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Biomedical subjects

I Horikoshi

Publications and source records attributed to I Horikoshi.

At least 19 recordsLinked to original sources
PubMed1995

Preparation and characterization of dextran magnetite-incorporated thermosensitive liposomes: an on-line flow system for quantifying magnetic responsiveness.

PURPOSE: Dextran magnetite (DM)-incorporated thermosensitive liposomes, namely thermosensitive magnetoliposomes (TMs), were prepared and characterized in order to investigate their possibility for magnetic drug targeting. METHODS: TMs containing calcein were prepared at various DM concentrations by reverse-phase evaporation of dipalmitoylphosphatidylcholine (DPPC). They were evaluated for their physicochemical properties including size, DM capture, magnetite distribution within liposomes, and temperature-dependent calcein release. Moreover, a novel on-line flow apparatus with a sample injector, a coil of tubing placed in an electromagnet, and a fluorescence detector was developed for quantifying the magnetic responsiveness of TMs. This device allowed us a real-time measurement of percentage holding of TMs by magnetic field. RESULTS: Due to water-soluble property of DM, higher contents of magnetite up to 490 mg per mmol DPPC were successfully incorporated into the liposomes with DM than with conventional magnetite (Fe3O4). Thermosensitivity and lipid integrity of TMs were not influenced by inclusion of DM. Using the on-line flow system, percentage holding of TMs by magnetic field was shown to vary with several factors; it increases as the magnetic field strength increases, the fluid flow rate decreases, the magnetite content increases, and the liposome concentration increases. Typically, at 490 mg incorporated magnetite per mmol DPPC, 0.5 ml/min-fluid flow rate, and high magnetic field strength (> or = 10 kiloGauss), approximately 100% of TMs were found to be held. CONCLUSIONS: The TMs were suggested to be useful in future cancer treatment by magnetic targeting combined with drug release in response to hyperthermia.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1995

Study on hepatic artery chemoembolization using temperature-sensitive liposome or lipiodol emulsion.

As a novel method for the medical application of liposomes, we have tried hepatic artery chemoembolization using temperature-sensitive liposomes with hyperthermia for the treatment of hepatic tumors. In this study, the effect of temperature-sensitive liposomes was compared with that of Lipiodol emulsion, which has been used clinically. The temperature-sensitive liposomes, consisting of dipalmitoylphosphatidylcholine or Lipiodol emulsions entrapping doxorubicin, were administered into the hepatic artery of hepatic tumor-bearing rats via a cannula. Doxorubicin administered in a liposomal form showed a high accumulative property toward tumors, with heating, while that in the emulsion form showed a slow release property toward tumors. Not only was tumor growth inhibited, but also, an actual diminishing of the tumor was observed in each form. Side effects were also examined: an abnormal rise in GPT, or necrosis of the normal tissues in liver, which was often observed in hepatic artery chemoembolization using Lipiodol emulsion, was remarkably reduced in the liposomal chemoembolization.

Animals↗
PubMed1994

Clinical effects of long-term administration of pimobendan in patients with moderate congestive heart failure.

The long-term efficacy of the positive inotropic and vasodilator drug, pimobendan, was assessed in 21 patients suffering from symptomatic heart failure. Patients were randomized to 16 weeks of double-blind therapy with either 2.5 or 5.0 mg/day of pimobendan (n = 10), or a matching placebo (n = 11). Patients were blinded on the study drug if their clinical status had not substantially worsened during the study. Of the placebo-treated patients, 5 patients were withdrawn from the study because of a deterioration of their heart failure, while none of the active treated group was withdrawn because of increased symptoms. Quality of life, assessed by the specific activity scale derived from the metabolic costs of individual physical activity, was 3.45 +/- 0.90 (SD) mets in the baseline state and increased significantly after week 16, averaging 5.07 +/- 1.40 and 4.67 +/- 1.47 mets at weeks 16 and 24, respectively. In the placebo-treated group, the specific activity scale was 3.27 +/- 1.21 mets at the baseline and remained unchanged throughout the study period. Patients treated with pimobendan were able to significantly increase their exercise duration. The accompanying increase in peak oxygen uptake was statistically insignificant, due to the limited number of patients enrolled in the study. These results suggest that in contrast to the recent pessimistic view of the long-term efficacy of cardiotonic drugs, pimobendan is beneficial in treating patients with congestive heart failure and may favorably modify their prognosis. Further large-scale evaluation of this agent is warranted.

Activities of Daily Living↗
PubMed1994

Enhancement of the intestinal absorption of a cyclosporine derivative by milk fat globule membrane.

A cyclosporine derivative, dihydrocyclosporine D, was used for the evaluation of milk fat globule membrane (MFGM) as an emulsifier of lipophilic cyclopeptides. As compared with olive oil formulation, MFGM emulsion significantly enhanced the blood and lymphatic fluid concentrations of the cyclosporine derivative after intraduodenal dosing in rats. Thus, it was suggested that MFGM can be used as an intestinal absorption enhancer of cyclosporines.

Animals↗
PubMed1994

Calcein release from temperature-sensitive liposome with or without stirring.

Characteristics of the calcein release from temperature-sensitive liposomes with or without stirring were studied. Calcein release from DPPC(dipalmitoylphosphatidylcholine) REV(reverse phase evaporation vesicle) with stirring occurred at a temperature lower by 8 degrees than that without stirring. DPPC-DSPC(distearoylphosphatidylcholine)-mixed REV showed the maximum release(%) for calcein, near 40 degrees C with stirring and 45 degrees C without stirring.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1994

Rectal absorption of ozagrel from suppositories in rabbits.

Rectal absorption of ozagrel (a selective thromboxane synthetase inhibitor) from suppositories was studied in rabbits. Two kinds of suppositories were prepared, one was from ozagrel powder (OPS, ozagrel powder suppository), and the other from ozagrel tablet (OTS, ozagrel tablet suppository). Ozagrel from OPS was absorbed quickly with a Tmax value of 26.3 +/- 7.5 min, and the peak plasma level was significantly higher than that involving intravenous infusion or oral dose (50.3 +/- 6.7 vs. 32.8 +/- 5.4 or 9.9 +/- 1.2 micrograms/ml), indicating that OPS may be a useful dosage form rather than injection. OTS was absorbed less rapidly than OPS, but the AUCs of both suppositories were similar. Because OTS was prepared using an ozagrel tablet, it is fairly easy to get an equal content in each suppository. Therefore, OTS is not only an experimentally interesting dosage form, like OPS, but is also a practical preparation for clinical use.

Absorption↗
PubMed1993

Enhanced therapeutic effect against liver W256 carcinosarcoma with temperature-sensitive liposomal adriamycin administered into the hepatic artery.

The antitumor activity of Adriamycin encapsulated in temperature-sensitive liposomes combined with local hyperthermia (HT) was tested in rats bearing well-developed liver W256 carcinosarcoma tumors. Two h after rats received Adriamycin encapsulated in temperature-sensitive liposomes via either the hepatic artery (i.a.) or the femoral vein (i.v.) or free Adriamycin i.a., liver HT was applied at 42 degrees C for 6 min. In animals treated with liposomal Adriamycin i.a., HT resulted in a 38% reduction in the tumor volume ratio and a 2.2-fold increase in the life span of the animals. In animals treated with liposomal Adriamycin i.v. or free Adriamycin i.a., HT did not alter the tumor volume ratio or life span of the animals. Administration i.a. of liposomal Adriamycin markedly increased the tumor drug levels (4-14-fold), reduced the systemic distribution of the drug, and slowed the drug decrease from both the tumor and liver compared with animals treated i.v.. Liver HT in animals treated with liposomal Adriamycin i.a. further increased tumor drug levels by 1.5-2.6-fold, further slowed the drug decrease from the tumor, and resulted in a dissociation of the parallel decrease of drug and lipid from the tumor. This latter effect was not observed in the other groups. These pharmacological findings combined with the lack of beneficial effect from HT in animals treated with free Adriamycin i.a. or liposomal Adriamycin i.v. suggest that i.a. administration of Adriamycin encapsulated in temperature-sensitive liposomes results in a significant retention of intact liposomes in the tumor vasculature that are able to release the encapsulated drug into the tumor cell compartment upon raising the temperature to the phase transition level.

Animals↗
PubMed1993

Organ distribution and antitumor activity of free and liposomal doxorubicin injected into the hepatic artery.

The plasma levels, organ distribution, and in vivo antitumor activity of free and liposomal doxorubicin injected into the hepatic artery of rats bearing W256 liver tumors were studied. The administration of liposomal doxorubicin resulted in liver-tumor and liver-parenchyma doxorubicin areas under the curve (AUCs) that were 4.7- and 3.8-fold, respectively, those obtained after the administration of free doxorubicin. Spleen and plasma AUCs were also increased by 2.8 and 2.5 times, respectively, following administration of the liposomal form. In contrast, liposomal doxorubicin did not affect heart AUCs; peak doxorubicin levels in heart tissue were three times lower in animals treated with liposomal doxorubicin. Following treatment with the liposomal form, the cumulative urinary excretion of doxorubicin at 8 h was 38 times lower. In good correlation with these findings, liposomal doxorubicin (2.35 mg/kg on day 7) was more effective than free doxorubicin against liver W256 tumors as measured by tumor-growth inhibition at 5 days after treatment (16% for liposomal doxorubicin versus -53.7% for free doxorubicin, P < 0.05) and increased life span (ILS; 108% for liposomal doxorubicin versus 27% for free doxorubicin, P < 0.05). These results demonstrate that as compared with free doxorubicin, the administration of liposomal doxorubicin into the hepatic artery results in higher drug levels in the liver tumor and enhanced antitumor activity while maintaining the cardioprotective effect of the liposome carrier as suggested by the decreased peak drug levels measured in the heart tissue.

Animals↗
PubMed1993

Inhibitory effects of tannins on NADH dehydrogenases of various organisms.

We examined the effects of purified tannins and related compounds (33 species) on NADH-ubiquinone-1 oxidoreductase activity in four kinds of organism (Paracoccus denitrificans, Bacillus subtilis, Photobacterium phosphoreum, and Thermus thermophilus HB-8) and rat liver mitochondria. In addition to pentagalloylglucose, which was reported as a potent inhibitor of NADH dehydrogenases (NDH), sanguiin H-11, oolonghomobisflavan A, and polymerized procyanidin are potent inhibitors for both types of NDH (NDH-1 and NDH-2). We found that some other tannins contained in tea are also inhibitors of NDH from all organisms.

Animals↗
PubMed1992

Targeting liver tumors by administering liposomal doxorubicin into the hepatic artery.

The plasma levels, organ distribution, and in vivo anti-tumor activity of liposomal doxorubicin administered i.v. or i.a. (hepatic) in rats bearing W256 liver tumors were studied. I.a. administration of liposomal doxorubicin resulted in 4-fold and 1.3-fold higher liver tumor and liver parenchyma doxorubicin levels, respectively, than i.v. administration, thus suggesting a more preferential distribution of liposomal doxorubicin into the liver tumor with i.a. administration. By contrast, the heart, spleen, and plasma AUCs were decreased 3.8-, 3.2-, and 16-fold, respectively, after i.a. administration. Cumulative urinary excretion at 8 hr was also 14 times lower in animals that received liposomal doxorubicin i.a. In good correlation with these findings, i.a. administration markedly enhanced the anti-tumor effect of liposomal doxorubicin against liver W256 tumors as measured by tumor growth inhibition 5 days after treatment (-16% for i.a. administration vs. +89% for i.v. administration, p less than or equal to 0.05) and prolongation of survival (ILS: 108% for i.a. administration vs. 26% for i.v. administration, p less than or equal to 0.05). Our results show that i.a. administration of liposomal doxorubicin results in preferential distribution of the anti-tumor agent into the tumor tissue and increased anti-tumor activity, while increasing the cardioprotective effect of the liposome carrier by decreasing the plasma peak and heart-tissue levels of the drug.

Animals↗
PubMed1992

Bioavailability of morphine in rabbits after rectal administration of suppository containing controlled release morphine tablet.

Two kinds of sustained release morphine suppositories have been prepared; one is an oleaginous base suppository (MSC) containing a controlled release morphine tablet (MST: MS Contin), and the other is a hollow-type suppository (MSCH) containing MST and morphine powder packed in its hollow space. In vitro release tests and in vivo rectal absorption experiments in rabbits were performed. The profiles of morphine release from MST and MSC in vitro were similar, and revealed that suppository bases had no effect on the release profile of morphine from the preparation. Morphine release from MSCH was rapid in the early phase, and then enclosed morphine was slowly and continuously released from MST. Phamacokinetics of morphine from the suppository were compared with the orally administered MST, and it was found that there was no difference in the maximum plasma concentration (Cmax) and the peak time (Tmax) between MSC and MST, but the mean residence time (MRT) of MSC was approximately three times longer than that of MST, and the extent of bioavailability (BA) of MSC was significantly larger than that of MST (71.6 +/- 14.2% and 11.9 +/- 4.0%, respectively). Cmax can be altered arbitrarily by changing the morphine content in the hollow space of MSCH. As in the case of MSC, the plasma concentration of morphine from MSCH was maintained. It is concluded from the above results that MSC is a satisfactory sustained release morphine suppository for the treatment of cancer pain, administering it twice a day, and that MSCH is effective due to its fast analgesic effect and sustained release nature not only for cancer pain but also for surgical operations.

Administration, Rectal↗
PubMed1991

Age-dependent changes in first-pass metabolism of acetaminophen in rats.

The contribution of gastrointestinal tract (GIT), liver, and lung towards the first-pass metabolism of acetaminophen was examined using 3-week-old, 10-week-old and 1-year-old rats after administration of 30 mg kg-1 doses by intra-arterial, intravenous, intraperitoneal, and oral routes. Plasma concentrations of acetaminophen and its two major metabolites, acetaminophen glucuronide and acetaminophen sulfate, were measured for about 5h after drug administration. Total oral extraction of acetaminophen was extensive in 10-week-old and 1-year-old rats (Eo = 0.46) and the major contribution to the overall first-pass metabolism was due to the GIT (Eg = 0.50-0.53). Oral extraction in 3-week-old rats was minimal (Eo = 0.10) and there did not appear to be an extraction by the GIT (Eg = 0.00). These results suggest that the ability of GIT to metabolize acetaminophen to glucuronide and sulfate is undeveloped in the infant rats. No changes in the contribution of different organs to the first-pass metabolism of acetaminophen was observed 10 weeks after birth. Pharmacokinetic parameters for acetaminophen in infant rats (3-week-old) and 10-week-old rats were similar after drug administration by the intra-arterial and intravenous routes.

Acetaminophen↗
PubMed1991

Sulphate conjugation enhances reversible binding of drug to human serum albumin.

Reversible binding of model compounds, their conjugated metabolites (sulphates and glucuronides), and also derivatives of the compounds, to human serum albumin (HSA) has been examined using an ultrafiltration method. p-Nitrophenol (p-NP), alpha-naphthol (alpha-NA) and beta-naphthol (beta-NA) were used as model compounds. Reversible binding of 500 microM p-NP sulphate to 4% HSA (96.6 +/- 0.35%, mean +/- s.d. n = 3) was significantly higher (P less than 0.001), whereas reversible binding of p-NP glucuronide to 4% HSA (33.3 +/- 9.82%) was much lower (P less than 0.001) than that of 500 microM p-NP (90.9 +/- 0.60%). Reversible binding of 500 microM p-NP glucopyranoside to 4% HSA (25.8 +/- 2.82%) was comparable with that of the glucuronide, with which it is structurally similar. In contrast, reversible binding of 500 microM p-NP phosphate, an anionic compound like p-NP sulphate, to 4% HSA (61.4 +/- 5.28%) was significantly lower than that of p-NP (P less than 0.001). Similar results were observed in reversible binding of sulphates of alpha-NA and beta-NA. Significant differences of dissociation constants for HSA binding were observed between the parent compound (alpha- or beta-NA) and its sulphate conjugate (P less than 0.005 for alpha-NA and alpha-NA sulphate, P less than 0.001 for beta-NA and beta-NA sulphate), but the number of binding sites was the same. These results indicated that sulphate conjugation enhances reversible binding of a parent compound to HSA by increasing the binding affinity of the parent compound to HSA. This enhancement appeared to be advantageous for preventing random distribution of this metabolite to organs in the body.

Acetaminophen↗
PubMed1991

Study on the cupric phenanthroline-induced beta-glucuronidase release in saponin-permeabilized polymorphonuclear leukocytes.

Saponin-permeabilized polymorphonuclear leukocytes (PMNs) released beta-glucuronidase, a lysosomal enzyme, dose-dependently in response to cupric phenanthroline (CuPh), a mild oxidant, which catalyzes the formation of disulfide bridges. The beta-glucuronidase release induced by CuPh was inhibited by ethylene glycol bis(beta-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA). Both dithiothreitol (DTT) and N-(6-aminohexyl)-5-chloro-naphthalene sulfonamide (W-7) also inhibited the beta-glucuronidase release induced by CuPh. CuPh elicited a decrease in protein-bound free sulfhydryls simultaneously, and this decrease was not restored by EGTA treatment. CuPh inhibited Ca2+ uptake into Ca2+ store sites, and promoted a Ca2+ efflux from Ca2+ store sites. It also inhibited Ca(2+)-adenosine triphosphatase (ATPase) activity in permeable PMNs. DTT, a sulfhydryl reducing agent, suppressed both the beta-glucuronidase release and the Ca2+ uptake in CuPh-treated permeable PMNs. On the other hand, chloromercuriphenylsulfonic acid (CMPS), a sulfhydryl modifier, decreased the amount of free sulfhydryls in protein and released beta-glucuronidase in permeable PMNs dose-dependently, but EGTA did not inhibit either reaction. Neither CuPh nor CMPS released beta-glucuronidase from intact PMNs. These results indicate that both CuPh and CMPS act on intra-PMN target molecules to exert their influence, but the involved mechanisms are different in nature. Alteration in calcium movement is responsible for the beta-glucuronidase release in the CuPh-treated permeable PMNs.

Animals↗
PubMed1991

[First-pass metabolism of acetaminophen in thyroxine treated rats].

The study on the first-pass metabolism of acetaminophen was carried out in normal and thyroxine-treated rats, administered 30 mg/kg by three routes of intravenous, intraperitoneal, and oral one. Unconjugated acetaminophen and two major metabolites, glucuronide and sulfate in the plasma and urine were then measured 5 and 24 h after the administration, respectively. It was found that there was no difference in total percentage of excreted amount, independent of the routes for administration, between normal and thyroxine-treated rats. This fact shows that acetaminophen is absorbed completely from the gastrointestinal tract. However, it was also found that the extraction ratio of gastrointestinal tract in thyroxine-treated rats became smaller, and that the volume of distribution and total body clearance became larger than those in normal rats. The first-pass metabolism of acetaminophen was found to be influenced by the continuous administration of thyroxine.

Acetaminophen↗
PubMed1991

[Promotion of intestinal drug absorption by milk fat globule membrane].

A soybean oil emulsion was prepared by using milk fat globule membrane (MFGM) materials as an emulsifier. Its stability and effect on the intestinal absorption of vitamin D3, amphotericin B and kanamycin were studied. The MFGM emulsion was as highly stable as a Tween 80 emulsion. When the MFGM emulsion was sonicated with ultrasonic disrupter, the emulsion became more stable. Quantification of vitamin D3 in the intestinal lymph indicated that the MFGM emulsion enhanced lymphatic absorption of vitamin D3. The recovered percentage of vitamin D3 emulsified with MFGM in the lymph was 1.4 times that by Tween 80, and 2.5 times that of oil-in-water suspension. Statistically significant difference was found among them (p less than 0.05). The volumes of an oil phase in the emulsion affected the absorption of vitamin D3. The recovered percentage of vitamin D3 from the lymph increased with reducing the volume of the oil phase. Sonication of the emulsion did not affect the intestinal drug absorption. Furthermore, the MFGM emulsion had no effect on the intestinal absorption of amphotericin B and kanamycin.

Amphotericin B↗
PubMed1991

[Investigation of temperature sensitive liposome encapsulated adriamycin injected into hepatic artery for targeted behavior and cancer therapy].

Temperature sensitive liposome entrapped adriamycin was injected into the hepatic artery of Wistar rats bearing implanted hepatic tumor. Two hours after the injection, the liver was heated to 42 degrees C and maintained at that temperature for 6 minutes using a local hyperthermia. The variation in the pattern of the concentration of the liposomal drug in circulation, and the drug distribution in tissues were investigated. Results indicated that adriamycin was released from the liposomes with the drug concentration peaking in circulation at 30 minutes after heating. Following the hyperthermia treatment, the total amount of drug in the liver decreased, while that in the tumor and urine increased. The 14C labeled liposome track test showed that a parallel relationship between the lipid and the drug was maintained for 8 hours after the hepatic injection, and physiological environment was a determinant of change and existence of liposomal carrier. However, the drug encapsulated in the liposomes can be controlled by hyperthermia to target the tumor. Therapeutic experiments showed that in the group treated with the hepatic artery-injected liposome plus hyperthermia control, the liver tumor growth of the rats administered at 7 days after W256 carcinosarcoma implantation on liver was notably inhibited and the life-span of the animal was greatly extended compared with those of aqueous administration groups and iv injected liposome group.

Animals↗