Time series analysis of the clinical laboratory test result on chemotherapy for gastric cancer.

PURPOSE: Time series analysis may be helpful to estimate hematological data on gastric cancer patients who receive S 1, but untreated raw clinical data are not suitable for this approach. Hematological monitoring data interpolated by spline were analyzed by an attractor plot, which is a form of time series analysis. METHODS: Hematological data of three gastric cancer patients were interpolated by cubic spline. The leave-one-out cross validation method was carried out and an attractor plot was adopted to evaluate red blood count (RBC) data. RESULTS: Well-predicted data, such as RBC, changed slightly; however, data with great deviation, such as the white blood count (WBC), were poorly predicted. The reaction of marrow function to chemotherapy was observable by spline interpolation of RBC data. Furthermore, an attractor plot clarified the tendency of the interpolated hematological monitoring data. CONCLUSIONS: It is suggested that spline interpolation is effective as a pretreatment to analyze clinical data from a time series.

Comparison of gastroretentive microspheres and sustained-release preparations using theophylline pharmacokinetics.

The objective of this study was to use the pharmacokinetics of theophylline to compare various gastroretentive microspheres. Three types of theophylline microspheres prepared from a hydrophobic dextran derivative were characterized in terms of drug release in-vitro and floating and mucoadhesive properties. Theophylline pharmacokinetic studies were conducted in Beagle dogs, comparing bulk powder, commercial sustained-release granules (Theodur), sustained-release microspheres, floatable microspheres and mucoadhesive microspheres. Theodur and sustained-release microspheres resulted in a lower maximum concentration (Cmax) (P < 0.01) and larger values for mean residence time (MRT) (P < 0.05) than bulk powder, whereas area under the concentraion-time curve (AUC) were lower. The floatable microspheres showed a larger value for MRT than bulk powder (P < 0.01), and a larger AUC than Theodur (P < 0.05). The pharmacokinetic parameters of the mucoadhesive microspheres indicated an increase in AUC without decreasing the rate of bioavailability. Overall, the gastroretentive microspheres improved the extent of bioavailability of theophylline, which is absorbable from the entire gastrointestinal tract. The mucoadhesive microsphere showed a prolonged serum drug level, indicating a superior sustained-release delivery system for theophylline.

Evaluation and optimization of preparative variables for controlled-release floatable microspheres prepared by poor solvent addition method.

The aim of this study was to evaluate and optimize preparative parameters for floatable theophylline microspheres prepared by the emulsion-solvent evaporation method. A three-factor three-level Box-Behnken design was employed using amount of poor solvent, temperature-increase rate and drug loading as independent factors, and percentage floating at 3 h and time required for 50% drug release as dependent variables. Simultaneous optimization of the parameters for maximum buoyancy and desirable drug release was conducted using a partitioned artificial neural network. A microsphere using 27.6% of drug loading, 0.29 degrees C/min of temperature-increase rate, and 1.7 mL of poor solvent was identified for maximizing buoyancy and sustaining drug release.

In vivo drug release from hydrophilic dextran tablets capable of forming polyion complex.

The aim of this comparative study was to investigate the in vivo drug release property of hydrophilic dextran tablets with or without swelling in the upper gastrointestinal tract (GIT) in humans. Two kinds of theophylline (TH) tablets were prepared by direct compression from a mixture of carboxymethyldextran and [2-(diethylamino)ethyl]dextran as a matrix capable of forming polyion complex (PIC-tablet), and a mixture of low and medium molecular weight hydroxypropylcellulose as a representative hydrophilic matrix (HPC-tablet). In these tablets, in vitro drug release behaviors and saliva TH level profiles after oral administration to humans were similar to each other, indicating equivalent AUC value. The tablets were then coated with Eudragit S100, enteric-coating polymer, by a dipping method in order to reveal drug release without full swelling in the upper GIT. Although the two enteric-coated tablets showed a similar in vitro release pattern, saliva level profiles were quite different as reflected in AUC values of 16.4 and 4.68 microg h/ml for enteric-coated PIC- and enteric-coated HPC-tablet, respectively. These results demonstrated that HPC-tablet could not release sufficiently without swelling in the upper GIT. In contrast, enteric-coated PIC-tablet showed an equivalent AUC value to PIC-tablet, indicating that TH was released well even in the lower GIT.

Effect of temperature-increase rate on drug release characteristics of dextran microspheres prepared by emulsion solvent evaporation process.

Microspheres containing theophylline (TH) were prepared from a hydrophobic dextran derivative by an emulsion solvent evaporation process using an acetone/liquid paraffin system. The effects of solvent evaporation rate on particle properties and drug release characteristic of the microspheres were evaluated. The solvent evaporation rate was controlled by the rate of increase in temperature of the water bath, ranging 7.5-30 degrees C/h. Drug release from the microspheres was examined using JPXIV 2nd fluid (pH 6.8) containing 0.1% Tween 80, and was found to be greatly affected by the solvent evaporation rate. The percentage of drug released until 8h varied; from 28% to 84% for 30 and 7.5 degrees C, respectively. Differential scanning calorimetry and powder X-ray diffraction studies revealed that TH partially interacted with the polymer and drug crystallinity was maintained intact in the microspheres. According to scanning electron microscopy observations, all microspheres showed a well-formed spherical particle with a solid interior. The appearances of the microspheres were, however, extremely different. Microspheres prepared at 30 degrees C/h had a very smooth surface, while those prepared at 7.5-15 degrees C/h had a rough surface with large craters. These findings demonstrated that the surface morphology and drug release characteristic were controlled by the rate of increase of temperature.

The effect of polyion complex formation on in vitro/in vivo correlation of hydrophilic matrix tablets.

The aim of this study was to investigate the effects of polyion complex formation on in vivo performance of hydrophilic matrix tablets. Three kinds of controlled release theophylline tablets were prepared by direct compression using carboxymethyldextran (CMD), a mixture of CMD and [2-(diethylamino)ethyl]dextran (EA), and a mixture of dextran sulfate (DS) and EA. According to a conventional dissolution test, in vitro drug release profiles of these tablets were similar to each other. In vivo absorption profiles of theophylline after oral administration to beagle dogs, however, were quite different and were not consistent with in vitro release profiles. Thus, we applied a modified in vitro release test considering destructive forces. An excellent in vitro/in vivo correlation was obtained in the cases of CMD/EA- and DS/EA-tablets. The results suggested that the drug was released constantly in the overall gastrointestinal tract, and even in the colon. Then, hydrophilic matrices were characterized by swelling rate, matrix density and strength in a wet state. DS/EA-tablets showed limited swelling, higher density and a larger value of wet strength than the others. These findings indicated that polyion complex formation in gel layer contributes to prevent over-swelling and strengthen the wetted matrices.

Study on jelly fig extract as a potential hydrophilic matrix for controlled drug delivery.

The principal component of aqueous extract of jelly fig (Ficus awkeotsang Makino) seeds is a pectin-type polysaccharide, gelling even at room temperature without adding any sugars, acids or ions. The objective of this study was to evaluate jelly fig extract (JF) as a matrix base for sustained release tablets. Drug release profile from JF tablet was examined using theophylline as a model drug, compared with those from USP graded pectin (USP-P). Release profile from JF tablet was a sustained release pattern and not affected by pH of medium. USP-P tablet showed a similar release profile of JF tablet, however, the release mechanisms differed. Matrix erosion studies revealed that the percentage of drug released from USP-P tablet was proportional to that of matrix eroded. On the other hand, JF tablet was eroded up to 50% of matrix for 4h and showed a constant value thereafter. According to water uptake studies, JF tablet showed an initial burst swelling followed by slow water uptake, suggesting diffusion-controlled kinetics in later phase. Moreover, theophylline release rate from JF tablet was modified by drug content in the tablet, increasing with decrease in drug amount. These findings indicated JF was a potential hydrophilic matrix for controlled drug delivery.

In vitro and in vivo evaluation of mucoadhesive microspheres consisting of dextran derivatives and cellulose acetate butyrate.

The objective of this study was to evaluate mucoadhesive properties and gastrointestinal transit of microspheres made of oppositely charged dextran derivatives and cellulose acetate butyrate (CAB). The microspheres were prepared by emulsion solvent evaporation method. A reference microsphere was made of lactose instead of dextran derivatives. Microspheres with a diameter of 425-710 microm were examined for in vitro mucoadhesion by the everted sac method. The results indicated that the percentage of adherence to the rat small intestine was affected by the amount of dextran derivatives in the microspheres. After 1.5h, the adhering percent of the reference microspheres and the microspheres containing 50% of dextran derivatives were 34 and 74%, respectively. Then gastrointestinal transit after oral administration to rats was evaluated by counting the microspheres remaining in the stomach and small intestine. The microspheres containing 40% of dextran derivatives adhered to the stomach rather than the small intestine. Mathematical analysis revealed that the time required for 50% of microspheres to leave the stomach was 1.42h, three times longer than the reference. These findings suggest that the microsphere is a promising device as a multiple-unit mucoadhesive system.

[The association between dispensing error factors and behavioral characteristics of pharmacists].

We evaluated error prevention education by clarifying the association between dispensing error factors and behavioral characteristics of pharmacists. The subjects were 98 pharmacists (27 men and 71 women) with a mean age of 29.7 years who gave informed consent for participation in our survey. Between November 2001 and January 2002, a questionnaire survey on dispensing errors was performed using the "Tokyo University Egogram, New Version" for the assessment of behavioral characteristics and the "Safety Behavior Questionnaire" for the assessment of error factors. An association was observed between the incidence of dispensing errors and behavioral characteristics. There was also an association between error contents and behavioral characteristics as well as error factors. With more experience, errors associated with becoming accustomed increased, suggesting that error prevention education is necessary not only for newly qualified pharmacists but also for managers.

Detailed analysis of clinical test data on chemotherapy for colorectal cancer.

We reported previously that spline interpolation is effective as a pretreatment before analyzing clinical data by time series. However, further improvement is required to understand the detailed tendency of clinical data. In this study, the tendency of interpolated hematological data was investigated in the period between the most tolerated dose (MTD) and low-dose chemotherapy (LDC) for colorectal cancer. All patients were received both MTD and LDC. Hematological data, white blood cell count (WBC), red blood cell count (RBC) and mean corpuscular volume (MCV), were interpolated. The accuracy of interpolation was verified using leave-one-out cross-validation. The difference, Δ(i), was calculated from interpolated data and exhibited as a function of time. The predictions of RBC and MCV were accurate with high correlation coefficients, although the interpolation of WBC data was inaccurate. A marked difference was observed in the trend of Δ(i) between LDC and MTD periods. SD-RBC showed significant differences between LDC and MTD periods. The SD-MCV average in the LDC period was larger than in the MTD period. SD-MCV showed no significant difference. An attractor plot of Δ(i) in RBC clarified the tendency of the interpolated RBC data. There is a possibility that Δ(i) of RBC and/or SD-RBC may contribute to monitoring adverse reactions and decision of medication. Moreover, it is also useful to check on attractor plot of Δ(i) in RBC together with SD-RBC in order to find out untoward reactions and decision of medication.

Effect of amount of water in dispersed phase on drug release characteristics of dextran microspheres prepared by emulsion-solvent evaporation process.

Microspheres containing theophylline (TH) were prepared from a hydrophobic dextran derivative by emulsion solvent evaporation method. The objective of this study was to evaluate the effects of poor solvent in dispersed phase on the particle properties and drug release characteristics of the microspheres. Mixtures of acetone and water were used as the dispersed phase and liquid paraffin as the continuous phase. The amount of water (poor solvent for polymer) was varied from 0.5 to 2 ml in 15 ml of dispersed phase. Drug release from the microspheres was examined using JPXIV 1st Fluid (pH 1.2) containing 0.02% Tween 20, and their structure was analyzed by scanning electron microscopy (SEM). The drug release behaviors were greatly affected by the amount of water. The percentage released until 8 h were 89% and 23% for 0.5 and 2.0 ml of water, respectively. The release mechanism shifted from Fickian diffusion to zero-order transport as the amount of water increased. According to SEM observations, TH was uniformly distributed over the entire microsphere prepared using 0.5 ml of water, and existed in the center of the microsphere, having a core-shell structure, when prepared using 2 ml of water. The amount of poor solvent in the dispersed phase was found to be a crucial factor determining the internal structure of microspheres and drug release characteristics.

Release profiles of theophylline from microspheres consisting of dextran derivatives and cellulose acetate butyrate: effect of polyion complex formation.

The objective of this study was to evaluate the utility of mixtures among oppositely charged dextran derivatives as constituents of a controlled release microsphere. Carboxymethyldextran (CMD) and dextran sulfate (DS) were used as polyanions, and [2-(diethylamino) ethyl] dextran (EA) and [2-hydroxypropyltrimethylammonium] dextran (CDC) as polycations. The microspheres consisting of hydrophilic and hydrophobic polymers were prepared by emulsion-solvent evaporation method. The mixtures, CMD/EA, CMD/CDC, DS/EA, and DS/CDC, were used as hydrophilic polymers, because they can interact with each other to form polyion complexes for the improvement of sustained-release performances. Cellulose acetate butyrate and theophylline were used as a model hydrophobic polymer and a model drug, respectively. The yield of microspheres was excellent (more than 95%). According to observation, by scanning election microscopy (SEM) microspheres were spherical with a rough surface. The in vitro drug release from microspheres was examined in the JP XIV first fluid, pH 1.2, and second fluid, p H 6.8, at 37 degrees C, and 100 rpm. In the DS/CDC system, drug release was depressed by formation of a polyion complex and not affected by pH of dissolution medium. The release rate was modulated by the ratio of hydrophilic and hydrophobic matrix. This particulate system, in which the polyion complex matrix is strengthened by a hydrophobic polymer, is a promising formulation for drug delivery.

Bioavailability of theophylline and thiamine disulfide incorporated into mucoadhesive microspheres consisting of dextran derivatives and cellulose acetate butyrate.

Mucoadhesive microspheres made of oppositely charged dextran derivatives and cellulose acetate butyrate (Ad-MS) were evaluated for their ability to improve the bioavailability of theophylline (TH) and thiamine disulfide (TDS). A drug suspension (or solution) and non-adhesive microspheres (MS) were used as references. In vitro drug release profiles from MS and Ad-MS were similar for each drug, whereas their gastrointestinal transits differed. The plasma concentration after oral administration of drug suspension (or solution), MS and Ad-MS was investigated in rats. In the case of TH, sustained plasma level profiles were observed after MS or Ad-MS administration, with similar C(max), T(max) and MRT( infinity ) values. AUC( infinity ) values of the suspension, MS and Ad-MS were statistically equivalence. These indicated that Ad-MS achieved a sustained plasma level profile without a decrease of AUC. In the case of TDS, MRT( infinity ) and AUC( infinity ) of Ad-MS were significantly larger than those of the solution and MS, indicating that the plasma level was sustained and the extent of bioavailability was increased. These results suggested that Ad-MS is a promising device for improvement of bioavailability of drugs those absorption windows are limited to upper part of the gastrointestinal tract.