmacies. The purpose of this study was to determine the economic effect of pharmaceutical interventions by BCPPPs. METHODS: This multicenter retrospective study included 27 medical centers and analyzed the medical economic effect of interventions by BCPPPs (17 pharmacists) and non-BCPPPs (24 pharmacists) on patients using medical narcotics for cancer pain in September 2021. RESULTS: The percentage of patients who received a pharmaceutical intervention and whose drug costs were reduced by pharmacist intervention was significantly higher in the BCPPP group than in the non-BCPPP group. Although there was no significant difference between the two groups in drug cost reduction per patient per month (BCPPP group: $0.89 [-$64.91 to $106.76] vs. non-BCPPP group $0.00 [-$1,828.95 to $25.82]; P = 0.730), the medical economic benefit of pharmacist intervention in avoiding or reducing adverse drug reactions was higher in the BCPPP group ($103.18 [$0.00 to $628.03]) than in the non-BCPPP group ($0.00 [$0.00 to $628.03]) (P = 0.070). The total medical economic benefit-the sum of these-was significantly higher in the BCPPP group ($88.82 [-$14.62 to $705.37]) than in the non-BCPPP group ($0.66 [-$1,200.93 to $269.61]) (P = 0.006). CONCLUSION: Pharmacological intervention for patients with cancer using medical narcotics may have a greater medical economic benefit when managed by BCPPPs than by non-certified pharmacists in Japan.

Relationship between the phase angle from bioelectrical impedance analysis and daily physical activity in patients with rheumatoid arthritis.

OBJECTIVES: This study aimed to examine the relationship between daily physical activity and the phase angle (PhA) obtained by bioelectrical impedance analysis in rheumatoid arthritis (RA) patients. METHODS: Data from a prospective cohort study of RA patients who were surveyed every year were analysed. The PhA was assessed by the bioelectrical impedance analysis method, and physical activity was assessed as the amount of time of exercise in metabolic equivalents (METs) per day using a triaxial accelerometer for 7 consecutive days. The association between physical activity and the PhA was evaluated using the isotemporal substitution model in multiple regression analysis. RESULTS: Seventy-six RA patients were included in the analysis (81% female and age 66.2 ± 13.1 years). On cross-sectional analysis, the isotemporal substitution model in multiple regression analysis showed that the PhA was 0.05 points higher every 10 minutes when activities with intensity of 1 ≤ METs < 2 were replaced by activities with intensity of ≥3 METs (P = .01). Over 1 year, the rate of change in the PhA was 0.69% higher every 10 minutes when activities with intensity of 1 ≤ METs < 2 were replaced by activities with intensity of ≥3 METs (P = .037). CONCLUSION: The PhA in RA patients may be related to physical activity level.

A study on the chemical stability of cholesterol-lowering drugs in concomitant simple suspensions with magnesium oxide.

BACKGROUND: Difficulty in taking solid medicines is a common issue particularly for the elderly because of a decline in swallowing function, also known as dysphagia. For patients with such a dysfunction, a simple suspension method, in which solid medicines are disintegrated and suspended using warm water, has been developed and widely used in Japanese clinical settings. However, there is little information on drug stability in the simple co-suspension of multiple formulations especially including acidic or alkaline ones. In this study, the chemical stability of typical cholesterol-lowering drugs was investigated in a simple co-suspension with alkaline magnesium oxide (MgO) which is frequently used as a laxative or antacid in Japan. METHODS: A cholesterol-lowering drug (one tablet) was soaked with or without MgO in warm water (55°C), and the vessel was left at room temperature for 10 min or 5 h. The suspensions prepared were then analyzed by high-performance liquid chromatography. Degradation products were analyzed by nuclear magnetic resonance spectroscopy and mass spectrometry for the structural elucidation. RESULTS: In the simple co-suspension with MgO, no significant degradation was observed for atorvastatin or pravastatin, while a significant decrease of the recovery from the co-suspension was observed for rosuvastatin after 5 h. On the other hand, simvastatin and ezetimibe co-suspended with MgO were partially degraded to simvastatin acid and a pyran compound, respectively. CONCLUSIONS: A simple co-suspension with MgO is feasible for atorvastatin, pravastatin, and rosuvastatin, although the rosuvastatin tablet should not be left soaking for a long time. Further it is inadvisable to suspend simvastatin or ezetimibe together with MgO because of their partial degradation.

Hospital pharmacist interventions for the management of oral mucositis in patients with head and neck cancer receiving chemoradiotherapy: a multicenter, prospective cohort study.

PURPOSE: Oral mucositis is a severe adverse event in patients with head and neck cancer (HNC) receiving chemotherapy and radiotherapy that may cause the termination of cancer treatment. In this study, we aimed to reveal the benefits of pharmacist interventions in oral health care for patients with HNC receiving concurrent chemoradiotherapy (CCRT). METHODS: We conducted a multicenter, prospective cohort study on 173 patients from September 2019 to August 2022. We evaluated the association between the occurrence of oral mucositis during CCRT and various factors in the absence or presence of direct medication instructions from hospital pharmacists. RESULTS: Sixty-eight patients received medication instructions from pharmacists (the pharmacist intervention group), whereas 105 patients did not receive instructions (the control group). Logistic regression analysis showed that grade 2 (Gr 2) oral mucositis was significantly lower in patients receiving pharmacist interventions than in patients in the control group (adjusted odds ratio [aOR], 0.42; 95% confidence interval [CI], 0.18-0.96; P = 0.04). The time to onset of Gr 2 oral mucositis was significantly longer in the pharmacist intervention group than in the control group (hazard ratio, 0.53; 95% CI, 0.29-0.97; P = 0.04). CONCLUSION: Direct intervention, especially when provided by hospital pharmacists, can have a real effect in supporting patients with HNC experiencing severe side effects of treatments. Moreover, the integration of pharmacists into the oral healthcare team is becoming even more essential to reduce the severity of side effects.

Lifestyle and body composition changes in patients with rheumatoid arthritis during the COVID-19 pandemic: A retrospective, observational study.

Objectives: Behavioral restrictions and staying at home during the COVID-19 pandemic have affected lifestyles. It was hypothesized that patients with rheumatoid arthritis (RA) decreased their activities of daily living (ADL) and exercise during the pandemic. The aim of this study is to investigate the changes in lifestyle and body composition. Methods: Data were obtained from an observational study (CHIKARA study). Of 100 RA patients, 70 (57 women, 13 men) were followed-up with measurements of grip strength, as well as muscle mass, fat mass, and basal metabolic rate by a body composition analyzer. Changes in ADL and exercise were evaluated using a visual analog scale. The relationships between changes in ADL or exercise and body composition were investigated. Results: Muscle mass and grip strength were significantly lower after behavioral restrictions compared to the periods before restrictions (34.0 vs 34.7 kg, P < 0.001; 16.2 vs 17.2 kg, P = 0.013, respectively). Fat mass was significantly greater after behavioral restrictions compared to the periods before restrictions (16.2 vs 15.5 kg, P = 0.014). The mean decrease in ADL was 44%, whereas that of exercise was 20%.The change in muscle mass (ß = -0.335, P = 0.007) was the only independent factor for the change in exercise on multivariate analysis. Conclusions: Muscle mass and grip strength decreased and fat mass increased in RA patients with the behavioral restrictions of the COVID-19 pandemic. Muscle mass decreased in patients without exercise. Maintenance of muscle mass may be important during the COVID-19 pandemic.

Computed Tomography Evaluation of Distal Screw Penetration in Volar Locking Plate Fixation for Intra-Articular Distal Radius Fractures.

PURPOSE: Volar locking plate fixation for distal radius fractures (DRFs) is a technically demanding procedure with a risk of distal screw penetration through the dorsal cortex or the articular surface. This study aimed to investigate the incidence and details of distal screw penetration after volar locking plate fixation for intra-articular DRFs using a CT scan and to evaluate the relationship between the incidence of screw penetration and fracture comminution severity and the clinical complications of screw penetration. METHODS: This was a retrospective case series of 91 adult patients (mean age, 63 years; 27 men) who underwent volar locking plate fixation for intra-articular DRFs from 2015 to 2018. The positioning of the distal screws was evaluated using a postoperative CT scan, and radiological outcomes were compared between the AO C1 and C3 groups. At the final follow-up, tendon rupture and arthritis severity were assessed as clinical complications of dorsal and intra-articular screw penetration. RESULTS: Distal screw penetration was observed in 44 wrists (48%), dorsal cortex screw penetration in 34, intra-articular screw penetration in 13, and both dorsal cortex and intra-articular screw penetration in three. The incidence of intra-articular screw penetration was significantly higher in the C3 group than in the C1 group. No tendon rupture was observed. Multivariable analysis revealed that intra-articular screw penetration was significantly related to high severity of arthritis. CONCLUSIONS: Approximately half of the study patients with intra-articular DRFs had distal screw penetration. The incidence of intra-articular screw penetration was associated with the severity of fracture comminution, and the intra-articular screw penetration was associated with the incidence of early radiocarpal arthritis. Intra-articularly penetrating screws should be replaced as soon as they are discovered, regardless of the length of penetrated screw or absence of patients' subjective symptoms. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

[Development and Verification of an irAEs Self-Reported Interview System(ISRIS)].

A variety of immune-related adverse events(irAEs)occur during the use of immune checkpoint inhibitors, and delayed detection may make it difficult to continue treatment. To detect irAEs as early as possible, we have been administering an irAEs self-reported interview system(ISRIS)to all outpatients using a tablet device. We conducted a retrospective study of outpatients who received pembrolizumab, nivolumab, atezolizumab, ipilimumab, and durvalumab and utilized the ISRIS from June 2019 to May 2020. The survey items were the primary disease, initial symptoms of irAEs, and detected irAEs. The total number of patients was 140, and the total number of interviews was 1,095. Overall, 42 irAEs occurred. The ISRIS is useful for detecting subjective skin disorders. However, its detection rate of myocarditis and thyroid, hepatic, and renal dysfunction was low, and there is room for improvement. We are currently developing an ISRIS application that maintains sensitivity and increases specificity to allow for early detection of irAEs at home.

Diagnostic imaging for elbow TRASH lesions in children and usefulness of ultrasonography using standard planes.

Fractures around the elbow in children should be carefully evaluated because the main portion is cartilaginous, and radiographs are not completely reliable. This study aimed to assess the diagnostic imaging for pediatric elbow fractures that require special attention and consider the usefulness of ultrasonography with seven standard planes for the diagnosis. Patients diagnosed with elbow fractures wherein TRASH (The Radiographic Appearance Seemed Harmless) lesions were evaluated retrospectively. The diagnoses on initial radiographs, final diagnoses, additional imaging excluding radiographs, and the treatments were investigated. The standard planes for ultrasonography to detect elbow fractures included an anterior transverse scan at the level of the capitellum and proximal radioulnar joint, an anterior longitudinal scan at the level of the humeroradial and humeroulnar joints, a longitudinal scan along the lateral and medial border of the distal humerus, and a posterior longitudinal scan at the level of the distal humerus. A total of 107 patients with an average age of 5.8 years (range, 0-12 years) at the time of diagnosis were included. Of 46 (43.0%) patients misdiagnosed at the initial radiograph, 19 (17.8%) needed additional treatments due to inappropriate initial management. Ultrasonography using the standard planes was useful for prompt diagnosis and appropriate treatment. Prompt and appropriate evaluation with ultrasonography can prevent the mismanagement of pediatric elbow injuries. Level of evidence: Level IV-retrospective case series.

Study on the Use of Ozone Water as a Chemical Decontamination Agent for Antineoplastic Drugs in Clinical Settings.

The exposure of healthcare workers to antineoplastic drugs in hospitals has been recognized to be harmful. To minimize the risk of exposure, the removal of these drugs from work environments, such as compounding facilities, has been recommended. In our previous paper, the degradation and inactivation efficacy of ozone water, which is being introduced into Japanese hospitals as a chemical decontamination agent, was reported for its effects on typical antineoplastic drugs (gemcitabine, irinotecan, paclitaxel). This article aims to further investigate the efficacy of ozone water for eight antineoplastic drugs to clarify its application limitations. A small amount (medicinal ingredient: typically ca. 1.5 µmol) of formulation containing 5-fluorouracil, pemetrexed, cisplatin, oxaliplatin, cyclophosphamide, ifosfamide, doxorubicin, or docetaxel was mixed with 50 mL of ozone water (~8 mg/L), and the resulting solutions were analyzed by high-performance liquid chromatography over time to observe the degradation. Consequently, the ozonation was overall effective for the degradation of the drugs, however this varied depending on the chemical structures of the drugs and additives in their formulations. In addition, after the parent drugs were completely degraded by the ozonation, the degradation mixtures were subjected to 1H nuclear magnetic resonance spectroscopy and evaluated for mutagenicity against Salmonella typhimurium strains and cytotoxicity against human cancer cells. The degradation mixtures of cisplatin and ifosfamide were mutagenic while those of the other drugs were non-mutagenic. Further, the ozonation resulted in clear decreases of cytotoxicity for 5-fluorouracil, oxaliplatin, and doxorubicin, but increases of cytotoxicity for pemetrexed, cisplatin, cyclophosphamide, and ifosfamide. These results suggest that the ozone water should be restrictedly used according to the situation of contamination in clinical settings because the ozonation enhances toxicity depending on the drug even if degradation is achieved.

The bioimpedance phase angle may be associated with frailty in rheumatoid arthritis patients: Results from a prospective, cohort study.

OBJECTIVES: This study investigated whether the phase angle (PhA) on bioelectrical impedance analysis is related to frailty in rheumatoid arthritis (RA) patients. METHODS: Data from a prospective cohort study of RA patients were analysed. The PhA was assessed by the bioelectrical impedance analysis method, and frailty was assessed by the Kihon Check List (KCL) annually. The cut-off value of the PhA for frailty was calculated by receiver-operating characteristic analysis. The relationships between the PhA and frailty were evaluated by logistic regression analysis. The relationships between the change in PhA and frailty status and the KCL score were evaluated by analysis of covariance and multiple regression analysis. RESULTS: A total of 170 patients (81.2% female, 66.2 ± 13.1 years) were included in the analysis. A PhA of less than the cut-off for frailty was significantly associated with frailty (odds ratio: 4.75, 95% confidence interval: 1.86, 12.17). The change in the PhA was significantly associated with the change in the KCL score (ß = -0.15). In robust patients, there was a significant difference in the rate of change of the PhA between the group that became pre-frail in the next year and the group that remained robust. CONCLUSIONS: The PhA may be associated with frailty in RA patients.

Congenital Palmar Duplication of the Index Finger: Ventral Polydactyly With Ventral Dimelia.

This report describes the case of a 10-month-old boy who presented with a duplicated index finger enveloped by palmar skin on the palmar side of the first web of the left hand. He was healthy without any other abnormalities except the hand anomaly. Surgical resection of the extra finger was performed with triangular flap at 15 months of age. The resected finger was composed of only palmar components: skin without nail or hair; flexor tendons; and digital nerves branching from the median nerve. Histological examination of the specimen demonstrated similar structures on both palmar and dorsal sides, that is, ridged, hairless, and glabrous skin with a high number of epithelial layers and thick corneous stratum and similar shaped tendons inserted into the symmetrical phalanx. This appears to be the first report in literature of an ectopic palmar index finger, a ventral polydactyly with ventral dimelia.

The bioimpedance phase angle is more useful than sarcopenia as a predictor of falls in patients with rheumatoid arthritis: Results from a 2-y prospective cohort study.

OBJECTIVES: The phase angle (PhA) is an index derived by bioelectrical impedance analysis that reflects the fragility of cell membranes, muscle mass, muscle strength, and nutritional status, and a decrease in PhA might be associated with falls. This study aimed to investigate the relationships of the PhA with sarcopenia and falls in patients with rheumatoid arthritis (RA). METHODS: Data from a prospective cohort study of 189 patients with RA (age 66.5 ± 13.3 y; 80% women) were analyzed. PhA, muscle mass, and grip strength (GS) were evaluated. Sarcopenia was assessed using the Asian Working Group for Sarcopenia 2014 criteria. The correlation between PhA and GS was investigated, and the cutoff value of the PhA for falls during a 2-y period was estimated with a receiver operating characteristic curve analysis. The effects of the PhA and sarcopenia on falls were examined with a Cox proportional hazards model. RESULTS: Of the 189 patients, 48 (25.4%) had falls. The PhA was significantly positively correlated with GS (r = 0.58; P < 0.001). The cutoff values for the PhA for falls were 4.06° for women and 5.26° for men. In the Cox proportional hazards model adjusted for sex, age, disease activity, glucocorticoid use, and activities of daily living at baseline, the hazard ratio for falls was significantly higher when the PhA was below the cutoff value at baseline (hazard ratio: 2.29; 95% confidence interval, 1.18-4.45). Sarcopenia was not a significant risk factor for falls. CONCLUSIONS: The PhA might be a useful surrogate marker to predict falls in patients with RA.

Daily physical activity measured by a wearable activity monitoring device in patients with rheumatoid arthritis.

INTRODUCTION: Activities of daily living in patients with rheumatoid arthritis (RA) have been evaluated by patient-reported outcomes. However, it has been difficult to measure activity intensity quantitively. Calories expended, exercise, and steps were measured quantitively by a wearable activity meter, and their associations with patients' background characteristics were examined. METHODS: Data from a prospective, observational study (CHIKARA study) were used. Eighty-five of 100 RA patients were entered and wore a wearable activity meter for 7 days. The daily calories expended and exercise for both walking and housework and steps were evaluated. Total daily calories expended and exercise was defined as the sum of walking and housework. The relationships of DAS28-ESR, mHAQ, body composition, muscle function, and general status were analyzed. RESULTS: The median age was 66.0 years, and the disease duration was 5.3 years. DAS28-ESR was 3.11, and mHAQ was 0.125. Total daily calories expended, exercise, and number of steps were 461.7 kcal, 3.97 METs h, and 4,788, respectively. MHAQ, walking speed, power, locomotive syndrome, and frailty were independently related to exercise. Total daily exercise and steps of the moderate and high disease activity group were significantly lower than those of the remission group. When the number of steps was < 3,333 and < 2,468, the odds ratios for locomotive syndrome and frailty increased 14.4-fold and 8.7-fold, respectively, using Fisher's exact test (P < 0.001). CONCLUSIONS: Daily physical activity and number of steps were significantly decreased in RA patients with moderate and high disease activity as measured by a wearable activity meter. Key Points • Total daily calories expended and exercise for both walking and housework and steps in patients with rheumatoid arthritis were 461.7 kcal, 3.97 METs h, and 4,788, respectively, using a wearable activity meter. • Daily physical activity, especially total daily exercise and number of steps, was significantly decreased in RA patients with moderate and high disease activity. • When total daily steps were < 3,333 and < 2,468, the odds ratios for locomotive syndrome and frailty increased 14.4-fold and 8.7-fold, respectively.

Is Repair of a Small Coronoid Fracture Required in the Surgical Treatment of Terrible Triad Injury of the Elbow?

Background: Multiple treatment protocols have been described in literature for the treatment of terrible triad injury (TTI) of the elbow. We believe that repair of the medial collateral ligament (MCL) should be performed in preference to repair of a small coronoid fracture if the elbow is unstable after fixation/replacement of the radial head and repair of the lateral collateral ligament (LCL). The aim of this study is to report the outcomes of surgical treatment of patients with TTI associated with a small coronoid fracture in whom the coronoid fracture was not addressed. Methods: This study is a retrospective case series of 12 consecutive patients who underwent surgery for acute TTI with a small coronoid fracture (9 Regan-Morrey type I and 3 Regan-Morrey type II). Ten patients had complete MCL injuries. All patients underwent repair of the torn LCL and MCL and treatment of the radial head. The coronoid fracture was not surgically treated. At the final follow-up, the range of motion, degree of flexion contracture, Mayo elbow performance score (MEPS) and Disabilities of the Arm, Shoulder and Hand (DASH) were measured. Results: The mean follow-up period was 13.5 months. At the final follow-up, the mean arc of elbow flexion was 132° and the mean flexion contracture was 10°. The mean arc of forearm rotation was 148°. None of the patients demonstrated elbow instability. The mean MEPS was 92.5 points with seven having excellent results and five having good results. The average DASH score was 11.2 points. Conclusions: Our results showed that good elbow stability, arc of motion and clinical outcomes could be achieved without repair of small coronoid fractures in the treatment of TTI. The repair of MCL injuries should be given priority over the fixation of small coronoid fractures to regain elbow stability. Level of Evidence: Level IV (Therapeutic).

Surgical Treatment of Ulnar Cleft Hand with All Fingers - A Report of Two Patients.

An ulnar cleft hand is a rare congenital deformity presenting with a cleft between the ring and little finger. It may be associated with the absence of a finger. The goals of treatment are cleft closure, increasing the length of the hypoplastic little finger and preservation of function. We report two patients with ulnar cleft hand without missing fingers. Both underwent cleft closure. One was treated by lengthening of the fifth metacarpal with an external fixator, and the other by finger translocation. Both patients achieved a near normal length of the little finger and a reasonable functional and aesthetic outcome. Level of Evidence: Level V (Therapeutic).

Frequency and component analysis of contaminants generated in preparation of anticancer agents using closed system drug transfer devices (CSTDs).

Occupational exposure of anticancer agents during their preparation has been recognized as a serious hazard. Closed system drug transfer devices (CSTDs) enable "safe" preparation of agents for medical personnel and ensure a safe hospital environment. However, artificial particles of infusion materials have been reported during CSTD use. Here, the incidence of insoluble fine particles during preparation of anticancer agents using CSTDs was examined. Visible insoluble fine particles were found in 465 (9.4%) of 4948 treatment cases at Ehime University Hospital with CSTD use. Contaminants occurred more frequently during preparation of monoclonal antibodies than cytotoxic anticancer agents (19.4% vs. 4.1%, respectively, P < 0.01). A similar survey was conducted at nine hospitals to investigate the incidence of insoluble fine particles with or without CSTDs. Insoluble fine particles were detected in 113 (15.4%) of 732 treatment cases during preparation of monoclonal antibodies with CSTD use. In contrast, the occurrence of insoluble fine particles without CSTDs was found in only 3 (0.073%) of 4113 treatment cases. Contamination with CSTDs might cause harmful effects on patients during cancer therapy. We strongly recommend the use of in-line filters combined with infusion routes after CSTD use to avoid contamination-associated adverse events.

The knee position at tourniquet inflation does not affect the gap balancing during total knee arthroplasty.

INTRODUCTION: The relationship between gap balancing and clinical outcome of total knee arthroplasty (TKA) has been researched. Tourniquet is widely used by most surgeons; however, there are little quantitative data about the gap depending on the tourniquet usage. We aimed to investigate whether the knee position at tourniquet inflation affected the gap measurement intra-operatively. METHODS: TKA was performed for 104 knees and the tourniquet was inflated with the knee at full flexion and extension. The gap was measured in each static knee flexion status (0°, 30°, 45°, 60°, 90°, 120°, and in full flexion) using a tensor. We measured the gap twice; under the tourniquet inflation and release. The gap difference at each static knee flexion status was calculated by subtracting the gap under release from that under inflation. RESULTS: When the tourniquet was inflated with the knee at full flexion, the mean gap differences were < 1 mm and < 1° in each static knee flexion status. When the tourniquet was inflated with the knee at full extension, the mean gap differences were < 1 mm and < 1°, respectively. All values of the gap difference were minimum, and were not affected by the tourniquet, whether the knee position at the tourniquet inflation was flexed or extended. CONCLUSIONS: We postulated that the knee position at tourniquet inflation would affect the gap, which was refuted by our results. This shows that we can measure the gap without considering the knee position at tourniquet inflation.

Degradation and inactivation efficacy of ozone water for antineoplastic drugs in hospital settings.

PURPOSE: Occupational exposure to antineoplastic drugs in hospital settings is recognized to be hazardous, and as such environmental decontamination including degradation and inactivation of such drugs is recommended. To data, although various agents such as oxidants have been reported to be useful for decontamination, simpler, safer, and more convenient methods are required. In this study, the degradation and inactivation efficacy of ozone water, which has newly been introduced for decontamination of antineoplastic drugs in spills, was investigated for formulations of gemcitabine, irinotecan, and paclitaxel. METHODS: Antineoplastic formulations (medicinal ingredient: ∼1.5 µmol) were mixed with 50 mL of ozone water (>4 mg/L). The reactions were monitored by high-performance liquid chromatography, and the degradation mixtures were analyzed by 1H nuclear magnetic resonance spectroscopy in order to obtain the structural information of the degradation products. The formulations of gemcitabine and irinotecan and those degradation mixtures were evaluated for their mutagenicity using the Ames test and cytotoxicity against human cancer cells. RESULTS: gemcitabine and irinotecan were found to be readily degraded by the ozone treatment, and their active sites were suggested to be degraded. In contrast, paclitaxel was hard to be decomposed, possibly owing to the consumption of ozone by the polyoxyethylene castor oil added as a pharmaceutical additive of the formulation. No significant mutagenic changes of Salmonella typhimurium strains used for the Ames test were observed for the samples within the concentration ranges examined. The ozone treatment showed obvious increases in cell viability for gemcitabine formulation, and mild increases for irinotecan formulation. CONCLUSIONS: Ozone water was shown to be effective as a decomposition agent for the antineoplastic drug formulations examined, although the efficacy depends on the chemical structures of the drugs and the pharmaceutical additives. It was also suggested that ozone treatment has a tendency to decrease the toxicity of the antineoplastic drug formulations. As such, further studies are required in order to clarify the effects and application limitations of ozone water.

Renin-Angiotensin-Aldosterone System Inhibitors Prevent the Onset of Oxaliplatin-Induced Peripheral Neuropathy: A Retrospective Multicenter Study and in Vitro Evaluation.

Oxaliplatin (OXA) is used in chemotherapy for various cancer types and is associated with acute and chronic neurotoxicity. However, a preventive strategy for OXA-induced peripheral neuropathy (OIPN) and its underlying mechanism remain unclear. We examined the effects of renin-angiotensin-aldosterone system inhibitors (RAASIs) on OIPN by performing a retrospective multicenter study and an in vitro assay. We retrospectively evaluated electronic medical records of 976 patients who underwent one or more courses of OXA-containing regimens at Ehime, Okayama, and Tokushima University Hospitals. The primary endpoint was the incidence of OIPN during or after OXA administration. The effects of RAASIs and OXA on the neurite length in PC12 cells were determined. The combined administration of an OXA-containing regimen and RAASI significantly inhibited the cumulative incidence grade-2 or higher OIPN (log-rank test; p = 0.0001). RAASIs markedly suppressed the development of both acute and chronic OIPN (multivariate analysis; p = 0.017 and p = 0.011). In an in vitro assay, 10 µM OXA suppressed the neurite length; treatment with 1 µM aliskiren, spironolactone, 10 µM candesartan, and enalapril significantly restored neurite length to the control level. Moreover, 1 µM SCH772984 (a selective inhibitor of extracellular signal-regulated kinase, ERK1/2) and 500 µM SQ22536 (a cell-permeable adenylate cyclase (AC) inhibitor) markedly abolished neurite-extending effects of candesartan and enalapril. These results indicate that RAASIs possess preventive or therapeutic effects in acute and chronic OIPN, candesartan and enalapril may increase in the activity of ERK1/2 and AC in PC12 cells.