Histamine plays an important role in both inflammation and gastric acid secretion, while it also acts as a neurotransmitter in the mammalian brain. In particular, histamine plays a central role in the immediate hypersensitivity and allergic response as a mediator released from mast cells and basophils.
The use of in vitro histamine release experiments to identify antigens in drug allergies is thus considered to be useful. A highly sensitive assay for histamine is required for in vitro release experiments.
We experienced a patient who developed an anaphylactic reaction to a barium sulfate suspension after under-going an upper gastrointestinal examination, and identified carboxymethylcellulose sodium (CMC-Na) to be an antigen in the barium sulfate suspension, using the skin-scratch test and in vitro histamine release.
A 63-year-old woman was admitted to the hospital because of an anaphylactic reaction after undergoing a double-contrast upper gastrointestinal examination. After obtaining the patient informed consent, we conducted skin-scratch tests for each of the components in the barium sulfate suspension to identify any antigens. A positive reaction was observed for CMC-Na. No such reaction was observed for any other components of the barium sulfate suspension and gas producing granules. The three normal subjects had no response to all agents tested. In addition, the degree of histamine release from the isolated leukocytes induced by CMC-Na was studied in vitro. The leukocytes were isolated by the centrifugation of the peripheral blood on the Ficoll-iothalamate meglumine solution. The histamine content was determined by lon-Pair HPLC.
The leukocytes from the patient responded to CMC-Na at a concentration range from 10^-4.5% to 10^-2.6%, while those from normal subjects did not. The dose-response curve for the effect of CMC-Na on the histamine release from leukocytes from the patient was bell-shaped. The results of the present study as a whole indicated CMC-Na to be the antigen responsible for the anaphylactic response to the barium suspension in our patient. Although not a common complication, such a reaction may occur in patients sensitized to CMC-Na.
CMC-Na is widely used as a suspending agent in pharmaceuticals, certain food products and cosmetics. Although CMC-Na has been thought to be inert and not absorbed, our findings suggest that the patient was sensitized to CMC-Na through such routes.

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Digoxin-like factor (DLF) is known to interfere with a digoxin assay and falsely elevate the digoxin concentration. DLF has been reported in patients with liver and renal diseases, terminal pregnant women and infants. In this study, cholestasic rats induced by a surgical bile-duct ligation were used to clarify the appearance of DLF in a fluorescence polarization immunoassay (FPIA), and finally a precipitation method was improved. DLF increased immediately and reached about 0.4 ng/mL at 48 hrs after the bile-duct ligation. After centrifugal deproteinization with a precipitation reagent, 6 % sulfosalitylic acid aq. solution : MeOH mixture (1 : 1) (SSA), 69 and 202μg of a residue were detected while using a membrane filter (cellulose acetate ; pore size, 0.45 μm) at room temperature for 20 and 60 min, respectively. The scattering-light intensity (480-490 nm) of the cholestasic plasma was 5.5 times higher than that of the normal plasma and moreover increased by 20% after 60 min of incubation at room temperature. However, this high scattering-light intensity diminished when kept at 4°C for 60 min after adding the precipitation reagent, and DLF could thus be reduced. Porphyrin, a mixture of bilirubin and urobirin, can easily be aggregated by increasing the ionic strength and acidity, therefore, the addition of NaCl into cholestasic plasma in order to elevate the ionic strength potentiated the scattering-light intensity and DLF. These findings suggested that DLF in the cholestasic plasma may arise as a result of the appearance of some large particles after centrifugation because of insufficient deproteinization, which can scatter excited light due to polarization.

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Translational research is becoming increasingly important at our hospital. Research must be carried out while maintaining the highest ethical and scientific standards and, in addition, it must always be medically justified. We think that the translational research coordinator (TRC) therefore has an important role to play in such clinical trials. Consequently, the management system for translational research should involve pharmacists, nurses, certified clinical psychologists and nutritionists, as TRCs in order to correctly carry out any translational research. In this paper, we describe : 1) the role of TRCs in translational research, 2) the management system governing translational research from its approval to completion and 3) the practical aspects of the TRC.
We allocate the role of doctors and each TRC in the research as follows : Doctor : draws up a protocol, carries our laboratory tests and any research based on the protocol, obtains complete information from each TRC to perform the research without any complaints from patients acting as volunteers. Pharmacist : manages data, explains the details of the protocol to the patient beforehand, visits patients, conducts drug consultations, detects at an early stage any adverse reactions and alerts doctors to such events, and performs a pharmacokinetic analysis. Nurse : manages data, explains the details of the protocol to the patient beforehand, makes out a care plan, performs patient care, and is aware of the patient's state of mind (in conjunction with a certified clinical psychologists). Certified clinical psychologist : Interviews patients before starting the research and gives instructions about correspondence between patients and doctors and TRCs, and investigates the patient's state of mind. Nutritionist : obtains information about the patient's appetite and discovers his/her dietary preferences before starting the research. All TRCs are responsible for ensuring that the medical ethical aspects of the study are complied with.
Essential documents have to be prepared regarding the management and evaluation of the study including obtaining the patient's informed consent, making up a schedule based on the protocol, devising a care plan and reporting on any adverse reactions, and keeping a patient study diary. In addition, the importance of the clinical research meeting to allow discussions about such matters as the registration of patients and the clinical courses is also discussed.

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Although vancomycin has been exclusively used for methicillin-resistant Staphylococcus aureus (MRSA) therapy, there are many patients recently observed to suffer from gram negative bacteria, Pseudomonas aeruginosa as well as MRSA.
Arbekacin (ABK), an aminoglycoside antibiotic (AG) is an alternative medication for such patients with those infection disease. However, it seems that the dosage of ABK used according to the manufacture's recommendations is insufficient for MRSA therapy to obtain a sufficient patient outcomes. Moreover, the relationship between the effectiveness of ABK on MRSA infection and the serum ABK concentration remains unclear. For the long-term treatment of AG, we can not rule out the possibility that AG may induce nephrotoxicity and ototoxicity.
Therefore, the present study was carried out to clarify the significance of therapeutic drug monitoring (TDM) of ABK for patients with an MRSA infection, and elucidate the relationship between the serum ABK level and its clinical outcomes, including its antibacterial action and side effects. We investigated 30 patients with an MRSA infection, who received ABK at the Anjo Kosei Hospital from September 1996 to June 1998. The treatment of the patients by ABK but without TDM showed a 46.6% (7/15) therapeutic efficacy, while the patients with drug monitoring had a remarkably successful therapeutic efficacy (100% : 21/21) with a peak serum ABK concentration over 10μg/mL. Dysphagia badly affected the efficacy of ABK therapy in patients with an MRSA infection even when the serum ABK level was well-controlled. The incidence of ABK induced nephrotoxicity was observed in all patients when ABK was administered at a total dose of over 5, 000mg, while it was 4% at a total dose of less than 5, 000mg. When the duration of ABK therapy was longer than 2 weeks, the incidence of nephrotoxicity also significantly increased.
These results thus suggest that TDM of ABK is useful for increasing the efficacy of ABK therapy in patients with an MRSA infection. In light of nephrotoxicity, these results indicate that ABK therapy may be completed within 2 weeks with an ABK dose of less than 5, 000mg, as the total dose.

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Di-2-ethylhexyl Phthalate (DEHP) is reported to have been formed and identified in a polyvinyl chloride (PVC) administration tube during the infusion of an injection fluid containing polyoxyethlated caster oil (HCO60) as a solvilizing agent.
This paper describes a experimental formula for estimating the amount of DEHP dissolution, which was obtained under several drip conditions and using an aqueous solution of HCO60.
The DEHP concentration was determined using HPLC. The DEHP dissolution followed a general pattern, in which the DEHP concentration in the solution linearly increased over time as first and thereafter reached a plateau. The amount of DEHP dissolution depended on the drip conditions. The maximum (plateau) DEHP concentration C_D (μg/mL) was proportional to the square root of the HCO60 concentration C_H (mg/mL), the length of the tube H (cm) and the inner diameter of the tube R (cm), but was inversely proportional to the drip rate S (mL/hr). The time T₁ (hr), which becomes C_D=aT₁ (a : inclination of the graph before reaching it in plateau), was proportional to H and R², but inversely proportional to S.T₁ was not dependent on C_H. Based on these results, the formula for calculating the total amount of dissolution of DEHP D_total (μg) during the total time of the infusion T (hr) was determined to be as follows :
D_total=4.09RH√C_H (T-0.755R²H/S).
The application of this formula will make it easier to estimate the amount of DEHP intake by patients during the infusion of an injection containing HCO60 using a PVC administration tube.

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For luteal support therapy with progesterone for luteal phase defects such as infertility, sterility, in vitro fertilization and embryo transfer, it is important to have both a rapid rise in the plasma concentration and constancy. The additive effect of sodium caprate for mixed type progesterone suppositories, consisting of Witepsol W35 and Witepsol E85 at 1 : 1, was therefore investigated in vitro and in vivo.
The strength, the thermodynamic characteristics, the surface structures, the drug release properties and the drug absorption properties were examined for these suppositories. The strength of the suppositories increased with the addition of sodium caprate. The addition of sodium caprate, however, had no effect on the thermodynamic characteristics of these formulas. The drug release from the progesterone suppositories occurred via the matrix and pores, and was confirmed by in vitro dissolution profiles in which the amount of progesterone is proportional to the square root of time. The sustained plasma concentration of progesterone was examined after the vaginal administration of mixed type suppositories.
The plasma concentration of progesterone at an initial phase after the administration of 2 % sodium caprate/ mixed suppository (formulation D) was found to be twice that of the mixed suppository (formulation A, no containing sodium caprate). Furthermore, the area under the plasma concentration-time curve from 0 to 6 hours for formulation D increased to 1.3 times that of formulation A. The findings of this study suggest that the mixed type progesterone suppositories with the additional of sodium caprate should improve the effectiveness of luteal support therapy.

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We performed comparative studies on the adsorption of recombinant factor VIII (rF VIII) to various infusion sets and various inline filters. The rFVIII used in this study was Kogenate^® (Bayer). The infusion devices included the polyvinylchloride (PVC-A) infusion set, and the polyvinylchloride (PVC-B) and polybutadiene (PB) pump infusion sets. Regarding the inline filters, we used degenerated polysulfon (DPS), polyethersulfon (PES) and degenerated polyethersulfon (DPES) filters. After 250IU of rFVIII was dissolved in 250mL of normal saline in a polypropylene bag, the infusion was then allowed to drip through the infusion devices (1mL/min). The rFVIII activity of the infusion through the infusion sets was temporarily decreased at 0.25 hours. The recovery rate of the rFVIII activity after dripping through the infusion sets were 103.6% for PB, 90.6% for PVC-B, and 83.7% for PVC-A. The recovery rate of the rFVIII activity after dripping through PVC-A and each inline filter was 84.1% for DPS, 59.8% for PES, 50.9% for DPES. The adsorption of rFVIII to various infusion sets and inline filters was confirmed to depend on the quality of the materials. As a result, the adsorption for PB was thus found to be much less than that for the PVC-A and PVC-B infusion sets.
The adsorption per unit area for each inline filter was DPS (-0.1IU/cm²). PES (1.48IU/cm²), and DPES (8.21IU/cm²). Consequently, the adsorption for DPS and PES was found to be dramatically less than for DPES.

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Tacrolimus (FK506) ointment has a good therapeutic effect on atopic dermatitis. The efficacy of Tacrolimus ointment, however, depends on the percutaneous adsorption of tacrolimus. To examine the influence of the ointment base on the percutaneous adsorption of tacrolimus, we performed a quantitative analysis of tacrolimus in the skin using an IMX (microparticle enzyme immunoassay) system. We prepared tacrolimus ointments using five kinds of ointment bases, i.e., Carbopol gel, White Petrolatum, Hydrophilic Ointment, Plastibase and Macrogol ointment. The concentration of tacrolimus in the rat abdominal skin were then determined 14 hours after the topical application of the different ointments to the rat skin by using the IMX system, and the effect of the various ointment bases was thus evaluated. As a result, the amount of tacrolimus in the skin measured 14 hours after topical application was as follows : Carbopol gel >White Petrolatum >Hydrophilic Ointment≅Plastibase > Macrogol ointment.

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The purpose of antihypertensive therapy is not only to normalize the blood pressure but also to prevent severe or fatal complications of the cardiovascular system. Since the presence or absence of target organ failure and major dangerous factors influence the prognosis of hypertension, an appropriate evaluation of these risk factors is important. It is therefore necessary to consider such complications when evaluating antihypertensive therapy.
In this investigation, we examined the current state regarding the use of antihypertensive drugs and their associated complications in Takarazuka City Hospital, to establish a more effective and safer pharmacotherapy from the pharmacist's viewpoint.
A total of 312 patients (138 males, 174 females) who received antihypertensive drugs at the Department of Internal Medicine in our hospital between August 23^rd and 27^th, 1999 were included in this study. The patients' records were examined with regard to age, the medication received and the complications observed.
The most common form of treatment, regardless of age, was calcium channel blockers (Ca blockers), followed by angiotensin converting enzyme inhibitors (ACE-I), and finally α-, and β-adrenergic blockers (α and β blockers, respectively).
The rates of congestive heart failure (CHF) and ischemic heart disease (IHD) tended to increase with age. On the other hand, those of endocrine metabolic diseases such as diabetes mellitus (DM), hyperlipidemia and gout were either unaffected or tended to decrease with age.
The peculiar use ratio of diuretics in patients with CHF was higher than that in non-CHF (p< 0.05). The use of β blockers was slightly higher in IHD. The ratio of a blockers correlated with the rates of DM (p< 0.05) and hyperlipidemia (not significant).
In conclusion, due to the variety of the patient profiles and the clinical backgrounds antihypertensive drug therapy has thus become a complex issue. In addition, GL is not applicable in all cases. However, the results of this study suggest that the current state regarding the use of antihypertensive drugs and their associated complications in our hospital was similar to that in previous reports. It is therefore necessary to further accumulate and analyze such findings including the types of treated diseases, the indications and dosage of each applied drug to establish more effective and safer antihypertensive pharmacotherapies.

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The ordering system for injections in the total medical informational system in the Akita University Hospital was established after modifying the old system in 1999. The Auto Ample dispense (AAD) system was combined with this ordering system by TCP/IP protocol and was also introduced in our department. The stable use of this total system has been underway for the dispensation of injections since November 1999. The usefulness and efficacy of this system was evaluated in our department based on the findings of working charts, time courses, and appropriate prescriptions of the injections.
The smooth and stable dispensation of all injections using this AAD system was carried out not only for regular orders, but also for temporary orders. All nurses gave this system a favorable evaluation. The statistical data indicated that more prescription sheets were issued with this system than with the previous system, and it required much time for the packaging of injections in this system compared with the manual way. However, the efficient transport of the drugs was maintained in all wards using this system. A minor revision in this system was introduced in order to promote the appropriate dosage for every injection. The incidence of injection mistakes was thus reduced to less than 10 per month.

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When inpatients are transferred to other medical facilities after discharge, we often have inquiries regarding patient medications from the medical staff of medical facilities or community pharmacies.
To pharmacists of medical facilities and community pharmacies, “Information of pharmaceutical care for inpatients” was issued by hospital pharmacists when patients were discharged. The “Information” included the pharmaceutical care records : any adverse reaction history, medical history in admission, the final prescription at discharge and so on.
A questionnaire survey evaluating the “Information” to pharmacists of medical facilities and community pharmacies was carried out by mail from April 1998 to March 1999. The response rate was 85. 1 % (80/94) : 26 were from pharmacists, 53 from physicians and one from a nurse. All of the pharmacists evaluated the “In-formation” as useful, good and understandable. The physicians evaluated as follows : 46/53; 45/53; and 44/ 53, respectively.
They indicated that the greatest necessity was the adverse reaction history, the prescription at discharge and the pharmaceutical care course. These results showed that the “Information” from hospital pharmacists to the pharmacists was generally considered to be good. It is necessary to improve the “Information” from hospital pharmacists to the other medical staffs because there are few clinical pharmacists and many doctors receive “Information” from hospital pharmacists.
It is therefore improvement to provide consistent and appropriate medications to assist hospital pharmacists, the medical staff of medical facilities and community pharmacies by sharing accurate patient information with them.

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Vancomycin hydrochloride (VCM) is widely used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. However, this drug can cause severe adverse reactions, such as nephrotoxicity and ototoxicity. As a result, monitoring the blood concentration of VCM is recommended. As VCM is excreted from the kidney without undergoing any metabolic changes, it is necessary to determine the loading dose of VCM and to monitor its blood concentration in patients with renal dysfunction. In patients with renal dysfunction, the loading dose of this drug can be determined using a nomogram. Although there have been various reports on the pharmacokinetics of VCM in both continuous ambulatory peritoneal dialysis (CAPD) patients and hemodialysis (HD) patients, no conclusive findings have yet been reported. The present study therefore investigated the pharmacokinetics of VCM in six patients with MRSA-induced CAPD peritonitis and five HD patients with an MRSA infection. Of the six patients with CAPD peritonitis, VCM was administered intravenously to one patient, intraperitoneally via the CAPD bag to two patients, and by a combination of these two methods to three patients. In terms of the VCM doses, 20 mg/kg were administered intravenously to the CAPD and HD patients, and 30 mg/kg were administered intraperitoneally via the CAPD bag. The blood concentration, pharmacokinetic parameters, inflammation findings, clinical effects and clinical laboratory tests were analyzed. When VCM was administered intravenously to CAPD patients, its half-life varied greatly from one treatment to the next and from one patient to the next, with the administration time ranging from 37.7 to 341 hours. Nonetheless, the tendency was as follows : the more improved the peritonitis, the longer the half-life of the drugs. These findings suggest that it will be necessary to determine the dose of administration and the interval each time VCM is administered intravenously, and to monitor its pharmacokinetics and inflammation parameters. When VCM was administered intraperitoneally via the CAPD bag, the transfer of the drug to blood was confirmed, and its pharmacokinetic parameters were also comparable among the patients. These findings suggest that the pharmacokinetics of this drug are therefore more stable when it is administered via a CAPD bag. Furthermore, a regression analysis showed an extremely high correlation between the VCM concentration in the blood and the drainage of CAPD during the elimination phase (Y = 1.046X +4.978, r = 0.95, p< 0.01). Moreover, the pharmacokinetics of VCM differed greatly between intraperitoneal and intravenous administrations in CAPD patients. In HD patients, the half-life of VCM ranged widely from 12.3 to 86.1 hours, and its distribution volume ranged from 0.55 to 1.96 L/kg. The removal rate of VCM with B 3 series dialysis utilizing a polymethyl methacrylate (PMMA) dialysis membrane ranged from 17.3 to 26.2%.
When VCM was administered intravenously to HD and CAPD patients, its pharmacokinetics varied greatly from one treatment to the next and from one patients to the next. It is therefore necessary to monitor the blood concentration of VCM each time this drug is administered intravenously. On the other hand, when VCM was administered intraperitoneally via the CAPD bag, its pharmacokinetics did not differ markedly from one patient to the next, thus suggesting that the blood concentration of VCM could thus be accurately estimated by measuring its concentration in the drainage of the CAPD.

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It is generally known that the regular use of inhalation steroids plays an important role in asthma treatment. However, when giving instructions for the inhalation of beclomerasone dipropionate using Inspire Ease^® spacers (BDP+IE), difficulty of inhalation techniques may sometimes lead to a reduction in patient compliance. The inhalation of fluticasone propionate (FP) using Diskhaler^®, which was newly introduced in Japan in December 1998, shows a stronger antiinflammatory action and thus requires a simpler inhalation technique. It is thus considered that switching from BDP + IE to FP might therefore improve patient compliance with inhalation steroids.
To investigate the patient preference for both inhalation agents, we conducted a questionnaire survey in 95 asthmatic patients in whom BDP + IE was switched to FP. Furthermore, we examined whether or not any improvement in the pulmonary functions was observed in the patient evaluation.
As a result, 76.8% of the patients preferred FP because of its easier portability, it was easier to use and required a smaller numbers of inhalations. The subjective symptoms improved in 58.9% of the patients while the pulmonary functions improved in most patients. However, some elderly patients reported BDP + IE to be preferable mainly due to the fact that they were accustomed to the procedure.
We conclude the use of FP improves compliance since 76.8 % of the patients preferred it to BDP+IE which thus increased patient compliance which therefore resulted in an improvement of pulmonary functions

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