The release behavior of diethylhexyl phthalate (DEHP, a plasticizer of polyvinyl chloride) from polyvinyl chloride (PVC) tubing caused by the coexistence of such surfactants as polysorbate 80 and polyoxyethylene castor oil (Tween 80 and HCO 60, a solubilizer for water insoluble drugs, respectively) in various solutions was investigated. The concentration of released DEHP increased as the concentration of Tween 80 increased. As the drip rate accelerated, the concentration of the released DEHP diminished. Based on a comparison of the release behaviors of DEHP observed in the solutions containing surfactant alone and a commercial injection, they were found to be compatible together. These results suggest that it is become feasible to predict the concentration of dissolved DEHP based on the concentration of the surfactant and the drip rate.

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Cimetidine (CIM), a histamine H²-receptor antagonist, has been demonstrated to reduce the clearance (CL) of a number of drugs. Up to date, 29 drugs, whose CL^s are reduced by the coadministration of CIM, are listed under their package insert. We reviewed the original articles investigating the potential drug interaction between CIM and these drugs, and analyzed the relationship between the daily dosage of CIM and the alteration of the CL of the coadministered drugs.
The decrease in the CL in the coadministration of CIM varied greatly from chlordiazepoxide with the largest decrease (56.7%) to mexiletine with the smallest (6.0%). The dose of the CIM described in original articles also varied greatly with the largest dose 2, 400 mg/day and the lowest 300 mg/day. A dose of over 800 mg/day of CIM, which is the upper limit of the usual dose in Japan, comprised 98% of all reported cases. A 1, 200 mg/day dose (16.6 mg/kg/day) of CIM, which was the most frequent dose described in the literature, was 2.5 times higher than the 400 mg/day dose (6.7 mg/kg/day) which is the usual dose in recent years in our country.
The CL and serum trough concentration of theophylline (TP) were measured before and after the oral coadministration with a dosage of 400 mg/day or 800 mg/day of CIM for 5 days in four healthy subjects. The alteration in the serum trough concentration (about a 35% increase) and the CL (about 20% decrease) of TP induced by the coadministration of 800 mg/day of CIM, was much greater than that observed after the coadministration at 400 mg/day.
These results suggest that the uniform change in prescriptions only based on the names of the drugs used in combination must be reexamined, and that it is necessary to improve the drug interaction-check system based on scientific evidence. after carefully evaluating the dose of the drug used.

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The adsorption characteristics of bile salt anions to spherical charcoal (Kremezin^®) were studied in vitro and then compared with those to powdered medicinal charcoal and an anionexchange resin, cholestyramine, from the standpoint of its possible usefulness for sequestering bile salts in the intestine. The adsorption equilibria of bile salts to medicinal charcoal and cholestyramine in 2 nd fluid JP X III were rapidly achieved within the first hr of incubation, whereas the adsorption process to spherical charcoal was very slow and continued even after 168 hrs.
Based on the data of 24-hr batch adsorption experiments under the conditions containing various additives, spherical charcoal was shown to have adsorptive capacities for bile salts to some extent, namely the power of spherical charcoal seemed to be almost equal for trihydroxy bile acids and approximately 30% for dihydroxy analogs, compared with those of medicinal charcoal and cholestyramine. These results suggest the possibilities of spherical charcoal as an oral adsorbent for further medical applications to diseases in addition to chronic renal failure, which bile salts in the gastrointestinal tract are involved in, such as hypercholesterolemia, pruritus, Crohn's disease, primary biliary cirrhosis and others.

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A novel approach for identifying the inter-individual variation in hepatic clearance was investigated based on physiological pharmacokinetic studies and estimations of the amount of cytochrome P450 (CYP)in vivo. This approach is referred to as the PKCYP-test. In order to correlate in vitro-in vivo metabolic parameters, we examined the apparent liver-to-blood free concentration gradient in vivo(qg). We confirmed the validity of the PKCYP-test using acetanilide and caffeine as the CYP1A2 probe and test drug, respectively, in rats.
Increased liver enzyme levels were induced in rats by the administration of 3-methylcholanthrene (MC) (MC-treated rats). We observed a 5-fold variation in the total body clearance (CL_tot) of acetanilide, and a 10-fold variation in the CL_tot of caffeine in control versus the MC-treated rats. Furthermore, the quantitation of CYP1A2 protein by Western blotting of liver microsomal protein, using a specific antibody, revealed a 20-fold increase in the MC-treated rats. The qg values were determined as the ratio of the in vivo-in vitro clearances. By considering the qg value of the control rats, we were able to predict the level of CYP1A2 in the MCtreated rats based on the CL_tot, value of acetanilide. The CL_tot values for caffeine in the MCtreated rats, as estimated from the predicted level of CYP1A2, closely correlated with the observed value.
In conclusion, we were able to show that it is possible to predict inter-individual differences in the metabolic clearance of patients with different amounts of CYP based on the specific qg value of a drug.

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A simple and fast determination of plasma panipenem (PAPM) in extremely low birth weight infants was established using reversed phase high-performance liquid chromatography. Solutions of 35% methanol (pH 5.8), including 5 mM NaH₂PO₄ and 5 mM sodium dodecylsulfate, were used for the mobile phase. The flow rate was 0.8 mL/min. UV detection was carried out at 300 nm. The pretreatment method was as follows: 200 mM 3-[morpholino] propansulfonic acid solution was added to the plasma as a stabilizer. It was then deproteinized with methanol. The calibration curve was linear in a range from 6.25μg/mL to 100μg/mL. The recovery rate from known concentration samples of PAPM was 98.4%. The within-run and day-to-day variations were below 2.5% and 2.7%, respectively. The PAPM concentrations in the plasma were determined in five infants. In immature patients, an extension of the half-life was also observed.

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In recent years, transdermal tape preparations have been widely used for numerous patients. A major problem related to the use of such tape is skin irritation. This adverse event is considered to be due to the impermeability of water through the tape material during adhesion and the occurrence of skin, eruption after its removal. As a result, the water permeability of the tape materials and the amounts of stratum comeum stripped from the skin were studied on five transdermal nitrate tape preparations. The water permeability of the preparation, in which the polyester membrane was used for the backing body, depends on the membrane thickness: a thinner membrane has a higher water permeability. The highest permeability was detected in the Antup^® preparation. On the other hand, the amount of stratum comeum stripped from the skin was significantly lower when the new Frandol tape S^® preparation was applied. According to these results and other drug information such as the cost of the preparation, we evaluated the quality of these products based on decision analysis criteria. This evaluation thus accurately indicated the effectiveness, safety and cost of the product. As a result, the highest score was obtained by the new Frandol tape S^® preparation among the five tested products. This product showed the lowest amount of stratum comeum and the low incidence of side effects. In other words, new Frandol tape S^® appears to be the most cost-beneficial transdermal nitrate tape preparation. The method used in this study was thus shown to be useful for the selection of the safest and most effective transdermal tape preparation.

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Recently improvements in the quality of life (QOL) for cancer patients in terminal care have been called for. Therefore, the palliative care units in hospital have been increased.
Pharmacists are not allowed to participate as members of the medical care team of the Rokko Hospital because the rewards for medical service are fixed. However, clinical pharmacy service plays an important role in improving the QOL and drug compliance. To provide the optimum clinical pharmacy service from pharmacist in palliative care units in the future, we surveyed such inpatients regarding their medication. As a result, it became clear that numerous patients exist who require improved drug information services from pharmacists. For example, some patients were not satisfied with the flavor of the morphine solution. As a result, we changed the flavor of the morphine solution according to each individual patient's taste.

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Recently many intrahospital infections and mass outbreaks of tuberculosis have been reported, and it is an urgent problem for us to reconsider the countermeasures against them. Since July of 1998, we have prepared and followed original guidelines as a general hospital in order to prevent the intrahospital infection of active tuberculosis. The pharmacists in our hospital have also contributed to the preparation of these guidelines concerning several intrahospital infections except for tuberculosis.
In this study we put the tuberculin reaction's test based on our guidelines into practice for 381 applicants by all staff members in our hospital. There was no significant difference in the positive-ratio among the different professions, sexes or ages. However the positive-ratio in subjects under-forty years of age was significantly smaller than that in those over-forty years of age, thus suggesting that subjects under-forty years of age are in danger of being infected with tuberculosis. Moreover, the diameter of reddening in subjects in their thirties tendes to be shorter than that for those in their twenties.
Based on the findings, it is speculated that the effects of the past tuberculin reaction and BCG on subjects under-twenty years of age might decrease as they grow older. The diameters of reddening in subjects in their forties were significantly longer than those in subjects in their thirties. This may be because of the disclosure of the tubercle bacillus in many subjects over forty years of age.

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The effect of grinding of the carbamazepine (CBZ) tablets (Tegretol^® tablet; Teg-tab.) on the physicochemical properties of carbamazepine was investigated using X-ray diffraction, differential scanning calorimetric and fourier transform infrared spectrophotometric measurements. The ground samples were prepared by grinding Teg-tab. using an electrical tablet grinder or an agate mortar and pestle. There were no changes in the crystallinity of CBZ before and after grinding. In the infrared spectra of the ground sample prepared by the electrical tablet grinder, a peak shift suggesting a molecular interaction between CBZ and its excipients were observed. The dissolution rates of CBZ from the ground samples prepared by using an electrical tablet grinder were faster than those of Tegretol^® fine granules or the ground samples prepared using the agate mortar and pestle. According to the measurements of the mean diameters of the ground samples, the differences in the dissolution behavior of the ground samples were due to the mean diameter of the ground samples, namely, the smaller the mean diameter by the elongation of the grinding time, the faster the CBZ dissolved. Furthermore, the dispensing characteristics of the ground samples were evaluated. As a result, the dispensing characteristics of the ground samples were observed to possibly greatly depend upon the micromeritical properties of the ground samples, such as the bulk density, compressibility and uniformity.

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Recently, pharmacists are playing actively roles in coordinating clinical trials under the protocol of each investigational new drug and also play an important role in the total management of clinical trials. Since April 1999, we initiated several new clinical research coordinator (CRC) services, such as, support for obtaining informed consent, the schedule setup of studies, followup of involved patients, monitoring and audit of studies and collaboration in writing case report forms.
As one of new trials we have developed in CRC services is a “Personal Booklet” of volunteers for clinical trials to inform the patients about the clinical trials and to also facilitate the communication between the patients and CRC. In addition, we made a “Subject Data Profile” to share all information concerning clinical studies among CRC's. We believe that such trials may help to greatly improve the quality of such CRC services.

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THEODUR^® Tablets 100 (TDR·T) and THEODUR^® Dry Symp 20%(TDR·DS) are sustained-releasepme pamations of theophylline. The dissolution test was used to examine the effects of TDR·T and TDR·DS soaked with milk on the release of theophylline from these preparations. The dissolution of theophylline from TDR·T soaked with milk was slower than that of the control thus indicating a delay in the release of theophylline. Milk did not affect the dissolution of theophylline from TDR·DS. In conclusion, the diffemence between the structures of TDR·T and TDR·DS seemed to produce dif5erences in the dissolution of theophylline soaked with milk. Accordingly, patients are recommended to take TDR·T with water apd not with milk.

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We analyzed the mixing services performed by pharmacists in the aseptic ward at Tokyo University Hospital as a model case, in order to establish a new mixing service system in clinical wards. The average number of prescriptions for injection was 5 per day during the 5 day investigation, and the number of injections prescribed and mixed were 44.6±4.4 and 33.2±4.6 per day, respectively. The most common drugs for the mixed injections were antibiotics (41.6%), antineoplastic agents and immunosuppressants agents (both together 21.6%). The ratios of the ampule/vial was 5: 5, and solution/lyophilized powder was 7: 3. When two pharmacists with 3 months and 3 years of mixing experience, respectively, mixed drugs, the required time for the three processes of preparation, mixing, and checking were approximately 40, 40, and 10 min, respectively, and the total time required was 90 min. The average required time per injection was 2.7 min (90min/33.3 injections), and the mixing time per injection in the laminar air flow cabinet was 1.2 min (40 min/33.3 injections). Regarding the mixing experiment, the average time required for 5 ampules (10 mL solution) was shorter than that for 5 vials (lyophilized powder) in all groups tested. In the 3 years-experience group, the average time was approximately 7 min/5 ampules and 13 min/5 vials, and these values were half of that for beginners. In the 3 years-experience group, the time required for ampules was almost the same as for the 3 months-experience group, and that of vials decreased to 8 min. We propose that the data from these time study can be utilized to estimate the effectiveness of the mixing services in the ward, in the hope that the fee for such important aseptic techniques in the mixing service provided by pharmacists, the same as for IVH admixturing, will be authorized by the regulatory agency in the future.

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Four patients developed severe oral mucositis after high-dose chemotherapy for a conditioning regimen of peripheral blood stem cell transplantation despite prevention with Povidone-iodine, Amphotericin B, and Allopurinol (PAA) mouthwashes. For such cases, we applied a mouthwash mixture of prostaglandin E₁ ointment and sodium alginate. Four patients were instructed to take a mixture of 20 mL t. i. d., and to keep it for more than 30 sec in the mouth. In all cases, oral mucositis showed an improvement within 3 days after mouthwashing and taking it, even before the leukocyte count was recovered. Prostaglandin E₁, which has been used for decubitus treatment, could effectively induce the recovery of the oral injury. Sodium alginate could help prostaglandin Ei to stay longer in the mouth and pharynx due to its adhesive nature, and could control inflammation by its own hemostatic effect. We can thus reduce the oral complications associated with radiotherapy and chemotherapy, and thereby improve the quality of life of these patients.

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GCP (Good Clinical Practice), a system to regulate clinical trial studies for investigating new drugs and postmarketing drugs, was revised and enforced in April 1997. Simultaneously, GPMSP (Good Post-Marketing Surveillance Practice) was enforced. We think that the regulatery authorities gave priority to GCP to improve the grade of postmarketing clinical trial studies to the rank of GCP in the first stage. However, PMS (Post-Marketing Surveillance) is expected to be strictly regulated in the near future.
Recently, emphasis on the work of clinical trial study shifts for configuration and management of Clinical Research Coordinator (CRC). In August 1999, even at Kinki University Hospital, the work of CRC started by pharmacists and a nurse. As well as the work of CRC, the coordinating work of PMS was started by pharmacists at kinki University Hospital in October 1999. We herein describe this new work in order to allow it to become a part of EBM (Evidence Based Medicine).
Concretely, we present the following five points regarding the coordinate work of PMS;(1) confirmation of the state of the prescription of the investigational drug (2) confirmation of the state of the prescription of the combination drugs (3) confirmation of the state of any adverse events (include unusual change in the laboratory data) (4) posting of objective data from source documents on the case report forms (5) the administration of the daily program for investigational drugs, and so on.
In addition, we also describe some pending subjects as well.

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