Prediction of the permeability of antineoplastic agents through nitrile medical gloves by zone classification based on their physicochemical properties.

BACKGROUND: Permeability of antineoplastic agents through medical gloves is an important factor that must be considered for the appropriate selection of gloves. However, predicting the permeability of antineoplastic agents through medical gloves based on their physicochemical properties remains difficult. Thus, this study aimed to elucidate the relationship between the physicochemical properties and permeability of antineoplastic agents through medical gloves. Additionally, we tried to predict the risk of permeation of antineoplastic agents through medical gloves based on physicochemical parameters. METHODS: Ten antineoplastic agents (carboplatin, carmustine, cisplatin, cyclophosphamide, doxorubicin, etoposide, fluorouracil, ifosfamide, oxaliplatin, and paclitaxel) with varying physicochemical properties were investigated, and their permeation rates (PRs) through nitrile medical gloves of varying thicknesses (0.05, 0.07, and 0.1 mm) were measured using a continuous flow in-line cell device. We also determined the apparent permeation clearance (CLP,app) values of the antineoplastic agents based on their PRs at 240 min (PR240) and assessed the relationship between CLP,app and physicochemical parameters [molecular weight (MW) and logarithm of octanol-water partition coefficient (LogP)]. RESULTS: The CLP,app values of the 10 antineoplastic agents through nitrile medical gloves (0.05 mm thickness) were significantly correlated with their MWs, but not their LogP values (P = 0.026 and 0.39, respectively; Spearman's rank correlation). This finding indicated that the rates of diffusion of the antineoplastic agents in the glove material showed greater effects on CLP,app than the rates of absorption into the glove surfaces within 240 min of exposure. We then classified the 10 antineoplastic agents into 3 zones (Zone A, high LogP/low MW drugs; Zone B, high LogP/high MW drugs; and Zone C, low LogP) and found that Zones A, B, and C corresponded to high (PR240 > 10 ng/min/cm2), moderate (PR240 < 10 ng/min/cm2), and low (no detectable permeation) permeation risk, respectively. CONCLUSIONS: The permeation risk of antineoplastic agents through nitrile medical gloves within the actual continuous wearing time in clinical settings could be predicted using MW and LogP values. We believe that the proposed zone classification of antineoplastic agents will be a useful tool for predicting the permeation risk of antineoplastic agents through medical gloves.

Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor.

Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 and represses gene expression to regulate cell proliferation and differentiation. Enhancer of zeste homolog 2 (EZH2) or its close homolog EZH1 functions as a catalytic subunit of PRC2, so there are two PRC2 complexes containing either EZH2 or EZH1. Tumorigenic functions of EZH2 and its synthetic lethality with some subunits of SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes have been observed. However, little is known about the function of EZH1 in tumorigenesis. Herein, we developed novel, orally bioavailable EZH1/2 dual inhibitors that strongly and selectively inhibited methyltransferase activity of both EZH2 and EZH1. EZH1/2 dual inhibitors suppressed trimethylation of histone H3 lysine 27 in cells more than EZH2 selective inhibitors. They also showed greater antitumor efficacy than EZH2 selective inhibitor in vitro and in vivo against diffuse large B-cell lymphoma cells harboring gain-of-function mutation in EZH2. A hematological cancer panel assay indicated that EZH1/2 dual inhibitor has efficacy against some lymphomas, multiple myeloma, and leukemia with fusion genes such as MLL-AF9, MLL-AF4, and AML1-ETO. A solid cancer panel assay demonstrated that some cancer cell lines are sensitive to EZH1/2 dual inhibitor in vitro and in vivo. No clear correlation was detected between sensitivity to EZH1/2 dual inhibitor and SWI/SNF mutations, with a few exceptions. Severe toxicity was not seen in rats treated with EZH1/2 dual inhibitor for 14 days at drug levels higher than those used in the antitumor study. Our results indicate the possibility of EZH1/2 dual inhibitors for clinical applications.

Evaluation of the permeation of antineoplastic agents through medical gloves of varying materials and thickness and with varying surface treatments.

BACKGROUND: Medical gloves are an important piece of personal protective equipment that prevents exposure to antineoplastic agents. The permeability of medical gloves to antineoplastic agents is a crucial factor in the appropriate selection of gloves. However, the relationship between glove permeability and material type, thickness, and surface treatment is poorly understood. METHODS: A continuous flow in-line cell device was used for the evaluation of the permeation of five antineoplastic agents (etoposide, cyclophosphamide, doxorubicin hydrochloride, paclitaxel, and fluorouracil) through medical gloves. Medical gloves made of three types of materials (chlorinated latex, non-chlorinated latex, and nitrile) were subjected to a permeability test. The antineoplastic agents in test solutions were tested at the highest concentrations employed in general clinical practice. Then, the relationship between glove thickness and permeability was assessed using chlorinated latex gloves with thicknesses of 0.1, 0.15, 0.2, and 0.1 mm × 2 (to represent the practice of "double gloving"). RESULTS: Only cyclophosphamide and fluorouracil showed detectable permeation through the tested latex gloves. The permeability of chlorinated latex was lower than that of non-chlorinated latex. Nitrile gloves showed no detectable permeability to any of the five antineoplastic agents tested. The permeability of chlorinated latex gloves depended on the thickness of the gloves; 0.1 mm × 2 (double gloving) exhibited the highest resistance to permeation by antineoplastic agents. CONCLUSIONS: The permeability of medical gloves was dependent on the type of material and the surface treatment and decreased as the thickness of the glove increased. The double glove was shown to prevent antineoplastic agent permeation more efficiently than did a single glove of the same total thickness. These results provided important information that will guide the appropriate selection of medical gloves.

Evaluation of the pharmaceutical characteristics of various enteric-coated aspirin tablets under different storage conditions.

The formulation characteristics of 6 brands of enteric-coated aspirin tablets under unpackaged conditions at 40°C and 60°C for 4 weeks were analyzed. Appearance, salicylic acid content, dissolution rates, and surface properties (by Raman microscopy) were evaluated to determine stability data, taking into account the clinical use of generic drugs. No change in appearance, decomposition, or dissolution rates was observed in unpackaged aspirin tablets stored at 40°C for 4 weeks. However, when stored at 60°C, tablets of 5 of the 6 brands showed whiskers on their surfaces along with an increase in salicylic acid content and a decrease in dissolution rate. Results of Raman mapping on the surface and cross sectional surface of the tablets with whiskers showed a salicylic acid peak associated with storage at 60°C for 4 weeks. However, for tablets from 1 of the 6 brands, no salicylic acid peaks were observed. For this tablet, Raman microscopy revealed 2 layers of film coating, and talc, which greatly affected the stability of the acetylsalicylic acid, was found only in the outer layer film. These results indicated that the protection of compatibility with talc is one of the important factors in enhancement of aspirin tablet stability in this tablet. We concluded that certification of the characteristics associated with stability and formulation is essential for generic drugs, which are not required to undergo stability testing under extreme storage conditions.

Results of the Tokyo trial of prevention of post-ERCP pancreatitis with risperidone-2: a multicenter, randomized, placebo-controlled, double-blind clinical trial.

BACKGROUND: Our previous study suggested that a combination of ulinastatin and risperidone reduced post-ERCP pancreatitis (PEP) compared with ulinastatin alone. OBJECTIVE: The aim of this study was to evaluate the efficacy of risperidone alone for prevention of PEP. DESIGN: A multicenter, randomized, placebo-controlled, double-blind clinical trial. SETTING: Two academic hospitals and 5 referral hospitals in Tokyo and Saitama, Japan. PATIENTS: Patients undergoing therapeutic or interventional-diagnostic ERCP. INTERVENTION: The patients were randomized to receive 2 mg of oral risperidone or oral placebo at 0.5 to 2 hours before ERCP. MAIN OUTCOME MEASUREMENTS: The primary endpoint was the incidence of PEP. Secondary endpoints were the incidence of hyperenzymemia and enzyme levels (amylase, pancreatic amylase, lipase). Risk factors for PEP were evaluated. RESULTS: We initially enrolled 500 patients in the study (250 in the risperidone group and 250 in the placebo group), but 17 (11 in the risperidone and 6 in the placebo group) were excluded after randomization. PEP developed in 24 patients (10.0%) in the risperidone group and 21 patients (8.6%) in the placebo group (P = .587). Serum amylase levels at 3 hours after ERCP were lower in the risperidone group (P = .007 in a single test of hypothesis, significance removed by Bonferroni correction for multiple testing). In multivariate analysis, a small papilla of Vater, total procedure time ≥40 minutes, and stenosis of the intrahepatic duct were significantly associated with PEP. LIMITATIONS: Multiplicity of study centers and a relatively wide time range of drug administration time. CONCLUSION: Risperidone did not show a benefit in prevention of PEP in this trial. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT000004592.).

Discovery of CS-0777: A Potent, Selective, and Orally Active S1P1 Agonist.

CS-0777 (3) is phosphorylated in vivo, and the phosphate of CS-0777 (CS-0777-P) (4) acts as a selective S1P receptor-1 (S1P1) modulator. We report herein the synthesis of CS-0777 and CS-0777-P, pharmacological effects such as S1P1 and S1P3 agonist activity in vitro, peripheral blood lymphocyte lowering effects and the suppressive effect on experimental autoimmune encephalomyelitis (EAE), and also the pharmacokinetics in rats. CS-0777-P had ∼320-fold greater agonist activity for human S1P1 (EC50; 1.1 nM) relative to S1P3 (EC50; 350 nM). Following administration of single oral doses of 0.1 and 1 mg/kg of CS-0777 in rats, lymphocyte counts decreased significantly, with a nadir at 12 h postdose and recovery to vehicle control levels by 5 days postdose. In the EAE model compared to the vehicle-treated group, significant decreases in the cumulative EAE scores were observed for the 0.1 and 1 mg/kg CS-0777 groups in rats. CS-0777 is currently in clinical trials for the treatment of multiple sclerosis (MS).

[Clinically significant drug-drug and drug-food interactions associated with calcium channel blockers].

Calcium channel blockers have been widely used for treatment of hypertension, angina pectoris, arrhythmia, and other heart diseases. Nowadays, combination therapy is widely common for these diseases. However, combination therapy is associated with increasing risks of pharmacokinetic or pharmacodynamic drug-drug interaction, and therefore clinicians should pay attention to prevent it. Furthermore, in addition to drug-drug interactions, we need to be cautions for drug interaction with food and drink including health-food and supplement.

[Investigation of the cause of polyurethane catheter cracking during constant infusion of etoposide (VP-16) injection (2)--Analysis of ethanol eluting materials from catheter].

We studied the cause of cracking of clinically used polyurethane (PU) catheters during the constant infusion of etoposide (VP-16) injection (Lastet inj.) without dilution. After the vehicles used for VP-16 injection, ethanol or polyethylene glycol 400 (PEG400), were infused into the PU catheters at a constant infusion rate (30 ml/h) for 24 h, obvious degradation of the internal wall of the catheter was observed under an electron microscope. When the PU catheter was immersed in ethanol for 24 h, condensed polymers of 1,4-butanediol (BD), contained in PU catheters as an elasticizer, were detected in the ethanol elute using the ESI/MS method. Moreover, time-dependent elution of BD from PU catheters with the infusion of ethanol into the catheter for 24 h at 30 ml/h was observed using the GC/MS method. The cumulative amount of BD eluted from the PU catheter with ethanol vehicle for 24 h was 130 micrograms. In conclusion, degradation and subsequent cracking of PU catheters during the infusion of VP-16 injection were caused by ethanol and PEG400 contained in the injection solution. Furthermore, to prevent the elution of BD from PU catheters, we suggest that PU catheters should not be used for the administration of VP-16 injection without dilution in consideration of safety and efficacy.

[Creation and usefulness of the "drug information card" for support of dispensing].

We placed a "drug information card" on each medication shelf to assist dispensing by pharmacists, education of students, and risk management of pharmaceutical practices at the Department of Pharmacy, University of Tokyo Hospital. To provide appropriate information items on the drug information cards, we conducted questionnaire survey of 41 pharmacists on the utility of the cards and reviewed questions received from medical staff in the drug information section in our hospital. Based on the results of these investigations, "usage and dosage," "interactions," "contraindications," "product name," and "effects" were printed as basic information items on the drug information cards. Furthermore, information on pharmacokinetics was added. To make maintenance easier, we classified drug information items into "renew often" and "not so often." A good response on the use of the drug information cards was received for dispensing support from 38 pharmacists (92.7%), 14 trainees (100%), and 16 students (94.1%) in the questionnaire investigation. The drug information cards make it possible to obtain precise information rapidly in pharmacies.