We studied the effects of various infusion containers materials on the fluid volumes, different infusion fluids and fluid concentrations of nartograstim (NT), a recombinant human granulocyte colony stimulating factor, on the adsorption of NT to containers, after adding NT preparations (Neu-up^® for injection 100) into infusion fluids. The NT concentrations in the infusion fluids after adding NT to containers were determined by a high-performance liquid chromatographic method or bioassay. When 1000 ng of NT was added to 500 ml physiological saline in glass containers (final concentration: 200 ng/ml), the residual rates in the fluids was to 89.5% immediately after addition, and thereafter decreased 73.3% at 6 hr and 59.1% at 24 hr. Similarly, when NT was added to the same solution in polypropylene containers, the residual rates was 74.2% immediately after adding, and 37.5% at 6 hr, and 27.8% at 24 hr. The results in the ethylenvinyl acetate and polyethylene containers were also similar to those in the polypropylene containers. No influence of the volumes (100 and 250 ml) or the kinds of fluids (physiological saline, 5% glucose solution and ringer lactate solution) on the residual rates of NT in fluids was observed. As the fluid concentrations of NT were higher, the residual rates were found to be larger within the range of 100-1200 ng/ml. These decreases in the NT concentrations in the infusion fluids could be prevented almost completely by adding commercially available total-vitamin injections containing polysorbate surfactants.

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For the purpose of treating intractable decubitus and skin ulcer, streptokinase (SK) jellies containing different types of thickening agents were prepared. Adhesion to the affected sites, the spreading ability of the jelly preparation, and the properties of the SK in the jelly, which are all considered to greatly affect the clinical efficacy, were examined pharmaceutically using the viscosity, spreading area, and release and stability of SK as indexes. Regarding the viscosity and spreading area which are thought to affect both adhesion and spreading greatly, when sodium polyacrylate (PANa) was used as a thickener, higher viscosity and smaller spreading area were obtained in comparison with carboxymethylcellulose sodium (CMCNa) and sodium alginate (Alg Na). In addition, the viscosity and the spreading area obtained with PANa were also slightly more affected by temperature than with CMCNa and AlgNa. Regarding the release of SK from the jelly preparations, with PANa no initial burst was observed and SK was continuously released at a constant rate in contrast with CMCNa and AlgNa, thus obviously showing the superiority of PANa in the retention of SK. Although no loss of the potency of SK was found in the jellies containing PANa, CMCNa or AlgNa at 5°C, for 30 days, the remaining potency was greatly decreased to 49-62% at 25°C after 30 days and 33-42% at 37°C after 30 days. These results showed that the adhesion, spreading ability and SK-release were greatly different among the tested thickening agents, and the properties of PANa were found to be clearly superior to those of the other agents. According to these results, SK jelly containing 2% PANa was used for the treatment of intractable decubitus and skin ulcer, and an excellent therapeutic effect was obtained.

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A pharmacokinetic study of theophylline and leukotriene receptor antagonist, pranlukast, was performed in 7 patients. After theophylline (100 to 200 mg twice daily) was administered for at least 4 weeks, pranlukast (225 mg twice daily) was concomitantly given for 4 to 8 weeks. The serum theophylline concentrations and the pharmacokinetic parameters of theophylline were measured before and after the pranlukast administrations. The distribution volume of theophylline at a steady state slightly increased after the concomitant pranlukast administration. However, the other parameters including the clearance, lag time, half-life, maximum and minimum serum concentrations of theophylline all remained unchanged after the pranlukast administration. The steady state concentrations of theophylline were not affected by the pranlukast intake. These results therefore indicate that no pharmacokinetic interaction exists in the conbination treatment of theophylline and pranlukast.

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We previously examined the methods for evaluating the population pharmacokinetics for Michaelis-Menten elimination, and estimated the population pharmacokinetic parameters of phenytoin in Japanese patients with epilepsy (Biol. Pharm. Bull., 19, 444, 1996). In the present study, we evaluated the predictive performance of the bayesian analysis based on this prior information. To estimate the individual pharmacokinetic parameters of phenytoin in 50 patients, 3 serum phenytoin concentration data at a stady-state after repetitive dosing were collected retrospectively for each subject. The bayesian analysis using from 1 to 2 feedback concentrations gave the accurate predictions for another dosage regimens. The bayesian regression-analysis method described here in thus appears to be useful for predicting the steady-state serum phenytoin concentration from the limited number of data obtained for therapeutic drug monitoring purposes.

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The availability of a method for predicting pH changes in multiple admixtures based on the acid-base equilibrium theory has been confirmed comparing the calculated pH's and the measured pH's in the admixtures of transfusions mixed with two or more injections. The pH's of the parenteral admixtures can be easily predicted by using a general theoretical equation for proton concentrations in a multicomponent-blended aqueous solution without any preliminary pH titration. The pH's of 59 injections and 26 transfusions were compared with pH's of the drugs described in the information leaflets. Three hundred and ninety-seven transfusions and parenteral solution mixture combinations (one transfusion and two injections) were examined for the efficacy of the predicted equation. As a result, the estimated pH closely agreed with the measured pH in all examinations, and a good correlation existed between the measured and calculated values of pH. Furthermore, to estimate the pH's of transfusions mixed with multicomponent injections, good agreements were also observed between the measured pH's and calculated pH's in any preparations with different mixing orders.

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The serum β-carotene concentration was measured by high performance liquid chromatography in anorexia nervosa (A. N.) patients who had taken a large quantity of seaweed such as tangle, toasted laver and wakame seaweed. The A. N. patients of twin sisters had the same findings of hypothyroidism which often accompany A. N. cases, and etiologically unknown yellow-tinged skin and enlarged goiter. Patient blood specimens were taken on the seventh and thirtieth days following the withdrawal of seaweed from their diets.
On the seventh day, the serum β-carotene concentrations were 2.2μg/ml in one patient and 2.9μg/ml in another. On the thirtieth day, the former and the latter decreased to 0.5μg/ml and 0.8μg/ml, respectively. Both symptoms of yellow-tinged skin and enlarged goiter improved with the decrease in these concentrations. These recoveries seemed to be influenced by the withdrawal of seaweed from their diets, and also due to an improvement in the hypothyroidism which had been caused by nutritional problems.

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Resolution of the problems appearing in the clinical departments with relation to drug utility is a very important task for hospital pharmacists. The chief nurse of the surgery section recently asked us to examine the crystal material often appearing in the continuous infusion line of Dormicum^®-Stadol^® (2: 1) several hours after infusion of other medicines. The crystals were examined by high performance liquid chromatography. The retention time of the crystals was the same as that of midazolam, and the crystals were identified to be midazolam. The main cause of the formation of crystals was found to be the rise in the pH of midazolam injection due to the mixing with butorphanol injection. Moreover, the changes in ion strength and ion components in the solution affected the appearance of the crystals. Thus, midazolam should not be infused with butorphanol. If a mixture of midazolam and other medicines must be infused continuously, medical workers should check for the appearance of the crystals.

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For the prevention or treatment of stomatitis caused by anticancer agents, allopurinol gargle has been used at Gifu University Hospital. The allopurinol gargle has been prepared by dispersing powdered allopurinol tablets and sodium carboxymethylcellulose into water for injection. As the result of examination of microbial contamination of the allopurinol gargle administered to a patient, Acinetobacter calcoaceticus var. anitratus, Burkholderia pickettii or Candida albicans were isolated. Benzoic acid (BA), sodium dehydroacetate (DA) and ethyl-p-hydroxybenzoate (EP) were used as preservatives for allopurinol gargle. Allopurinol gargles containing 0.05% of BA, 0.1 % of BA, 0.05% of DA, 0.1 % of DA or 0.05% of EP were prepared and antimicrobial activities against strains isolated from allopurinol gargles and those from clinical specimens were assessed based on the criteria for topical preparations in British Pharmacopoeia. Among the alloprinol gargles prepared, only alloprinol gargle containing 0.1% of BA had antimicrobial activity against all strains at storage conditions of 25°C and 37°C. The alloprinol gargle containing 0.1 % of BA did not demonstrate sufficient antimicrobial activity at 4°C. The BA added to allopurinol gargles had no influence on either the stability of allopurinol or on the inhibition of xanthine oxidase by allopurinol. No growth of organisms appeared in the remaining allopurinol gargle containing 0.1 % of BA used by the patient.
These findings suggest that the addition of BA at the concentration of 0.1 % is suitable for allopurinol gargle.

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19970825The plasma concentration of fleroxacin (FLRX) was significantly lower (P<0.05) than the control at 0.5 and 1 hour but was significantly (P<0.05) higher at 4, 8, 12 and 24 hurs after the simultaneous oral administration of FLRX with sodium valproate (VPA). The pharmacokinetic parameters, the volume of distribution (Vd) and the area under the plasma concentration-time curve from 0 to 24 hours (AUC_0→24) were 1.2-and 2.3-times higher, while the elimination half-life (T1/2) and time to maximum plasma concentration (T_max), were delayed by 2.9-and 2.6-times after the simultaneous administration with VPA and all changes were significant (P<0.05). In addition, the absorption rate constant (Ka) and clearanse (CL) were, in contrast, 0.5 and 0.5 times lower than the control, and the difference was also significant (P<0.05). The unbound flaction (%) of FLRX in the plasma increased 54 to 80% at 2 minutes and to 76% at 15 minutes after the intravenous administration of VPA. On the other hand, the total levels of FLRX decreased by 31.9 and 27.7% at 2 and 15 minutes after the intravenous administration of VPA, respectively. The urinary concentration of FLRX, demethyl-FLRX and FLRX N-oxide decreased by 50, 40 and 50%, respectively, at 8 hours after the intravenous administration of VPA. These results that VPA may decrease the protein binding and inhibit the metabolic rate of FLRX simultaneously, when they are administered concurrently.

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For the accurate recognition and use of prescribed drugs by patients, we developed a system that provides patients with printed drug envelope labels showing a color photo and explanation of each drug based on the physician's instructions.
Based on a questionnaire survey in 116 patients, 929 detailed explanations were thus producedconcerning the items that most patients strongly hope to know such as the drug efficacy, side effects, and interaction. All documents were reviewed by the physicians at our hospital and revised according to their suggestions and requests.
Patient's reactions to this system were examined before the introduction of this system. Satisfactory results were obtained in terms of explanations that are easy to understand and this system also was found to help reduce the incidence of patients taking an incorrect dosage.

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Medication program should be designed by giving careful consideration to the QOL of each patient individually. We would like to report a case that showed marked improvement in the QOL, in which patient counseling played an important role.
A 30-year-old male patient with acquired immunodeficiency syndrome was started on treatment with pentamidine/ganciclovir at admission. Either the daily injection (5 mg/kg daily) or 5 time injections weekly (6 mg/kg daily) is known as the standard prescription regimen of ganciclovir maintenance therapy for ambulant patients. However, with such a drug regimen the QOL of such patients becomes quite restricted due to the need to visit the hospital. In such cases the patient strongly desires to need to visit the hospital in order to maintain his normal social activities. To reduce the number of hospital visits, we discussed possible modifications in the protocol together with the patient. After being convinced that the patient fully understood the therapy regimen, we proposed a prescription on 12 mg/kg daily, and he only had to visit the hospital 2 days a week. For reducing the injection times, the most important points are the correspondence of the new prescription, the patient's understanding of the therapy, and patient compliance. We therefore explained the importance of the therapy involving the pharmacology, effectiveness, dosage, pharmacokinetics, and adverse effects of ganciclovir. After the patient understood our explanation, a prescription, consisting of twice/week injections, was tried. The effectiveness of the therapy seemed to be equivalent to that of frequent hospital attendance. The reduction in the required hospital attendance improved the QOL of the patient markedly. This case demonstrates the importance of patient counseling in order to achieve an optimal outcome and improve the patient's QOL.

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The rational use of medications has been a serious social problem since the Sorivudine accident occurred. One of the reasons why the use of medications is not always correct is that the presentation of medical information is sometimes insufficient.
We performed another questionnaire survey mainly for outpatients at other hospitals to obtain the status of drug consultation. According to the survey at other hospitals (80 hospitals surveyed, 59 responded, rate of retrieval 73%), drug consultation to outpatients is done at 29/59 (49%) hospitals, and thus only half of all hospitals provide drug consultation to inpatients.
We performed a questionnaire survey for outpatients at the University of Tokyo Hospital to find out the type of information and communication method requested by patients. In the study at the University of Tokyo Hospital, the patients wanted information regarding drug effects, adverse reactions, and directions for use. Furthermore, an explanation with pictures or samples of the tablets was also desired.
These studies suggested that it is necessary to illustrate serious drug adverse reactions and interactions with pictures or samples using lay terms, and in addition, such consultations should be individualized for each patient.

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We interviewed 539 patients (268 males, 271 females) treated with angiotensin converting enzyme (ACE) inhibitors to survey the incidence of dry cough caused by ACE inhibitors. In addition, we identified the latent patients with dry cough induced by ACE inhibitors and surveyed the incidence of discontinuance or change in the ACE inhibitors after the interview.
The incidence of dry cough induced by the ACE inhibitors was 18.9%, and a serious dry cough was found in 4.9%. After the interview, the incidence of discontinuance or change in the ACE inhibitor administration was 20.6% in all patients with dry cough, 68.0% in the patients with a serious dry cough and 5.2% in the patients with a slight dry cough. All patients who either discontinued or changed the ACE inhibitors soon stopped soffering from dry cough. These results indicate that dry cough caused by the ACE inhibitors may be a clinically severe problem. Moreover, the detection and suitable treatment of latent patients with dry cough induced by ACE inhibitors is also important in order to perform proper drug therapy.

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