Salt-Sensitive Hypertension of the Renal Tubular Cell-Specific NFAT5 (Nuclear Factor of Activated T-Cells 5) Knockout Mice.

[Figure: see text].

Palonosetron versus Granisetron in Combination with Aprepitant and Dexamethasone for the Prevention of Chemotherapy-Induced Nausea and Vomiting after Moderately Emetogenic Chemotherapy: A Single-Institutional Retrospective Cohort Study.

The triplet antiemetic regimen is administered to prevent chemotherapy-induced nausea and vomiting (CINV) after moderately emetogenic chemotherapy (MEC). However, the superiority of palonosetron over first-generation 5-hydroxytryptamine-3 receptor antagonists in triplet antiemetic therapy remains unclear. In this study, we evaluated the efficacy of palonosetron (PALO) and granisetron (GRA) in triplet antiemetic therapy for CINV. This study included 267 patients who received MEC at our hospital between April 2017 and September 2020. Patients were pretreated with antiemetic therapy comprising PALO or GRA and dexamethasone on day 1 and aprepitant on days 1-3. We evaluated the rate of complete response (CR) (i.e., no vomiting and no use of rescue medication) in the acute phase (0-24 h), delayed phase (24-120 h), and overall phase (0-120 h) after first-cycle chemotherapy. Furthermore, multivariate analysis was conducted to identify risk factors for non-CR. The rate of CR in the overall and delayed phases was significantly higher in the PALO group (91.9 and 91.9%, respectively) than in the GRA group (74.1 and 75.5%, respectively). In the acute phase, the incidence was not different between the GRA and PALO groups (96.5 and 99.2%, respectively). Multivariate analysis revealed that female sex and the use of GRA were risk factors for non-CR. Subgroup analysis revealed the superiority of PALO over GRA in female patients, but not in male patients. In conclusion, PALO was more effective than GRA in triplet antiemetic therapy in preventing CINV during MEC, especially for female patients.

Clinical pharmacokinetics of oxaliplatin in a hemodialysis patient with advanced gastric cancer.

We administered FOLFOX (oxaliplatin (L-OHP) plus infusional 5-fluorouracil (5-FU) and leucovorin) to an hemodialysis (HD) patient with advanced gastric cancer (AGC), and investigated pharmacokinetics (PKs) and dialyzability of L-OHP. The patient was a 54-year-old Japanese man with a diagnosis of inoperable AGC. FOLFOX was instituted 3 h prior to the start of a 4 h HD period with the L-OHP and 5-FU doses reduced by 50% for the first cycle, and 30% reduced dose was administered for the second cycle. We performed an analysis of the PKs of L-OHP during these two cycles. Volume of distribution and area under the curve of the 30% reduced L-OHP dose were 56.7 L and 30.0 µg·h/mL, respectively. A dose reduction of L-OHP by 30%-50% may be advisable for the initial administration, given the need for careful administration of chemotherapy in HD patients, with particular attention to the development of hematological toxicities and neuropathy.

[A Case of Advanced Esophageal Cancer Treated with Nedaplatin in a Patient Undergoing Maintenance Hemodialysis].

Herein, we investigated the pharmacokinetic (PK) profile of nedaplatin (cis-diamine-glycolateplatinum; CDGP) in a hemodialysis (HD) patient with advanced esophageal squamous cell carcinoma (ESCC) by administering the CDGP immediately prior to HD. Our patient was treated with CDGP (45 mg/m2 for a total dose of 60.2 mg) and 5-fluorouracil (560 mg/m2 for a total dose of 750 mg) before initiating HD. The total platinum (Pt) concentration (Pt_total) and free Pt concentration (Pt_free) 2 h after completion of HD were 0.4 µg/mL and 0.3 µg/mL, respectively. The removal rates of Pt_total and Pt_free by the dialyzer were 76.5% and 84.6%, respectively. Twenty-four hours after CDGP administration, the Pt_free was below the detection limit of the method of analysis. Pt_free within the range of the recommended CDGP target AUC0-24 was 8-10 µg/mL•h, the AUC0-24 of Pt_total and Pt_free were 16.5 µg/mL•h and 8.8 µg/mL•h, respectively. We conclude that HD should be performed after the end of CDGP infusion as part of the CDGP chemotherapy regimen for HD patients with ESCC, and suggest that HD is effective for obtaining a PK profile of CDGP similar to patients with normal renal function.

Insufficiency of urinary acid excretion of overweight or obese patients with chronic kidney disease and its involvement with renal tubular injury.

AIM: Metabolic acidosis occurs due to insufficient urinary ammonium excretion as chronic kidney disease (CKD) advances. Because obese subjects tend to have excessive consumption of protein and sodium chloride, they are prone to chronic acid loading and may therefore be predisposed to acid-induced kidney injury. We investigated the involvement of obesity in ammoniagenesis within damaged kidneys. METHODS: In the clinical study, urinary ammonium excretion was compared between 13 normal-weight and 15 overweight/obese CKD outpatients whose creatinine clearance was higher than 25 mL/min. For animal experiments, NH4 Cl was loaded to KKAy/TaJcl (KKAy), a metabolic syndrome model, and control BALB/c mice for 20 weeks. Kidney injury was evaluated through histological analysis and the expression of proinflammatory markers. RESULTS: Urinary ammonium excretion was lower in overweight/obese patients than in normal-weight patients, while intakes of protein and sodium chloride were higher in overweight/obese patients, implying that subclinical metabolic acidosis occurs in overweight/obese patients. The increase in urinary ammonium excretion induced by NH4 Cl loading was attenuated in KKAy mice after 16 weeks, whereas the increase was maintained in BALB/c mice throughout the study period. Histological study and real-time polymerase chain reaction analysis showed proximal tubular injury and enhanced expression levels of neutrophil gelatinase-associated lipocalin (NGAL) protein and messenger RNA, respectively, in KKAy mice but not in BALB/c mice. Finally, urinary NGAL concentration was higher in overweight/obese patients than in normal-weight patients in the early stage of CKD. CONCLUSION: Obesity could facilitate the induction of subclinical metabolic acidosis and acid accumulation in the kidney, which may potentially exacerbate kidney injury in CKD patients.

Preparation and Evaluation of a Modified Mohs Paste Mixed with Zinc Oxide 10% Topical Oil-Based Ointment.

BACKGROUND: The skin fixative used in Mohs chemosurgery contains zinc chloride and is referred to as Mohs paste (MP). However, MP shows a remarkable change in rheological characteristics after its preparation. OBJECTIVE: To prepare an MP with stable rheological characteristics, we prepared a modified MP (mMP) using zinc oxide 10% single ointment (Zn_ointment), which is an oil-based ointment. METHODS: We evaluated mMP by determining its rheological characteristics, depth of tissue fixation, and observation of the tissue surface after treatment. RESULTS: The viscosity of mMP increased after three months. However, the treatment-dependent viscosity of mMP could be obtained by mixing with glycerin. The viscosity and spreadability of mMP_3mth, which was three months after preparation, were 1992.0 ± 376.5 Pa·s and 2.1 ± 0.1 cm, respectively. In contrast, the viscosity and spreadability of MP mixed with glycerin were 436.9 ± 0.0 Pa·s and 2.8 ± 0.0 cm, respectively. The fixed invasion depth of MP was significantly higher than that of mMP (p < 0.05). CONCLUSION: This study of a mixture of MP and Zn_ointment showed that the viscosity of mMP could be adjusted with glycerin. Also, the tissue fixation of mMP progressed slowly compared with that of MP. This finding suggests that mMP is effective and safe for Mohs treatment.

Generation and functional analysis of monoclonal antibodies against the second extracellular loop of human M3 muscarinic acetylcholine receptor.

The M3 muscarinic acetylcholine receptor (M3R) plays a crucial role in the activation of salivary and lachrymal glands. The M3R contains four extracellular domains (the N-terminal, and the first, second, and third extracellular loops), and we recently detected antibodies against each of these four domains in a subgroup of patients with Sjögren's syndrome (SS). Functional analysis indicated that the influence of such anti-M3R antibodies on salivary secretion might differ based on the epitopes to which they bind. To clarify the relationship between B-cell epitopes on the M3R and its function, we generated two hybridomas producing anti-M3R monoclonal antibodies against the second extracellular loop of M3R (anti-M3R(2nd) mAbs) and analyzed their function by Ca(2+)-influx assays, using a human salivary gland (HSG) cell line. These two anti-M3R(2nd) mAbs suppressed Ca(2+)-influx in the HSG cells induced by cevimeline stimulation, suggesting that autoantibodies against the second extracellular loop of M3R could be involved in salivary dysfunction in patients with SS.