Nalfurafine is a pharmaceutical agent used in the treatment of cutaneous pruritus. Although its orally disintegrating (OD) film agent is approved, noninferiority of its disintegration and elution to various OD tablet agents has yet to be demonstrated. This study aimed to evaluate the pharmaceutical characteristics of the nalfurafine OD film agent. Disintegration and elution performance were tested for 4 different types of nalfurafine OD pharmaceutical agents including 1 film agent and 3 tablet agents. Visual evaluation was employed for the disintegration test, while measurement of concentration using high performance liquid chromatography with ultraviolet was employed for the elution test. As a result of disintegration evaluation (n = 3), the OD film agent repeatedly exhibited the same complete disintegration time (60 s), while the other three OD tablet agents showed the time variability (120 s - 30 min). After the test start, the OD film agents began disintegration at 20 s while the OD tablet agents began disintegration immediately. As a result of elution evaluation (n = 6), after the test start, the OD film agent was eluted 100.6% in 5 min, while the OD tablet agents were eluted 95.8%, 75.8% and 80.5%, respectively. In conclusion, this study indicates that the nalfurafine OD film agent was not inferior to the OD tablet agents in terms of disintegration and elution.
Cisplatin-induced AKI is caused by several toxicological and pathological mechanisms, including inflammatory responses, oxidative stress, DNA damages and apoptosis in renal tubules. Among low-molecular weight uremic solutes, indoxyl sulfate (IS), a representative sulfate-conjugated uremic toxin, accumulates markedly in serum and most tissues of animal models with cisplatin-induced AKI. IS is exclusively produced in the liver through detoxification pathway mediated by metabolizing enzymes, including CYP2A6/2E1 and Sult1a1.
(1) Background: multiple myeloma patients have benefited from bortezomib therapy, though it has often been discontinued owing to diarrhea. The objective of this study was to verify serum bortezomib concentration in the emergence of diarrhea. (2) Methods: this prospective, observational case-control, and monocentric study was performed with an approval by the Ethics Committee of Kumamoto University Hospital in 2015 (No. 1121) from February 2015 to April 2017. (3) Results: twenty-four patients with bortezomib therapy were recruited; eight patients (33.3%) developed diarrhea at day 3 as median. Median measured trough bortezomib concentration at 24 h after first or second dose for patients with or without diarrhea was 0.87 or 0.48 ng/mL, respectively (p = 0.04, Wilcoxon signed rank test). Receiver operation characteristic (ROC) analysis produced the cut-off concentration of 0.857 ng/mL (area under the ROC curve of 0.797, sensitivity of 0.625, specificity of 0.875). The survival curves between patients with and without diarrhea were similar (p = 0.667); those between patients with higher and lower concentration than median value (0.61 ng/mL) were also similar (p = 0.940). (4) Conclusions: this study indicated the possible involvement of serum bortezomib concentration in the emergence of diarrhea in bortezomib therapy in patients with multiple myeloma.
Endogenous factors involved in the progression of cisplatin nephropathy remain undetermined. Here, we demonstrate the toxico-pathological roles of indoxyl sulfate (IS), a sulfate-conjugated uremic toxin, and sulfotransferase 1A1 (SULT1A1), an enzyme involved in its synthesis, in cisplatin-induced acute kidney injury using Sult1a1-deficient (Sult1a1-/- KO) mice. With cisplatin administration, severe kidney dysfunction, tissue damage, and apoptosis were attenuated in Sult1a1-/- (KO) mice. Aryl hydrocarbon receptor (AhR) expression was increased by treatment with cisplatin in mouse kidney tissue. Moreover, the downregulation of antioxidant stress enzymes in wild-type (WT) mice was not observed in Sult1a1-/- (KO) mice. To investigate the effect of IS on the reactive oxygen species (ROS) levels, HK-2 cells were treated with cisplatin and IS. The ROS levels were significantly increased compared to cisplatin or IS treatment alone. IS-induced increases in ROS were reversed by downregulation of AhR, xanthine oxidase (XO), and NADPH oxidase 4 (NOX4). These findings suggest that SULT1A1 plays toxico-pathological roles in the progression of cisplatin-induced acute kidney injury, while the IS/AhR/ROS axis brings about oxidative stress.
Abstract Background and Aims Obstructive nephropathy is the result of functional or anatomic lesions located in the urinary tract, and renal interstitial fibrosis is a common finding associated with long-term nephropathy. Many factors are suggested to be involved in the pathogenesis of renal fibrosis, such as infiltration of macrophages, growth factors, oxidative stress and cytokines. Indoxyl sulfate (IS), a typical sulfate-conjugated uremic solute, accumulates markedly in serum and renal tissue of cisplatin- or ischemia/reperfusion-induced acute kidney injury model animals, thereby inducing generation of oxidative stress. However, the relationship between IS and obstructive nephropathy or renal fibrosis remains unclear. IS is produced in the liver by CYP2A6/2E1-dependent oxidative metabolism of dietary protein-derived indole, followed by sulfotransferase 1a1 (SULT1A1)-mediated sulfate conjugation of indoxyl. IS in the blood circulation is efficiently taken up by renal proximal tubules via basolateral membrane-localized organic anion transporters, OAT1 and OAT3, and excreted into urine via unidentified apical membrane-located transporter. Thus, we established SULT1A1 gene-deficient (SULTKO) mice and developed UUO mice to investigate the pathological role of IS in UUO-induced renal fibrosis. Method The left ureter of C57BL/6J mice (wild type (WT), 8 weeks-old) and SULTKO mice (8 weeks-old) were obstructed last for 2 weeks. IS concentration in serum and kidney was determined by LC-MS/MS. Changes in histology and interstitial fibrosis were examined with PAS staining and Sirius red staining, respectively. Quantitative PCR was applied for determining expression levels of col1a1 encoding the major component of type I collagen, fibronectin, plasminogen activator inhibitor (PAI)-1, the activator of plasminogen and hence fibrinolysis, pro-inflammatory cytokine interleukin 6 (IL-6), Wnt4 encoding one protein of Wnt and Sfrp5, a gene that codes for antagonist of Wnt pathway. Renal fibrosis also evaluated through the expression of alpha smooth muscle actin (SMA) by Western blotting. Results By UUO treatment, the concentration of IS in serum, kidney and liver were elevated, which were suppressed in SULTKO mice. Ureter dilation was obviously observed in the obstructed kidney of WT mice, which was slightly prevented in SULTKO mice with UUO. Sirius red staining revealed that severe collagen deposition was found in the interstitium of WT kidney with UUO, but it was partly prevented in the kidney of KO mice with UUO along with the decrease in IS accumulation. The high expression of SMA, col1a1 and fibronectin in the kidney of WT mice with UUO were significantly suppressed in the kidney of SULTKO mice, 2.3-fold, 1.4-fold and 2.3-fold, respectively, suggesting that renal fibrotic responses were ameliorated in SULTKO mice. The expression of PAI-1, which was upregulated in WT mice with UUO, was also suppressed (1.8-fold) in SULTKO mice with UUO. The elevated expression of IL-6 in the kidney of WT mice with UUO was inhibited (1.8-fold) in SULTKO mice with UUO, indicating the possibility that inflammation-related signalling pathway also participated in the IS-exacerbated renal fibrosis. The enhanced expression of Wnt4 in the kidney of WT mice with UUO was suppressed (1.8-fold) in SULTKO mice with UUO, and the gene of Sfrp5 exhibited a higher expression level (3.2-fold) in the kidney of SULTKO mice with UUO compared with WT UUO mice. Conclusion Sult1a1-deficient mice showed the suppressed accumulation of IS in the kidney with UUO. Renal IS accumulation during pathological progression of obstructive nephropathy could enhance interstitial fibrosis through the activation of Wnt signalling pathway. Hepatic SULT1A1 could be a therapeutic target for preventing the progression of renal interstitial fibrosis by suppressing IS production during obstructive nephropathy.
