Ketamine is an injectable anesthetic that inhibits n-methyl-D-aspartate (NMDA) receptors. At doses smaller than the anesthetic dose, it has recently been shown to decrease neuropathic pain, such as postherpetic neuralgia, which does not respond to nonsteroidal anti-inflammatory drugs or opioid analgesics. Furthermore, its main metabolite, norketamine, has also been reported to contribute to the analgesic effect. However, since ketamine is available only in an injectable form, the development of new formulations for outpatient use has been eagerly awaited. With this in mind, we developed non-injectable ketamine preparations for neuropathic pain relief, determined their theoretical dosage regimen, and prepared information on their proper use. The non-injectable preparations we made were oral tablets (wet-granulation, Formulation 1 ; direct compression, Formulation 2), sublingual tablets, a suppository, and nasal drops (spray). Upon performing various pharmaceutical property tests on the two types of oral tablets, we found that Formulation 1 was superior to Formulation 2 in this respect. We also measured the plasma concentrations of ketamine and norketamine for each ketamine preparation after administering them to three healthy volunteers, finding that the bioavailability of the oral tablets was the lowest at approximately 20%. The bioavailability of both the sublingual tablets and the suppository was approximately 30%, and that of the nasal drops approximately 45%. Next, after administering 50 mg of each of the preparations, their analgesic effects were predicted by NMDA receptor occupancy with the results suggesting that their analgesic effects were almost equal. Therapy with oral tablets 50 mg tid was predicted to produce a 10% or greater decrease in pain score and when they were administered according to a predetermined regimen to 7 patients with neuropathic pain who gave prior consent, the pain score decreased by 58±12%. Since this value was near the maximum decrease of 72%, a value estimated from simulated plasma concentrations, this dosage regimen seemed to be adequate. A study on the metabolic properties of ketamine suggested that in its n-demethylation (the major metabolic pathway for ketamine), CYP 2 B 6 may represent high-affinity activity, whereas CYP 2 C 9 and CYP 3 A 4 may represent low affinity. Hospitals make their own preparations in cases where the problem cannot be resolved by commercially available drugs but such in-hospital preparations have not been sufficiently studied for safety and effectiveness. In this study, in addition to developing various ketamine preparations for home treatment, we measured changes in plasma concentrations, estimated the analgesic effects, and prepared information on the proper use of ketamine as an analgesic. Our study significantly contributed to the enhancement of QOL in patients with neuropathic pain.
We describe a rapid and sensitive method for the quantitative analysis of the immunosuppressant sirolimus in whole blood using liquid chromatography/electrospray tandem mass spectrometry (LC/ESI-MS/MS). Ascomycin was first added to samples as the internal standard and then they were purified by precipitating blood protein with a zinc sulfate/methanol solution. Next, chromatographic separation was conducted using a Capcell Pak UG 120 (1.5 x 150 mm, 5μm) column with the mobile phase consisting of methanol/10 mM ammonium acetate (70/30, v/v, pH 7.0) at a flow-rate of 0.1 mL/min. Selected reaction monitoring (SRM) of the above compounds (m/z 932>m/z 865 for sirolimus and m/z 809>m/z 765 for ascomycin, respectively) was performed using ESI in the positive ion mode. In whole blood samples from healthy subjects and a patient receiving sirolimus, no interfering peaks were observed. The assay produced a linear dynamic range of 1-100 ng/mL (r<0.999) for sirolimus in whole blood and the lower limit of detection was 0.5 ng/mL (S/N>3). The method of analysis we studied provides acceptable intra-and inter-assay accuracy and precision in the expected therapeutic range. In conclusion, the simplicity and sensitivity of our method make it suitable for the therapeutic drug monitoring of sirolimus.
CS analysis is a useful statistical method for improving the quality of a service in which a questionnaire is given to gauge people's level of satisfaction with it and then the results are analyzed. It enables areas for improvement to be pinpointed both objectively and specifically. In the present study, we administered a questionnaire on the comprehension of hospital training and achievement of its aims and subjected the results to CS analysis in order to pinpoint the areas for improvement in a model core training curriculum. As regards drug preparation, the results indicated that the area requiring most improvement in the comprehension and achievement of training aims was knowledge required to explain the preparation of cytotoxic drugs (rating of 12.50). In the training on injections and drug formulations, the ability to ensure that all items listed in an injection prescription were present was deemed to be the area requiring the most improvement (rating of 8.59), while with regard to drug control guidance, ability to explain warnings and adverse effects of drugs to patients was considered to require the most improvement (rating of 13.85) We felt that CS analysis had been used effectively to determine the areas requiring improvement in the model core training curriculum from the aspects of comprehension and achievement of its goals.
A comparative study was carried out to evaluate the quality of one brand name tablet (A) and five generic tablets (B∼F) containing 5 mg of enalapril maleate (ENA). Tablet quality was evaluated based on such characteristics as content, impurities, dissolution profile, hygroscopic properties, and stability. In the purity test, we measured the quantities of degradation products such as diacid compound (DA) and diketopiperazine compound (DKP) and in the hygroscopicity test, the weight and hardness of the tablets without blister packaging was measured initially and after 2 weeks and 4 weeks of storage at 0%, 43%, 75% and 93% relative humidity (RH). To test stability, we measured the quantities of ENA, DA, and DKP in tablets stored without blister packaging at 40°C and 75% RH for 12 weeks. The ENA content in all preparations was approximately equal to the indicated content. Initially, DA was not detected in any of the preparations. About 0.3% DKP was detected in preparation B and C. The dissolution profiles of all generic tablets were similar to those of the brand name tablet. For preparations A, B, and D, a marked increase in tablet weight and decrease in tablet hardness was observed with increasing RH. In the stability test, the remaining ENA content in preparations A, B, and D after 12 weeks was significantly lower than the initial content. The DA content in preparations A and D had increased markedly after 12 weeks and so had the DKP content in preparation B. Our study showed that the quality of the generic tablets C, E, and F was comparable to that of brand name tablet A with respect to stability and resistance to humidity. We conclude that if generic manufacturers continue to produce such high quality drugs, this will lead to greater confidence in their effectiveness and an increase in their use in the clinical setting.
The large dose administration of the carcinostatic agent methotrexate (MTX), a folic acid antagonist, is effective in treating osteosarcoma but its use is often accompanied by critical adverse effects. Forty-eight hours after administering MTX to a 9-year old female osteosarcoma patient the blood concentration of MTX was 283μM, approximately 280 times higher than the reference level, due to delayed excretion. However, the full amount of calcium folinate (Leucovorin® : LV) needed to antagonize such a high concentration of MTX in the blood was not available since it is produced in very small amounts. Therefore, we recommended blood purification methods such as hemodialysis plus hemoperfusion (HD+HP) and plasma exchange (PE) to reduce the high MTX concentration. HD+HP and PE achieved decreases in the MTX level of 76% and 34%, respectively. Though clinical tests implied hypofunction of the kidney and liver and myelosuppression, serious adverse effects such as decrease in urine volume, jaundice, and infection were not observed. Thus, the blood purification methods of HD+HP and PE were effective in emergency treatment for a patient with delayed excretion of MTX.
Flat-sum payment systems for treatment costs, such as the Diagnosis Procedure Combination (DPC) system, are now being introduced in medical institutions. Owing to the introduction of such payment systems, hospital pharmacists are now required to be more actively involved in the selection of drugs through the provision of appropriate drug information including that on cost effectiveness. In Japan, however, very few pharmacoeconomic evaluations by hospital pharmacists have been reported to date. In view of this, we conducted a pharmacoeconomic evaluation of HMG-CoA reductase inhibitors using information that hospital pharmacists can obtain comparatively easily. Referring to an analytical method reported in Britain, we investigated the amounts of four kinds of HMG-CoA reductase inhibitors, Pravastatin, Simvastatin, Fluvastatin, and Atorvastatin, used for each strength in the target medical institutions. Responders to treatment was defined as patients whose lipid values (low density lipoprotein cholesterol and total cholesterol) improved to the level suggested in the 2002 edition of the Japan Atherosclerosis Society Guidelines for Diagnosis and Treatment of Atherosclerotic Cardiovascular Diseases. Based on this, we calculated response rates for the present investigation and other clinical studies conducted in Japan. Drug treatment costs were estimated based on the volume of the drugs administered and the drug prices listed in the National Health Insurance price list. The results of the current investigation showed that cost effectiveness was highest for atorvastatin followed by simvastatin, fluvastatin, and pravastatin. In addition, they indicated that based on treatment data available in their hospitals, hospital pharmacists are able to make practical pharmacoeconomic evaluations of drugs that reflect the actual practice of treatment.
The Outpatient Oncology Unit of Kyoto University Hospital, which has a full-time staff, was established in October 2003. Before it was established, different kinds of regimens for outpatient chemotherapy were independently used by various departments for the same types of cancer. In order to further improve the safety of chemotherapy for outpatients, we unified the regimens under the control of the oncology Unit and registered the set prescriptions for them in the ordering system. These regimens were checked by pharmacists as to whether they were suitable as infusions and complied with health insurance indications. Sixty-three regimens were registered when the Unit was established. There was a further increase in the number of prescriptions during the half-year period after the Unit was established, and they were registered between June and December 2004, bringing the total number of registered regimens to 79. The registration of chemotherapy regimens has enabled all the medical staff of the Unit to have access to the same information, and pharmacists are able to check them easily. The use of such set prescriptions has helped prevent simple mistakes and allowed chemotherapy to be conducted more safely. In addition, the rate of questions about prescriptions decreased from 10% at the time of establishing the Unit to 3% in January 2005 due to the introduction of a prescription support system. In conclusion, the registration of the regimens has helped the Outpatient Oncology Unit to conduct standard chemotherapy more safely and improve cooperation with each department on outpatient chemotherapy.
Recently, based on the knowledge that operability of the dosing device is closely related to patient compliance, a beclomethasone dipropionate dry powder inhaler (BDP-DPI) in a multi-dose device has been developed for allergic rhinitis. In the present study, we conducted a questionnaire survey at 45 hospitals in Hiroshima prefecture (targeting 62 otolaryngologists and 48 pharmacists) to evaluate the operability and usefulness of the newly developed BDP-DPI in a multi-dose device. More than half of otolaryngologists had never prescribed a BDP-DPI in a single-dose device giving the difficulty of using it as the most important reason. Both otolaryngologists and pharmacists showed a preference for the multi-dose device in the aspects of simplicity of use, clear explanatory leaflet for patients, usefulness, comprehensive evaluation and necessity. Further, otolaryngologists rated the simplicity of use of the multi-dose device over the single-dose device and conventional liquid inhalers differently from the pharmacists indicating a difference in understanding of medication adherence between otolaryngologists and pharmacists. These results indicate that in addition to being a useful alternative to conventional inhalers, the BDP-DPI in a multi-dose device also raises medication adherence among patients for allergic rhinitis. When giving instructions on the device to patients, however, pharmacists should be aware of the fact that some patients may have difficulties in understanding.
A 76-year-old man with hypercholesterolemia had been taking simvastatin for about 2 years prior to admission. He had also been taking several other drugs-for gastric ulcer, myocardial infarction and reflux esophagitis. He had experienced numbness in his upper and lower extremity muscles for a month before admission and in the 2 weeks prior to admission, he had been taking mosapride citrate for lack of appetite. The reason for hospitalization was muscle pain in both shoulders and difficulty in walking. Echography on admission suggested bilateral renal cystic disease with dysfunction of the left kidney. Laboratory tests revealed reduced 24 hr creatinine clearance (CK : 47 mL/min). On the day of hospitalization, simvastatin was withdrawn due to the possibility of rhabdomyolysis, resulting in an improvement in CK and the muscular symptoms. Judging by the time course of the myopathy, simvastatin was thought to be a possible cause. Since simvastatin had been administered for the past 2 years, certain factors were considered to have increased its plasma levels and induce the myopathy. Among them were decreased excretion due to malfunction of the kidney, inhibition of p-glycoprotein by the omeprazole he had been taking for gastric ulcer and metabolic interaction with the mosapride citrate that was administered 2 weeks prior to admission. Both mosapride citrate and simvastatin are metabolized by cyp 3 A 4 and the protein binding affinity of mosapride citrate was highest (99%) among the drugs prescribed. So far there has been no other report of an interaction between simvastatin and mosapride citrate, a drug commonly used for digestive troubles. In conclusion, in view of the myopathy that was apparently caused by the co-administration of these two drugs, it is necessary to observe special caution in the use of mosapride citrate.
Pre-training in clinical pharmacy practice for third year students at Kobe Pharmaceutical University consists of three sections-pharmaceutical technology practice, dispensing and pharmacokinetics practice, and drug information and consultation practice. The dispensing part of the dispensing and pharmacokinetics practice section includes transcribing usage information into Braille for blind patients and in the pharmacokinetics part, students analyze pharmacokinetic parameters of model compounds according to a one-compartment model. In creating a medication dosage plan for several model patients, they monitor vancomycin concentrations. On evaluating students' understanding of the various pharmaceutical practices by means of a questionnaire, it was found that most students had attained a good level of understanding through the pretraining program for their pharmacy internship.
We investigated whether theophylline concentrations in saliva (Csaliva) are correlated with its serum concentrations (Cserum) to see if they may be used for the therapeutic drug monitoring (TDM) of theophylline when patients refuse blood sampling. Saliva and serum samples were obtained from 6 healthy adult volunteers after administration of single dose of theophylline, and 40 patients of 3 different age groups (infants group aged 0-3 years, n=10 ; childrens group aged 7-12 years, n=9 ; adults group aged 27-81 years, n=21). All patients had been taking theophylline for a time and blood concentrations had reached a steady state. Saliva samples were taken using a sampling pad (OraSure® ; Epitope inc.), and theophylline concentrations in the saliva and serum samples were measured by fluorescence polarization immunoassay (TDx). In the healthy adult volunteers, there was a very good correlation between Csaliva and Cserum (y=0.48 x-0.10, r=0.991, p<0.001), and the ratio of Csaliva to Cserum (Csaliva/Cserum) was 0.46±0.03. The pharmacokinetics parameters Cmax and AUC for saliva were about 0.46 times those for serum and thus their ratios were almost the same as for Csaliva/Cserum. Vd/F for saliva was about 2.2 times that for serum, which was almost the inverse of the ratio for Csaliva/Cserum. There were no significant differences between saliva and serum for Tmax MRT, Ka, Ke, and T1/2. For the patients who had been taking theophylline for a time, there was also a very good correlation between Csaliva and Cserum (y=0.52 x-0.12, r=0.957, p<0.001). Csaliva/Cserum was 0.48±0.10 for the infants group, 0.51±0.07 for the childrens group and 0.50±0.08 for the adults group, so there were no significant differences among the patient groups in this respect. The results of this study show that Cserum can be estimated approximately from Csaliva measurements. Thus in the case of patients from whom it is difficult to obtain blood, it may be possible to check compliance and avoid overdosing using Csaliva. We therefore consider that the use of saliva samples for the TDM of theophylline is an important and convenient method for ensuring that drug therapy is conducted effectively.
Using Microsoft Access 2000, we developed a pharmaceutical management and counseling support system that enables us to produce explanatory leaflets on medicines. However, a growing number of foreigners have been admitted to our hospital recently and most of them cannot read Chinese characters, though they can read the Japanese katakana and hiragana scripts, so they could not use our leaflets. To solve this problem, we improved the software so that the system would produce leaflets in English for them. We translated various items in leaflets into English such as the effects of medicines, initial symptoms of severe adverse events and changes in colors of stools and urine. We also asked eleven foreign patients to complete a questionnaire regarding the usefulness of the new explanatory leaflets, and they all thought the leaflets were useful. At present, no similar software is available on the market and even if such software were available, it would be very expensive. Since we feel that our software is very useful, we have made it freely available at no cost.