Shin-ichi Sugiura

Phencyclidine Impairs Latent Learning in Mice: Interaction between Glutamatergic Systems and Sigma1 Receptors

The effect of phencyclidine (PCP) on latent learning was investigated using a one-trial water-finding task in mice. Mice without water deprivation were given PCP or saline before a training trial, which consisted of exposure to a novel open-field environment with an alcove containing a water tube. Twenty to twenty-four hours after water deprivation, animals were placed in the same apparatus and the time required to find the water tube measured (test trial). Saline-treated trained mice showed a significantly shorter time to find the water tube during the test trial (finding latency) than naive mice that had not been trained. When PCP (1mg/kg i.p.) was administered before the training trial, the finding latency was significantly prolonged in comparison with that in the saline-treated mice, indicating that PCP induced impairment of latent learning. 1-(3,4-Dimethoxy-phenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503: 0.3 mg/kg s.c.) and (+)-pentazocine (1 mg/kg s.c.), selective sigma1 receptor agonists, or D-cycloserine (10 and 30mg/kg, s.c.), a glycine binding site agonist, significantly counteracted the PCP-induced impairment of latent learning, whereas (+)-SKF-10,047 (0.1–3 mg/kg s.c.), a putative sigma1 receptor agonist, did not. The ameliorating effects of SA4503 and (+)-pentazocine were antagonized by N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy) phenyl) ethylamine (NE-100: 1 mg/kg i.p.), a selective sigma1 receptor antagonist. SA4503 also ameliorated the impairment of latent learning induced by dizocilpine, a non-competitive N-methyl-D-aspartate receptor antagonist, the effect being antagonized by NE-100. These results suggest that PCP induces an impairment of latent learning, this effect being mediated via glutamatergic systems, and that activation of sigma1 receptors ameliorates impairment of latent learning induced by PCP.

Risks to health professionals from hazardous drugs in Japan: a pilot study of environmental and biological monitoring of occupational exposure to cyclophosphamide

Purpose. In Japan, concerns exist regarding the dangers inherent when handling cytotoxic drugs, particularly drugs such as 5-FU, Thiotepa, Cytarabine, Tegaful, and Sizofiran which are contained in ampoules or vials, since nurses and medical doctors have been preparing these cytotoxic drugs in the open spaces of wards in the absence of appropriate garments and personal protective equipment. In addition, the administration tubes for these dangerous drugs have been exchanged at the patients’ bedside, typically in rooms shared by several patients. To gain insight into the severity of the occupational hazards posed by these practices, we conducted a pilot study of environmental and biological monitoring of occupational exposure to cyclophosphamide (CP). Setting. At Nagoya University Hospital, Nagoya, Japan, in February 2006, two departments, A and B, were monitored with surface-wipe, and urine samples were analyzed using the Sessink method (exposure control, The Netherlands). Department A had a preparation room with biological safety cabinet (BSC) where the pharmacists prepare cytotoxic drugs. Department B did not have a BSC. Results. Many areas of the treatment rooms were contaminated with CP. CP was detected on tables and telephone stands where cytotoxic drugs were not used as well as tables used to prepare cytotoxic drugs. Significant differences in CP concentrations were detected from the urine of two of the three nurses who cared for the same patients without gloves. The nurses rotated and inherited the patient who had the highest risk of contamination. CP was detected only once from the urine of the medical doctor who prepared CP. He was not wearing any PPE other than gloves. All of the pharmacists wearing PPE were free from contamination of CP. Discussion. Regardless of the use of BSC, wards were contaminated with CP. The contamination may not occur due to the sealing used in CP containers and administration tubes when discarding them. CP was detected only once in the urine of a medical doctor who prepared CP by warming it. The cause may be inhalation of CP gas from the injector. The contamination of the nurses may be from dermal absorption because absorption continued even after the shift ended and the nurses left the facility. CP was not detected in pharmacists who followed the guidelines for preparation of CP. All of the medical staff should follow the guidelines when they handle CP.

Multicenter study for environmental and biological monitoring of occupational exposure to cyclophosphamide in Japan.

Purpose. A multicenter field survey of environmental contamination and exposure of healthcare professionals to anticancer drugs were performed. Setting. Three university hospitals, one cancer specialty hospital and two corporate hospitals from across Japan. Method. The environmental contamination with cyclophosphamide (CP) was investigated. A wipe examination was performed at six sites apiece in two divisions. The urinary excretion of the CP over 24 h was determined. The subjects of the survey included physicians, pharmacists, and nurses, for a total of seven at each facility irrespective of job title. The wipe samples were collected at 12 sites within two divisions at each facility. For the exposure survey, the total urine volume was determined, and a portion of the urine sample was then collected from each participants at each facility. Urine was collected for 24 h. The samples were determined by using the GC-MS method. Results. Wipe examination: contamination with CP was identified at 50% of the sites. The concentration was high (CP > 1.00 ng/cm2) in the general environment in two hospitals and in the safety cabinet in one hospital. In the survey for the exposure of staff to anticancer drugs, 276 samples were obtained from 41 healthcare professionals. CP was detected in 90 samples obtained from 23 subjects. The amount of exposure was greatly different among the facilities. The urinary excretion of CP per subject was between 2.7 and 462.8 ng/24 h. The range of urinary excretion for each hospital was between 4.6 and 211.2 ng/24 h.

Guide for medical professionals (i.e., dermatologists) for the management of Rhododenol-induced leukoderma.

Because some users develop depigmentation after the use of melanogenesis‐inhibiting products containing the quasi‐drug ingredient Rhododenol, Japanese Dermatological Association (JDA) established a Special Committee on the Safety of Cosmetics Containing Rhododenol on July 17, 2013 and management guide for dermatologists has been updated on the website in order to delineate the diagnostic criteria for Rhododenol‐induced leukoderma and provides a broad guide for standard treatment based on current knowledge. This guide is produced on the basis of the guide (version 7) updated on June 20, 2014 in the website. Rhododenol‐induced leukoderma refers to depigmentation of varying severity that develops after the use of cosmetics containing Rhododenol, mainly at the site of use. In most cases, repigmentation of part or all the affected area is evident after discontinuation. Histopathologically cellular infiltration around the hair follicles and melanophages are present in most cases. The number of melanocytes in the lesion is declined but not totally absent in most cases. Rhododenol itself is a good substrate for tyrosinase, resulting in the formation of Rhododenol metabolites (e.g., Rhododenol quinone). Melanocytes are damaged by Rhododenol metabolites during the subsequent metabolic process. The continued use of cosmetics containing Rhododenol thus induces tyrosinase activity‐dependent cytotoxicity in melanocytes in the epidermis at application sites, resulting in decreasing the amount of melanin produced by melanocytes; the addition of some other factor to this process is believed to subsequently cause the decrease or disappearance of melanocytes themselves from the epidermis.

Acid load during total parenteral nutrition: comparison of hydrochloric acid and acetic acid on plasma acid-base balance.

The effects of hydrochloric acid and acetic acid on the plasma acid-base balance were investigated in four rabbits receiving parenteral nutrition. Hyperchloremic metabolic acidosis was observed only in the animals receiving total parenteral nutrition (TPN) whose pH was adjusted with hydrochloric acid. The observed acidosis was due to an excess of hydrogen ions with chloride ions as judged by the plasma-base excess and urinary net-acid excess and not by the infusion of solution having a high titratable acidity. The hydrogen ion released from the acetic acid added to TPN is consumed by the metabolism of the acetate ion and thus does not contribute to the net hydrogen-ion load. A reduction in the chloride load by using acetic acid to adjust the pH of the TPN solution when it is formulated can be safely achieved and prevents acidosis.

The Latent Risk of Acidosis in Commercially Available Total Parenteral Nutrition (TPN) Products: a Randomized Clinical Trial in Postoperative Patients

To evaluate the latent risk of acidosis in commercially available total parenteral nutrition (TPN) products, three types of commercially available TPN products were compared in postoperative patients. Sixty-four hospitalized patients with gastro-intestinal disease who undertook curative gastro intestinal resection were studied prospectively and administered with TPN solutions. Three types of commercially available TPN products were assigned randomly to eligible patients. Serial studies of blood acid-base status, serum electrolytes, and urinary acid-base status were conducted in the three groups administered with different TPN solutions. Patients received appropriate electrolytic solutions on the operation day and TPN solution from 2 to 7 days after operation. There were no differences among any of the serum electrolytes in the three groups. In one group, urinary pH decreased slightly and urinary net acid excretion (NAE) increased significantly after administration. This TPN product contains about 40 mEq/L of non-metabolizable acid to avoid the Maillard reaction that produces a complex of glucose and amino acids. Urinary NAE did not change in the other two groups. These TPN products do not use non-metabolizable acid to adjust pH. The present results suggest that the non-metabolizable acid may be a risk factor of metabolic acidosis.

Testing the degradation effects of three reagents on various antineoplastic compounds

Objective Studies for decontamination of antineoplastic compounds have been conducted for decades. Nevertheless, recent studies indicate the contamination of work place in hospitals, and the exposure of workers. In this study, to develop an effective cleaning method for contaminated environments, the degradation efficacies of antineoplastic compounds by reagents were evaluated. Methods The degradation efficacies of various combinations of three reagents (sodium hypochlorite, sodium thiosulfate, and sodium hydroxide) were evaluated with four antineoplastic compounds (cyclophosphamide, epirubicin, cisplatin, and carboplatin). The residues of antineoplastic compounds were measured with high-performance liquid chromatography. Results Of the three reagents, sodium hypochlorite was the most effective to all antineoplastic compounds used in this study. Although sodium hypochlorite degraded 86.6% of cyclophosphamide, it degraded other three antineoplastic compounds completely. The combination with sodium hypochlorite and sodium thiosulfate degraded only 3.3% of cyclophosphamide, since sodium thiosulfate inhibited the degradation ability of sodium hypochlorite. Similarly, the combinations used in all three reagents failed to degrade cyclophosphamide. Conclusion Although three of four antineoplastic compounds were degraded successfully, any combinations of three reagents could not degrade cyclophosphamide completely. However, the addition of sodium thiosulfate which inhibits the corrosion of metal by sodium hypochlorite is essential for daily cleaning. Therefore, the evaluation of reaction time before the addition of sodium thiosulfate may be required. We will continue to investigate the reagents for degradation.

Absorption process of salazosulfapyridine in human intestinal epithelial cells and rat intestine

Introduction: Salazosulfapyridine (SASP) is an oral medication used to treat rheumatoid arthritis and inflammatory bowel disease, particularly ulcerative colitis. It has been reported that various transporters such as P-glycoprotein (Pgp) and multidrug resistance-associated protein 2 (MRP2), are involved in the transport of SASP. P-gp and MRP2 are expressed in the brain, intestine, and various tissues in both humans and rats. In the intestine, P-gp limits the absorption of certain drugs, however, its mode of absorptive action with regard to SASP has not, as of yet been studied. The aim of this study was to investigate the intestinal transport of SASP and examine whether transporters such as P-gp and MRP2 are involved in this process. Method: Bidirectional permeability and inhibition transport studies were performed using Caco-2 and T84 cell lines. Transcellular transport studies were conducted using isolated rat intestinal tissue mounted in an Ussing-type chamber. The intestinal absorption was examined using an in-situ closed-loop experiment in rats. Results: SASP showed secretory-directed transport across Caco-2 and T84 cells, as well as rat intestinal tissue. Cyclosporine A (CsA), a P-gp inhibitor, was found to decrease this secretory-directed transport. In the intestinal closedloop experiment, addition of CsA resulted in increased accumulation of SASP; however, this was too miniscule to be considered. The inhibition study showed that both secretory and absorptive transporters sensitive to probenecid are involved in the process of SASP absorption in the small intestine. Conclusion: In the process of SASP absorption in the intestine, CsA-sensitive secretory transporters including P-gp as well as probenecid-sensitive absorptive and secretory-transporters are involved and the total of the absorption of SASP is regulated by these transporters. It is likely that these transporters are coordinated in a complex manner to effectively regulate absorption of SASP and other biochemically similar drugs.