Effect of Patient Age, Dose, and Chronic Kidney Disease on the Risk of Adverse Reactions to Distigmine.

Although distigmine is known to sometimes cause severe adverse drug reactions (ADRs), such as cholinergic crisis, there are limited data on the risk factors for these ADRs. In this study, we defined a serum cholinesterase (sChE) cutoff level for early detection of ADRs to distigmine and sought to identify risk factors for these ADRs based on this value. This retrospective cohort study included all patients who were prescribed distigmine and underwent measurement of sChE over a period of 8 years at Kaetsu Hospital. Ninety-three patients were included. The sChE cutoff level below which there was an increase in risk of ADRs was defined as 129 U/L based on the levels in patients who had ADRs by receiver operating characteristic analysis. The percentage of ADRs tended to increase with advancing chronic kidney disease (CKD) stage. Multivariate logistic regression analyses showed that a distigmine dose >0.1 mg/kg/d (odds ratio 3.19, 95% confidence interval 1.24-8.19) and age >85 years (odds ratio 3.04, 95% confidence interval 1.18-7.82) were positively associated with an sChE level ≤129 U/L. An sChE cutoff level of 129 U/L is a useful predictor of the risk of an ADR to distigmine, and dose per body weight, age, and CKD progression may pose potential risk of an ADR to distigmine. Therefore, for patients taking distigmine who have these risk factors, the risk of a severe ADR to distigmine can be reduced by decreasing the dose of distigmine and close monitoring of the sChE level.

[Is Concomitant Therapy with Acetaminophen and Low-dose Aspirin a Risk Factor for CKD Progression? A 6-Year Cohort Study].

Concomitant therapy with acetaminophen (APAP) and low-dose aspirin is often used in clinical settings; however, it is unclear whether this combination is involved in the progression of chronic kidney disease (CKD). We hypothesized that concomitant therapy with APAP and low-dose aspirin may cause CKD progression. We carried out a retrospective 6-year cohort study that included all patients who received low-dose aspirin from January 2011 to December 2016 at Kaetsu Hospital. Primary outcome was defined as CKD progression at the end of the study compared with baseline. Among the 441 patients treated during the study period, we identified 89 cases of CKD progression. Multivariate regression analysis showed that exposure to APAP>50 g [odds ratio (OR), 2.68, 95% confidence interval (CI), 1.08-6.70], age increase by 1 year (OR, 1.05, 95% CI, 1.02-1.08), and diabetes mellitus (OR, 2.40, 95% CI, 1.41-4.08) had positive associations with CKD progression. Our findings suggested that concomitant therapy with APAP and low-dose aspirin increased the risk of CKD progression. Therefore, we recommend more thorough monitoring of serum creatinine when patients are on such concomitant therapy. Moreover, it is important to advise users of low-dose aspirin to avoid unnecessary use of APAP, in order to reduce the risk of CKD progression.

[Low Continuity Rate of Sucroferric Oxyhydroxide among Japanese Hemodialysis Patients with High Phosphate Binder Pill Burden].

This prospective observational study was conducted to evaluate the continuity, efficacy, and tolerability of sucroferric oxyhydroxide (SO) among hemodialysis (HD) patients who switched to SO from sevelamer hydrochloride (SH) or bixalomer (BX). Participants were 9 HD patients in Kaetsu Hospital who had been receiving more than 9 tablets/d of SH or BX and were switched to SO 750 mg/d. All the participants were men. Over a 6-month observational period, 6 of the 9 patients (67%) discontinued SO because of adverse events, including diarrhea, atheroma, and polycythemia. Although the diarrhea and atheroma were mild, the affected patients did not wish to restart SO. On the other hand, 3 of the 9 patients (33%) continued taking SO throughout the observation period. These patients tended to have increased levels of serum calcium, hematocrit, and serum ferritin; a decreased number of phosphate binder tablets (from 21 tablets/d to 8 tablets/d); and a decreased dosage of erythropoiesis-stimulating agents. Serum phosphate levels tended to decrease in continuers, but tended to increase in discontinuers. It may be preferable to increase the SO dosage gradually rather than switching from SH or BX all at once, and patients who switch to SO should be carefully monitored.

Interstitial lung disease following FOLFOX + FOLFIRI and bevacizumab therapy associated with leucovorin: A case report.

Chemotherapy-induced interstitial lung disease in colorectal cancer patients is rare but represents a life-threatening adverse reaction. We report here a case of interstitial lung disease following chemotherapy for metastatic colorectal cancer and the interesting results of the drug-induced lymphocyte stimulation test and leukocyte migration test. After chemotherapy with oxaliplatin plus infusional 5-fluorouracil and leucovorin (FOLFOX) plus bevacizumab followed by irinotecan plus infusional 5-fluorouracil and leucovorin (FOLFIRI), the patient was hospitalized with fever and chills. Laboratory data showed neutropenia and eosinophilia. Computed tomography revealed ground-glass opacities in both lungs; therefore, we diagnosed chemotherapy-induced interstitial lung disease. Steroid therapy was effective. We suspected irinotecan to be the etiological drug for interstitial lung disease in this patient because interstitial lung disease developed after switching the regimen from FOLFOX to FOLFIRI. However, drug-induced lymphocyte stimulation test and leukocyte migration test results were positive for only leucovorin and negative for irinotecan and 5-fluorouracil. This is the first case to show positive results on the drug-induced lymphocyte stimulation test and leukocyte migration test for only leucovorin and negative results for antineoplastic drugs. Our findings suggest that all drugs included in chemotherapy regimens have the potential to induce interstitial lung disease, and if rechallenge chemotherapy is considered, the drug-induced lymphocyte stimulation test and leukocyte migration test are expected to be useful for determining the drug that needs to be excluded.

Comparison of Clinical Advantage between Topiroxostat and Febuxostat in Hemodialysis Patients.

To determine the response of hemodialysis (HD) patients to topiroxostat after a switch from febuxostat, we evaluated the efficacy, tolerability, and serum concentration of topiroxostat in HD patients after the switch. In this 16-month prospective observational study, we assessed the serum uric acid (UA) levels, other laboratory data, and serum topiroxostat concentrations of 10 HD patients who had been receiving febuxostat at a dose of 10 mg/d for over 1 year. No statistical difference was observed between the tolerability index at baseline and 16 months after the switch to topiroxostat. Serum UA after the switch in all patients (attained serum UA levels of ≤6 mg/dL) was 5.6±1.7 mg/dL (60%) at baseline, 4.9±0.5 mg/dL (100%) at 6 months and 5.7±0.4 mg/dL (50%) at 16 months (p=0.25), respectively. In patients with baseline serum UA levels >6 mg/dL, serum UA was significantly reduced at 6 and 16 months compared with baseline. Minimum serum concentrations of serum topiroxostat were lower than the limit of quantification (<25 ng/mL). Our results indicate that a switch from febuxostat 10 mg/d to topiroxostat 40 mg/d might reduce serum UA levels, with no change in other clinical laboratory data over the long term. These effects were more frequent in patients with high serum UA levels. Furthermore, topiroxostat therapy was more cost effective than febuxostat therapy. Thus, topiroxostat therapy could be a better treatment option for HD patients who develop high serum UA levels after febuxostat 10 mg/d administration.

Switching from allopurinol to febuxostat: efficacy and tolerability in hemodialysis patients.

BACKGROUND: Febuxostat is a novel xanthine oxidase inhibitor. However, few studies have examined the long-term efficacy and tolerability of febuxostat after switching from allopurinol in hemodialysis (HD) patients. Therefore, the present study evaluated the long-term efficacy and tolerability of febuxostat in HD patients after switching from allopurinol. FINDINGS: We monitored the levels of hemoglobin, hematocrit, platelet count, blood urea nitrogen, serum creatinine, serum sodium, serum potassium, serum chloride, serum calcium, serum inorganic phosphorus, aspartate transaminase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, and total protein that were considered overall as a tolerability index, while the serum uric acid (UA) level was considered an index of efficacy. All values were measured at baseline and at 1, 6, 12, and 16 months after the switch to febuxostat therapy. All subjects switched from allopurinol (100 mg/day) to febuxostat (10 mg/day) in August 2013. Clinical laboratory data were collected at baseline in July 2013 until December 2014. Nine patients were included in the study analysis. Results showed that clinical laboratory data at baseline versus those at 16 months were not significantly different. Serum UA levels, which represented the efficacy index, were significantly different between the baseline level (6.8 ± 1.4) and those at 1, 6, 12, and 16 months (5.2 ± 1.1, 5.1 ± 1.1, 4.6 ± 0.9, and 5.4 ± 1.8 mg/dL, respectively; all p < 0.05). CONCLUSION: Switching from allopurinol to febuxostat in HD patients reduced serum UA levels, with no changes in other clinical laboratory data in the long term.

Cloning and functional characterization of a novel up-regulator, cartregulin, of carnitine transporter, OCTN2.

Acetylcarnitine exerts therapeutic effects on some neurological disorders including Alzheimer's disease. OCTN2 is known as a transporter for acetylcarnitine, but its expression in the brain is very low. To examine a brain-specific transporter for acetylcarnitine, we screened a rat brain cDNA library by hybridization using a DNA probe conserved among an OCTN family. A cDNA homologous to OCTN2 cDNA was isolated. The cDNA encoded a novel 146-amino acid protein with one putative transmembrane domain. The mRNA was expressed not only in rat brain but also in some other tissues. The novel protein was localized in endoplasmic reticulum when expressed in COS-7 cells but exhibited no transport activity for acetylcarnitine. However, when co-expressed with OCTN2, it enhanced the OCTN2-mediated transport by about twofold. The enhancement was accompanied by an increase in the levels of mRNA and protein. When OCTN2 was expressed in Xenopus oocytes by injection of its cRNA, its transport activity was enhanced by co-expression of the novel protein. These data suggest that the novel protein increases OCTN2 by stabilizing the mRNA in endoplasmic reticulum. The protein may be an up-regulator of OCTN2 and is tentatively designated cartregulin.

Reciprocal changes in endothelium-derived hyperpolarizing factor- and nitric oxide-system in the mesenteric artery of adult female rats following ovariectomy.

1. To explore the effects of estrogen on arterial functions, we examined endothelium-derived hyperpolarizing factor (EDHF)- and NO-mediated responses in isolated mesenteric arteries of female rats, 4 weeks after sham-operation (CON), ovariectomy (OVX) and OVX plus chronic estrogen treatment (OVX+E(2)). Tissue levels of connexins-40, 43 (major components of gap junction), inducible NOS (iNOS), endothelial NOS (eNOS) and eNOS regulator proteins such as calmodulin, heat shock protein 90 (hsp90) and caveolin-1 were also examined using Western blot. 2. In OVX, acetylcholine (ACh)-induced EDHF-mediated relaxation and membrane hyperpolarization of arterial smooth muscles were reduced, whereas ACh-induced NO-mediated relaxation was enhanced, leading to no change in ACh-induced relaxation. 3. In OVX, connexin-40 and 43 were decreased. Tissue levels of eNOS and its positive regulators (calmodulin and hsp90) were unchanged, but that of its negative regulator, caveolin-1, was decreased. The levels of iNOS in mesenteric artery and aorta and plasma levels of NO metabolites and cholesterol were elevated. 4. In OVX, contraction of the artery by phenylephrine was reduced, but augmented by nonspecific inhibitor of NOS to the comparable level as that in CON group. The contraction in OVX group unlike that in CON group was augmented by specific iNOS inhibitor, and the difference between contractions in the presence of nonspecific and specific inhibitor as an index of eNOS activity was increased. 5. In OVX+E(2), all these changes were recovered. 6. In all groups, EDHF-mediated relaxation was suppressed by 18beta-glycyrrhetinic acid, an inhibitor of gap junction. 7. These results indicate that estrogen deficiency does not change the diameter of mesenteric artery: it reduces EDHF-mediated relaxation by decreasing gap junction, whereas it augments NO-mediated relaxation via an increase in NO release. Increased NO result from increased activity of eNOS subsequent to a decrease in caveolin-1 and from induction of iNOS. However, excessive NO generation with elevated plasma cholesterol would raise a risk for atherosclerosis.