Characterization in Dual Activation by Oxaliplatin, a Platinum-Based Chemotherapeutic Agent of Hyperpolarization-Activated Cation and Electroporation-Induced Currents.

Oxaliplatin (OXAL) is regarded as a platinum-based anti-neoplastic agent. However, its perturbations on membrane ionic currents in neurons and neuroendocrine or endocrine cells are largely unclear, though peripheral neuropathy has been noted during its long-term administration. In this study, we investigated how the presence of OXAL and other related compounds can interact with two types of inward currents; namely, hyperpolarization-activated cation current (Ih) and membrane electroporation-induced current (IMEP). OXAL increased the amplitude or activation rate constant of Ih in a concentration-dependent manner with effective EC50 or KD values of 3.2 or 6.4 µM, respectively, in pituitary GH3 cells. The stimulation by this agent of Ih could be attenuated by subsequent addition of ivabradine, protopine, or dexmedetomidine. Cell exposure to OXAL (3 µM) resulted in an approximately 11 mV rightward shift in Ih activation along the voltage axis with minimal changes in the gating charge of the curve. The exposure to OXAL also effected an elevation in area of the voltage-dependent hysteresis elicited by long-lasting triangular ramp. Additionally, its application resulted in an increase in the amplitude of IMEP elicited by large hyperpolarization in GH3 cells with an EC50 value of 1.3 µM. However, in the continued presence of OXAL, further addition of ivabradine, protopine, or dexmedetomidine always resulted in failure to attenuate the OXAL-induced increase of IMEP amplitude effectively. Averaged current-voltage relation of membrane electroporation-induced current (IMEP) was altered in the presence of OXAL. In pituitary R1220 cells, OXAL-stimulated Ih remained effective. In Rolf B1.T olfactory sensory neurons, this agent was also observed to increase IMEP in a concentration-dependent manner. In light of the findings from this study, OXAL-mediated increases of Ih and IMEP may coincide and then synergistically act to increase the amplitude of inward currents, raising the membrane excitability of electrically excitable cells, if similar in vivo findings occur.

High Efficacy by GAL-021: A Known Intravenous Peripheral Chemoreceptor Modulator that Suppresses BKCa-Channel Activity and Inhibits IK(M) or Ih.

: GAL-021 has recently been developed as a novel breathing control modulator. However, modifications of ionic currents produced by this agent remain uncertain, although its efficacy in suppressing the activity of big-conductance Ca2+-activated K+ (BKCa) channels has been reported. In pituitary tumor (GH3) cells, we found that the presence of GAL-021 decreased the amplitude of macroscopic Ca2+-activated K+ current (IK(Ca)) in a concentration-dependent manner with an effective IC50 of 2.33 µM. GAL-021-mediated reduction of IK(Ca) was reversed by subsequent application of verteporfin or ionomycin; however, it was not by that of diazoxide. In inside-out current recordings, the addition of GAL-021 to the bath markedly decreased the open-state probability of BKCa channels. This agent also resulted in a rightward shift in voltage dependence of the activation curve of BKCa channels; however, neither the gating charge of the curve nor single-channel conductance of the channel was changed. There was an evident lengthening of the mean closed time of BKCa channels in the presence of GAL-021, with no change in mean open time. The GAL-021 addition also suppressed M-type K+ current with an effective IC50 of 3.75 µM; however, its presence did not alter the amplitude of erg-mediated K+ current, or mildly suppressed delayed-rectifier K+ current. GAL-021 at a concentration of 30 µM could also suppress hyperpolarization-activated cationic current. In HEK293T cells expressing α-hSlo, the addition of GAL-021 was also able to suppress the BKCa-channel open probabilities, and GAL-021-mediated suppression of BKCa-channel activity was attenuated by further addition of BMS-191011. Collectively, the GAL-021 effects presented herein do not exclusively act on BKCa channels and these modifications on ionic currents exert significant influence on the functional activities of electrically excitable cells occurring in vivo.

Grazoprevir/elbasvir in peginterferon alfa plus ribavirin experienced patients with chronic genotype 1 HCV/HIV co-infection: a non-randomized, open-label clinical trial.

Background and aims: We aimed to evaluate the efficacy and tolerability of grazoprevir/elbasvir in patients with chronic genotype 1 hepatitis C virus (HCV) and HIV co-infection who experienced peginterferon alfa plus ribavirin (PegIFN/RBV) (clinicaltrials.gov NCT03098121). Methods: This non-randomized, open-label trial study was conducted in Taoyuan General Hospital. HIV-infected patients were screened for HCV antibody since June 1, 2012, and HCV and HIV co-infected patients were tested for HCV RNA. The subjects who experienced PegIFN/RBV were enrolled in the study, and of whom with chronic genotype 1a or 1b received grazoprevir 100 mg and elbasvir 50 mg in a fixed-dose combination tablet once daily with or without ribavirin for 12 to 16 weeks. Results: Of 2,419 HIV-infected patients, 40 patients with chronic genotype 1 HCV and HIV co-infection who failed PegIFN/RBV treatment were enrolled. Sixteen patients had genotype 1a and 24 patients had genotype 1b, with or without cirrhosis. The median age was 42 (41-47) years, and 5 patients (12.5%) were diagnosed with liver cirrhosis (child Pugh score A). The median CD4 count was 504 cells/µL (321-689). All patients (100%) had HIV viral load <200 copies/mL, and HCV viral load was 6.3 log10 IU/mL (3.98-7.12). At the end of treatment, all patients (100%, 40/40) had undetectable HCV viral load, and 95.0% (38/40) of patients achieved sustained virologic response at 12 weeks. Conclusion: Grazoprevir/elbasvir was effective in genotype 1 patients co-infected with HIV with or without cirrhosis. This finding is consistent with that of previous trials of this regimen in monoinfected population.

Muscular thickness of lower esophageal sphincter and therapeutic outcomes in achalasia: A prospective study using high-frequency endoscopic ultrasound.

BACKGROUND AND AIM: Patients with achalasia typically have thicker lower esophageal sphincter muscles, which can affect the distensibility of the esophagogastric junction. We aimed to assess whether these muscular features, measured using high-frequency endoscopic ultrasound, affect treatment outcomes. METHODS: Consecutive adult patients with suspected achalasia were enrolled prospectively. They underwent a comprehensive diagnostic workup, including endoscopic ultrasound. The thickness of the lower esophageal sphincter, including the internal circular and outer longitudinal muscles, was measured using a 12-MHz ultrasonic miniprobe. Follow-up was performed at 1 month and then at 6-month intervals, after treatment. Treatment response was defined as a reduction in Eckardt score to ≤3 or an improvement in the height of the timed barium esophagogram of ≥50%. RESULTS: Of the 29 patients who received pneumatic dilatation, all but one (96.6%) exhibited a good short-term treatment response. At an average follow-up time of 18.5 (12-55.5) months, patients who had a mid-term recurrence after pneumatic dilatation had a significantly thicker outer longitudinal muscle (1.8 [1.5-1.8] vs 0.9 [0.8-1.7] mm, P = 0.036), but not internal circular muscle (2.0 [1.9-2.5] vs 2.1 [1.2-2.7] mm, P = 0.874) or total lower esophageal sphincter (3.7 [3.5-4.4] vs 3.6 [2.0-4.1] mm, P = 0.362). Patients with an outer longitudinal muscle ≥1.3 mm thick had a significantly lower mid-term remission rate than others (36.3% vs 100%, P = 0.01). CONCLUSION: Thickening of the outer longitudinal muscle at the lower esophageal sphincter is associated with poor mid-term treatment outcomes for achalasia patients treated with pneumatic dilatation.

Ecotoxicological effect of ketamine: Evidence of acute, chronic and photolysis toxicity to Daphnia magna.

Ketamine has been increasingly used in medicine and has the potential for abuse or illicit use around the world. Ketamine cannot be removed by conventional wastewater treatment plants. Although ketamine and its metabolite norketamine have been detected to a significant degree in effluents and aquatic environments, their ecotoxicity effects in aquatic organisms remain undefined. In this study, we investigated the acute toxicity of ketamine and its metabolite, along with the chronic reproductive toxicity of ketamine (5-100µg/L) to Daphnia magna. Multiple environmental scenarios were also evaluated, including drug mixtures and sunlight irradiation toxicity. Ketamine and norketamine caused acute toxicity to D. magna, with half lethal concentration (LC50) values of 30.93 and 25.35mg/L, respectively, after 48h of exposure. Irradiated solutions of ketamine (20mg/L) significantly increased the mortality of D. magna; pre-irradiation durations up to 2h rapidly increased the death rate to 100%. A new photolysis byproduct (M.W. 241) of norketamine that accumulates during irradiation was identified for the first time. The relevant environmental concentration of ketamine produced significant reproductive toxicity effects in D. magna, as revealed by the reduction of the number of total live offspring by 33.6-49.8% (p < 0.05). The toxicity results indicate that the environmental hazardous risks of the relevant ketamine concentration cannot be ignored and warrant further examination.

Increased acute toxicity to fish caused by pharmaceuticals in hospital effluents in a pharmaceutical mixture and after solar irradiation.

Hospital effluents are an important source of residual drugs and other classes of pharmaceuticals in aquatic environments. The raw wastewater from the studied hospital exhibited acute toxicity to vertebrate organisms, and Cyprinus carpio was the most sensitive organism tested. A mixture of 19 commonly used pharmaceuticals caused acute toxicity to C. carpio with an LC50 value of 60.68mgL(-1) after 96h. This study demonstrated that irradiation for 1-5days significantly increased the acute toxicity of the pharmaceuticals to fish, leading to increased mortality after a 2-h exposure and approximately 40% of the surviving fish died within 28days. The pre-irradiated pharmaceutical mixture also induced strange behaviors in the fish that survived the test. The synergistic increase in toxicity caused by the photolysis and mixing of pharmaceuticals cannot be ignored and warrants further examination.