Quantitative assessment of skin disorders induced by panitumumab: a prospective observational study.

PURPOSE: Acneiform rash is frequently observed in patients undergoing cancer treatment with anti-epidermal growth factor receptor (EGFR) antibody drugs and can often necessitate treatment discontinuation. However, the specific changes in skin parameters resulting from anti-EGFR antibody drug administration are poorly understood. Therefore, this study aimed to longitudinally and quantitatively evaluate the changes in skin parameters (transepidermal water loss [TEWL], hydration level, and sebum level) caused by anti-EGFR antibody drugs and investigate their potential as control markers for skin disorders. METHODS: This prospective study included 12 patients with colorectal cancer who received anti-EGFR antibody drugs for the first time. The assessment items included the grade of acneiform rash and skin parameters (TEWL, hydration level, and sebum level), which were observed for up to 6 weeks after administration of the medication. RESULTS: The enrolled patients were classified into two groups based on the grade of acneiform rash caused by anti-EGFR antibody drugs: "Grade 1 and lower," and "Grade 2 and higher." The skin parameters were compared between these groups. The results showed that in the "Grade 2 and higher" group, TEWL in the face (at week 2 of administration), chest (baseline, weeks 2 and 6 of administration), and back (at week 2 of administration) were significantly higher than those in the "Grade 1 and lower" group. However, the two groups showed no significant differences in hydration or sebum levels at any time point. CONCLUSION: TEWL can serve as a marker for acneiform rashes induced by anti-EGFR antibody drugs during cancer treatment.

Relationship between Ca2+ and cAMP as second messengers in ACTH-induced cortisol production in bovine adrenal fasciculata cells.

In adrenal fasciculata cells stimulated by ACTH, Ca2+ and cAMP play indispensable roles as second messengers in cortisol production. However, whether their second messengers cooperatively or independently participate in steroid production remains unclear. We focused on the roles of Ca2+ and cAMP in cortisol production in bovine adrenal fasciculata cells stimulated by ACTH for a relatively short period (1 h). Incubation of the cells with 100 pM ACTH in Ca2+-containing (normal) medium for 1 h increased cortisol production without affecting cAMP content. In contrast, treatment of the cells with the peptide at a higher concentration (1 nM) significantly augmented both cortisol production and cAMP content. However, ACTH did not increase either of them in the Ca2+-free medium. ACTH rapidly increased the intracellular free Ca2+ concentration ([Ca2+]i) in the normal medium, but did not influence [Ca2+]i in the Ca2+-free medium, indicating that ACTH caused Ca2+ influx into the cells. ACTH-induced Ca2+ influx and cortisol production were suppressed by a voltage-sensitive L-type Ca2+ channel blocker but not by a T-type, N-type, or P-type Ca2+ channel blocker. In contrast, dibutyryl cAMP, a cell-permeable cAMP analog, greatly enhanced cortisol production in the normal or Ca2+-free medium and slowly caused Ca2+ influx into the cells. These results strongly suggest that Ca2+, as a second messenger, is more critical than cAMP for cortisol production. However, both second messengers jointly participate in the production in adrenal fasciculata cells stimulated by ACTH.

High level of C-reactive protein as a predictive factor for immune-related adverse events of immune checkpoint inhibitors in non-small cell lung cancer: a retrospective study.

Background: Several risk factors for the immune-related adverse events (irAEs) during treatment with immune checkpoint inhibitors (ICIs) have been reported, of which include high levels of C-reactive protein (CRP). In this study, we aim to evaluate CRP levels before ICIs treatments as potential predictive biomarkers of irAEs incidence rate and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC). Methods: Between December 1, 2015 to December 31, 2019, we retrospectively collected all adult patients with NSCLC who received at least one dose of an ICI targeting the PD-1/PD-L1 axis at the Iwate Medical University Hospital in Japan. In this study the patients were categorized into low and high groups with a cut-off value of 10 mg/L as the baseline level of CRP before the ICI treatment. The primary endpoint was relationship between CRP levels at baseline and incidence of irAEs. The secondary endpoints were the relationship of progression-free survival (PFS) and OS. Results: A total of 101 irAEs, and 25 severe irAEs were observed. The incidence of the most irAEs was higher in the high CRP group compared to the low CRP group (54.4% vs. 34.5%, respectively, P=0.003). The most frequent irAEs were skin rush (28.8%), followed by pneumonitis (19.2%), hypothyroidism (15.4%), and hepatotoxicity (9.6%). The most common grade 3 or 4 irAEs was pneumonitis (7.9%), which tended to be more frequent in the high CRP group. In multivariate analysis, patients with high CRP levels had an adjusted OR of 2.41 and were associated with an increased risk of developing irAEs (95% CI: 1.16-4.43, P=0.020). The high CRP group was related with shorter PFS compared to the low CRP group (2.2 vs. 3.3 months, respectively, P=0.006). The high CRP group were also related with shorter OS compared to the low CRP group (8.9 vs. 39.1 months, respectively, P<0.001). Conclusions: The results suggest that higher level of pretreatment CRP is involved in the development of irAE and poor prognosis. Identification of patients at high risk of irAEs would be of great help. Future multicenter prospective studies are needed to expand on this study.

Plasma endothelin-1 may predict bevacizumab-induced proteinuria in patients with colorectal cancer.

PURPOSE: Proteinuria is one of the most common adverse events leading to the discontinuation of bevacizumab therapy. We analyzed plasma ET-1 levels as an indicator of renal endothelial dysfunction in colorectal cancer patients, to determine the utility of plasma ET-1 for identification of patients at high risk of proteinuria when treated with bevacizumab. METHODS: Patients (n = 40) were recruited from an outpatient chemotherapy center between December 2020 and January 2022. Blood samples for plasma ET-1 levels were collected before treatment with bevacizumab (baseline), and after treatment for 3 and 6 months, and plasma ET-1 was determined by ELISA. Proteinuria was evaluated based on CTCAE v5.0 using urine protein-creatinine ratio instead of 24-h urine protein. RESULTS: Plasma ET-1 levels at baseline were significantly higher in the group with grade ≥ 2 proteinuria than in the non-proteinuria group (p = 0.019). After adjusting for age, systolic and diastolic blood pressure, and hypertension following bevacizumab, plasma ET-1 levels at baseline were found to be an independent predictor of development of grade ≥ 2 proteinuria (OR = 17.8, 95% CI 1.42-223, and p = 0.026). Receiver operating characteristic curve analysis indicated an optimal cut-off value of the plasma ET-1 level of 1.19 pg/mL for predicting grade ≥ 2 proteinuria, with a sensitivity of 80.0% and specificity of 73.3%. CONCLUSION: In conclusion, higher plasma ET-1 levels before treatment might increase the risk of proteinuria in colorectal cancer patients treated with bevacizumab. This might have important implications in the early detection of the risk of proteinuria.

Identifying risk factors for opioid-induced neurotoxicity in cancer patients receiving oxycodone.

PURPOSE: The aim of this study was to determine the frequency of opioid-induced neurotoxicity (OIN) in cancer patients receiving oral controlled-release oxycodone and to define risk factors for OIN. METHODS: This was a single-center, retrospective study of hospitalized adult cancer patients receiving oral controlled-release oxycodone between April 1, 2013, and April, 30, 2020. The onset of OIN within 30 days after oxycodone initiation in the study patients was investigated. OIN was defined as any of the following: delirium, hallucinations (visual or auditory), seizure, myoclonus, hyperesthesia, and excessive somnolence. Multivariate logistic regression analysis was performed to identify risk factors for OIN in patients receiving oxycodone. RESULTS: In total, 520 patients were included in this study. The number of patients with OIN was 65 (12.5%). The median time until onset of OIN after oxycodone initiation was 7.5 days. Multivariate logistic regression analysis revealed that age ≥ 65 years (OR = 2.74, 95% CI [1.30-5.78], p = 0.008), total bilirubin ≥ 1.3 mg/dL (OR = 4.85, 95% CI [2.13-11.0], p < 0.001), and concomitant use of pregabalin or mirogabalin (OR = 3.11, 95% CI [1.47-6.61], p = 0.003) were significant independent risk factors for OIN. CONCLUSION: Age ≥ 65 years, liver dysfunction, and concomitant use of pregabalin or mirogabalin were independent risk factors for OIN in patients receiving oxycodone. Patients with these risk factors who are receiving oxycodone should be monitored for OIN, especially early in the administration of oxycodone.

Effect of risk factors for acneiform rash induced by anti-epidermal growth factor receptor antibody drugs on survival: a retrospective observational study.

BACKGROUND: We previously reported that high body weight was a risk factor affecting the onset of anti-epidermal growth factor receptor (EGFR) antibody drug-induced acneiform rash. The current study investigated the relationship between risk factors for anti-EGFR antibody drug-induced acneiform rash and survival probability in colorectal cancer patients, as well as effects of drug withdrawal, dose reduction, or treatment discontinuation on treatment continuation. METHODS: This retrospective study included 67 patients with unresectable advanced or recurrent colorectal cancer treated with anti-EGFR antibody drugs for the first time. RESULTS: The survival time and acneiform rash grade of patients with high body weight (≥ 67.2 kg) were significantly longer and higher than those of patients with low body weight (< 67.2 kg). Moreover, the treatment continuation time of patients with drug withdrawal or dose reduction was significantly longer than that of patients without drug withdrawal or dose reduction or with/without treatment discontinuation. Meanwhile, the treatment continuation time of patients with treatment discontinuation was significantly shorter than that of patients with drug withdrawal or dose reduction or those without drug withdrawal, dose reduction, or treatment discontinuation. CONCLUSIONS: High body weight is a novel prognostic factor for patients receiving cancer drugs with anti-EGFR antibody drugs. Hence, the results of this study suggest that patients with high body weight should be carefully monitored for the development of acneiform rash when receiving anti-EGFR antibody drugs as cancer drug therapy.

Renin-angiotensin system inhibitors may have an advantage over calcium channel blockers in reducing proteinuria in gastric cancer patients receiving ramucirumab.

This study aimed to investigate whether renin-angiotensin system inhibitors (RAS-I) have an advantage over calcium channel blockers (CCB) for suppression of proteinuria in hypertensive patients with gastric cancer receiving ramucirumab (RAM) treatment. Adult Japanese patients with gastric cancer who were outpatients at Asahikawa Medical University Hospital, National Hospital Organization Hokkaido Cancer Center, and Iwate Medical University Hospital between July 1, 2015, and March 31, 2021, were included in this study. Of these patients, those who had received first-time RAM treatment, and those treated with antihypertensive agents including RAS-I or a CCB at initial RAM administration were included. A total of 36 patients were analyzed in this study. Of these patients, 17 patients were classified into the RAS-I group and the remaining 19 into the CCB group. After 12 weeks of RAM administration, the prevalence of proteinuria in the RAS-I group was significantly lower than that in the CCB group. Additionally, Kaplan-Meier analysis showed that the cumulative occurrence of proteinuria in the RAS-I group over 12 weeks following RAM administration was significantly lower than that in the CCB group. Furthermore, simulation of the time course of RAM blood concentrations based on the O'Brien model showed that there may not be differences in the RAM blood concentration profiles over 12 weeks between the two groups. RAS-I may have an advantage over CCB for suppressing proteinuria in hypertensive patients with gastric cancer treated with blood pressure antihypertensive agents. Our results provide useful information to healthcare professionals involved in the administration of RAM treatment.

Bevacizumab Increases Endothelin-1 Production via Forkhead Box Protein O1 in Human Glomerular Microvascular Endothelial Cells In Vitro.

Molecular mechanisms underlying the nephrotoxicity associated with bevacizumab are unclear. Endothelin-1 (ET-1) is involved in podocyte injury and proteinuria, and its level increases in most cases of kidney disorders. Forkhead box protein O1 (FoxO1), a transcription factor, is a major determinant of ET-1 promoter activation and is regulated by protein kinase B (Akt) phosphorylation-dependent nuclear exclusion. We evaluated the effect of bevacizumab on ET-1 production in human glomerular microvascular endothelial cells (hGECs). We analyzed the changes in the mRNA and protein levels of ET-1 in hGECs treated with bevacizumab using real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Changes in the protein levels and phosphorylation status of Akt and FoxO1 in hGECs treated with bevacizumab were analyzed by western blotting. After cell lysis, FoxO1 protein was isolated from the cytoplasmic and nuclear fractions. We also investigated the effects of AS1842856 (a FoxO1 inhibitor) on bevacizumab-induced ET-1 production. Bevacizumab significantly and dose-dependently increased the mRNA and protein levels of ET-1 in hGECs (p < 0.05). Bevacizumab treatment also led to a decrease in phosphorylated Akt protein levels. Inhibition of Akt activity by LY294002 promoted ET-1 production. Bevacizumab also induced an increase in FoxO1 protein levels in the nucleus. Inhibition of FoxO1 activity by AS1842856 resulted in decreased ET-1 levels in bevacizumab-treated hGECs. ET-1 axis activation, Akt inactivation, and FoxO1 nuclear localization are the molecular mechanisms underlying bevacizumab-induced nephrotoxicity. Therefore, inhibition of renal ET-1 production could be a promising approach to protect against or treat bevacizumab-induced nephrotoxicity.

Effect of antipsychotics on serum lithium levels and white blood cell counts.

Lithium carbonate is used to increase white blood cell counts as a means of counteracting leukopenia caused by the administration of antipsychotic drugs. To evaluate the effect of antipsychotics on the leukocyte-enhancing effect of lithium, we compared white blood cell counts, serum lithium levels, and lithium dosage in patients receiving antipsychotics and lithium in combination and patients receiving lithium alone. Chlorpromazine equivalent values were used as an indicator of the antipsychotic dose. Lithium serum levels were measured in 41 hospitalized patients. The lithium dose in the combination group (median, 800 mg) was significantly higher than that in group receiving only lithium (median, 400 mg) (P = 0.03). The lithium doses in the combination group receiving ≥1000 mg chlorpromazine equivalents (overdosing; median lithium dose 800 mg) and the combination group treated with 600-999 mg chlorpromazine equivalents (high dosing; median lithium dose 800 mg) were significantly higher than the group that was not treated with antipsychotic medication, with median lithium dose 400 mg (P < 0.05).There were no significant differences in the white blood cell counts and serum lithium levels. Because of the large variety of antipsychotic drugs used in combination with lithium and the various doses used, it was difficult to evaluate the effects of lithium, with or without antipsychotic administration, on leukocyte count enhancement. We are planning to study a larger number of patients and, since renal function could not be assessed in this study, we will also focus on renal function, including urine output.

Analysis of risk factors for skin disorders caused by anti-epidermal growth factor receptor antibody drugs and examination of methods for their avoidance.

WHAT IS KNOWN AND OBJECTIVE: Cancer drug treatment is often discontinued because of skin disorder aggravation. However, information on risk factors for skin disorders caused by anti-epidermal growth factor receptor (EGFR) antibody drugs is limited. The aim of this study was to analyse the factors associated with skin disorders caused by anti-EGFR antibody drugs and establish a method to minimize such aggravations. METHODS: We retrospectively examined 67 colorectal cancer patients treated with anti-EGFR antibody drugs for the first time. RESULTS AND DISCUSSION: A higher proportion of males than females experienced drug withdrawal, dose reduction or treatment discontinuation. The multiple logistic regression analysis revealed body weight as a risk factor affecting drug withdrawal, dose reduction or treatment discontinuation because of an acneiform rash. An examination of methods to avoid the aggravation of skin disorders revealed the acneiform rash grade in patients who received prophylactic minocycline was significantly lower than that in patients who did not receive prophylactic minocycline. Furthermore, among patients with grade 1 acneiform rash at the initiation of minocycline, the proportion of those who withdrew, required dose reduction or discontinued treatment was lower than that among patients with grade 2 acneiform rash. WHAT IS NEW AND CONCLUSION: High body weight was identified as a novel factor for skin disorder aggravation caused by anti-EGFR antibody drugs. The aggravation of skin disorders during cancer treatment with anti-EGFR antibody drugs can potentially be avoided by carefully observing the onset of acneiform rash in affected patients with high body weight and using minocycline prophylactically or as an early-stage intervention.

Switching from Intravenous to Oral Tacrolimus Reduces its Blood Concentration in Paediatric Cancer Patients.

BACKGROUND/AIM: Tacrolimus is an essential immunosuppressant for successful allogeneic haematopoietic stem cell transplantation (Allo-HSCT). This study aimed to examine the change in the blood concentration of tacrolimus during switching from intravenous to oral administration in allo-HSCT for paediatric cancer to predict the optimal dosage. PATIENTS AND METHODS: We retrospectively examined the medical records of 63 patients who received allo-HSCT and were administered tacrolimus. To compare bioavailability among different dose ranges, the blood concentration was divided by the dose (C/D). RESULTS: Thirty-nine patients (age range=children 1-15 years, adults 17-67 years) were switched to oral administration of tacrolimus. The C/D after switching was significantly lower in children than in adults (p=0.039). There was a strong positive correlation between age and C/D in children, whereas no correlation was observed in adults. CONCLUSION: In paediatric cancer patients, switching tacrolimus administration route may result in reduced blood concentrations. This tendency is more prominent in younger children.

Disproportionality Analysis of Safety Signals for a Wide Variety of Opioid-Related Adverse Events in Elderly Patients Using the Japanese Adverse Drug Event Report (JADER) Database.

Opioids are widely used for the treatment of moderate/severe pain in cancer and noncancer patients. In this study, we searched for safety signals for a wide variety of opioid-related adverse events (AEs) in elderly patients by disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Data from the JADER database from April 2004 to May 2018 were obtained from the Pharmaceuticals and Medical Devices Agency website. Safety signal detection of opioid-related AEs in elderly patients was defined using the relative elderly reporting odds ratio (ROR). Among the analyzed AEs, opioid-induced neurotoxicity (OIN) was assessed based on the time to onset using the Weibull shape parameter. The following safety signals were detected in elderly patients: respiratory depression, somnolence, hallucinations, akathisia and OIN. Fentanyl, tramadol, oxycodone and morphine exhibited a large relative elderly ROR for OIN. The median time to onset of OIN of transdermal fentanyl, oral tramadol, oral oxycodone and oral morphine was 13.5, 6, 9, and 6 d, respectively. These opioids were classified as early failure types using the Weibull distribution. Our results showed that elderly patients who are administered opioids should be closely monitored for AEs, such as respiratory depression, OIN and akathisia.

Appropriate usage of food thickening agents to prevent non-disintegration of magnesium oxide tablets.

Food thickening agents are used to aid the administration of medicine to elderly patients with dysphagia. Magnesium oxide tablets are sometimes administered with food thickening agents. Non-disintegration and disintegration delay of these tablets in the body are problems associated with food thickening agent use. However, the appropriate usage of food thickening agents for administering tablets is not established. Here, the reasons for the non-disintegration of magnesium oxide tablets administered with food thickeners and appropriate usage of food thickeners were examined using a disintegration test of newly opened and moisture-absorbed magnesium oxide tablets. Immersion of magnesium oxide tablets for 10 and 30 min in xanthan and guar gum-based food thickening agents caused disintegration delay and non-disintegration in the first fluid (pH 1.2). However, tablets immersed for 1 min quickly disintegrated. The disintegration of xanthan gum-based food thickening agents was faster than guar gum-based food thickening agents. Moisture absorption by magnesium oxide tablets caused a significant delay in their disintegration in water. The tablets that absorbed moisture disintegrated within 1 min in the first fluid, even when immersed in food thickening agents for a short time. Overall, a short immersion of magnesium oxide tablets in food thickening agents can avoid non-disintegration.

Physiologic changes in serotonin concentrations in breast milk during lactation.

OBJECTIVES: Serotonin (5-hydroxytryptamine; 5-HT) plays an important role in milk volume homeostasis in the mammary glands during lactation, and 5-HT in milk also may affect infant development. The aim of this study was to investigate changes in 5-HT concentration in breast milk according to the duration of lactation and evaluate whether the 5-HT concentration varied before and after nursing. METHODS: Healthy nursing Japanese women who had a natural delivery or underwent a cesarean delivery at Iwate Medical University Hospital were included in this study. RESULTS: The mean 5-HT concentration in milk was obtained from multiparous mothers 6 to 7 d after delivery (colostrum) and was significantly higher compared with primiparous mothers (24.3 ± 2.63 versus 18.5 ± 2.60 ng/mL). Additionally, mean 5-HT concentration increased with increasing lactation duration in primiparous women (colostrum: 18.5 ± 2.60; 1 mo postdelivery: 19.8 ± 2.46; 3 mo postdelivery: 22.7 ± 2.55 ng/mL); in particular, the mean 5-HT concentration in breast milk 3 mo after delivery was significantly higher than in colostrum. The mean 5-HT concentrations in breast milk in primiparous mothers immediately before nursing, 1 to 2 h after nursing, and immediately before the next nursing event were 23.6 ± 1.48, 22.82 ± 1.65, and 21.84 ± 1.31 ng/mL, respectively; mean 5-HT concentrations in multiparous women were 25.4 ± 1.65, 23.6 ± 2.20, or 22.4 ± 2.09 ng/mL, respectively. There was no significant difference in 5-HT concentrations at each time point between the groups. CONCLUSION: This information may be useful in determining the role of 5-HT in breast milk on infant development and growth.

Cancer Cachexia May Hinder Pain Control When Using Fentanyl Patch.

The objective of this study was to evaluate the influence of cancer cachexia on pain control in cancer patients receiving a transdermal fentanyl patch (FP) and to investigate whether dry skin was a factor related to cancer cachexia and uncontrolled pain. We retrospectively reviewed the medical records of 77 patients receiving FP treatment for the first time, who were classified into cancer cachexia and non-cancer-cachexia groups, according to European Palliative Care Research Collaborative criteria. On day 7 after FP administration, the mean FP dose and morphine equivalent dose (MED) in the cancer cachexia group were significantly higher than in the non-cancer-cachexia group. Additionally, in the cancer cachexia group, there was a significantly larger degree of variation in pain intensity over 7 d than in the non-cachexia group. In patients who were switched from FP to morphine injection, the mean pain intensity and MED on day 3 after morphine injection were significantly lower than those immediately before morphine injection. Subsequently, to investigate whether dry skin was involved in poor pain control in the cancer cachexia group, transepidermal water loss (TEWL) was compared between 15 additional patients classified into cancer cachexia and non-cancer cachexia groups; the mean TEWL in the cancer cachexia group was found to be significantly lower. Our data suggest that cancer cachexia may be a risk factor for poor pain control in patients receiving FP treatment, and that uncontrolled pain in FP treatment may be caused by the inhibition of fentanyl transdermal absorption due to dry skin.

Effect of food thickener and jelly wafer on the pharmacokinetics of levofloxacin orally disintegrating tablets.

This study was designed to determine the effects of a food thickener and deglutition aid jelly for oral administration, jelly wafer, on the pharmacokinetics of levofloxacin orally disintegrating tablets. With an increase in immersion time, the disintegration time of levofloxacin orally disintegrating tablets immersed in food thickener was prolonged, whereas that of the tablets immersed in jelly wafer was shortened. The dissolution behavior of non-immersed levofloxacin orally disintegrating tablets was not similar to that of tablets immersed in food thickener, but was similar to that of tablets immersed in jelly wafer. The time to reach the maximum systemic levofloxacin concentration was the same for non-immersed orally disintegrating tablets and tablets immersed in food thickener and jelly wafer. Moreover, there was no significant difference in the maximum concentration after administration between non-immersed orally disintegrating tablets and tablets immersed in food thickener or jelly wafer. These findings suggest that drugs with a high bioavailability, such as levofloxacin, enter the systemic circulation even when administered with a food thickener or jelly wafer.

Stress-Induced Suppression of Milk Protein Is Involved in a Noradrenergic Mechanism in the Mammary Gland.

Stress decreases milk components such as milk protein and milk yield. The objective of this study was to investigate whether noradrenaline (NA) in milk constituted a factor associated with stress-induced changes in milk proteins such as ß-casein. Breast milk obtained from eight healthy, nursing women contained NA at concentrations ranging from 12.7 to 115.5 nM. The expression of tyrosine hydroxylase (TH), a rate-limiting enzyme of NA synthesis, was observed in primary normal human mammary epithelial cells (HMECs), and in MCF-12A and MCF-10A cell lines. The mean NA concentration in culture medium used by MCF-12A transfected with TH small interfering RNA (siRNA) was significantly lower than that of cells transfected with control siRNA. NA concentration in milk in restraint-stressed nursing mice was significantly higher than that in nonstressed nursing mice, owing to elevated TH expression in the mammary epithelium. The mean ß-casein concentration in milk in restraint-stressed mice was significantly lower than that in nonstressed mice. NA treatment resulted in a concentration-dependent decrease in ß-casein expression in HMECs. ß2 adrenergic receptor (ADRB2) expression was observed in HMECs, MCF-12A, and MCF-10A, and immunohistochemical analysis of ADRB2 using mammary epithelium sections obtained from mice at day 10 of lactation showed that ADRB2 was expressed at the apical membrane of mammary epithelium. Treatment with salbutamol, an ADRB2 stimulant, decreased ß-casein expression in a concentration-dependent manner in MCF-12A. Our results showed that endogenous NA derived from mammary epithelial cells likely comprises one of the factors involved in stress-induced changes in milk proteins such as ß-casein.

Effect of deglutition aids on the inhibitory effect of orally disintegrating tablets of voglibose on the postprandial elevation of blood glucose levels: a case investigating the interaction between xanthan gum and voglibose.

In this study, we first performed a disintegration test of the voglibose orally disintegrating (V-OD) tablet immersed in jelly-wafer (JW, V-ODims/jw) for 10 min and compared it with the disintegration time of V-OD that was not immersed in JW. We then orally administered the V-ODims/jw tablet to 7 healthy adults and compared the shift in blood glucose levels (BGLs), after loading with a sucrose solution (Suc-sol, 100 g/150 mL), with that after administration of the non-immersed V-OD tablet. The disintegration time of V-ODims/jw tablet was shorter than that of V-OD. When administered to healthy adults, the BGL after loading with Suc-sol was higher with V-ODims/jw tablet administration than with V-OD tablet. We predict that the expression of the efficacy of voglibose is reduced as a result of the interaction between voglibose and the polysaccharide, xanthan gum (XG), since it is a common additive in JW. This study shows that deglutition aids with additives that do not affect pharmacokinetics must be carefully selected for administering along with pharmaceuticals, because of a suggested possibility that the interaction between these pharmaceuticals and the additives in the deglutition aids weaken the drug efficacy. A more careful selection of deglutition aids from the wide selection of medication is especially important when administered to patients who use these deglutition aids often, such as elderly individuals or individuals with a deglutition disorder.

Deterioration of Glycemic Control Contributes to the Prevalence of Proteinuria among Bevacizumab-Treated Cancer Patients with Type 2 Diabetes Mellitus.

The objective of this study was to investigate whether improving glycemic control reduces the prevalence and progression of proteinuria among bevacizumab (BEV)-treated cancer patients with type 2 diabetes mellitus (DM). We retrospectively reviewed the medical records of 55 patients with type 2 DM who were treated with BEV between July 1 2011 and May 31 2018 at Iwate Medical University Hospital. The patients were classified based on changes in glycated hemoglobin (HbA1c) level during the 3 months following BEV administration into the "HbA1c elevated" group (+0.5% or above, n=24) and the "HbA1c non-elevated" group (indicating no change or decrease; n=31). At 3 months following BEV administration, the means of HbA1c and its change rate in the 'HbA1c elevated' group was significantly higher than that in the 'HbA1c non-elevated' group, and the prevalence of proteinuria in the 'HbA1c elevated' group was significantly higher than that in the 'HbA1c non-elevated' group. Additionally, our subjects were classified into the proteinuria group and non-proteinuria group. The mean HbA1c level in the proteinuria group was significantly higher than that in the non-proteinuria group at 3 months following BEV administration. Furthermore, the mean rates of change of HbA1c level in patients experiencing grades 1 and 2 proteinuria were +9.97±2.26 and +14.0±3.82%, respectively. These values were significantly higher than those of patients with no proteinuria (-2.15±1.96%). Our results suggest that deterioration of glycemic control contributes to the prevalence of proteinuria among BEV-treated cancer patients with type 2 DM.

The efficacy of sodium azulene sulfonate L-glutamine for managing chemotherapy-induced oral mucositis in cancer patients: a prospective comparative study.

BACKGROUND: The efficacy of sodium azulene sulfonate L-glutamine (GA) in treating oral mucositis caused by the administration of anticancer agents has not been previously elucidated. Therefore, this prospective comparative study was conducted to evaluate the efficacy of GA in treating oral mucositis caused by chemotherapy regimens involving fluorinated pyrimidine anticancer drugs. METHODS: The subjects of this study were patients with oral mucositis of grade 2 or higher while on outpatient chemotherapy regimens involving fluorinated pyrimidine anticancer drugs for colorectal or breast cancer. The subjects were randomly divided into a group that received GA (the GA group) or a group that did not receive GA (the control group) by using the closed-envelope method. GA was administered three times a day every day from the first day of the regimen until the final day. The primary endpoint was the development of oral mucositis of grade 2 or higher. The secondary endpoint was the severity of oral pain, which was judged using an 11-stage numerical rating scale (NRS) ranging from 0 to 10. RESULTS: The proportion of patients with oral mucositis of grade 2 or higher was 32.4% in the GA group and 57.6% in the control group. The GA group had a significantly lower frequency of occurrence. The changes in the NRS scores before and after the trial began were - 2.9 ± 0.6 in the GA group and - 1.2 ± 0.5 in the control group. The NRS score decreased more significantly in the GA group than in the control group (P = 0.046). One patient stopped GA treatment voluntarily due to nausea; other than nausea, no GA-related side effects were observed. CONCLUSIONS: GA protects against oral mucositis and reduces the severity of prevailing oral mucositis symptoms. Our findings indicate that GA is a highly safe and convenient drug.