Combination therapy with mizoribine for severe childhood IgA nephropathy: a pilot study

In two previous randomized controlled trials we showed that treatment of severe childhood immunoglobulin A nephropathy (IgA-N) using prednisolone, azathioprine, heparin–warfarin, and dipyridamole prevented any increase of sclerosed glomeruli and that prednisolone alone did not prevent a further increase of sclerosed glomeruli. Accordingly, the immunosuppressant is considered to be important. Often, however, we were unable to complete azathioprine regimen due to toxicity. Therefore, a different but effective immunosuppressant may be worth trying. Mizoribine, like azathioprine, is an antimetabolite that exerts its immunosuppressant effect by inhibiting lymphocyte proliferation. In this pilot study, we administered mizoribine instead of azathioprine as part of the combination therapy for treating 23 children with severe IgA-N and evaluated the efficacy and safety. Eighteen patients reached the primary endpoint (urine protein/creatinine ratio <0.2) during the 2-year treatment period. The cumulative disappearance rate of proteinuria determined by Kaplan–Meier was 80.4%. Median protein excretion was reduced from 1.19 g/m²/day to 0.05 g/m²/day (p < 0.0001). After treatment, the median percentage of glomeruli showing sclerosis was unchanged in comparison with that before treatment. No patients required a change of treatment. In conclusion, the efficacy and safety of the mizoribine combination seems to be acceptable for treating children with severe IgA-N. *Participants listed at end of paper.     

Cobalt chloride induces apoptosis and zinc chloride suppresses cobalt-induced apoptosis by Bcl-2 expression in human submandibular gland HSG cells

To determine the effects of cobalt chloride on human submandibular gland cells, HSG cells were exposed to various concentrations of cobalt chloride. Cobalt chloride induced cytotoxicity and cell death in HSG cells as determined by phase-contrast microscopy and WST-1 cell viability assay. By using the Hoechst 33342 staining, marked nuclear condensation and fragmentation of chromatin were observed in cobalt chloride-treated cells. Cobalt chloride induced DNA ladder formation in HSG cells in both dose- and time-dependent manner with maximal effect at a concentration of 0.5 mM and 48 h, respectively. Cobalt chloride inhibited the expression of both Bcl-2 protein and mRNA in dose- and time-dependent manner. Zinc chloride recovered the cobalt-suppressed Bcl-2 expression and protected against cobalt-induced apoptosis in HSG cells. Our results show that the pathway of the apoptosis in HSG cells is regulated by cobalt chloride and zinc chloride. Our results also indicate that cobalt-induced apoptotic steps in HSG cells are related to the production of Bcl-2 protein.     

Effects of mouth washing procedures on removal of budesonide inhaled by using Turbuhaler

Mouth washing after inhalation of corticosteroids is effective for prevention of local adverse effects. We determined the amounts of drug residues remaining on the oropharyngeal mucosa following inhalation of budesonide (BUD) via a Turbuhaler (BUD-TH) (100 microg). Further, we studied the effects of mouth washing on the removal of drug residues by quantification of BUD in expectorated wash solution using an HPLC method. The amount of BUD recovered after gargling and rinsing for 5 s each was 19.4+/-9.4 microg, as compared to 23.8+/-13.6 microg after rinsing alone for 10 s and 18.3+/-8.9 microg after gargling alone for 10 s, though the differences were not significant. Our results indicated that about 20% of the dose was remaining on the oropharyngeal mucosa after inhalation. In a comparison of washing times, the amounts of BUD recovered were 26.3+/-3.2 microg after gargling and rinsing for 3 s each, and 19.4+/-9.3 microg after those for 5 s each. As for the effect of lag time before beginning mouth washing, the ratio of BUD recovered following mouth washing with a lag time of 1 min was 73.2%, while it was reduced to 27.8% after 10 min, as compared to immediate mouth washing following administration. Our results suggest that the amount of BUD removed by mouth washing is associated with the lag time between inhalation and mouth washing, however, not with the duration of mouth washing. We concluded that immediate mouth washing after inhalation is most useful for the removal of drugs following BUD-TH administration.     

Analysis of antiemetic effect of various dosage regimens of azasetron hydrochloride based on 5-HT3 receptor occupancy of serotonin

Antineoplastic drugs have been shown to exert direct effects on the gut and induce the release of serotonin from the enterochromaffin cells of small intestinal mucosa. It is thought that released serotonin stimulates vagal afferent fibers through 5-HT3 receptors located in the vagal afferent terminals in the gastrointestinal tract and initiates sensory signals to the area postrema and the emetic center, thereby initiating nausea and vomiting. A 5-HT3 antagonist competitively inhibits serotonin at its specific binding sites, 5-HT3 receptors, and thereby elicits an antiemetic effect. Therefore 5-HT3 receptor occupancy of serotonin may be an appropriate indicator of the antiemetic activity of 5-HT3 antagonists. We analyzed 5-HT3 receptor occupancy of serotonin by integrating pharmacokinetic and receptor-binding kinetic parameters based on the receptor occupancy theory to compare the strength of the antiemetic effects of three dosage regimens of azasetron hydrochloride. The inhibitory effects on the binding of serotonin to 5-HT3 receptor of regimen 2 (an intravenous bolus injection of 5 mg of azasetron hydrochloride before and 8 h after chemotherapy) and regimen 3 (an intravenous bolus injection of 2.5 mg followed by 7.5 mg continuous intravenous infusion for 24 h) were longer-lasting than those of regimen 1 (an intravenous bolus injection of 10 mg before the start of chemotherapy). Furthermore, a positive relationship was found between the time of inhibitory effects on the binding of serotonin to 5-HT3 receptor and antiemetic effects of azasetron hydrochloride. From these results, dosage regimens 2 and 3 were considered to be more effective in the long term than regimen 1 in prophylaxis of nausea and vomiting induced by cisplatin.     

Recovery from insulin dependence in immune checkpoint inhibitor-associated diabetes mellitus: A case report

Immune checkpoint inhibitor-associated diabetes mellitus (ICI-DM) is a rare immune-related adverse event and is usually considered permanent. Here, we report the first case of a 54-year-old man with ICI-DM who recovered from insulin dependence. He was diagnosed with lung cancer and started pembrolizumab therapy. After seven cycles, he developed ICI-associated secondary adrenal insufficiency and started hydrocortisone supplementation. Subsequently, he complained of fatigue, and blood examinations showed hyperglycemia with ketosis. A glucagon challenge test indicated insulin dependence. He was diagnosed with ICI-DM and insulin therapy was initiated. Pembrolizumab therapy was discontinued due to concomitant ICI-associated hepatitis. Six months later, a glucagon challenge test result showed an improvement in insulin secretion, and insulin therapy was discontinued. The lung cancer lesions continued to shrink. Even if ICI-DM develops, it might be possible to control the underlying cancer while avoiding lifelong insulin therapy through early discontinuation of ICI.     

Cystatin C-based equation for estimating glomerular filtration rate in Japanese children and adolescents

Background

Renal inulin clearance is the gold standard for evaluation of kidney function, but is compromised by problems of collecting urine samples in children, especially those <6 years or with a bladder dysfunction. Therefore, we should utilize the serum cystatin C (cysC)-based estimated glomerular filtration rate (eGFR) for measuring serum cysC. The purpose of the present study is to determine the applicability of the new serum cysC-based eGFR in Japanese children and adolescents, including infants with chronic kidney disease (CKD), for evaluation of renal function.

Methods

Inulin clearance and standardized serum cysC level determined by the colloidal gold immunoassay were measured in 135 pediatric CKD patients between the ages of 1 month and 18 years with no underlying disease that affects renal function except CKD, to determine serum cysC-based eGFR in Japanese children and adolescents.

Results

We showed the inulin clearance by expression of 1/serum cysC in pediatric CKD patients, which resulted in the equation: inulin GFR (mL/min/1.73 m²) = 104.1 × 1/serum cysC (mg/L) ? 7.80. We also validated the cysC-based eGFR formula for Japanese adults. eGFR values obtained with the adult formula significantly underestimated GFR by approximately 8 % in children with CKD.

Conclusion

We determined the new cysC-based eGFR formula is useful for clinical screening of renal function in Japanese children and adolescents, including infants.     

Postoperative outcome in aortic stenosis with diastolic heart failure compared to one with depressed systolic function

BACKGROUND: In patients with aortic stenosis (AS), the clinical outcome worsens after the development of angina, syncope, and heart failure. This study was performed to elucidate whether the outcome with AS was also poor in patients with diastolic heart failure. METHODS AND RESULTS: Fifty-two patients who had undergone aortic valve replacement (AVR) for AS were retrospectively classified into 3 groups (G) on the basis of LV ejection fraction (EF) and pulmonary wedge pressure (PWP): G-1) normal LVEF, low PWP (EF > or = 45% and PWP < 16 mmHg; n = 35), G-2) normal LVEF, high PWP (EF > or = 45% and PWP > or = 16 mmHg; n = 8), and G-3) low LVEF (EF < 45%; n = 9). Among these 3 groups, we compared the outcome after AVR. None of the patients died after the operation in AS with preserved LVEF irrespective of the PWP, whereas there were 3 cardiac deaths in AS with low EF irrespective of the PWP. CONCLUSIONS: In patients with AS, diastolic heart failure developed in addition to systolic heart failure. The development of LV systolic dysfunction in AS was regarded as poor during the postoperative course, but diastolic heart failure did not affect the outcome. The occurrence of heart failure with preserved systolic function may have a slightly better prognosis and may still be suitable for AVR.     

Alterations of plasma ghrelin levels in rats with lipopolysaccharide-induced wasting syndrome and effects of ghrelin treatment on the syndrome

Ghrelin not only strongly stimulates GH secretion, but is also involved in energy homeostasis by stimulating food intake and promoting adiposity through a GH-independent mechanism. These effects of ghrelin may play an important role in the pathophysiology of inflammatory wasting syndrome, in which both the somatotropic axis and energy balance are altered. In this study we investigated plasma ghrelin concentrations after lipopolysaccharide (LPS) administration to rats, a model of the wasting syndrome and critical illness. In addition, the therapeutic potential of the antiwasting effects of ghrelin was explored using LPS-injected rats. A single LPS injection suppressed plasma ghrelin levels 6 and 12 h later. Maximal reduction was observed 12 h after LPS injection, in a dose-dependent manner. In contrast, plasma ghrelin levels were elevated after repeated LPS injections on d 2 and 5. Peripheral administration of ghrelin twice daily (10 nmol/rat) for 5 d increased body weight gain in repeated LPS-injected rats. Furthermore, both adipose tissue weight and plasma leptin concentrations were increased after ghrelin administration in these rats. In conclusion, plasma ghrelin levels are altered in LPS-injected rats, and ghrelin treatment may provide a new therapeutic approach to the wasting syndrome and critical illness.     

Alanine aminotransferase (ALT) levels in a normal population and interferon therapy in chronic hepatitis C patients with normal ALT

BACKGROUND/AIMS: The aims of this study were to determine the distribution of serum alanine aminotransferase levels in a normal population and to clarify whether interferon treatment is justified in HCV-infected patients with persistently normal alanine aminotransferase levels. METHODOLOGY: The distribution of alanine aminotransferase levels was examined among 949 normal subjects who were negative for hepatitis viruses, denied regular alcohol use. Nineteen patients with chronic hepatitis C and persistently normal alanine aminotransferase levels were treated with alpha interferon (six or ten million units thrice weekly for six months). RESULTS: Peaks of alanine aminotransferase distribution among the normal subjects were seen at 16-20 IU/L and 11-15 IU/L in males and females, respectively. Fourteen of the 19 patients who received interferon treatment had favorable factors of response to interferon (eight with low pretreatment virus load, four with HCV genotype 2 and two with both). A sustained virological response was achieved in eight (57%) of 14, and alanine aminotransferase levels decreased significantly to within the normal range after interferon treatment in six of eight. CONCLUSIONS: Patients with chronic hepatitis C and persistently normal alanine aminotransferase levels should be treated with high doses of interferon if they have favorable factors of response to interferon treatment.     

A case of subclinical hypothyroidism developing marked pleural effusions and peripheral edema with elevated vascular endothelial growth factor

A 69-year-old woman was admitted for the treatment of marked pleural effusions and peripheral edema. Analytical studies of the pleural effusion revealed exudates. Culture for bacterial organisms and tuberculosis were negative, and cytology was normal. She had a mediastinal tumor at the age of 61 and regular follow-up showed no evidence of malignancy. She underwent the mediastinal tumor resection, because we thought this was the cause of her symptoms. However, her clinical symptoms persisted after surgery. Next, we noticed subclinical hypothyroidism, in which serum TSH level was elevated with concomitant normal thyroid hormone levels. In addition, serum vascular endothelial growth factor (VEGF) levels, which have been reported to be related to the pathophysiology of the extravascular volume overload, were elevated. Although her TSH level was slightly elevated (15.4 microU/ml), we started thyroid hormone replacement therapy. This therapy gradually ameliorated her clinical manifestation and abnormal laboratory data, including elevated VEGF levels. These observations indicate that even subclinical hypothyroidism may cause severe clinical manifestations. Furthermore, elevated VEGF may be a contributing factor in the pathogenesis of extravascular volume overload in hypothyroid patients.