L type Ca2+ channel blockers prevent oxaliplatin-induced cold hyperalgesia and TRPM8 overexpression in rats

<p>Abstract</p> <p>Background</p> <p>Oxaliplatin is an important drug used in the treatment of colorectal cancer. However, it frequently causes severe acute and chronic peripheral neuropathies. We recently reported that repeated administration of oxaliplatin induced cold hyperalgesia in the early phase and mechanical allodynia in the late phase in rats, and that oxalate derived from oxaliplatin is involved in the cold hyperalgesia. In the present study, we examined the effects of Ca²⁺channel blockers on oxaliplatin-induced cold hyperalgesia in rats.</p> <p>Methods</p> <p>Cold hyperalgesia was assessed by the acetone test. Oxaliplatin (4 mg/kg), sodium oxalate (1.3 mg/kg) or vehicle was injected i.p. on days 1 and 2. Ca²⁺(diltiazem, nifedipine and ethosuximide) and Na⁺(mexiletine) channel blockers were administered p.o. simultaneously with oxaliplatin or oxalate on days 1 and 2.</p> <p>Results</p> <p>Oxaliplatin (4 mg/kg) induced cold hyperalgesia and increased in the transient receptor potential melastatin 8 (TRPM8) mRNA levels in the dorsal root ganglia (DRG). Furthermore, oxalate (1.3 mg/kg) significantly induced the increase in TRPM8 protein in the DRG. Treatment with oxaliplatin and oxalate (500 μM for each) also increased the TRPM8 mRNA levels and induced Ca²⁺influx and nuclear factor of activated T-cell (NFAT) nuclear translocation in cultured DRG cells. These changes induced by oxalate were inhibited by nifedipine, diltiazem and mexiletine. Interestingly, co-administration with nifedipine, diltiazem or mexiletine prevented the oxaliplatin-induced cold hyperalgesia and increase in the TRPM8 mRNA levels in the DRG.</p> <p>Conclusions</p> <p>These data suggest that the L type Ca²⁺channels/NFAT/TRPM8 pathway is a downstream mediator for oxaliplatin-induced cold hyperalgesia, and that Ca²⁺channel blockers have prophylactic potential for acute neuropathy.</p

Programmed Chemotherapy for Patients with Metastatic Unresectable Gastric Cancer

BACKGROUND: Recent advances in the treatment of metastatic unresectable gastric cancers (MGC) include the development of new antitumor drugs and new regimens for their use. However, the selection of individually designed regimens by gastric cancer (GC) subtype remains problematic. Here, we investigated the clinical usefulness of programmed chemotherapy. METHODOLOGY/PRINCIPAL FINDINGS: MGC patients were classified into three groups by clinical condition. We implemented a chemotherapy program consisting of S-1 combination regimens. Median survival time (MST) of level 1 patients was 416 days (95% CI: 313-506 days), with an overall response rate of 47%. MSTs of level 2 and 3 patients were 208 (95% CI: 153-287 days) and 95 days (95% CI: 28-136 days), respectively. Grade 3-4 toxicities were neutropenia in 12% and anorexia in 6%. All treatment- related toxicities were resolved, and no treatment-related deaths occurred. CONCLUSIONS/SIGNIFICANCE: This program provided reasonable selection of case-matching regimens and may improve the survival of patients with MGC. Further, it may represent the first clinical tool to provide efficient chemotherapy course selection for MGC. Ongoing analysis of newly developed drugs and regimens will allow the efficacy of this chemotherapy program to be improved

Chemical Composition of Large and Giant Aerosols at Syowa Station, Antarctica

Atmospheric large and giant aerosol particles collected at Syowa Station, Antarctica were analyzed by instrumental neutron activation analysis. A large part of the total mass concentration of aerosol particles could be attributed to sea salt particles, both in winter and summer. The weight ratio Cl/Na for giant particles was larger than the bulk sea water ratio, whereas for large particles in summer it was smaller than that of bulk sea water. It can be explained that giant particles in the present study were blowing snow or drifting snow which was chlorine-enriched, and that large particles in summer were attacked by sulfuric acid droplets to release gaseous Cl to the atmosphere

Pre-Stroke Loop Diuretics and Anemia in Elderly Patients Are Associated Factors of Severe Renal Dysfunction at the Time of Acute Stroke Onset

Background: Severe renal dysfunction (SRD), an advanced stage of chronic kidney disease (CKD), can limit the treatment options for acute stroke (AS) patients. Therefore, it is important to investigate the associated factors of SRD in AS patients to inhibit CKD progression to SRD before AS. Sex differences exist in the renal function. Therefore, we investigated the frequency of SRD and its associated factors among AS patients by sex. Methods: Our cross-sectional study included patients admitted within 24 h of AS onset between 2013 and 2019 with available pre-stroke medication information. We used the Cockcroft–Gault equation for calculating the creatinine clearance (Ccr) and defined SRD as a Ccr < 30 mL/min. We performed multivariable logistic regression analysis to identify the independent factors associated with SRD. Results: Out of 4294 patients, 3472 matched our criteria. Of these, 1905 (54.9%) were male, with median ages of 75 and 81 years for males and females, respectively. The frequency of SRD was 9.7% in males and 18.7% in females. Loop diuretics and anemia were associated factors of SRD. Conclusions: Pre-stroke loop diuretics and anemia in elderly patients were associated factors of SRD in both sexes. Individualized drug therapy and anemia management are essential to prevent SRD

An Alternative Method for Generating Arynes from ortho-Silylaryl Triflates: Activation by Cesium Carbonate in the Presence of a Crown Ether

An alternative method for generating arynes from ortho-silylaryl triflates using cesium carbonate and 18-crown-6 is reported. The method was efficiently applied to a variety of reactions between several arynes and arynophiles. We also demonstrated that the efficiency of aryne generation is significantly affected by the alkali metal countercation of the carbonate

Pulmonary Pharmacokinetic and Pharmacodynamic Evaluation of Ampicillin/Sulbactam Regimens for Pneumonia Caused by Various Bacteria, including <i>Acinetobacter baumannii</i>

This study aimed to assess the dosing regimens of ampicillin/sulbactam for pneumonia based on pulmonary pharmacokinetic (PK)/pharmacodynamic (PD) target attainment. Using the literature data, we developed pulmonary PK models and estimated the probabilities of attaining PK/PD targets in lung tissue. Against bacteria other than A. baumannii (the general treatment), the PK/PD target was set as both 50% time above the minimum inhibitory concentration (T > MIC) for ampicillin and 50% T > 0.5 MIC for sulbactam. For the A. baumannii treatment, the PK/PD target was set as 60% T > MIC for sulbactam. The pulmonary PK/PD breakpoint was defined as the highest minimum inhibitory concentration (MIC) at which the target attainment probability in the lung tissue was ≥90%. The lung tissue/serum area under the drug concentration–time curve from 0 to 3 h (AUC0–3h) ratios for ampicillin and sulbactam were 0.881 and 0.368, respectively. The ampicillin/sulbactam AUC0–3h ratio in the lung tissue was 3.89. For the general treatment, the pulmonary PK/PD breakpoint for ampicillin/sulbactam at 3 g four times daily in typical patients with creatinine clearance (CLcr) of 60 mL/min was 2 μg/mL, which covered the MIC90s (the MICs that inhibited the growth of 90% of the strains) of most gram-positive and gram-negative bacteria. For the A. baumannii treatment, the pulmonary PK/PD breakpoint for ampicillin/sulbactam at 9 g 4-h infusion three times daily (27 g/day) in patients with a CLcr of 60 mL/min was 4 μg/mL, which covered the MIC90 of A. baumannii. A PK/PD evaluation for pneumonia should be performed in the lung tissue (the target site) rather than in the blood because sulbactam concentrations are lower in lung tissue. These findings should facilitate the selection of ampicillin/sulbactam regimens for pneumonia caused by various bacteria, including A. baumannii

Pulmonary Pharmacokinetic and Pharmacodynamic Evaluation of Ampicillin/Sulbactam Regimens for Pneumonia Caused by Various Bacteria, including Acinetobacter baumannii

This study aimed to assess the dosing regimens of ampicillin/sulbactam for pneumonia based on pulmonary pharmacokinetic (PK)/pharmacodynamic (PD) target attainment. Using the literature data, we developed pulmonary PK models and estimated the probabilities of attaining PK/PD targets in lung tissue. Against bacteria other than A. baumannii (the general treatment), the PK/PD target was set as both 50% time above the minimum inhibitory concentration (T &gt; MIC) for ampicillin and 50% T &gt; 0.5 MIC for sulbactam. For the A. baumannii treatment, the PK/PD target was set as 60% T &gt; MIC for sulbactam. The pulmonary PK/PD breakpoint was defined as the highest minimum inhibitory concentration (MIC) at which the target attainment probability in the lung tissue was &ge;90%. The lung tissue/serum area under the drug concentration&ndash;time curve from 0 to 3 h (AUC0&ndash;3h) ratios for ampicillin and sulbactam were 0.881 and 0.368, respectively. The ampicillin/sulbactam AUC0&ndash;3h ratio in the lung tissue was 3.89. For the general treatment, the pulmonary PK/PD breakpoint for ampicillin/sulbactam at 3 g four times daily in typical patients with creatinine clearance (CLcr) of 60 mL/min was 2 &mu;g/mL, which covered the MIC90s (the MICs that inhibited the growth of 90% of the strains) of most gram-positive and gram-negative bacteria. For the A. baumannii treatment, the pulmonary PK/PD breakpoint for ampicillin/sulbactam at 9 g 4-h infusion three times daily (27 g/day) in patients with a CLcr of 60 mL/min was 4 &mu;g/mL, which covered the MIC90 of A. baumannii. A PK/PD evaluation for pneumonia should be performed in the lung tissue (the target site) rather than in the blood because sulbactam concentrations are lower in lung tissue. These findings should facilitate the selection of ampicillin/sulbactam regimens for pneumonia caused by various bacteria, including A. baumannii