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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.

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.

Methyldopa, an antihypertensive, is a very close analogue of DOPA. Drug interaction accompanied by degradation in a banana juice mixture was reported for DOPA. However, the effect of banana on methyldopa has not been reported. Therefore, we have investigated the impact of banana juice on methyldopa. The drug and supernatant of banana pulp were mixed, and the mixture was observed for changes in color, drug concentration, and ultraviolet-visible absorption spectra at 30 °C. The originally clear and colorless mixture started to acquire a yellow coloration after about 30 seconds after the mixing. The color tone increasingly deepened, then blistered solid particles that do not dissolve were observed after 3 hours. Concentration of methyldopa in the mixture decreased by 60% after 5 min, to 0.5% after 30 min of the mixing. From these findings, it was suggested that the drastic alterations were caused by banana polyphenol oxidase that plays a role in the biosynthesis of melanin pigment from levodopa in banana pulp. Because the degradation of methyldopa occurs extremely fast, it was suggested concomitant use of this anti-hypertensive and banana juice consumption should be avoided in clinical practice.

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.

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.

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.

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.

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.

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.

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.