Oral formulation of bendamustine hydrochloride for patients with advanced solid tumors; a phase 1 study.

To determine the maximum tolerated dose (MTD) and recommended dose (RD) of orally-administered bendamustine in Japanese patients with advanced solid tumors. The optimal dosing schedule, safety, pharmacokinetics, and preliminary antitumor effects were also evaluated. A multicenter, open-label trial with a standard 3 + 3 design and dose escalation by dose-limiting toxicity (DLT) was conducted. The treatment schedules were once daily for 7, 14, and 21 days every 3 weeks as one cycle. The total dose per cycle was increased from 175 to 840 mg/m2. Eighteen patients were enrolled in this study. DLT occurred in one of six patients at 75 mg/m2/day × 7 days, and one of three patients at 37.5 mg/m2/day × 14 days and 25 mg/m2/day × 21 days. However, the delayed recovery from a decrease in neutrophil or platelet count hampered the start of subsequent treatment cycles, and the trend was more prominent at 37.5 mg/m2/day × 14 days and 25 mg/m2/day × 21 days than in 75 mg/m2/day × 7 days. MTD was determined as 75 mg/m2/day × 7 days to allow acceptable hematologic recovery. The pharmacokinetics of orally-administered bendamustine were generally dose-dependent; however, the inter-individual variability is relatively large. The major adverse events were hematologic toxicities; gastrointestinal disorders were generally mild. Adverse drug reactions did not lead to the discontinuation of the drug. A partial response was observed in two of six patients (prostatic small cell carcinoma and thymic carcinoma) at 75 mg/m2/day × 7 days. The RD and optimal dosing schedule of orally-administered bendamustine was 75 mg/m2 once daily for 7 days every 3 weeks for the treatment of advanced solid tumors. (Trial registration number ClinicalTrials.gov NCT03604679. Registration date July 27, 2018).

Electrocardiographic and chronobiological features of paroxysmal AV block recorded by ambulatory electrocardiography.

The goal of this study was to investigate the electrocardiographic and chronobio-logical features of paroxysmal atrioventricular (AV) block (PAVB) using data from ambulatory electrocardiography (AECG). The study population consisted of five men and six women aged from 47 to 82 years of age. Main presenting symptoms were pre-syncope in five patients (45.5%) and syncope in three patients (27.3%). Organic cardiovascular diseases were seen in eight patients (72.7%), and AV conduction disturbances were seen in six patients (54.5%), such as right bundle branch block, first to second degree AV block on standard 12-lead electrocardiography. Incidence of PAVB events were 1-329 (37.9 ± 98.0) episodes/patient/day, and the maximum pause during Holter recordings was 3.3-12.4 (6.39 ± 3.09) seconds. This maximum pause caused by intrinsic AV block was longer than that of vagally mediated AV block (8.4 ± 3.2 sec vs 4.7 ± 1.0 sec, p<0.05). In chronobiological analysis, episodes of PAVB exhibited a circadian rhythm characterized by a peak between 2:00 am and 4:00 am and a trough between 0:00 pm and 2:00 pm. AECG is a useful tool to detect the maximum pause occurring during sleep and provides critical data necessary to prevent the sudden cardiac death caused by PAVB.

Method of simultaneous stir bar sorptive extraction of phenethylamines and THC metabolite from urine.

Stir bar sorptive extraction is a technique used for extracting target substances from various aqueous matrixes such as environmental water, food, and biological samples. This type of extraction is carried out by rotating a coated stir bar is rotated in the sample solution. In particular, Twister bar is a commercial stir bar that is coated with polydimethylsiloxane (PDMS) and used to perform sorptive extraction. In this study, we developed a method for simultaneous detection of amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, 3,4-methylenedioxymethamphetamine, and a Δ(9)-tetrahydrocannabiniol (THC) metabolite in human urine. For extracting the target analytes, the Twister bar was simply stirred in the sample in the presence of a derivatizing agent. Using this technique, phenethylamines and the acidic THC metabolite can be simultaneously extracted from human urine. This method also enables the extraction of trace amounts of these substances with good reproducibility and high selectivity. The proposed method offers many advantages over other extraction-based approaches and is therefore well suited for screening psychoactive substances in urine specimens.