Evaluation of Tumor Tissue Fixation Effects of Formulation Modified Mohs Pastes in Mice and Their Water-Absorbing Properties.

Mohs paste (MP) is a hospital preparation containing zinc hydrochloride and zinc oxide starch. It is a topical medication used to fixate tissues for the removal of inoperable skin tumors and the management of hemorrhage and exudates, and to prevent foul odor resulting from secondary infections. However, it has problems, such as changes in hardness and viscoelasticity with time and liquefaction by exudate. It has been reported that the modified MP with D-sorbitol (S-MP) and the modified MP using the cellulose instead of starch (C-MP) have excellent physicochemical stability and better handling than original MP (O-MP). In this study, the effect of prescription improvement of MP on the pharmacological effect was examined with reference to water absorbing property, and its tumor tissue invasion fixation depth as an indicator. In the S-MP and C-MP, the amounts of water absorption did not differ significantly from those in the O-MP. The hardness of S-MP was decreased and liquefied like O-MP after absorbing water. In contrast, C-MP retained its form even after water absorption. The subcutaneous tumors in mice treated with modified MP formulations were measured for invasion fixation depth at 6 and 24 h after application. And the tissue status was observed using computed tomography. In all MPs, invasion fixation depth increased depending on application time. S-MP and O-MP depths did not differ significantly. The invasion depths of the C-MP significantly increased compared with those in the O-MP. These results suggest that C-MP had a high tissue fixation rate.

[Clinical Application of Basic Research on Mohs' Paste to Meet Medical Needs].

　Mohs' paste (MP), which is widely used in medical services as a specific hospital preparation, has been considered to have demerits, such as increased hardness after preparation and marked adhesiveness. However, factors associated with variations in its physical properties have not yet been clarified. Therefore, we conducted studies to clarify the physicochemical phenomena influencing such variations, and also examined prescription drug designs of MP preparations that are difficult to use clinically due to the above-mentioned demerits, with a view to improving their usability. Furthermore, with cooperation from the director of the Department of Palliative Care and Maintenance Therapy and certified wound ostomy and continence (WOC) nurses of Yokohama Minami Kyousai Hospital, we clinically applied an improved form of MP I. We also examined the effects of an improved MP II (designed as a stable formulation) in mice. This is an example of the clinical application of basic research to design a new clinical formulation in order to meet medical needs.

Preparation and Evaluation of Modified Mohs Paste without Starch.

Mohs paste is an external preparation containing zinc hydrochloride and zinc oxide starch as the main ingredient, and it is used for the palliative treatment of patients with surgically untreatable malignant tumors. However, it has problems, such as changes in hardness and viscoelasticity with time and liquefaction by exudate. To overcome these problems, we modified the formulation of Mohs paste by excluding starch, which is the cause of physical changes, and investigated the base. In the modified Mohs paste using the macrogol ointment for the base, no marked change with time was noted in the hardness, malleability, or elongation property, and the water-absorbing properties were equivalent to those of Mohs paste immediately after preparation. The hardness did not decrease even after absorbing water. The drug release rate increased 1.5 times with the modified Mohs paste. Based on these findings, the risk of liquefaction-associated damage of the surrounding skin decreased on using the modified Mohs paste, and preparing in advance became possible. These results suggest that the modified Mohs paste using the macrogol ointment for the base exhibits an equivalent effect for control of exudate and a high effect for tissue fixation.

Nurturing Pharmacists Who Contribute to Clinical Practice through Galenical-pharmaceutical Studies.

In clinical environments, difficulty in the uniform preparation of Mohs paste has been noted, due to variations in its physical properties, and despite preparations being based on the same prescriptions. Therefore, studies have been conducted to clarify the physicochemical phenomena influencing such variations, and then to develop a prescription design that will improve the usability of this product through the use of additives with sufficient safety, thereby addressing the above-mentioned demerit. An improved form of Mohs paste, not containing the starch that is responsible for the variations in physical properties, was developed in consideration of appropriate bases, and its pharmacological mechanisms were examined, with a focus on its hemostatic effects. Furthermore, clinical training regarding reliably consistent Mohs paste preparation was provided in medical institutions performing collaborative drug therapy management (CDTM).

Usefulness of Oral Care-related Information Provision at Drugstores to Prevent Pneumonia.

Although the removal of bacteria in the oral cavity is regarded as an important preventive measure against pneumonia, the majority of elderly individuals are rarely provided with oral care-related information. This study examined the usefulness of oral care-related information provision for the elderly by pharmacists working at drugstores. A questionnaire survey was conducted, involving 387 pharmacists working at drugstores and 51 elderly individuals who visited such stores. Oral care-related information had been actively provided by 14.5% of the pharmacists, and 62.5% of all oral care products were being sold as care products. When focusing on the elderly, 70.6% showed interest in oral care, but the proportion of those who had performed self-care to promote such health was limited to 5.9%. After being provided with oral care-information, 97.6% answered "I wish to regularly perform oral self-care", and 86.3% regarded oral care-related information provision by pharmacists as "very useful". The results of this study demonstrate the usefulness of information provision by pharmacists at drugstores to promote oral self-care among the elderly.

Raloxifene glucuronidation in liver and intestinal microsomes of humans and monkeys: contribution of UGT1A1, UGT1A8 and UGT1A9.

1. Raloxifene is an antiestrogen that has been marketed for the treatment of osteoporosis, and is metabolized into 6- and 4'-glucuronides by UDP-glucuronosyltransferase (UGT) enzymes. In this study, the in vitro glucuronidation of raloxifene in humans and monkeys was examined using liver and intestinal microsomes and recombinant UGT enzymes (UGT1A1, UGT1A8 and UGT1A9). 2. Although the K(m) and CL(int) values for the 6-glucuronidation of liver and intestinal microsomes were similar between humans and monkeys, and species differences in Vmax values (liver microsomes, humans > monkeys; intestinal microsomes, humans < monkeys) were observed, no significant differences were noted in the K(m) or S50, Vmax and CL(int) or CLmax values for the 4'-glucuronidation of liver and intestinal microsomes between humans and monkeys. 3. The activities of 6-glucuronidation in recombinant UGT enzymes were UGT1A1 > UGT1A8 >UGT1A9 for humans, and UGT1A8 > UGT1A1 > UGT1A9 for monkeys. The activities of 4'-glucuronidation were UGT1A8 > UGT1A1 > UGT1A9 in humans and monkeys. 4. These results demonstrated that the profiles for the hepatic and intestinal glucuronidation of raloxifene by microsomes were moderately different between humans and monkeys.

Adsorption of histones on natural polysaccharides: The potential as agent for multiple organ failure in sepsis.

Histones are intracellular proteins that are structural elements of nuclear chromatin and regulate gene transcription. However, the extracellular histones released in response to bacterial challenges have been identified as mediators contributing to endothelial dysfunction, organ failure, and death during sepsis. In the present study, the adsorption of histones as well as plasma proteins (α1-acid glycoprotein (AGP), albumin, and γ-globulin) on alginic acid, pectin, dextran, and chitosan was examined in order to evaluate the potential of natural polysaccharides as therapeutic agents for multiple organ failure in sepsis. Alginic acid and pectin strongly adsorbed histones, whereas the adsorption abilities of dextran and chitosan toward histones were very low or negligible. Among the natural polysaccharides examined, only alginic acid did not adsorb any of the plasma proteins. These results demonstrated that alginic acid strongly adsorbed histones, but not plasma proteins; therefore, it has potential as a candidate drug for the treatment of multiple organ failure in sepsis.

Involvement of reactive oxygen species in the enhancement of membrane lipid peroxidation by sonodynamic therapy with functionalized fullerenes.

BACKGROUND/AIM: Sonodynamic cancer therapy is based on the preferential uptake and/or retention of a sonosensitizing drug (sonosensitizer) in tumor tissues and subsequent activation of the drug by ultrasound irradiation. In the present study, we investigated the participation of lipid peroxidation in the mechanism of the sonodynamically-induced antitumor effect with functionalized fullerenes, such as polyhydroxy fullerene (PHF. MATERIALS AND METHODS: Ultrasonically-induced cell damage and lipid peroxidation with PHF were compared in the same in vitro insonation setup. Sarcoma 180 cells suspended in PBS were exposed to 2 MHz ultrasound in the presence and absence of PHF. Cell viability was determined by the Trypan Blue exclusion test. Lipid peroxidation in cell membranes was estimated by measuring the amount of malondialdehyde as the thiobarbituric acid-reactive-substances. RESULTS: Significant enhancement of the rates of both ultrasonically-induced cell damage and lipid peroxidation was observed in the presence of PHF, both of which were positively correlated with PHF. The enhancement of cell damage and lipid peroxidation with PHF was suppressed by reactive oxygen scavengers such as histidine and tryptophan. CONCLUSION: The good correlation observed in the presence of PHF suggests that membrane lipid peroxidation is one of the important intermediary events in sonodynamically-induced cellular damage. The inhibitory effects of histidine and tryptophan also provide evidence that singlet oxygen plays an important role in PHF-mediated sonosensitization of membranes and that this moiety may be an important mediator of cell destruction in sonodynamic therapy associated with PHF and ultrasound.

Butylbenzyl phthalate hydrolysis in liver microsomes of humans, monkeys, dogs, rats and mice.

Butylbenzyl phthalate (BBzP) is used as a plasticizer to import flexibility to polyvinylchloride plastics. In this study, hydrolysis of BBzP to monobutyl phthalate (MBP) and monobenzyl phthalate (MBzP) in liver microsomes of humans, monkeys, dogs, rats and mice was examined. The kinetics for MBP formation by human, dog and mouse liver microsomes followed the Michaelis-Menten model, whereas the kinetics by monkey and rat liver microsomes fitted the Hill model. The kinetics for MBzP formation fitted the Hill model for all liver microsomes. The Vmax and in vitro clearance (CLint or CLmax) ratios of MBP/MBzP formation varied among animal species, although the Km for MBP and MBzP formation in each liver microsomes were generally comparable. The hydrolysis of BBzP to monoester phthalates in mammalian liver microsomes could be classified into two types: MBzP>MBP type for humans and dogs, and MBP>MBzP type for monkeys, rats and mice. These findings suggest that the formation profile of MBzP and MBP from BBzP by liver microsomes differs extensively among animal species.

Functional characterization of cynomolgus monkey UDP-glucuronosyltransferase 1A9.

UDP-glucuronosyltransferase 1A9 (UGT1A9) contributes to the glucuronidation of numerous drugs. Cynomolgus monkeys are regarded as experimental animals similar to humans in studies on safety evaluation and biotransformation for drug development. In this study, the similarities and differences in the enzymatic properties of UGT1A9 between humans and cynomolgus monkeys were precisely identified. UGT1A9 cDNAs of humans (humUGT1A9) and cynomolgus monkeys (monUGT1A9) were cloned, and the corresponding proteins were heterologously expressed in Sf9 cells. The enzymatic properties of UGT1A9s were characterized by kinetic analysis of propofol glucuronidation. The amino acid homology between humUGT1A9 and monUGT1A9 was 93.2 %. Propofol glucuronidation by recombinant humUGT1A9 and monUGT1A9 exhibited substrate inhibition and monophasic Michaelis-Menten kinetics, respectively. The K m, V max and CL int values of humUGT1A9 were 15.0 µM, 1.56 nmon/min/mg protein and 107 µL/min/mg protein, respectively. The K m value of monUGT1A9 was 8.8-fold higher than humUGT1A9, and the V max and CL int values of monUGT1A9 were 15 and 2 % of humUGT1A9, respectively. These findings suggest that the enzymatic properties of UGT1A9 are considerably different between humans and cynomolgus monkeys, although humUGT1A9 and monUGT1A9 were highly conserved at the amino acid level. The information on species differences in UGT1A9 function gained in this study should help with the in vivo extrapolation of drug metabolism.

[Preparation of a gel-forming ointment base applicable to the recovery stage of bedsore and clinical evaluation of a treatment method with different ointment bases suitable to each stage of bedsore].

An ointment base for better treatment of bedsores was developed to improve the release rate of minocycline hydrochloride (MH) and the water absorption capacity using various types of hydrophobic to hydrophilic ointment bases. The effect of purified lanolin (PL) on the release behavior of MH from a hydrophilic ointment (HO) base was the primary focus. It was found that the drug release rate from the ointment base was modified according to the method of preparation of the ointment base and the type of cyclodextrins admixed. The physicochemical properties, such as viscosity, elution volume, and water absorption, of the ointment base were also modified by those factors. To develop an ointment formulation suitable for the recovery stages of bedsores, including the proliferation period of granulation and the formative period of epidermis, the physicochemical properties of Macrogol ointment containing various hydrophilic polymers, which have gel-forming ability, were tested. A novel ointment base suitable for the treatment in the recovery stage of bedsores was developed using hydrophobically modified hydroxypropyl methylcellulose (HM-HPMC). Considerably sustained release of MH (T50 of 170 at a min) was attained with a macrogol ointment mixed with HM-HPMC and Carbopol formulation ratio of 3:7. We clinically evaluated the effectiveness of bedsore treatment by applying different ointment bases to patients with different stages of bedsores.