Extrashot-ODS, a syringe-type minicolumn sample injector for a reversed-phase high-performance liquid chromatographic column. Application to antiepileptics in human sera.

Extrashot-ODS (EXS-ODS) is a syringe-type minicolumn developed for sample injection into reversed-phase high-performance liquid chromatographic columns. EXS-ODS consists of (a) a stainless-steel needle fitted to an ordinary syringe-loading sample injector for HPLC, (b) a 45-microl minicolumn tube made of polytetrafluoroethylene (PTFE) and packed with ODS-silica and (c) a minicolumn holder made of polystyrene, which is connected to the needle on one side and the other side is shaped so as to be fitted with a solvent syringe. Using the device, we simultaneously analyzed three antiepileptics in 20 microl of human sera. First, we introduced a 20-microl serum specimen diluted with 100 microl of buffer solution into the device and, second, 100 microl of distilled water. Then the device was attached to the HPLC injector and 130 microl of methanol were introduced into the HPLC column through the device. Then, reversed-phase HPLC was conducted in the usual manner, with the chromatogram reading at a wavelength of 210 nm for the assays of 5,5-diphenylhydantoin, phenobarbital and carbamazepine. The results obtained by direct peak-height calibration were comparable to those given by the immunological method.

[Development of syringe-type off line pre-column and simultaneous quantitation of four xanthine derivatives (caffeine, theobromine, theophylline and paraxanthine) in serum].

A new syringe-type minicolumn, called Extrashot-Silica (EXS-Silica), containing diatomaceous earth granules was described. The EXS-Silica differs from the conventional pretreatment column. Using the EXS-Silica we can execute the simultaneous extraction-injection to HPLC, column. Therefore, an analysis using the EXS-Silica is an easier and faster method than the general HPLC analysis method. In this study, we carried out the simultaneous determination of four xanthine derivatives, such as caffeine, theobromine, theophylline and paraxanthine, in serum specimens. We used dichloromethane containing 4% ethanol (v/v) for the extraction-injection and water-acetic acid-ethanol-dichloromethane (0.2:0.2:4:95.6, v/v) for the mobile phase of HPLC. The eluent was monitored with a UV detector at 275 nm. A linear relationship between the amount of drug and the peak height was confirmed in the range of 1-40 micrograms/ml for the above-mentioned four xanthine derivatives in the serum. When a 5 microliters aliquot of the serum was subjected to this method, the observed detection limits of the drug were far less than therapeutic concentrations. The analytical accuracy of our method was finally confirmed by comparing the obtained analytical data by the new method with those obtained using the fluorescense polarization immunoassay method. Serum concentrations of theophylline obtained by these two methods correlate satisfactorily. Except for minor modifications in the injector, the existing liquid-chromatographic equipment can be used.

Development and evaluation of a new automated dispensing system.

Promptness of medicine preparation is one of the important tasks the pharmacy has to tackle. A new automated dispensing system has been developed in order to adopt parallel preparation of the prescription. The system consists of a large LAN system which is connected to a host-computer, control-computer, automatic preparation machines and conveyer lines. The prescription data issued by each physician are first audited by the host computer and then used as the date for preparation. Prepared data checked by pharmacists are delivered to the manual preparation station (tablets, powder, topical drugs, and solutions) as a preparation instruction sheet and transmitted directly to the automatic preparation machines (e.g. medicine bag printing machines and automatic tablet dispensing and packaging machines). In collecting the prepared medicines, a controlled conveyer line was established. The waiting time decreased significantly after the system was introduced. This system not only reduces actual medicine preparation time but also improves the progress of the dispensing operation efficiency.

Simple and accurate high-performance liquid chromatographic method for the measurement of three antiepileptics in therapeutic drug monitoring.

A high-performance liquid chromatographic method for simultaneous determination of three antiepileptics, phenytoin, phenobarbital, and carbamazepine, in serum for therapeutic drug monitoring is described. The drugs were extracted and injected onto a silica-gel column using a syringe-type minicolumn, Extrashot-Silica, packed with diatomaceous earth granules. We used dichloromethane for extraction-injection and n-hexane containing 0.2% acetic acid, 2% ethanol, and 15% dichloromethane for the mobile phase of a silica-gel HPLC. The eluent was monitored with a UV detector set at 240 nm. Linear relationships between the amount of drug and peak height were confirmed at 1-20 micrograms/ml in serum for carbamazepine and 5-40 micrograms/ml in serum for phenytoin and phenobarbital. When a 5-microliters aliquot of serum was subjected to this method, the observed detection limits of the drugs were far less than therapeutic concentrations. Thus, our method was simple and accurate enough to be used in routine therapeutic drug monitoring and basic pharmacokinetic studies.

Effect of molecular weight in amphipathic polyethyleneglycol on prolonging the circulation time of large unilamellar liposomes.

The effect in mice of the molecular weight of polyethyleneglycol on prolonging the circulation time of large unilamellar liposomes (LUVs) was examined using four different distearoyl N-(monomethoxy polyethyleneglycol succinyl) phosphatidylethanolamines (DSPE-PEGs). The molecular weights tested were 1000, 2000, 5000 and 12000. Incorporation of 6 mol% of DSPE-PEG in LUV composed of distearoylphosphatidylcholine (DSPC) / cholesterol (CH) (1:1 in molar ratio) increased the blood circulation half-life significantly more than those without DSPE-PEG derivatives. DSPE-PEGs with molecular weights of 1000 and 2000 prolonged the circulation time of liposomes more than other DSPE-PEGs with higher molecular weights, such as 5000 and 12000. Their effects are also higher than ganglioside GM1, a well described glycolipid with this effect. DSPC/CH LUV-incorporated DSPE-PEG with a molecular weight of 2000 displayed a high concentration in the blood, approximately 40% of the dose, 6 h after the injection.

Computerized dispensing system: reducing the time of dispensing medicines.

We have developed a new computerized dispensing system which reduces the time needed to dispense medicines. This system is so designed to assist the pharmacist with various tasks. These include receiving prescriptions, dispensing of medicines, checking for accuracy, and payment. This system consists of automated dispensing devices, a tray-transfer line, a reception number indicator screen installed in the waiting room, and a terminal to provide patients with additional information. The prescription data are instantly transmitted to the respective dispensing positions and the prescriptions are dispensed simultaneously. The trays travel efficiently on the tray-transfer line. The host computer performs such functions as input of information of prescriptions, accounting calculations, integrating prescription audit, and preparation of printing data for medicine bags. The control computer, which receives prescription data from the host computer, sorts and sends instruction data on prescriptions to the automated dispensing machines, outputs instructions on the preparation of medicines in the manual dispensing sector, and controls the tray-transfer line, the turn tables and the reception number indicator screen. This computerized dispensing system has produced the following results: (1) improvement in the quality of the dispensing work; (2) reduction in the time required for dispensing medicines; (3) improvement in the quality of service to patients; (4) improvement in the efficiency of the clerical work in non-dispensing work; (5) improvement in work efficiency.

Computerized prescription checking system.

This is a report on a validation system which was developed by utilizing medication history profiles of drugs prescribed to patients. Upon entering the current prescription data of a patient, the system will automatically retrieve the patient's history of past medication and the previous prescription, and print out the contents of both the current and previous prescriptions in order to validate the treatment. As a result of the Prescription Validation System, the safety of dispensing drugs by the pharmacists has been greatly improved compared to the past by checking on operator's errors of input of data, by identifying transcription error and by matching the spelling in the prescription. Medication instruction to the patients become more accurate since it is easier to monitor any changes on the prescription.

Evaluation of a computerized drug interaction checking system.

A real-time computer-based system for checking drug interaction is reported. Out of 169230 prescriptions checked by our drug interaction standards, 8.8% or 14965 were found to contain those which may cause drug interaction, while 47.3% of those were prescribed in the Department of Internal Medicine and 39.8% in Psychiatry. It was found that use could be made of some of the therapeutic prescriptions written in A group (Prescriptions containing the drugs with highly dangerous interactions), or Department of Psychiatry when sufficient cooperation was available between the physicians and the pharmaceutics. By this screening system, it became easy to advise the prescribing physicians about items of clinical tests required, treatment in order to prevent side effects, etc.