Cilostazol is an antithrombotic drug expected to be useful in the treatment of chronic arterial occlusive diseases. Cilostazol is a potent inhibitor of human platelet aggregation and selectively inhibits human platelet cyclic adenosine monophosphate phosphodiesterase type III. In this paper, we describe a pharmacokinetic-pharmacodynamic model for ascertaining the antiplatelet effect of cilostazol considering the reversible inhibition of phosphodiesterase in the platelet. All data used for analysis were obtained from the literature. The estimation of average inhibition of phosphodiesterase was 59.7% following an oral administration with usual dose. A significant linear relationship between the calculated inhibitory effects on phosphodiesterase and on collagen-induced platelet aggregation was obtained (p< 0.05). Based on this finding, a new method was developed. for predicting inhibitory effects on the collagen-induced platelet aggregation following oral administration of cilostazol. This method is useful for planning a rational dosage regimen of cilostazol and for predicting the duration of antiplatelet activity after discontinuance of the drug.

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During 1996, 1188 patients with acute drug poisoning were admitted to 59 critical care departments in Japan. The patients were predominantly female (68.4%) and relatively young (69.2%, under the age of 40). Further analysis of the 1188 patients indicated that the majority (77.9%) were admitted as a result of deliberate self-poisoning, while 15.1 % of the cases were admitted due to accidental poisoning (unknown cause 7%). A total of 2517 drugs was taken by these patients. The most common group of drugs involved were benzodiazepines (32.1 %), followed by neuroleptics (12.2%), antidepressants (10.2%), analgesics (9.1%), antihistamines (7.3%) and barbiturates (6.2%).
An important difference observed in the pattern of acute drug poisoning, when compared with that in other countries, was the preferential use of bromvalerylurea by young individuals for deliberate self-poisoning. This drug has not been used in any other country recently.
There were twelve cases of fatal drug poisoning in the 59 critical care departments during 1996, including nine women. Four patients had taken barbiturates and six patients had taken a combination of benzodiazepines. In order to treat patients with acute drug poisoning, it is important to provide physicians with essential information on the incidence, mechanism of poisoning, and metabolism of the drug involved. In the case of rare drug poisoning, however, as it would take consideiable time for any one critical care department alone to amass enough admissions for generating a reliable information databese regarding management and prognosis, we therefore believe that a national approach is required to address the issue of management of patients with acute drug poisoning.

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One of the important therapeutic indices in acute drug poisoning is the prediction of the drug's pharmacokinetic parameters. At present, there are many data available concerning therapeutic drugs and it is possible to search data banks for the pharmacokinetic parameters of these drugs. However, there are few data available on the drugs concerning the pharmacokinetic parameters in acute drug poisoning which occurs when drugs are ingested in extremely large doses. Therefore, to establish an appropriate treatment for acute drug poisoning, the concentrations of benzodiazepines (BZDs) in the sera of patients with acute BZD (triazolam, nitrazepam) poisoning were measured at intervals and the elimination rate constants were estimated. Comparisons of the BZDs concentrations measured and those predicted were made. To assess the elimination rate of BZDs when patients were subjected to hemoperfusion in the management of acute BZD poisoning, the concentrations of BZDs in the sera of patients were measured before and after they underwent direct hemoperfusion. To determine promptly BZDs in serum, a fluorescence polarization immunoassay (FPIA) using a TDx analyzer system (Abbott) was performed and each sample was reexamined and identified by high-performance liquid chromatography (HPLC).
Prediction of pharmacokinetic parameters following the rapid determination of drug in the sera of patients with acute drug poisoning is helpful for confirming a clinical diagnosis and selecting an appropriate treatment. this is because the elimination half-life of the drug in a patient who has ingested extremely high doses is not the same as that after ingestion of a therapeutic dose of the drug.

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The mixed-type diclofenac sodium suppository consistsng of two kinds of hard fat (Witepsol W 35, Witepsol E 85) was prepared. The area under the drug release curve (ADT) increased and mean release time (MDT) decreased with the increase in the mixing ratio of Witepsol W35. When the drug release was examined at 36°C, the amount of drug released from the marketing suppository was only 9% of the mixed-type suppository which consisted of 50% Witepsol W35.
A strength, surface morphology, thermal analysis parameters and penetration of methylene blue were measured as characteristics of mixed suppositories. The methylene blue penetrating ratio was measured by image analysis using a scanner and computer after the suppository was put into the methylene blue solution at 36°C. The fusion peak temperature and methylene blue penetrating ratio were strongly correlated with ADT and MDT values, while the strength and heat of fusion did not correlate well with these values. The penetrating ratio increased with the increase in the mixing ratio of Witepsol W35 in the suppository. While the suppository had retained its shape in the test fluid at 36°C, diclofenac sodium was fully released. The mixed-type suppository is therefor thought to be useful for patients with a low body temperature in order to eliminate their chronic pain.

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A sensitive and specific double-antibody enzyme immunoassay (EIA) for a calcitonin generelated peptide-like immunoreactive substance (CGRP-IS) was developed. In competitive reactions, the CGRP-antibody was incubated with CORP standard (or sample) and β-D-galactosidaselabeled synthetic human αCGRP fragment [residue (8-37)](delayed addition). Free and antibody -bound enzyme haptens were separated by using an anti-rabbit IgG coated immunoplate. Activity of the enzyme on the plate was fluorometrically determined. The present immunoassay allows the detection of 2.1 to 19.5 fmol/mL of CORP. Using the proposed EIA, CGRP-ISs in human saliva and plasma were determined.
The levels of CGRP-IS in human saliva were about 3.2 fmol/mL, which were much higher than that in human plasma.

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Administration of H2-brocker with “multi-vitamin” (mixed vitamin preparations for IVH) as constituents of the IVH admixture is important for the patient developing anastomatic ulcer following surgical operation.
Time courses of each consistuent concentration, such as that of famotidine as H₂-blocker and various vitamins, were assayed using HPLC (high performance liquid chromatography). The data were evaluated by means of Weibull plot method. As a results, famotidine was found not stable in both heated acidic and basic solutions, but is stable in neutral solution. In case of the IVH admixture, V.B₁ is regarded as a key vitamin of stability of solution, and light-protection was not effective in V.B₁ stability. No distinctive interaction was noted between famotidine and vitamins. The kinetic rate in the degradation process of vitamins and famotidine were evaluated using the Weibull-plot method under the conditions of controlled room temperature, use no protective film, and refrigeration. Thefitting precision of the Weibull-function is more accurate than thefirstorder and zero-order decay function, and which is more applicable as a stability nomogram.

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KREMEZIN^® (KR) is an oral adsorbent of spherical carbon, administered to patients with chronic renal failure to prolong the time between hemodialysis through adsorbing uremic toxins in the digestive tract. However, KR has been considered to adsorb not only uremic toxins but also other relative medicines. Therefore, it seems that administration of KR concomitantly with other medicines should be avoided, its influence has not been studied in detail yet. We studied the interaction of KR and aspirin (ASA) as model medicines, in vitro and in five healthy volunteers.
In vitro, the interaction of KR and ASA was studied in 1 St and 2 nd JP XIII solution at 37°C, and the concentration of ASA was decreased after 6 hours in the solutions. Healthy volunteers were administered ASA (810 mg) alone or ASA with KR (2 g) at the same time or 1 hour later, and we continuously monitored the serum concentration of salicylates, the metabolites of ASA. The simultaneous administration with KR was found to significantly lower the C_max and AUC compared with ASA alone or 1 hour later.
These findings suggested that KR adsorbs ASA in the digestive tract when administered simultaneously and thus that KR should be administered 1 hour or more after ASA.

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Final filters have not been always used for injections in the pediatric ward of our hospital. Since thore has been no report on the particulate matters of five dissolved antibiotics in vial, we measured those amounts using a particle counter. The amounts of particulate matters in the solutions of cefpirome sulfate, flomoxef sodium and panipenem/betamipron were below the limits defined by the Japanese Pharmacopoeial Forum (1996) or United States Pharmacopoeia (USP XXIII). However, particles above 10μm in imipenem/cilastatin sodium and vancomycin hydrochloride immediately after dissolution were about 70% of the limit. Scanning electron micrographs of the filter membrane surface showed the existence of insoluble particulate contaminants in those injections. Final filters are recommended for these antibiotic injections to be used safely in pediatric patients.

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A computer system was developed to improve the preparation procedures of intravenous hyperalimentation (IVH) for patients with such affections as acute renal failure and short-bowel syndrome, and its utility was evaluated with the novel indices: compatibility of prescription (C), ease of IVH preparation (E), design time of prescription (t), and objective index (C*E/t). The computer system was developed using the d-Base III programming software. The mixing volume of elemental solutions were either calculated with this computer system or hand calculated depending on the kind of IVH prescription. The mixing volumes of each component could be easily and quickly determined and the prescriptions satisfactorily prepared. While in the novel indices, the compatibility and ease of preparation were slightly improved, the design time was markedly shortened and the objective index was markedly improved using the computer system compared with the hand calculation. When this program was used to educate new pharmacists, the key points of IVH preparations were more rapidly understood. These results indicate that our computer system was very useful to the preparation of specific IVH prescriptions for severe patients, was also very effective in the education of IVH preparations to new pharmacists, and that the novel indices were more useful in evaluating the IVH preparation procedures.

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A bitter stomachic powder, named NGD powder, has been prepared at our hospital. However, a questionnaire survey conducted by the Japanese Society of Hospitai Pharmacists reveals that elderly patients complain of difficulty in taking this formula because of its bitter taste and dustiness. Therefore, we attempted to reformulatier this NGD powder in tablet form and to study the pharmaceutical properties of the subsequently produced NGD tablets. Microcrystalline cellulose (MCC) was added in amounts of 20%, 30% and 40% to its amount of NGD powder, and compressed using a compression force of 0.5, 1.0, 1.5 or 2.0 ton/cm² These tablets were then examined for their crushing strength, friability, disintegration time, neutralizing capacity and amylosaccharifying activity. Moment analysis was carried out especially for the neutralizing capacity of the tablets. Optimum regression equations were obtained using multiple regression analysis for each of the characteristics. The results suggest that the optimum amount of MCC and compression force are 30% and 1.0 ton/cm², respectively.

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Prescription order entry systems began to be introduced into university hospitals a decade ago. Compared to the handwritten prescription system, the computerized system offers a lot of advantages and possibilities. Some issues are arguable. We conducted research similar to this report two years ago. Since then, however, several institutions have introduced a prescription order entry system and/or added new functions to their systems.Therefore, we again carried out our survey concerning prescription order entry system used in university hospitals and analyzed the present status of the systems and its evaluation by physicians. We compared the results with those obtained from our previous survey. In most institutions where a prescription order entry system is being used, more than 80% of doctors answered that the “Do prescription function” and the “I nput check on entry” were useful. Evaluation of the other functions by doctors showed a tendency to be low, though institutions which provided these functions were too few to drow make a significant conclusion. It was proved that introduction of a prescription order entry system contributed to making prescription order entry more efficient because it was able to save labor necessary to writing prescriptions and to having to write it again on a chart, avoid the duplication of prescriptions among different departments, and diminish clarification calls from the pharmacy.
We found that doctors using prescription order entry systems give them high ratings but were dissatisfied with their processing speed. It was suggested that comparison and examination be made of models of machines and versions of systems used by the respective institutions.

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The intranasal preparation of glucagon has been used instead of injections in patients with pancreotectomy or hypoglycemia to improve the metabolism of lipids and amino acids and maintain liver function. However, only a few reports were appeared on the evaluation of the quality of the intranasal preparation of glucagon. Therefore, we examined the stability of glucagon in the intranasal preparation and its absorption into a patient with pancreotectomy. Glucagon in the preparation and in the patient's serum were respectively determined by ion-pair high-performance liquid chromatography and with reversed phase column and radioimmunoassay. Two surfactants, sodium glycocholate and sodium caprate, were used as the absorption promoters of glucagon.
The residual contents of glucagon in the intranasal preparations with sodium glycocholate and sodium caprate were 93.9±2.5% and 79.8±2.4%, respectively, 7 days after their preparation. Sodium caprate was more effective than sodium glycocholate in the enhancement of glucagon absorption; the AUC_0-30min values were respectively 77.8 and 48.2 ng·h/L. Also considering the less irritating character of the preparation added sodium caprate, we selected this preparation in our hospital on the condition that it is renewed every week.

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The compatibility of irinotecan hydrochloride injection (Topotecin^® injection) was studied on changes in external appearance, pH and contents of both irinotecan and admixed drugs following mixing with 24 kinds of other injections. Admixtures of irinotecan hydrochloride injection with each of the 24 kinds demonstrated neither a change in external appearance nor a change in pH over a 24 h period under the study conditions except for a slight change in pH in the admixtures of ATP for inj.(DAIICHI) ^® or INOSIE^®. In the case of the admixture with ATP inj.(DAIICHI) ^®, MEYLON^®, INOSIE^®, NUTRASE for inj.(KYORIN) ^® or Stronger Neo-Minophagen C^®, the contents of irinotecan hydrochloride fell to 90% with in 3 h after mixing. In addition, after mixing URONASE ^® 60, 000 U or LEUCON^® INJECTION, their contents fell to 90% in 3 to 6 h.
The concentrations of closed lactone of irinotecan hydrochloride increased periodically and returned to the former state in 3 h when the alkaline solutions after mixing irinotecan hydrochloride injection with each ATP inj. (DAIICHI) ^®, MEYLON ^® and INOSIE ^® were converted to pH 4.0. It has been established that the compatibility of irinotecan hydrochloride injection depends on the delactonization reaction of the drug.
This study suggests that admixing of irinotecan with high pH hydrochloride injection and with other injections of high pH value must be done very carefully. A possible drop in the contents of irinotecan would be predictable by checking pH described in the package inserts and by considering the buffering capacity of the admixed injections.

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To elucidate the current status of the dosage regimen of digoxin (DX), we reviewed its therapeutic drug monitoring (TDM) data obtained from 50 patients on whom TDM was performed for the first time following the beginning of DX treatment. The serum trough level of DX in 50% the subjects deviated from its therapeutic range (0.5-1.5 ng/ml) because the uniform dosage (0.125-0.148 mg/day) was administered for the patients with various degrees of renal functicns. The serum levels of DX in about 70% of the patients with normal renal function (80 ml/min≤ creatinine clearance. CLcr) were less than its lower limit (0.5 ng/ml), and those in about 70% of patients with severe abnormal renal function (CLcr<40 ml/min) exceeded its upper limit (1.5 ng /ml).
To design a simple index for the dosage regimen of DX whith closely corresponded to the renal functions in patients, 286 samples of TDM data obtained from 87 patients who were not coadministered drugs known to alter DX pharmacokinetics were reviewed by dividing then into three groups according to the CLcr values. The mean serum DX levels (0.7-1.2 ng/ml) in each group could be kept at their therapeutic range, as the dosages were respectively 0.25 mg/day (80 ≤CLcr group), 0.125-0.25 mg/day (40≤CLcr<80 group), or 0.0625-0.125 mg/day (CLcr< 40 group).
These results indicate that the minimum dosages of DX in each reual function group, which were expected to maintain its effective serum level (0.7 ng/ml) within the lower limit of the therapeutic range, are desirable from a safety, that is, the optimal dosages of DX as an indication in the early dosing stage are respectively 0.25 mg/day for patients with normal renal function (80≤CLcr), 0.125 mg/day for patients with moderate abnormal renal function (40≤CLcr< 80), and 0.0625 mg/day for patients with severe abnormal renal functicn (CLcr<40).

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We have started to offer drug information to patients with a focus on the initial signs of severe adverse effects. We classified the adverse effects into groups according to the regions of occurrence and edited the initial signs of each group into a compact form to ensure that only the minimum essential information was given out.

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