Adverse reactions induced by cibenzoline at this hospital showed the trough value of cibenzoline at the time to be above 400ng/mL. In these cases, by adjusting the trough values to 150-230ng/mL and also by reducing the cibenzoline dosage, the effects of cibenzoline could thus be maintained while adverse reactions were avoided. Therefore, the relationship between the trough value based on cibenzoline dosage and the creatinine clearance in 19 cases who took cibenzoline was examined. In order to adjust trough level to 150-250ng/mL as the goal concentration based on the relation formula, the recommended dosage of cibenzoline and the creatinine clearance were calculated. The utility of an initial dosage setting according to the combination a recommended dosage of cibenzoline and the creatinine clearance nomogram reported by Nielsen et al. was examined in 9 cases.
As a result, using this nomogram, the percentage of the goal concentration thus significantly increased, while the percentage of hypoglycemia significantly decreased. Accordingly, the nomogram of cibenzoline prepared in our hospital was thus concluded to be clinically acceptable.

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The aim of the present study was to prepare a heat-sensitive melting gel using κ-carrageenan and gelatin as the gelation agents. The two agents have similar melting points (40-50°C for κ-carrageenan and 20-30°C for gelatin). When mixed together, they have a coexisting grid structure, which is favorable for the preparation of a gel with a melting temperature close to the human body temperature. Gel preparation showed a clearly different melting behavior from that of many other compounds and began to soften significantly below its melting temperature.κ-carrageenan at 0.5% may thus be the preferred concentration because preparations having a melting temperature just below the human body temperature are easy to chew, with a rapidly decreasing viscosity. We studied the plasma concentrations of acetaminophen as a function of time after the oral administration of a bulk powder or gel preparation of acetaminophen to rabbits after overnight fasting. A comparison of the AUC for both oral and intravenous administration indicated the bioavailability of acetaminophen gel to be about 90%. The heat-sensitive acetaminophen melting gel prepared using κ-carrageenan and gelatin thus shows promise for clinical use because of its favorable physicochemical and pharmaceutical characteristics.

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Sodium Valproate (VPA-Na) syrup is used in the management of patients following brain surgery for conditions such as traumatic injury or arteriovenous malformation. In our hospital, 65% of post-neurosurgical patients administered VPA-Na syrup were also given enteral nutrition (EN) and/or antacids (AA). We therefore investigated possible drug interactions between VPANa syrup and EN or AA. In a random crossover study, 250 mL of Ensure Liquid^® (EN), 20mL of Maalox^® (AA) or 50 mL of Purified water were administered to nine normal subjects mixed with 12mL Depakene^® (VPA-Na) syrup. Following administration, the serum concentration of valproic acid was then repeatedly measured over the next 48 hours using the FPIA method. Data were analyzed by non-parametric analysis and by population pharmacokinetic analysis using the NONMEM system. The results showed that the coadministration of Ensure and Maalox delayed the rate, but not the extent of bioavailability of VPA-Na syrup.

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Cilostazol is being developed for the treatment of intermittent claudication due to peripheral arterial disease (PAD). In this study, we measured the serum cilostazol concentrations and platelet aggregations induced by adenosine diphosphate (ADP) and collagen, and also investigated the pharmacokinetics and pharmacodynamics of cilostazol in inpatients receiving cilostazol therapy. No significant difference was observed in C/D (serum trough concentration/dose) between males and females. A trend toward increasing the serum cilostazol concentration by increasing the dose (mg/kg) was observed (P<0.05). The interindividual variation of the C/D for cilostazol was found to be very large. No significant difference was observed between the C/D for cilostazol and the age, GPT or Ccr. A statistical correlation was observed between the serum cilostazol concentration and the maximum extent of aggregation (%) induced by ADP and collagen (P<0.05).

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The adsorption of marketed elcatonin (3 preparations) and salmon calcitonin (2 preparations) was examined. Each aqueous preparation in an ample was drawn into plastic syringes and then was stored still for 0, 1, 3, 5, 10, 30 or 60 min. The preparation was thereafter squeezed out of the syringe, and the remaining rate of elcatonin or salmon calcitonin in the solution was measured.
In every elcatonin preparation, the remaining rate just after suction into the syringe was about 90%, and thereafter, the amount markedly decreased with time showing a rate of about 50% after 30 min. On the other hand, two salmon calcitoin preparations did not show any clear difference in these ratea. Namely, preparations containing gelatin as an ingredient showed a remaining rate of about 90% after up to 60 min of storage, and only a slight decrease was observed.
In other preparations, the remaining rate at the point of suction into the syringe was about 90 %, but the rate thereafter decreased markedly to 50-60% affer 10 min.
When administering elcatonin and salmon calcitonin preparations, sufficient attention should thus be paid to such adsorption in syringes.
However, for elcatonin and salmon calcitonin preparations in syringes which do not require suctioning into the syringes, we found that the appropriate dose could be reliably administered.

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Noncompliance with drug therapy was suspected based on the results of therapeutic drug monitoring (TDM) in two 3-and 4-year-old children with epilepsy. An analysis of the data for both children showed the serum concentration of the antiepileptic drugs estimated from individual parameters to deviate remarkably from those established based on population parameters, and that the difference between these values varied after each measurement.
After a careful evaluation of patient compliance according to the results of TDM, it was revealed the dosage due to the fact that mother had not realized her inaccurate dosage while another mother admitted that she had reduced the dosage due to the fact that her child refused to take the drug. The time needed to correct the noncompliance after its discovery using TDM was 3 months in the case of inaccurate dosage, and 12 months in the case where the child had refused to take the drug, by means of compliance education and training given to the mothers once -a-month at the outpatient clinic.

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The effects of the medicative consultations and counseling to eight outpatients with familial hypercholestrolemia on colestyramine medications mainly by pharmacists were investigated. Eight outpatients had showed a frequent noncompliance for colestylamine but also other therapeutic drugs would be considered. In this study, a questionnaire survey on the patient's view regarding colestyramine resulted in the conclusion that large doses in suspension were difficult to swallow. In addition, some of the patients did not have sufficient knowledge of their own diseases. These above reasons were considered to be the main causes for noncompliance.
Trial of the medicative consultations and counseling were thus performed with both patients and pharmacists regarding colestyramine dosing and dieteric problems. These trials were thus found to improve medication compliance and the patient's understanding of their own diseases. Furthermore, the mean values of total cholesterol (T-Chol) and low density lipoprotein-cholesterol (LDL-Chol) concentrations in the eight patients all significantly decreased after the medicative consultations and counseling compared to the period before starting the therapy (p<0.01) and these trials (p<0.05), respectively. In addition, decreases in the percentages of T-Chol and LDL-Chol per month after medicative consultations and counseling increased to about 2.5 times based on the values before medicative consultations and counseling and the difference was significant (p<0.01 in T-Chol, p<0.05 in LDL-Chol).
These results suggested that the medicative consultations and counseling with pharmacists and patients were found to improve pharmaceutical compliance in patients with familial hypercholesterolemia.

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Aminopyridine (4-AP) capsules were prepared as a hospital preparation and clinically administered to patients with multiple screlosis (MS) after obtaining the approval of the ethical committee of our university and the informed consent of the patients. 4-AP in the trituration was extracted with methanol and quantified at 262 nm using absorption spectroscopy. 4-AP triruration was used to fill the capsules using a Semi Automatic Capsule Filling Machine. Quality tests of the preparation, weight variation tests and content uniformity tests, were then performed according to the Japanese Pharmacopoeia XIII. At first, trituration was prepared from well-ground 4-AP crystal. However, the capsules prepared from this trituration were unsuitable for the quality tests. Accordingly, 4-AP was dissolved in a small amount of water and pigment. After lactose or corn starch was gradually added as a diluent, the triturations were then dried at 60°C. The residual percentage of 4-AP in lactose heated for 4 hours was 54.1% and was lower than that in starch, 69.5%. But the percentage improved to 99.4% after drying the trituration at room temperature for 24 hours in a desiccator. The capsules prepared with this trituration were suited for the tests (5 mg of 4-AP per one capsule). Moreover, the residual 4-AP percentage in these capsules after 6 weeks was 98.0%. These 4-AP capsules were given to the patients (3-9 capsules/day p.o. in 3 divined doses). Though 4-AP itself irritates the mucous membrance, no mouth and/or esophageal irritation was observed using these capsules. The patients' quality of life all improved because both muscle weakness and impaired vision were relieved by this treatment. 4-AP capsules are thus considered to be another valuable medicative option for MS.

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The relationship between the serum trough concentrations of cibenzoline and the fasting blood glucose (FBG) levels were evaluated in 78 inpatients received cibenzoline therapy. As a result, as the serum trough concentrations of cibenzoline increased, the FBG levels decreased in inverse proportion. The FBG levels after the administration of cibenzoline decreased significantly (P<0.01) more than before administration. In addition, when the serum cibenzoline concentrations were higher the FBG levels also decreased significantly (P<0.01) more than when the serum concentrations were lower. The mean serum concentration when the FBG levels were less than 80mg/dL was higher than that when the FBG levels were lover 90mg/dL (383±273 vs 284±189ng/mL, P<0.071). These results suggest that more careful monitoring of the side effects of cibenzoline caused by a decrease in the FBG is thus needed in patients receiving cibenzoline therapy.

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Inhibitors of angiotensin convering enzyme (ACE) are widely used for the treatment of hypertension and cardiac insufficiency. However, such patients demonstrate a wide range diseases and conditions, and hence appropriate ACE inhibitors must be selected depending upon the condition of each individual patient. In the present study, we prepared model rats for various circulatory disorders and investigated which medicine should be used for various disorders based on pharmacokinetic investigations of the ACE inhibitor drug excreted in the bile and from the kidney (temocapril hydrochloride, Acecol^®) and another ACE inhibitor excreted from the kidney (lisinopril, Longes^®) using the models. In the temocapril dosed groups, the elimination rate constant (Ke, 1/hr) was 1.03 for the hepatic disorder model group and 0.15 for the cholestatic model group, and both were significantly smaller than the 1.58 rate constant for the control group. Although no significant difference was noted, the renal disorder model group showed a slightly decreased Ke value of 1.27 compared with the control group. In the lisinopril dosed groups, the half-life was long, and no intergroup difference was observed in the pharmacokinetic parameters until 6 hr after administration. The results of the present study suggest that the use of temocapril is safer when renal disorders occur while the use of lisinopril is safer for hepatic disordes. In order to minimize the development of adverse reactions and to obtain the desired clinical efficacy, it is necessary to select drugs only after sufficiently analyzing the condition of each illness and taking into account the characteristic properties of the individual drugs.

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The chemical stability of morphine hydrochloride in a total parenteral nutrient solution wasevaluated using a HPLC-ultraviolet detection system. This method is sensitive enough to measure morphine hydrochloride at concentrations as low as 0.2 nmol and produces highly reproducible results and requires 5.5 min per sample for separation and quantitation. Solutions of morphine hydrochloride in a total parenteral nutrient solution are chemically stable for 1 month when stored at 4°C and room temperature (20°C) with protection and no protection from environmental light. No loss of morphine hydrochloride due to adsorption in the polyethylene chloride (PEC) bags was found.

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The dominant factor of iron-induced gastromucous injury and how to prevent it are herein discussed.The iron content from an iron tablet dissolved into J. P. 1 solution, J. P. 2 solution and sterilepurified water was compared among three kinds of different iron products. As a result, ironslowly dissolved in J. P. 1 solution and sterile purified water or slightly dissolved in J. P. 2 solutionin FERO-GRADUMET^®. Iron rapidly dissolved in J. P. 1 solution and then slowly dissolved in J. P. 2 solution or sterile purified water in Ferromia^®. Iron rapidly dissolved in J. P. 1 solution, but did not dissolve in J.P.2 solution or sterile purified water in Ferrum Capsules^®. The iron which dissolved in each solution was thus shown to be affected by pH or anion ions in the solution and great differences were seen among the three different iron products. In addition, the oxidation rate of linoleic acid by iron compounds was measured in each solution and the effect of antiulceratives toward it was evaluated. As a result, the oxidation rate of linoleic acid by iron compounds increased in J. P. 1 solution independently of the formation of iron compounds, thus indicating that gastromucous injury would be accelerated in acidic conditions. The oxidation rate of linoleic acid by iron compounds decreased by Rebamipid and Plaunotol as antiulceratives, thus suggesting that these antiulceratives could prevent iron-induced gastromucous injury. The oxidation rate of linoleic acid by iron compounds also decreased after the administration of α-Toc, but increased after the addition of ascorbic acid, thus suggesting that α-Toc as an antioxidative reagent possibly prevents iron-induced gastromucous injury, whereas ascorbic acid, which is a reductive reagent instead exacerbates it.

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To reduce the time and cost needed to make hospital preparations, an automatic dispensing device to prepare disinfectants was developed. We prepared 200 bottles of disinfectant (500 mL) containing 7% ethanol and 0.1% benzalkonium chloride with an automatic device and 200 bottles using the manual process, and then randomly selected preparations were evaluated concerning variations in drug concentrations, stability for long periods and preparation cost. The variations in the drug concentrations in the preparations made with the device were narrower than those observed when using with the manual process. Although the volume of the preparations with the device was less than that when using the manual process, the variation range in the volume in both preparations was similar. Both preparations were stable for 4.5 months at room temperature. The preparation time and cost using the device was about half of that when using the manual process. These results indicate that our automatic dispensing device was found to be very useful in preparing disinfectants.

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The purpose of this report is to clarify the relationship between the dosage of furosemide and the occurrence of hyperuricemia. 59 patients with heart failure who were treated with furosemide were analyzed retrospectively. We defined hyperuricemia to be more than 7.0mg/dL in males and 5.5mg/dL in females. Any patients with renal failure, gout, diabetes mellitus and an abnormal purine-metabolism were excluded from this investigation.
The frequency of hyperuricemia was 78.0% in the 59 patients receiving furosemide. The incidence of hyperuricemia due to furosemide medication was as follows: 80% in the 20mg treated group (n=10); 81.5% in the 40mg treated group (n=27); 100% in the 60mg treated group (n=2); and 100% in the 80mg treated group (n=14). Furthermore, in the groups receiving 20 mg, 40mg and 80mg of furosemide, the average doses of allopurinol (urate synthesis inhibitor) were 50.0±16.7mg (mean±SE, n=10), 88.5±15.0mg (mean±SE, n=26) and 130.2±26.0mg (mean±SE, n=10), respectively. These results indirectly suggest that the increases in the amount of furosemide correlated with the serum urate level.
In conclusion, to avoid hyperuricemia, the serum urate levels should be carefully checked in patients treated with furosemide.

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The hygroscopicity of the contents of clorazepate dipotassium (Mendon^®) capsule (CM) divided in packages made of polyethylene laminated glassine was investigated by storing the capsules at various relative humidities (RHs). The CM capsules were found to significantly absorb water vapor at an RH of more than 61.5%. The hygroscopicity of CM decreased after placing the CM capsules into air-tight containers, e. g., polyethylene laminated glassine. At the same time, a marked discoloration of CM was also observed during storage, in which the color changed from white to yellow. The discoloration of the CM capsules accelerated at high RH levels and after expose to fluorescent light. As a result, when Mendon^® capsules must be prepared in a powdered dosage form, CM should be stored below an RH of 31.3% and be protected from light to avoid any adsorption of water vapor and/or discoloration.

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Objectives: Teicoplanin is an antibiotic complex consisting of five closely related components of similar polarity designated A2-1, 2, 3, 4 and 5 and a more polar factor A 3. The variations in the constitution ratio of the six major components were measured to evaluate the validation of teicoplanin preparations.
Methods: The concentrations of each component of teicoplanin were measured in 14 lots by high performance liquid chromatography.
Results: No significant differences were observed regarding the variation in the constitution ratio between the A 2 and A 3 groups. However, significant differences were found in the A 2-1 component.
Conclusions: Variations of the constitution ratio in Teicoplanin preparations may possibly affect the pharmacokinetics of teicoplanin. More care is thus called for during the manufacturing process.

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