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This study was aimed to investigate the capacity of a standardized root water extract of Eurycoma longifolia (Tongkat Ali, TA), Physta® to modulate human immunity in a middle-aged Japanese population. This randomized, double-blind, placebo-controlled, parallel study was conducted for 4 weeks. Eighty-four of 126 subjects had relatively lower scores according to Scoring of Immunological Vigor (SIV) screening. Subjects were instructed to ingest either 200 mg/day of TA or rice powder as a placebo for 4 weeks [TA and Placebo (P) groups] and to visit a clinic in Tokyo twice (weeks 0 and 4). SIV, immunological grade, immunological age, and other immune parameters were measured. Eighty-three subjects completed the study; 40 in the TA group and 41 in the P group were statistically analyzed, whereas two were excluded from the analyses. At week 4, the SIV and immunological grade were significantly higher in the TA group than those in P group (p

Concomitant consumption of grapefruit juice (GFJ) causes increases in the plasma concentration of a variety of drugs due to inhibition of intestinal CYP3A enzyme. Dihydropyridine calcium channel blockers belong to the category of drugs that are most prone to undergo such interaction. Increases in area under the plasma concentration-time curve (AUC) due to GFJ differ greatly depending on the dihydropyridine administered. Therefore, a meta-analysis of each dihydropyridine was performed based on available literature. The criteria for using a publication were: subjects were healthy adults, dihydropyridines were taken with GFJ concomitantly or within one hour after intake of the juice, and the control group administered water in place of GFJ. In these studies, the investigations on GFJ interactions with 13 dihydropyridines such as amlodipine, azelnidipine, benidipine, cilnidipine, efonidipine, felodipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine and pranidipine were reported. As a result of meta-analyses, statistically significant interactions were not identified in amlodipine. Next, correlation analyses between the physicochemical properties and interaction strengths of the dihydropyridines were performed to clarify the cause of the variation in the strengths that was dependent on the dihydropyridine. LogP, molecular weight, topological polar surface area (tPSA), molar refractivity, water diffusion, molecular volume, molecular density, molecular polarizability, and refractive index were calculated from the chemical structures. The interaction strength was defined as the logarithmic values of the increasing AUC ratio. The correlation analyses indicated a relationship of logP and tPSA with the interaction strengths. These findings suggest that the wide difference in the potency of interaction of each dihydropyridine may be explained by the presence of hydrophobic and electrostatic interactions between dihydropyridines and intestinal CYP3A enzyme.

We performed a meta-analysis to assess antihypertensive effect, lipid metabolism, insulin resistance index, and body weight changes in patients with borderline diabetes and diabetes treated with angiotensin II receptor blockers (ARB) and dihydropyridine calcium channel blockers (CCB). Literatures for analysis were searched in MEDLINE, the Cochrane Library, and Japana Centra Revuo Medicina. Reports on randomized controlled trials in which the therapeutic results in borderline and diabetic patients were compared between those treated with ARB and CCB were retrieved, and 16 reports met the objective of this study. The efficacy in the two drug treatment groups were divided into 8 outcomes and evaluated. The efficacy outcomes on handling continuous data were integrated using the weighted mean difference, in which the random-effects model was selected for the statistical model. The statistical heterogeneity of each outcome was also tested. The systolic and diastolic blood pressures were significantly reduced in the CCB compared to the ARB treatment group. No significant differences were noted between the two groups in the triglyceride or low-density lipoprotein cholesterol level or body weight changes. It was shown that the CCB was more effective than ARB for the improvement of systolic and diastolic blood pressures in patients with borderline diabetes and diabetes, while no significant differences were noted in the efficacy other than the antihypertensive effect between ARB and CCB treatment groups. This study would provide information in selecting antihypertensive agents for borderline and diabetic patients.

Oxybutynin hydrochloride (OB) is often used in intravesical instillation therapy for spastic neurogenetic bladder.The purposeof this study was to determine the expiration date and administration device for intravesically administered OB solutionscontaining sodium hyaluronate (HYA) as a pharmaceutical additive to enhance the muco-adhesiveness of the solution.The stability of OB in containers made of glass,polystyrene (PS),polypropylene (PP) and polyethylene (PE) was investigatedunder various temperature and light exposure conditions.Sorption of OB was observed in PP and PE containers andfor the latter,it was enhanced at higher temperatures and pHs.Based on these results,the optimal expiration date and storageconditions of OB solution were determined to be 84 days in a cool place (4°C),in a PP container.

The barbituric acid derivative bucolome (BCP) is a nonsteroidal anti-inflammatory drug. The present study investigated whether BCP N-glucuronide (BCP-NG, the primary metabolite of BCP) was produced in mammalian species other than rats, and attempted to identify the UDP-glucuronosyltransferase (UGT) isoform (s) responsible for formation of BCP-NG in humans. BCP-NG was detected in all species tested. The results were as follows (pmol equivalent/ min/mg protein): rat, 479 ± 83; Mongolian gerbil, 378 ± 9; rabbit, 275 ±26; guinea pig, 257 ± 10; human, 242 ± 18; hamster, 177 ± 22; and mouse, 167 ± 15. Since human liver microsomes formed BCP-NG, we investigated the metabolites of BCP excreted in the urine of a patient after oral administration of BCP (600 mg). BCP and BCP-NG were excreted in the urine at amounts of 2.9 mg (about 0.5% of the dose) and 14.4 mg (about 2.5% of the dose) over 12 hours. In order to identify the UGT isoforms involved in formation of BCP-NG in humans, we investigated BCP-NG formation by the microsomes of insect cells expressing each of twelve UGT isoforms (hUGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, and 2B17). As a result, BCP-NG formation (pmol equivalents/min/mg protein) was observed with microsomes expressing hUGT1A1 (142), 1A3 (196), 1A4 (8), 1A7 (8), 1A8 (66), 1A9 (38), 1A10 (9), 2B4 (7) and 2B7 (16). In particular, the activity of hUGT1A1 and 1A3 was high. These results suggest that the UGT isoforms responsible for formation of BCP-NG exist in various mammalian species, including humans, and that the UGT 1A family is primarily responsible for BCP N-glucuronide formation in humans.

Bucolome N-glucuronide (BCP-NG, main metabolite of bucolome (BCP) is the first N-glucuronide of barbituric acid derivatives isolated from rat bile. The objective of this study was to identify the main tissue producing BCP-NG and the molecular species of BCP-NG-producing UGT. Four target tissues were investigated: the liver, small and large intestines, and kidney. To identify the UGT molecular species responsible for BCP-NG formation, yeast microsomes expressing each rat UGT isoform were prepared. BCP-NG formation was detected in all microsomal fractions of the 4 tissues. The liver microsomal BCP-NG-producing activity was the highest, followed by that in the small intestinal microsomes, showing about 41% of the liver microsomal activity level. BCP-NG-producing activity (min-1) was determined in yeast microsomal fractions expressing rat UGT isoforms, and the activity was detected in UGT1A1 (0.059), UGT1A2 (0.318), UGT1A3 (0.001), UGT1A7 (0.003), UGT2B1 (0.004), UGT2B3 (0.091), and UGT2B6 (0.031), showing particularly high levels for UGT1A1 and UGT1A2 among the UGT1A isoforms. It was clarified that UGT1A1, widely distributed in rat tissues, is the molecular species responsible for BCP-NG formation.

To investigate the relation between tendency of feverishness and patient profile in pegylated interferon (peginterferon) and ribavirin combination therapy, we performed a retrospective survey of the medical charts of patients with chronic hepatitis C that have been on interferon therapy for the past two years. The sample was 36 patients (18 males, 18 females, aged 30 to 67 years, average of 57.5 years) who were hospitalized for the introduction of peginterferon-alpha 2b and ribavirin combination therapy and did not use NSAIDs before the administration of interferon. We examined body temperature and laboratory values (AST, ALT, WBC, Hb, PLT, BUN, Cr, HCV RNA level, and HCV genotype) for one week from the initiation of peginterferon administration to one week after the administration. Tendency of feverishness was classified into two groups according to the time to reach maximum body temperature. The early fever-developing group reached maximum body temperature within 12 hours of the administration, and the slow fever-developing group reached maximum body temperature after 12 hours post administration. The early fever-developing group had a significantly higher maximum body temperature (early group, 38.5 degrees C+/-0.55; slow group, 37.8 degrees C+/-0.55), more persistent fever (early group, 71.0 h+/-31.3; slow group, 36.5 h+/-41.8), and a higher percentage of females (early group, 80.0%; slow group, 28.6%). Moreover, females and elderly patients developed significantly higher fever (temperature difference 0.78 degrees C) early (8.5 h) after peginterferon administration. These results indicate the need for careful observation of females and elderly patients in the early stage of an initial treatment of chronic hepatitis C with peginterferon.

It has been reported that the intestinal absorption of celiprolol, an antihypertensive drug, is inhibited when it is taken with orange juice; it has been suggested that element(s) in citrus juice are responsible for this. In the present study, the pharmacokinetic interaction between celiprolol and orange juice was characterized through in vivo experiments with rats. Celiprolol 5 mg/kg was injected into the rat duodenum together with 5 ml/kg of neutralized orange juice or the same concentration of hesperidin as in the orange juice. Plasma celiprolol concentrations were measured by liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS). Concomitant administration of orange juice or hesperidin with celiprolol significantly decreased the area under the plasma concentration-time curve (AUC) by 74% and 75%, respectively, compared with control. These findings suggest that hesperidin is responsible for the decreased absorption of celiprolol and that orange juice taken with celiprolol has an inhibiting effect on intestinal absorption of the drug.

The secondary and adverse effects when biguanides, alpha-glycosidase inhibitor or thiazolidine derivative was used with sulphonylurea agent (SU) as compared with those with SU alone in Type 2 diabetes patients by using Systematic Review. Two-agent concurrent treatment groups, taken from studies in which subjects were assigned to a group given only a sulfonylurea agent and a group given a sulfonylurea agent with the other glycemic control agent (combination of a sulfonylurea agent and a biguanide agent (I), combination of a sulfonylurea agent and an alpha-glucosidase inhibitor (II), and combination of a sulfonylurea agent and thiazolidinedione (III)), were studied in a randomized controlled trial. The secondary efficacy outcome measures were total cholesterol (TC), triglyceride (TG), HDL-C, LDL-C, and change in body weight. The incidence of hypoglycemia, feeling of fullness, diarrhea, liver dysfunction, and edema was investigated as a safety outcome measure, and the clinical significance of concurrent treatment with a sulfonylurea agent in addition to the other glycemic control agent was investigated. With respect to (II), an antidiabetic effect was showed. As for (III), it had the disadvantage of increased body weight. Furthermore, increase of HDL-C levels, in particular, was observed. The improving effect of (III) on serum lipids may be clinically effective for considering the pathologic condition of diabetes, which is often complicated by hyperlipidemia.

This study was aimed to investigate the capacity of a standardized root water extract of Eurycoma longifolia (Tongkat Ali, TA), Physta® to modulate human immunity in a middle-aged Japanese population. This randomized, double-blind, placebo-controlled, parallel study was conducted for 4 weeks. Eighty-four of 126 subjects had relatively lower scores according to Scoring of Immunological Vigor (SIV) screening. Subjects were instructed to ingest either 200 mg/day of TA or rice powder as a placebo for 4 weeks [TA and Placebo (P) groups] and to visit a clinic in Tokyo twice (weeks 0 and 4). SIV, immunological grade, immunological age, and other immune parameters were measured. Eighty-three subjects completed the study; 40 in the TA group and 41 in the P group were statistically analyzed, whereas two were excluded from the analyses. At week 4, the SIV and immunological grade were significantly higher in the TA group than those in P group (p 0.05). The numbers of total, naïve, and CD4(+) T cells were also higher in the TA group than those in P group (p 0.05). No severe adverse events were observed. The results suggest that ingestion of the root water extract of TA (Physta®) enhances comprehensive immunity in both middle-aged men and women. This study is registered in UMIN-CTR (UMIN000011753).

Little information is available about drug interactions with cranberry juice (CJ). Using microsomes from the human liver and rat small intestine, this study was designed to determine whether CJ could inhibit CYP3A-mediated nifedipine (NFP) oxidase activity; it showed that CJ was a potent inhibitor of human and rat CYP3A. Preincubation with 10% vol/vol of CJ and 1 mM NADPH for 10 min resulted in significant inhibition of the NFP oxidation activity of human and rat CYP3A (18.2 and 12.6% decreases, respectively, compared with preincubation experiments without NADPH). In addition, the pharmacokinetic interaction between CJ and NFP in vivo was confirmed in rats. In comparison with a control group, the area under the concentration-time curve (AUC) of NFP was approximately 1.6-fold higher when CJ (2 mL) was injected intraduodenally 30 min before the intraduodenal administration of NFP (30 mg kg−1). However, the mean residence time, the volume of distribution and the elimination rate constant were not changed significantly. These data suggest that CJ component(s) inhibit the function of enteric CYP3A. In conclusion, it was found that CJ inhibits the CYP3A-mediated metabolism of NFP in both rats and humans. Furthermore, CJ alters NFP pharmacokinetics in rats.

It has been reported that grapefruit juice (GJ) causes pharmacokinetic interactions with many drugs after co-ingestion, but the effects of the juice of sweetie fruit, a cross between a pomelo and a grapefruit, on the pharmacokinetics of medicines have not been clear. The present study investigated the drug interaction capability of sweetie juice (SJ). The effect of SJ on nifedipine (NFP) pharmacokinetics in rats was studied. Two milliliters of SJ, GJ, or saline was administered to the rat duodenum. After 30 min, NFP was administered intraduodenally at a dose of 3 mg/kg body weight. The NFP concentrations in the plasma samples were determined by high performance liquid chromatography (HPLC). Although GJ increased the area under the plasma concentration-time curve (AUC) of NFP (1.6-fold), SJ had no significant effect on the NFP pharmacokinetics in rats. Furthermore, concentrations of furanocoumarin derivatives in SJ were measured by HPLC equipped with a photodiode array detector, and compared with those in GJ. SJ contained lower concentrations of bergamottin (0.53 microg/ml), 6', 7'-dihydroxybergamottin (0.19 microg/ml), and bergaptol (0.2 microg/ml) than the GJ used in this study (6.3 microg/ml, 3.6 microg/ml, and 9.4 microg/ml, respectively). In conclusion, the results suggest that SJ had no effect on the NFP pharmacokinetics in rats due to low furanocoumarin concentrations in SJ.

Dulcin (DL), 4-ethoxyphenylurea, a synthetic chemical about 200 times as sweet as sucrose, has been proposed for use as an artificial sweetener. DL is excreted as a urinary ureido-N-glucuronide after oral administration to rabbits. The phenylurea N-glucuronide is the only ureido conjugate with glucuronic acid known at present; therefore, DL is interesting as a probe to search for new functions of UDP-glucuronosyltransferases (UGTs). Seven UGT isoforms (UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT2B13, UGT2B14, and UGT2B16) have been identified from rabbit liver, but these UGTs have not been investigated using DL as a substrate. In this work, the identities of UGT isoforms catalyzing the formation of DL glucuronide were investigated using rabbit liver microsomes (RabLM) and cloned/expressed as rabbit UGT isoforms. DL-N-glucuronide (DNG) production was determined quantitatively in RabLM and homogenates of COS-7 cells expressing each UGT isoform by using electrospray liquid chromatography-tandem mass spectrometry. Analysis of DNG formation using RabLM, by Eadie-Hofstee plot, gave a Vmax of 0.911 nmol/min/mg protein and the Km of 1.66 mM. DNG formation was catalyzed only by cloned expressed rabbit UGT1A7 and UGT2B16 (Vmax of 3.98 and 1.16 pmol/min/mg protein and a Km of 1.23 and 1.69 mM, respectively). Substrate inhibition of UGT1A7 by octylgallate confirmed the significant contribution of UGT1A7 to the formation of DNG. Octylgallate was further shown to competitively inhibit DNG production by RabLM (Ki = 0.149 mM). These results demonstrate that UGT1A7 is the major isoform catalyzing the N-glucuronidation of DL in RabLM.

We examined hydrogenated purified egg yolk lecithins, having practical advantages over non-hydrogenated ones, as liposomal membrane materials. Liposomes were prepared by the microencapsulation vesicle (MCV) method in which liposomes are formed through two-step emulsification and dispersion. Three types of purified egg yolk lecithins with different iodine values were examined after being dissolved in one of three lipid solvents. The liposome size increased as the temperature during the second emulsification increased, being closer to the boiling temperature of the solvent. The preparation temperature in relation to the transition temperature of each lecithin was also a factor affecting liposome sizes. As for the encapsulation efficiencies of the model compound calcein in liposomes, they differed mainly depending on the solubility of each lecithin in a lipid solvent and it was more obvious in hydrogenated lecithins. A high preparation temperature resulted in lower encapsulation efficiencies, suggesting that leakage of encapsulated calcein was facilitated at high temperature in the MCV methods. There was a significant correlation between liposome sizes and encapsulation efficiencies in non-hydrogenated purified egg yolk lecithin but not in hydrogenated ones. When using hydrogenated purified egg yolk lecithins as liposomal membrane materials, it was suggested that a lipid solvent should be chosen so that a lecithin completely dissolves under the preparation condition in order to achieve a higher encapsulation efficiency. Smaller liposome particles were obtained when the second emulsification was performed at a lower temperature compared with the boiling point of the lipid solvent. These findings can be applied to control encapsulation efficiencies and particle sizes in each particular liposome preparation enclosing therapeutic agents.

Bucolome (BCP) is a non-steroidal anti-inflammatory drug, which is used in the treatment of chronic articular rheumatism. Bucolome N-glucuronide (BCP-NG), a metabolite of BCP, is the first unique N-glucuronide of barbituric acid derivatives. First, the stability of BCP-NG in various pH aqueous solutions was studied. BCP-NG was quite unstable under neutral and acidic conditions, and is easily hydrolyzed to BCP. Based on these characteristics of BCP-NG, a simple, rapid and highly sensitive method for the simultaneous determination of BCP and BCP-NG with phenylbutazone (I.S.) in biological fluids was developed using high-performance liquid chromatography (HPLC). A reversed-phase ODS column was used for the separation of BCP, BCP-NG and I.S. A pharmacokinetic study for BCP and BCP-NG was carried out in male Wistar/ST rats following i.v. administration of BCP at a dose of 10 mg/kg body weight. The slow plasma elimination of BCP with time was shown. A major metabolite of BCP in bile was N-glucuronide. The cumulative amounts of BCP and BCP-NG in the bile over 8 h were approximately 2.4±1.4% and 12.6±2.3% of the dose, respectively. BCP and BCP-NG in the urine were 2.7±0.7% and 3.2±0.3% of the dose. Although BCP had a long half-life (over 8.5 h), the preliminary pharmacokinetic parameters (0–8 h) were determined: t1/2, 8.52±1.96 h; AUC, 419.9±45.2 μg·h/ml; MRT, 3.29±0.11 h; CLtot, 5.93±0.54 ml/h; and Vdss, 19.5±1.3 l. These observations are the first pharmacokinetic findings for the N-glucuronide of the barbituric acid derivatives.

Purpose. It has been reported that grapefruit juice (GJ) causes a pharmacokinetic interaction with many drugs after co-ingestion. It is postulated that the substances in GJ may inhibit the first-pass metabolism during the intestinal absorption process. In recent years, several furanocoumarin derivatives that inhibit P450 activity in intestinal microsomes were isolated from GJ. In this study, we report the effects of the furanocoumarin derivatives in GJ on the nifedipine (NFP) pharmacokinetics in rats. Methods. Three furanocoumarin derivatives (bergaptol [BT], bergamottin [BG], and 6′,7′-dihydroxybergamottin [DHB]) found in GJ were used in this study. Each furanocoumarin was reconstituted in orange juice at the same concentration as in the GJ. Two milliliters of each sample was administered into the rat duodenum. After 30 min, NFP was intraduodenally administered at a dose of 3 mg/kg body weight. The NFP concentrations in the plasma samples were determined by HPLC. Results. A significant increase in the AUC of NFP was observed only in the rats administered BG; 1.5 times that of the control group. The result was quite identical with that of the group that was administered GJ. BT and DHB had no significant effects on the NFP pharmacokinetics. Conclusions. The results strongly suggested that BG in GJ might be the substance that elevates the NFP plasma concentrations.

An isocratic HPLC method for the simple and selective determination of adenine nucleoside and nucleotides has been developed. The separation is achieved at room temperature by reversed-phase chromatography (Shiseido, Capcell Pak C18). A mixture of 0.1 M triethylamine (TEA) phosphate buffer and methanol (95:5, v/v) is used as a standard eluent. Influence of pH and concentrations of organic modifiers and TEA ion on capacity factors of adenine compounds has been investigated. It has been also found that the TEA ion in the eluent is adsorbed onto the reversed-phase surface. The results clearly demonstrate that ion-pair formation with TEA ion occurs probably both in the mobile phase and on the stationary phase and governs the retention of adenine and nucleotides in the present system. The HPLC system is applied to the analysis of adenine nucleotides formed as intermediates in the synthesis of 3'-phosphoadenosine 5'-phosphosulphate (PAPS) and to the assays of ATPases and 5'-nucleotidase activities in rat liver plasma membrane. This method is a new type of ion-pair reversed-phase HPLC system and is suitable for the separation of highly polar organic anions, especially for adenine nucleotides.

We have previously reported on the relative cytotoxicity of a total of 38 1,2,3,4-tetrahydroisoquinoline derivatives against human oral squamous cell carcinoma cell lines and human normal oral cells, and the correlation between the cytotoxicity and 17 chemical descriptors. However, the correlation between the tumor-specificity of these compounds and the chemical descriptors has never been investigated so far. Using these previous data, we investigated various parameters for their applicability in predicting tumor specificity.Original data of 50% cytotoxic concentration (CC(50)) values exceeding the maximum concentration in experimental conditions were corrected by the introduction of a harmonic mean, reducing the number of compounds analyzed to 30. The mean pCC(50) (=-log CC(50)) values for normal and tumor cells were defined as N and T, respectively. Tumor specificity was defined as the ratio of the difference of these values to their sum: (T-N)/(T+N). The chemical descriptors were obtained by quantum chemical calculations using semi-empirical (AM1, PM3, and PM6) and density functional theory methods. The relationship between the chemical descriptors and tumor specificity was analyzed by linear regression and artificial neural networks.Out of 17 chemical descriptors, water-accessible surface area showed the highest correlation coefficient with tumor specificity, regardless of the method of calculation. Furthermore, neural network analysis demonstrated the importance of quantum chemical calculations in predicting the specificity of tetrahydroisoquinoline derivatives.The present study suggests the applicability of quantum chemical descriptor in the estimation of tumor specificity of related compounds.

A simple, selective, sensitive, and rapid high-performance liquid chromatographic (HPLC) method is described for the quantitation of erythromycin (EM) in plasma and whole blood. The volume of plasma and whole blood and analytical time were only 0—2 ml and ∼15 min. Analytical recovery of EM at concentrations of 0.2, 1.0 and 5.0 μg/ml after the complete extraction procedures with diethyl ether from alkalinized plasma and whole blood was > 75%. The coefficients of variation (CVs) for intra- and inter- day assay riabilities at 0.2, 1.0 and 5.0 μg/ml of EM were

In order to improve the bioavailability of 6-mercaptopurine (6-MP), the elixir and two kinds of suppositories (Witepsol (WH) base and macrogol (MC) base) of 6-MP were prepared and administered to a child with acute lymphoblastic leukemia (ALL) in a balanced crossover design. Plasma levels and the area under the plasm concentration-time curve (AUC) values for 6-MP were determined following the powder, elixir and suppositories administrations of 6-MP. Compared with the AUC value after the powder administration, the relative bioavailabilities (Fret) for the elixir and suppositories were evaluated, respectively. The concentration of 6-MP in the elixir was prepared to 0.25%.The suppositories of 6-MP were prepared by the fusion method and the content was 20 mg/g/one suppository. The release of 6-MP from the suppositories was examined by the dissolution test in vitro before the clinical study. The release ratio of 6-MP was higher from the MC base suppository than from the WH base suppository. 6-MP was administered orally (50 mg/m2) and rectally (30 mg/m2) to the child with ALL, respectively. The plasma levels of 6-MP were determined by the high-performance liquid chromatography method. The AUC values (ng·hr/ml) from the powder, elixir, WH suppository and MC suppository administrations were 82.3, 204.0, 197.0 and 714.4, respectively.The Frel for the elixir, WH suppository and MC suppository were 2.48, 3.99 and 14.47, respectively, that was extremely increased by the MC suppository administration.This finding indicates that the rectal administration by the MC suppository of 6-MP could avoid the first-pass metabolism of this drug, and that this rectal administration of 6-MP will be effective on the treatment of children with ALL, especially for the patients with nausea and/or vomiting.

A formulation study of intravesical oxybutynin (OB) preparations was carried out in order to improve the effectiveness in intravesical instillation therapy for spastic neurogenetic bladder. Sodium hyaluronate (HYA) was introduced to enhance the muco-adhesiveness of the instillation preparation, and the physicochemical properties of the OB formulation were evaluated in comparison with a conventional formulation containing hydroxypropylcellulose (HPC). The viscous properties and in vitro adhesiveness increased with the amount of the polymeric additives, and retention properties of OB in rabbit bladder were comparable after addition of 0.4% HYA and 1.0% HPC. HYA was able to enhance the intravesical retention properties of OB instillation solution to a lesser degree than HPC, it seemed to be a useful additive in the OB instillation due to its safety and mucosal-protective effect.

It is well known fact that the strengths of drug interactions with grapefruit juice (GFJ) differ greatly depending on the 1,4-dihydropyridine calcium channel antagonist (DHP) used. However, there are no available data on the relationship between interactions with GFJ and its physicochemical attributes. Therefore we endeavored to study the correlation between calculated logP values, indicating lipophilicity, from chemical structures of DHPs as well as water diffusion, molecular volume, molecular polarization, molecular density, refractive index, topologic polar surface area, and calculated molar refractivity. Thirteen forms of DHP, amlodipine, azelnidipine, benidipine, cilnidipine, efonidipine, felodipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and pranidipine were analyzed due to clinical trials performed with GFJ and these agents. The pharmacokinetic interaction strengths were defined in common logarithmic values of increasing ratios of area under the plasma concentration-time curve (AUC) with GFJ intake compared with controls. Physicochemical properties including three categories of predicted logP values were calculated from the structures of DHPs and their estimated relationship with the interactions. As a result, the logP values indicated significant positive correlations with the interaction strengths. This finding suggests that lipophilicity is an important factor in the strengths of pharmacokinetic interactions of DHPs with GFJ intake.

Grapefruit juice (GJ) contains components that may increase the bioavailability of drugs; however, approaches to the removal of these components have been little investigated. It is known that furanocoumarin derivatives (FCs), such as bergamottin (BG) and 6',7'-dihydroxybergamottin (DHB) in GJ, induce such drug interactions. In the present study, it was found that the heat treatment of grapefruit juice decreases concentrations of BG and DHB as well as their interactions both in vitro and in vivo. We incubated GJ for 10, 20, 30, 40, 50, and 60 min at 37, 62, 72, and 95 degrees C; FCs in each sample were then measured, using high-performance liquid chromatography (HPLC). The concentrations of BG and DHB were decreased in a time- and temperature-dependent manner, by 82.5 and 97.9% respectively, after incubation for 1 h at 95 degrees C. In contrast, the concentration of bergaptrol (BT) increased in a time- and temperature-dependent manner (27.7% after 60 min at 95 degrees C). In addition, the effect of each GJ sample on testosterone 6beta-oxidation in human liver microsomes was observed. The inhibitory effects of GJ heated to 95 degrees C were decreased in a time-dependent manner, as in the case of BG and DHB concentrations. Furthermore, 2 ml of GJ treated for 60 min at 95 degrees C was administered into the rat duodenum. After 30 min, nifedipine (NFP) was administered intraduodenally at a dose of 3 mg/kg body weight. The concentrations of NFP in the plasma samples were determined by HPLC. No significant increase in the AUC of NFP was observed in the rats given heat-treated GJ. These results suggest that the heat treatment of GJ reduces the concentrations of FCs, thus eliminating the potential for drug interactions.

In the present study, UV-irradiated grapefruit juice was used to investigate the effects of UV light on nifedipine pharmacokinetics. Grapefruit juice in quartz vessels was UV irradiated (302 nm) with a transilluminator for 0 to 6 h at 4 degrees C, and furanocoumarins, potent contributors to the pharmacokinetic interaction, in each juice sample were measured using HPLC. The concentrations of all three types of furanocoumarins, bergamottin, 6',7'-dihydroxybergamottin, and bergaptol, decreased in a time-dependent manner. Concentrations of bergamottin, 6',7'-dihydroxybergamottin, and bergaptol were decreased to 1.66, 1.98, and 5.58%, respectively, after UV irradiation for 6 h. Two milliliters of untreated and UV-irradiated grapefruit juice were preadministered into the duodenum in rats to assess the effects of UV irradiation on nifedipine pharmacokinetics in vivo. After 30 min, nifedipine was intraduodenally administered at a dose of 3 mg/kg body weight. The nifedipine concentrations in the plasma samples were determined using HPLC. A significant increase in the area under the concentration-time curve of nifedipine was observed in untreated grapefruit juice to 1.6-fold that in the control group, but not in the UV-irradiated grapefruit juice. These findings suggest that UV irradiation is useful to eliminate pharmacokinetic interactions with grapefruit juice.

Dulcin (DL), now banned, was once a widely used artificial sweetener. DL possesses an ureido group that is metabolized by direct glucuronidation in rabbit liver microsomes. Dulcin N-glucuronide (DNG) is the only type of ureido N-glucuronide known to date; ureido glucuronidation in humans has not been previously reported. Accordingly, the glucuronidation of DL was studied using human liver microsomes (HLM) and expressed human UDP-glucuronosyltransferase (UGT) enzymes. The average K m and V max values from nine HLM samples were 2.10 mM and 0.156 nmol/mg/min, respectively. Of the six human UGT isoforms screened for their ability to glucuronidate DL, only UGT1A1 and UGT1A9 showed activity. The apparent K m values using UGT1A1 and UGT1A9 were 5.06 and 6.99 mM, and the apparent V max values were 0.0461 and 0.106 nmol/min/mg, respectively. Phenolphthalein, a substrate for UGT1A9, inhibited DL glucuronidation in HLM competitively (K i = 0.356 mM), but bilirubin, a substrate for UGT1A1, did not. These results suggest that UGT1A9 is a key enzyme catalyzing the glucuronidation of DL.

Stomatitis is a harmful side effect induced by high and/or multiple dosing of cytotoxic drugs such as 5-fluorouracil. Allopurinol mouthwash has been used to prevent stomatitis induced by cancer chemotherapy. In the present study, the pharmaceutical utility of allopurinol mouthwash (Alkox-mw), which consists of polyethylene(oxide) (Alkox) and iota-carrageenan (INA), was investigated as a possible material for a new oral dosage preparation for improving the adhesiveness onto the oral mucosa. From the observation of the gel formation, which was studied as a function of the variety of the added Alkox and/or INA, the preferential compositions of Alkox-mw (Alkox:INA % ratio) seemed to be 1.0:(0-1.0) and (0-3.0):0.4, respectively. The adhesiveness and the spinnability of various allopurinol mouthwashes were also investigated using a creep meter. The adhesiveness of Alkox-mw increased with the increase in the amount of added Alkox. Furthermore, the adhesion force of Alkox-mw was greater than that of allopurinol mouthwash consisting of sodium carboxymethylcellulose (CMC-Na). From the in vitro assessment of mimicking the effusion of the allopurinol mouthwashes from the surface of the oral mucosa, the effusion of Alkox-mws was retarded by the added Alkox. The results obtained in the present study suggest that Alkox-mws may be useful as a new dosage form that adheres to the oral mucosa.

The pharmaceutical utility of the allopurinol gel (APNgel) which consists of allopurinol (APN), carrageenan (kappa-CG or iota-CG) and polyethylene (oxide) (Alkox) was investigated as a possible material for an oral dosage preparation for ease in handling and/or swallowing. The gel formation was studied as a function of a variety of the concentration of Alkox and/or CG added. The APNgel gelled with kappa-CG was not appropriate to the oral dosage form because of its original taste and odor. In contrast, since iota-CG has no odor and/or taste, we added iota-CG as a gel material. From the investigation of the gelation behavior and the handling of the gelled material, the preferred composition of APNgel (Alkox: iota-CG% ratio) seemed to be that of 0.5:2.0, 1.0:2.0 and 2.0:2.0. The gel strength and the in vitro assessment of the adhesiveness of APNgels were evaluated using a creep meter. The gel strength of the APNgel was affected by the amount of the added Alkox. From the in vitro assessment of the adhesiveness of APNgels, the adhesiveness of APNgel increased with an increase in the amount of added Alkox. The release behavior of APN from APNgels was investigated by the paddle bead method, mimicking the chewing action in mouth. The APNgel was sheared by the beads and the release of APN completed within 480 s. From the results of the sensory test, APNgel consisting of 2.0% iota-CG and 1.0% Alkox seemed to be favorite to the jelly-like preparation.

A simple, selective, sensitive and rapid high-performance liquid chromatographic method for the simultaneous determination of amfenac sodium (AMF) and its metabolite (7-benzoyl-2-oxindole, S1) in plasma was established. To 100 microliters of plasma, purified water (100 microliters), ammonium sulphate (0.2 g) and ethanol (100 microliters) containing fenbufen (100 micrograms/ml, internal standard) were added. After centrifugation the ethanol layer was directly injected into a reversed-phase ODS column. AMF and S1 were eluted using a gradient buffer system of 20-80% acetonitrile-phosphate buffer (pH 7.0), and detected at 245 nm. The analytical recoveries of AMF at concentrations of 0.5, 2 and 10 micrograms/ml in plasma were ca. 92.1, 95.4 and 94.6%, respectively. The coefficients of variation of the AMF recoveries were below 4.6%. The S1 recoveries at the concentrations of 40, 200 and 400.ng/ml were ca. 93.4, 98.7 and 95.3%, and the coefficients of variation were below 6.0%. The coefficients of variation for intra- and inter-day variation of AMF (5 micrograms/ml) and S1 (100 ng/ml) were 4.5 and 3.6% and 4.2 and 4.2%, respectively. The detection limits of AMF and S1 in plasma were as low as 0.1 microgram/ml and 20 ng/ml, and the coefficients of variation were 4.0 and 4.4%, respectively. The method was applied to determine the plasma concentrations of AMF and S1 after oral administration of AMF capsules (100 mg of AMF) to human volunteers.

An automated column-switching high-performance liquid chromatographic (HPLC) method with ultraviolet detection is described for a simple and rapid determination of melphalan, an alkylating agent, in human plasma following direct sample injection. The system consists of a pretreatment column and an analytical column connected in series via a switching valve. Plasma samples are loaded onto a pretreatment column with an aqueous mobile phase, with which the sample to be analyzed is retained and the solubilized plasma proteins are flushed to be discarded. The retained compound is eluted from the pretreatment column onto the analytical column by using the chromatographic mobile phase with a higher elution capacity. The column-switching technique can be used to achieve an automated assay. Analytical recovery of the compound was 99.1%, and the coefficients of both intra- and interday variations did not exceed 3.5%. The detection limit was 10 ng/ml for the compound. Recovery of melphalan in plasma was only 2.1% after 4 weeks at 25 degrees C, as compared to 24.5% at 5 degrees C and 100.1% at -20 degrees C.

From the Fortnosan ferns, Plenasium banksiaefolium and Bolbitis subcordata, the phytoecdysones ponasterone A and ecdysterone, respectively, have been isolated.