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.

Reconstitution of L-Asparaginase in Siliconized Syringes with Shaking and Headspace Air Induces Protein Aggregation.

The aim of this study was to characterize protein aggregation during reconstitution of a highly concentrated solution of lyophilized L-asparaginase (L-ASP). The effect of the preparation method on L-ASP aggregation using siliconized or non-siliconized syringes and the effect of storage after preparation were evaluated by far-UV circular dichroism spectroscopy, Raman microscopy, flow cytometry, and flow particle image analysis. To investigate the effect of syringe type in combination with shaking and headspace air on L-ASP aggregation, four kinds of L-ASP in 5% glucose solutions were prepared (in the presence or absence of silicon oil and headspace air). Slight differences in L-ASP secondary structure were observed between the siliconized and non-siliconized syringe systems before shaking. Large numbers of sub-visible (0.1-100 µm) and submicron (0.1-1 µm) particles were formed by preparation with siliconized syringes and the combination of shaking and headspace air. The number of aggregated particles was not decreased with increased storage time. The Raman microscopy, flow cytometry and flow particle image results suggested that L-ASP interacted with silicone oil, which induced aggregation. Nevertheless, sub-visible and submicron particles were also formed with non-siliconized syringes. However, using non-siliconized syringes, the number of aggregated particles decreased with storage. No changes in particle character were observed before or after shaking with headspace air in non-siliconized syringes, indicating that soluble aggregates formed and dissolved with storage. Silicone oil in syringes, in combination with shaking and headspace air, strongly affected the aggregation of lyophilized L-ASP formulations during preparation.

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.).

Caffeine increases tear volume depending on polymorphisms within the adenosine A2a receptor gene and cytochrome P450 1A2.

PURPOSE: The primary aim of the present study was to examine the effect of caffeine on tear volume. The secondary aim was to investigate the relation between caffeine-induced changes in tear volume and polymorphisms in ADORA2A and CYP1A2. DESIGN: Double-masked, placebo-controlled, crossover study. PARTICIPANTS: Seventy-eight healthy volunteers were recruited for the study. METHODS: Subjects participated in 2 sessions in which they received capsules containing either placebo or caffeine. The caffeine capsules were given to the subjects to keep the caffeine volume per body weight within 5 to 7 mg/kg. After caffeine intake, tear meniscus height (TMH) was measured. Subjects provided a blood sample for genotyping. MAIN OUTCOME MEASURES: Tear meniscus height, single nucleotide polymorphism. RESULTS: The tear volume increased after caffeine consumption. The net increase in TMH was 0.08 mm (95% confidence interval, 0.05-0.10) greater when participants were given caffeine than when given placebo (P<0.0001). In ADORA2A, the difference in the net increase in TMH for participants who were heterozygous at rs5751876 and rs2298383 was 0.07 mm (P = 0.001) and who were minor homozygous was 0.08 mm (P = 0.007). In CYP1A2, the net increase in TMH for participants who were minor homozygous at rs2472304 was lower than for those who were major homozygous; the difference was 0.06 mm (P = 0.039). CONCLUSIONS: Caffeine intake increases tear volume and polymorphisms within ADORA2A, and CYP1A2 is associated with the tear increase after caffeine intake. Genetic polymorphisms had a significant effect on tear meniscus that was of limited clinical significance.

Analysis of pharmacokinetic data provided in Japanese package inserts and interview forms focusing on urinary excretion of pharmacologically active species.

In optimizing oral pharmacotherapy for patients with renal failure, information on actual urinary excretion ratio of the unchanged drug, which is obtained by dividing a urinary excretion ratio by a bioavailability after oral dose, is quite helpful. In addition, urinary excretion ratio of the active species is sometimes equally important where metabolites have a pharmacological potency. In the present study, we conducted a survey of Japanese package inserts and interview forms of drugs, which is being prescribed at the University of Tokyo Hospital, on pharmacokinetic data that enables an estimation of actual urinary excretion ratio. The total urinary excretion of a drug was documented in 70.1% of package inserts and 84.5% of interview forms, respectively. The total urinary excretion is often measured by radioactivity and thus includes its metabolites and degradation products. However, inclusion of degradation products/metabolites was described explicitly for 43.7% and 66.2%, and the absolute fraction of the unchanged drug or degradation product/metabolite was given only for 29.0% and 48.9% in package inserts and interview forms, respectively. The pharmacological activity of metabolite(s) was documented for 19.8% and 54.3%, and the oral bioavailability was described only for 5.7% and 30.6% in respective documents. For some drugs, the time period for the urine collection was too short to evaluate the urinary excretion ratio. With regard to 65 drugs (38.7%), more detailed information on urinary excretion was found in published books, but not provided in the package inserts or interview forms. It is hoped that more distinct and sufficient descriptions on the urinary excretion and bioavailability will be associated to the package inserts and the interview forms in future, for safe and efficient use of prescription drugs.

The Val158Met polymorphism of the catechol-O-methyltransferase gene is associated with the PSA-progression-free survival in prostate cancer patients treated with estramustine phosphate.

OBJECTIVE: The aim of our study is to find out the good responders for estramustine phosphate (EMP) therapy in patients with prostate cancer. We have focused on the metabolism of EMP and studied the association between a functional single-nucleotide polymorphism in the catechol-O-methyltransferase gene (Val158Met of COMT) and PSA-progression-free survival in Japanese patients with prostate cancer treated by EMP. METHODS: Seventy-two Japanese patients with previously untreated prostate cancer who were found to be eligible for low-dose EMP therapy were enrolled in the study. Genotyping of the Val158Met polymorphism of COMT was conducted by both the polymerase chain reaction-based restriction fragment length polymorphism method and TaqMan assay. RESULTS: Patients with the Val/Val genotype of COMT had a significantly higher PSA-progression-free rate as compared to those with the Val/Met or Met/Met genotype (p=0.027). The adjusted hazard ratio of biochemical PSA failure for the Val158Met genotype of COMT was 2.164 (95% CI, 1.111 to 5.525). CONCLUSIONS: The Val158Met polymorphism of COMT is associated with the PSA-progression-free rate of EMP-treated patients in prostate cancer.

Effect of mixing method on the mixing degree during the preparation of triturations.

By using lactose colored with erythrocin, we investigated the effects of mixing methods on mixing degree during the preparation of trituration with a mortar and pestle. The extent of powder dilution was set to 4 to 64 fold in the experiments. We compared the results obtained by using two methods: (1) one-step mixing of powders after addition of diluents and (2) gradual mixing of powders after addition of diluents. As diluents, we used crystallized lactose and powdered lactose for the preparation of trituration. In the preparation of 64-fold trituration, an excellent degree of mixing was obtained, with CV values of less than 6.08%, for both preparation methods and for the two kinds of diluents. The mixing of two kinds of powders whose distributions of particle sizes were similar resulted in much better degree of mixing, with CV values of less than 3.0%. However, the concentration of principal agents in 64-fold trituration was reduced by 20% due to the adsorption of dye to the apparatus. Under conditions in which a much higher dilution rate and/or much better degree of dilution was required, it must be necessary to dilute powders with considering their physicality and to determine the concentrations of principal agents after the mixing.

Effect of particle size on mixing degree in dispensation.

By using lactose colored with erythrocin, we examined the effect of particle size on mixing degree during the preparation of triturations with a mortar and pestle. We used powders with different distributions of particle sizes, i.e., powder that passed through 32-mesh but was trapped on a 42-mesh sieve (32/42-mesh powder), powder that passed through a 42-mesh sieve but was trapped on a 60-mesh sieve (42/60-mesh powder), powder that passed through a 60-mesh sieve but was trapped on a 100-mesh sieve (60/100-mesh powder), and powder that passes through a 100-mesh sieve (> 100-mesh powder). The mixing degree of colored powder and non-colored powder whose distribution of particle sizes was the same as that of the colored powder was excellent. The coefficient of variation (CV) value of the mixing degree was 6.08% after 40 rotations when colored powder was mixed with non-colored powder that both passed through a 100-mesh sieve. The CV value of the mixing degree was low in the case of mixing of colored and non-colored powders with different particle size distributions. After mixing, about 50% of 42/60-mesh powder had become smaller particles, whereas the distribution of particle sizes was not influenced by the mixing of 60/100-mesh powder. It was suggested that the mixing degree is affected by distribution of particle sizes. It may be important to determine the mixing degrees for drugs with narrow therapeutic ranges.

[The effects of indomethacin spray on the pain of stomatitis in the patients for hematopoietic stem cell transplantation].

We studied the effects of 0.25% indomethacin (IM) spray as an in-hospital preparation on the pain of stomatitis after hematopoietic stem cell transplantation in 9 patients with various types of leukemia by measuring the change in pain and the decrease in morphine dose. Stomatitis above grade 2 (painful erythema, edema, or ulcers but can eat or swallow) appeared in all patients as white blood cell (WBC) counts declined after transplantation, and clockwise hysteresis was observed between WBC counts and the grade of stomatitis. When the patients used IM spray for the pain of stomatitis and were judged the grade of pain using a face scale of five grades (0-4) before and after the use of this spray, the mean grades of pain at the maximal pain during the appearance of stomatitis declined from 3.4 to 1.8 (n = 5). Furthermore, the concurrent intravenous dose of morphine markedly decreased during IM spray use. There was no complaint concerning the taste and convenience of IM spray by patients. The risk of systemic adverse effects was considered relatively low based on the small amounts of IM applied to the mouth mucosa. In conclusion, it is suggested that IM spray is effective for the relief of stomatitis pain in patients who have undergone hematopoietic stem cell transplantation and is a useful preparation for immediate self-medication upon the appearance of stomatitis pain. We considered that the application of IM spray will contribute to the improvement of patient quality of life.

Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers.

Ketamine is known to provide analgesic effects without an anesthetic when administered in a low dose. We previously reported that a tablet containing ketamine had analgesic effects in patients with neuropathic pain. In the present study, we compared the plasma concentration profiles of the enantiomers of ketamine and its active metabolite, norketamine, up to 8 h after the administration of 20 mg of ketamine by injection, after the administration of two tablets containing 25 mg of ketamine, after the administration of two sublingual tablets containing 25 mg of ketamine, after the insertion of a suppository containing 50 mg of ketamine, and after the application of a nasal spray containing 25 mg of ketamine to three healthy volunteers. The plasma concentration of ketamine biexponentially declined after the administration by injection; the value of T(1/2beta) for ketamine was approximately 120 min. The bioavailability of the tablet was estimated to be approximately 20%; the area under the plasma concentration-time curve, (AUC)(0-->8 h), of norketamine was approximately 500 ng h/ml in both enantiomers. The bioavailabilities of the sublingual tablet and the suppository were estimated to both be approximately 30%; the AUC(0-->8 h) of norketamine was 280-460 ng h/ml in both enantiomers. The plasma concentration profiles of the sublingual tablet and the suppository were almost similar to that of the tablet. The bioavailability of the nasal spray was estimated to be approximately 45%, which was the highest value among the preparations tested, and the AUC(0-->6 h) of norketamine was low (approximately 100 ng h/ml) in both enantiomers. These pharmacokinetic findings suggested that all of the ketamine preparations tested in this study may be useful for the alleviation of neuropathic pain. We propose that the type of ketamine preparation should be selected in accordance with the patient's disease condition and the required dosage amount of ketamine.