To obtain an adequate immunosuppressive effect of mycophenolate mofetil (MMF), various equations have been used for estimating the area under the concentration curve (AUC) for mycophenolic acid (MPA) under a limited sampling strategy. Most of them, however, involved cyclosporine (CYA) -based immunosuppression. In this study, we measured chronological blood concentrations of MPA when included in tacrolimus (TAC, alternative calcineurin inhibitor) -based triple-drug immunosuppression in renal transplant recipients and investigated the effectiveness of a limited sampling strategy which minimized patients' inconvenience. Measurement of MPA concentrations in consecutive samplings over a 24-hour period in 6 renal transplant recipients receiving TAC-based triple-drug immunosuppression therapy (MMF dose : 1250-2000 mg/day, twice a day), showed substantial inter-patient and intra-patient variability in MPA pharmacokinetics. The second MPA peak was observed in 8 concentration profiles. There were no significant differences in Tmax, Tlag, dose-normalized Cmax, pre-dose concentration (C0), and AUC (0-12) (AUC (τ)) between morning and evening dosing. Regarding a relationship between AUC (τ) and the MPA concentrations for each sampling point, despite the substantial variation in MPA pharmacokinetics, a significant correlation was found between C0 and AUC (τ) (r2= 0.734). The highest r2 value was obtained at C8 (r2=0.852). The optimum combination of sampling time points for estimating AUC for MPA using stepwise linear regression was C0, C3, C8 (r2= 0.964) and this combination had the lowest maximum prediction error (22.6%) in the estimation of AUC (τ). From the above findings, we recommend the use of the formula AUC (τ) (μg·h/ mL) = 7.82 +3.58· C0 + 1.87· C3 + 7.15 ·C8 for estimating the AUC for MPA in renal transplant recipients also receiving TAC.
The effects of sucralfate, magnesium oxide and sodium ferrous citrate on the pharmacokinetics of sparfloxacin were studied in 6 healthy subjects. According to a four-way crossover design, each subject received the following drug combinations in a random order : (A) a single 200 mg dose of sparfloxacin alone ; (B) a single 200 mg dose of sparfloxacin with a 900 mg dose of sucralfate ; (C) a single 200 mg dose of sparfloxacin with a 1 g dose of magnesium oxide ; (D) a single 200 mg dose of sparfloxacin with a 100 mg dose of sodium ferrous citrate. The four regimens were given to subjects in the fasting state. Blood samples were collected over a 24- hour period, and plasma concentrations of sparfloxacin were determined by high-performance liquid chromatography. The area under the curve from 0 to 24 hours (AUC0-24) for sparfloxacin for regimen B was significantly lower (52.9% less, p<0.005) than that for regimen A. However, for regimens C and D, the reductions in AUC0-24 as compared with regimen A were not significant (19.4% and 28.2%, respectively). Also, the peak plasma concentrations (Cmax) of sparfloxacin for regimens B and D were significantly lower (54.7 % less, p< 0.001 and 31.4% less, p<0.05, respectively) than that for regimen A. However, the Cmax for regimen C was not significantly lower than that for regimen A (22.1% less). These results suggest that aluminum containing drugs should not be given in combination with sparfloxacin.
We examined the usability of eleven brands of ophthalmic solution available on the market. This involved measuring the squeezing force on ophthalmic solution containers and drop volume using a force gauge. We also examined the usability of the ophthalmic solution containers for our subjects with regard to the ease of squeezing out the contents. The squeezing force on containers differed among products, ranging from 0.7 kg (Tobramycin) to 2.9 kg (Levocabastine hydrochloride). For five products, there was a large change in the squeezing force on the container between the beginning and the end of the usage period, the coefficients of variation of which ranged from 6.9 % to 16%. The drop volume differed among products ranging from 34 mg (Ibudilast, Tropicamide) to 49 mg (Levofloxacin). There were three products with a large change in the drop volume during the usage period, the coefficients of variation of which ranged from 12.2% to 22.2%. Ibudilast had a particularly large change in drop volume during the usage period. The usability test with our subjects showed that usability decreased when the squeezing force for a container was 1.5 kg or more. Our findings showed that it would be effective to use the variation in the squeezing force and drop volume during the usage period as an index when evaluating the usability of ophthalmic solutions.
An inhibitor of melanin synthesis, kojic acid (KA) is prescribed for the treatment of skin diseases such as chloasma in hospitals. To select the optimal formulation for achieving efficacy with KA, the relationship between KA release via a synthetic membrane filter and the permeability and penetration in rat skin were investigated. Further, the coefficient of friction of KA ointments was measured as an index of their spreading on the skin. Hydrophilic, white vaseline and macrogol ointments were prepared for this study. The KA content for all three ointments was 1%. Both studies were conducted with a Franz-type diffusion cell. For the in vitro permeability and penetration study, skin samples were taken from the abdominal region of male SD rats from which the hair had been removed. In the study in which KA release via a filter membrane was measured, the release rate for the hydrophilic and macrogol ointments was greater than for white vaseline. In the rat skin test, the hydrophilic ointment produced the highest KA level. Unexpectedly, the white vaseline ointment demonstrated the next highest penetration rate for KA. We therefore concluded that in addition to KA being directly transferred from the ointment, there may also be penetration of the KA within oily ointment bases. Another finding was that lanolin (added as a solubilizing agent), increased the coefficient of friction of the hydrophilic ointment. Overall, the hydrophilic KA ointment without lanolin was considered to be the best formulation among the ointments we prepared.
Triclofos sodium syrup (Tricloryl® syrup) is mainly used for pretreatment in EEG examinations and sedation before CT and MRI. The unpleasant taste of the syrup, however, occasionally causes compliance problems with children. As we had also experienced difficulties in obtaining sufficient supplies of this medicine for a few months, we prepared a chloral hydrate syrup in our hospital as a substitute for triclofos sodium syrup, aiming to reduce the unpleasant taste and smell of chloral hydrate in the process. Stability and sterility were also investigated. The results of a taste test in healthy volunteers showed that the taste and smell of a 4% chloral hydrate syrup were improved by using an apple flavor, aspartame and a simple syrup base. In our stability and sterility study under the storage condition of 4°C with shading over 6 months, the potency of the syrup was maintained (95 %) and there was no bacterial contamination. These results suggest that the 4% chloral hydrate syrup prepared in our hospital as a substitute for triclofos sodium syrup could improve the compliance of children.
To identify adverse drug effects or other problems associated with medication that patients themselves or their physicians may not be aware of, pharmacists at our institution devised a “Medication Monitoring Report” scheme, by which pharmacists are often able to recognize adverse drug effects or other problems associated with administered drugs through dialogue with patients. This scheme was introduced at our institution in September 1993. Each report includes information on various signs and symptoms occurring in patients receiving a given medication. Pharmacists obtain this information by interviewing patients directly. Problems or concerns associated with a medication identified in this manner are described in detail in the report, which when complete, is sent to the physician. Physicians and pharmacists later discuss the reports together. In the present study, we collected and analyzed a total of 174 Medication Monitoring Reports completed between January 2000 and July 2001. In 122 of the 174 reported cases (70%), prescription changes, such as decrease in dosage, medication withdrawal, or change in medication, were made. This suggests that our Medication Monitoring Report scheme has contributed significantly to the improvement of patients' quality of life (QOL). Thus, partnership of this kind between the physician and the pharmacist may play an important role in the prevention of adverse drug effects. Also, by assuming responsibility for dispensing in clinical practice, pharmacists may help ensure the efficacy of drugs and that patients are satisfied with their medication.
Standard deviation (SD) and standard error (SE) are frequently used to express variation in pharmacokinetic data but they should be used properly since their purposes are totally different. With this in mind, we examined the documentation of pharmaceutical products and conducted a questionnaire survey of pharmaceutical companies to see how the terms SD and SE were being used. SD was more frequently used in product documentation and recent quoted references. However, in the questionnaire survey, while most pharmaceutical companies said that it was more appropriate to use SD, responses suggested that SE was used improperly to improve the appearance of data.
We previously reported that in long-term studies on residual ratios of insulin added to high-calorie infusions, the ratio decreased daily in some formulations but did not in other formulations. In the present study, the reasons for the above difference were investigated by measuring long-term residual insulin ratios in specimens that contained sodium bisulfate and saccharides in the same ratios as in high-calorie infusions (Unicaliq® L. Unicaliq® N, Aminotripa® No.1 and Aminotripa® No.2), those in which glucose, fructose or xylitol was substituted for the saccharides in these infusions and those in which substitute saccharides were added in the same ratios as the saccharides in Aminotripa® No.1 and Aminotripa® No.2 (glucose : fructose : xylitol =4 : 2 : 1). The results indicated that the residual ratio of insulin added to high-calorie infusions was not influenced by types of saccharides or their combination ratios but by the relative quantities of sodium bisulfate and saccharides. The residual insulin ratio decreased when the gram amount of saccharide per 1g of sodium bisulfate (G/g) was 364.8 or below and there was a marked decrease when G/g was particularly small. There was no decrease in residual insulin ratio when G/g was 466.0 or above. The above results could be used as reference indices in the selection of high-calorie infusions for HPN that will demonstrate high stability when insulin is added.
We focused on pharmacists' inquiries concerning inpatient prescriptions in order to evaluate their role as a risk manager. Our study of inpatient prescriptions was conducted in two months, April and July of 2002. The frequency of inquiries concerning fixed prescriptions was twice that of emergency, urgent, and stockpiled prescriptions. Major inquiries with regard to fixed prescriptions concerned number of days and number of times, and relatively few concerned dosages. On the other hand, relatively few inquiries with regard to emergency, urgent, and stockpiled prescriptions concerned number of days and number of times, though a relatively large number concerned dosages. About 1.6% of inpatient prescriptions were subject to inquiries and for about 75% of these 1.6%, prescription was changed or stopped. These results suggest that through making inquiries regarding prescriptions, a very important task, pharmacists are fully functioning in their role of risk manager.
The approval of ribavirin for reimbursement under the health insurance scheme in Japan in 2001 started a new era in interferon (IFN) therapy against chronic hepatitis C, enabling a change from IFN mono therapy to combination therapy with IFN and ribavirin. As the major safety problems of ribavirin, teratogenicity, hemolytic anemia and skin symptoms may be given. Also, there is known to be a greater incidence of decreased hemoglobin (Hb) in combination therapy with IFN α-2b and ribavirin than in the case of IFN mono therapy. Despite this, however, it has been considered that combination therapy may be accomplished if the criteria for reducing the dosage of ribavirin are strictly followed. In this study, patients receiving combination therapy with IFN α-2b and ribavirin in Osaka National Hospital were followed up to evaluate the decrease in Hb in cases in which the ribavirin was reduced in dosage or discontinued (reduced/ discontinued group). Hb levels in this group decreased by 3.0± 1.6 g/dL on average after 4 weeks, significantly lower than pretreatment levels. In these subjects, it seemed that the decreased Hb levels after 4 weeks of the combination therapy aggravated anemia symptoms and subjective symptoms such as general fatigue, with the result that combination therapy could not be accomplished.