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Biomedical subjects

H Yoshitomi

Publications and source records attributed to H Yoshitomi.

At least 73 records · Page 4Linked to original sources
PubMed1993

Evaluation of enteric coated tablet sensitive to pancreatic lipase. II. In vivo evaluation.

Plain tablets containing a model drug, sulfamethizole (SMZ), were coated with triolein (TO), trilaurin (TL) and ethylcellulose (EC). The biological behavior of the coated tablets (TOTL-Tab), which are pH independent and sensitive to pancreatic lipase, was investigated in humans. Results of the administration of the tablets with or without an antacid, under fasting and non-fasting conditions, and at 0.5 h before and 0.5 h after meals, were examined. A comparison of the in vivo behavior of SMZ after the administration of these tablets was done using the following data: the lag time of urinary excretion (Ulag), the total urinary recovery percentage (X infinity u), and the mean residence time after Ulag (MRTaf). A typical pH-sensitive tablet coated by cellulose acetate phthalate (CAP-Tab) was used as a reference. For the administration of a CAP-Tab alone, the Ulag obtained under both the non-fasting and fasting condition was longer than that of the plain tablet. However, Ulag after the administration of a CAP-Tab with an antacid became considerably shorter. This lag time was about the same as that obtained from the plain tablet, regardless of food ingestion. The obtained CAP-Tab MRTaf and X infinity u values were not significantly different in comparison to the plain tablets. Under the non-fasting condition, Ulag, MRTaf and X infinity u of TOTL-Tab were not affected by the co-administration of an antacid, and these values were virtually the same as those obtained from a CAP-Tab without an antacid. The urinary excretion data obtained after the administration of TOTL-Tab alone under fasting was analogues to the non-fasting case.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Evaluation of enteric coated tablet sensitive to pancreatic lipase. I. In vitro disintegration test.

We designed a new enteric coated preparation which is pH independent and functions by pancreatic lipase activity in the duodenum. Triolein (TO) and trilaurin (TL) were selected as lipase sensitive components and ethylcellulose (EC) was used as the support film for TO and TL. Tablets (330 mg, d = 10 mm) containing a model drug, sulfamethizole (SMZ), were coated with 1% each of TO, TL and EC solution by the fluidized bed coating technique. Disintegration tests were carried out in the media including JPXI 1st fluid (pH 1.2, JP-1), 2nd fluid (pH 6.8, JP-2) and JP-2 with gall powder and pancreatic lipase (JP-2-GL). The lag time of disintegration of the tablet (TOTL-Tab) coated 5-7 mg/tab with TO, TL and EC was about 10 min and all of the tablets disintegrated completely within 30 min in JP-2-GL. However, in the other media, which did not contain lipase, TOTL-Tab did not disintegrate for at least 2 h. It was confirmed that TO and TL in the coating film were digested by lipase. In addition, the tensil strength of the film decreased quickly after incubation in JP-2-GL. These results suggest that the application of TO, TL and EC to tablet coating is useful for an enteric release preparation sensitive to pancreatic lipase, even if patients have low gastric acidity or are taking antacids.

Chemistry, Pharmaceutical↗
PubMed1992

[Reproductive and developmental toxicity study of prednisolone farnesylate (PNF)--study by subcutaneous administration of PNF prior to and in the early stages of pregnancy in rats].

A fertility study of Prednisolone farnesylate (PNF), a newly synthesized corticosteroid, was conducted in Sprague-Dawley rats. This compound was administered subcutaneously at dose levels of 0(control), 0.04, 0.2 and 1 mg/kg/day to males for 63 days before mating and during the mating period, and to females for 14 days before mating, through the mating period and until day 7 of pregnancy. Each 24 male and female rats were mated, and females were killed on day 20 of pregnancy to examine their fetuses. 1. In the parental animals, loss of fur or thin fur and incrustation of treated site occurred in male rats treated at doses of 0.2 mg/kg or more and female rats treated at dose of 1 mg/kg, and at the same dose groups, the thinning of skin, atrophy of the thymus and intention of the substance at the injected site were noted. Moreover, body weight gains and food consumption were suppressed in both sexes treated at the dose of 1 mg/kg. 2. Fertility and reproductive ability in both sexes, and estrus cycles in female rats were not affected by administration of PNF. 3. In the fetuses, no embryonic or fetal lethal effect and teratogenic effect were noted. From these results, the no-effect dose levels of PNF on the parental general states, the parental reproductive ability and those of the fetuses are thought to be 0.04 mg/kg/day, 1 mg/kg/day or more and 1 mg/kg/day or more, respectively, under the experimental conditions of this study.

Animals↗
PubMed1991

In vitro transport of sodium diclofenac across rat abdominal skin: effect of selection of oleaginous component and the addition of alcohols to the vehicle.

The in vitro percutaneous transport of sodium diclofenac from various oil vehicles was examined using rat abdominal skin as a model skin membrane. The overall transport of diclofenac through the skin from the oleaginous vehicles was very poor because of a poor solubility of sodium diclofenac in nonpolar oils. To increase the solubility and the permeability of sodium diclofenac, ethanol and n-octanol were added to each oil (designated as the formulated vehicles). The addition of ethanol and n-octanol to the nonpolar vehicles resulted in an extreme increase in drug solubility in each vehicle, with a remarkable increase in the permeation of diclofenac. The effects of oil components in the formulated vehicle on the permeation of diclofenac across the skin were in the following order: squalane greater than or equal to squalene greater than liquid paraffin greater than middle chain triglyceride greater than olive oil greater than castor oil. In order to clarify the reason for the differences in permeation of diclofenac from these formulated vehicles, the release of diclofenac and n-octanol from these vehicles in vitro was studied. The release rates of n-octanol from the formulated vehicles were in the following order: liquid paraffin greater than squalene greater than or equal to squalane greater than middle chain triglyceride greater than or equal to olive oil greater than castor oil. On the other hand, a linear correlation was observed between the initial release rate of diclofenac from the formulated vehicle and the in vitro permeation of diclofenac through the vehicle to the skin.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Preparation and biological activity of 2-[4-(thiazol-2-yl)phenyl]propionic acid derivatives inhibiting cyclooxygenase.

A series of 2-[4-(thiazol-2-yl)phenyl]propionic acids substituted at various positions were prepared by the reaction of diethyl 2-methyl-2-(4-thiocarbamoylphenyl)malonates with alpha-bromoaldehyde diethyl acetals or alpha-haloketones followed by hydrolysis of esters. The inhibition of prostaglandin H synthetase (cyclooxygenase) was assayed by use of an enzyme preparation from guinea pig polymorphonuclear leukocytes. Examination of the structure-activity relationship of these compounds indicated that the substitution pattern with halogens at position 3 (R1) of the benzene ring and a methyl group in position 4 (R2) and/or 5 (R3) of the thiazole ring were favorable for inhibitory activity. The compounds bearing bulky alkyl or polar functional groups at the R2 position were weak inhibitors. The potent inhibitors of cyclooxygenase were tested for their ability to reduce carrageenin-induced inflammation of rat paws. These derivatives had strong anti-inflammatory activity based on their strong inhibition of cyclooxygenase, with some exceptions, including those with a thiomethyl group at R1.

Animals↗
PubMed1991

In vitro percutaneous transport of sodium diclofenac and diclofenac from oleaginous vehicle.

The penetration enhancement of sodium diclofenac and diclofenac by alcohols with various alkyl chains (C8 to C14) was evaluated by the steady state flux of diclofenac through rat abdominal skin. Decanol showed the greatest effect in this series. A more remarkable enhancing effect of the alcohols was observed in sodium diclofenac than in diclofenac. Diclofenac can penetrate through the ethylene-vinyl acetate membrane as a lipoid model membrane, but sodium diclofenac can not. Decanol enhanced the penetration of phenol red being dependent on its concentration in the vehicle. Therefore, decanol may interact with lipoid components of the skin and increase the aqueous pathway in the skin. These results indicate that sodium diclofenac and diclofenac may be penetrated through partially different pathways.

Animals↗
PubMed1990

Specific inhibitory conformation of dipeptides for chymotrypsin.

Based on the analyzed conformation of a chymotrypsin inhibitor H-delta Phe-Phe-OMe, we have designed a series of diastereomeric phenylalanylphenylalanine methyl esters and derivatives as possible inhibitors. Among the peptides synthesized, H-D-Phe-L-Phe-OMe was found to be very resistant to chymotrypsin in spite of its L-Phe-OMe structure at the C-terminus. It inhibited the enzyme fairly strongly and competitively with Ki = 9.0 x 10(-5) M in the assay using Ac-Tyr-OEt as a substrate. The measurements of the NOEs in high-resolution 1H-NMR analyses indicated the presence of the hydrophobic core built by the intramolecular interaction between the D-Phe-phenyl and ester-methyl groups. It was suggested that this core interacts with the chymotrypsin S2 site (Trp215) and Phe2 with the S1 site. The backbone structure of this dipeptide was assumed to be in an inhibitory conformation that fits the active center of the enzyme.

Amino Acid Sequence↗
PubMed1990

Mode of action of the gramicidin S analogs lacking hydrophilic amino acid residues on biomembranes.

The gramicidin S analog lacking basic ornithine residues, cyclo(-Val-Ala-Leu-delta Phe-Pro-)2 (where delta Phe represents alpha, beta-dehydrophenylalanine), increased the K+ permeability of human erythrocytes and Staphylococcus aureus similarly to the parent gramicidin S. This analog altered the normal discoid shape of human erythrocytes to an invaginated form. The direction of the shape change was opposite to the case of gramicidin S causing crenated cells. We suppose that the analog accumulated predominantly into the inner half monolayer of membrane and destabilized the membrane structure, resulting in a break in the membrane.

Amino Acids↗
PubMed1989

Enzyme inhibition by dipeptides containing 2,3-methanophenylalanine, a sterically constrained amino acid.

Both isomers of (E)-2,3-methanophenylalanine (delta EPhe), a sterically restricted amino acid, were incorporated into peptides in order to examine their possible enzyme inhibitory activity. Both (2R,3S)- and (2S,3R)- delta EPhe-Phe(or Leu)-OMe were found to inhibit effectively the hydrolysis of Ac-Tyr-OEt by chymotrypsin in a competitive manner. The ester groups of these dipeptides were quite resistant to chymotrypsin hydrolysis, and the delta EPhe-Phe peptide bond was also entirely stable. The inhibition constant (Ki) of the most potent dipeptide of H-(2R,3S)-delta EPhe-Phe-OMe was 0.16 mM at 25 degrees C. The inhibitory action of delta Phe-containing peptides was found to depend on the configuration of the delta Phe residue. The electrophilic nature of the cyclopropane ring which is conjugated with both the phenyl ring and the ester carbonyl group appears to be relevant to the inhibitory activity. Fully irreversible inactivation of chymotrypsin was achieved by its incubation with H-(2R,3S)- delta EPhe-Leu-OMe. An enzyme carboxylate group is thought to be responsible for nucleophilic attack on the cyclopropane ring leading to irreversible inactivation.

Chemical Phenomena↗
PubMed1987

Effect of triglyceride on small intestinal absorption of cefoxitin in rats.

Coadministration of trilaurin or monolaurin with sodium cefoxitin increased its absorption from the small intestine of the rat. Its absorption from the rectum was effected to a lesser extent except when lipase was present. Lipase, a natural constituent of the small intestine fluid, may therefore be essential for the adjuvant action of trilaurin on cefoxitin absorption across the intestinal membrane. Among the triglycerides used, trilaurin and tricaprin were the most effective enhancers of cefoxitin absorption. Both the rate of degradation of triglyceride to its fatty acid component and subsequently the rate of fatty acid absorption were factors influencing the enhancing action. Maintenance of fatty acid concentration at the small intestinal absorption site was shown to be necessary to obtain a cefoxitin bioavailability of up to 70%.

Animals↗
PubMed1986

Intestinal absorption of sodium cefoxitin in rats: effect of formulation.

The absorption of cefoxitin from rat intestine, rectum and small intestine was greater when the powdered form was administered than when an aqueous solution was given. Cefoxitin absorption from the small intestine was significantly increased after its administration in suppository form prepared with a triglyceride base, although rectal absorption from the suppository did not differ from that of the drug in powdered form. The increase in absorption by the small intestine from the suppository form may be due to fatty acids produced from triglyceride by lipase.

Animals↗
PubMed1984

Plasma protein binding of frusemide in renal failure rabbits: investigation of endogenous protein binding inhibitors.

The reduction mechanism of frusemide-protein binding in the plasma of renal failure was investigated. The drug-albumin binding was inhibited by the low molecular-weight fraction obtained from acute renal failure rabbits, suggesting the presence of the inhibitors in the plasma. Further, this fraction was divided into six subfractions by Bio-Gel P-2. Fractions II and V2 showed significant inhibition of the protein binding of frusemide. Among uraemic toxins, four indole derivatives markedly inhibited the protein binding. Analysis by hplc confirmed that the concentration of indican was markedly increased in acute renal failure rabbit plasma. It is suggested that this compound could be one of the major inducers of the protein binding defect.

Acute Kidney Injury↗
PubMed1983

Distribution of diuretics and hypoglycemic sulfonylureas in rabbit erythrocytes.

The distribution of three sulfonylureas and six diuretics in rabbit erythrocytes was studied in vitro at 37 degrees C. The drugs were taken up by the erythrocyte compartment, and distribution equilibrium was reached within 60 min of incubation. A distribution percentage in erythrocyte compartment was maintained at roughly constant value over the whole concentration range of drugs. Therefore, a linear relationship was established between total concentrations of drug in whole blood or erythrocyte suspension and in the erythrocyte compartment. Bovine serum albumin combined with the erythrocyte suspension appeared to reduce drug distribution in the erythrocyte compartment. Whole blood obtained from renal failure rabbits showed greater distribution of drug in the erythrocyte compartment compared with the whole blood of a normal rabbit. This might be due to a change in plasma protein binding ability related to the progress of renal failure.

Acute Kidney Injury↗
PubMed1981

Further investigations on the binding of loop diuretics to serum proteins from patients with liver disease.

The binding of three loop diuretics, piretanide, bumetanide and furosemide, to serum proteins from patients with liver cirrhosis or fulminant hepatitis was investigated using equilibrium dialysis. A good correlation was found between serum albumin concentration and the percentage of each unbound (free) loop diuretic in patients with liver disease. The binding data obtained from patients with liver cirrhosis was compared with that of patients with chronic renal failure. Calculations made according to the Sandberg-Rosenthal's formula revealed that the maximum binding concentration (nP) varied in some cases. These findings necessitated a detailed investigation into whether the increased percentage of each unbound loop diuretic in patients with liver disease is attributable not only to lowered serum albumin concentration but also to inhibition of the protein binding by some endogenous substances. Thus, similar experiments were performed using rats with experimental liver cirrhosis. The binding of the loop diuretics to serum proteins in cirrhotic rats differed greatly from the findings obtained from cirrhotic patients. The percentage of unbound loop diuretic was well correlated with serum albumin concentration but not with the concentration of serum bilirubin (an endogenous substance) in cirrhotic rats.

Adult↗