Biomedical subjects

N Aoyagi

Publications and source records attributed to N Aoyagi.

At least 19 recordsLinked to original sources

PubMed1995

Oral solid controlled release dosage forms: role of GI-mechanical destructive forces and colonic release in drug absorption under fasted and fed conditions in humans.

PURPOSE: This study was undertaken to examine the effects of mechanical destructive forces on drug release from controlled release (CR) dosage forms in vitro and in vivo and their colonic release, using two CR tablets of acetaminophen A and B, showing slower and faster erosion rates, respectively. METHODS: In vitro release rates were determined by several official methods. Tablets were administered to healthy volunteers under fasting and fed conditions. RESULTS: Both tablets showed similar release rates under mild destructive conditions (e.g., paddle method at 10 rpm) but CR-B showed faster release under highly destructive conditions (e.g., rotating basket method at 150 rpm), where the tablet was eroded. The in vivo release from CR-B was faster than from CR-A, possibly because of enhanced erosion. The variable in vivo release from CR-B indicated large inter-subject differences in destructive GI forces. The fastest in vivo release from CR-B among individuals was approximated by the in vitro dissolution determined by destructive methods such as the rotating basket at 150 rpm. The slowest in vivo release from tablets A and B was lower than the dissolution by the paddle method at 10 rpm. The release from both tablets was markedly reduced at 3-4 hrs after dosing irrespective of feeding conditions which can be attributed to release inhibition in the colon. CONCLUSIONS: Effects of GI destructive forces on the tablet erosion and the release inhibition in the colon must be considered in the development of CR dosage forms.

Acetaminophen↗

PubMed1992

Gastric emptying of tablets and granules in humans, dogs, pigs, and stomach-emptying-controlled rabbits.

Rates of gastric emptying of nondigestible tablets and granules in humans were compared with those in three animal models: dogs, minipigs, and stomach-emptying-controlled rabbits. The rates of gastric emptying of both dosage forms in dogs tended to be faster than or similar to those in humans, whereas the rates in pigs were slower. In stomach-emptying-controlled rabbits, no tablets were emptied from the stomach because of their large size. The rate of gastric emptying of granules in rabbits was slow and variable. Food delayed gastric emptying in dogs, especially for tablets. In rabbits, the rate of gastric emptying of granules was faster when the granules were given before feeding, in comparison with that after feeding or under fasting conditions. We concluded that the dog is a better animal model for bioavailability studies under fasting conditions than the pig and the rabbit.

Adult↗

PubMed1991

Endothelin-3 stimulates the hypothalamic-pituitary-adrenal axis.

Endothelin-3 (ET-3) is a member of the novel vasoconstrictive peptide family, identified in porcine central nervous system. Intravenous bolus injection of 1000 pmol/kg of ET-3 in freely moving rats caused significant increases in plasma ACTH and corticosterone levels, almost equivalent to those of 100 pmol/kg of rat corticotropin-releasing hormone (rCRH). The action of ET-3 was virtually abolished by pretreatment of CRH-antagonist, alpha-helical CRH. When ET-3 was added to cultured anterior pituitary cells, neither direct stimulation of ACTH release nor potentiation of rCRH action was noted. The results indicate that ET-3 may function as a neuropeptide and stimulation of the CRH-neurons, direct or inderect, is mainly responsible for activation of ACTH and corticosterone release.

Adrenal Glands↗

PubMed1991

Effect of food on the bioavailability of cyclandelate from commercial capsules.

The bioavailability of five capsules of cyclandelate that are commercially available in Japan was determined in ten healthy volunteers by measuring mandelic acid (a main metabolite of cyclandelate) excreted in the urine. Bioinequivalence among the five capsules was demonstrated. The relative cumulative excretion of mandelic acid of the most poorly bioavailable capsule was 38% of the most highly bioavailable capsule. The effect of food on the bioavailability of these two capsules was investigated by use of two different kinds of food, one containing fat and one containing high carbohydrates but very low fat. The bioavailability of the two capsules was increased when subjects consumed both types of food before drug administration, although there was a greater effect on bioavailability with food containing fat. This suggests that the absorption of cyclandelate was incomplete in fasting subjects, even from the capsule with the highest bioavailability. Bioinequivalence between the two capsules remained after postprandial drug administration.

Administration, Oral↗

PubMed1991

Bioavailability of cyclandelate from capsules in beagle dogs and dissolution rate: correlations with bioavailability in humans.

The bioavailability in beagle dogs and the dissolution rates of cyclandelate from five capsule preparations commercially available in Japan were measured. One of the capsules that showed an extremely low bioavailability in humans also showed the lowest bioavailability in beagle dogs, although the difference in bioavailability with the highest preparation was smaller than in humans. A significant correlation was obtained between the results of the studies in humans and beagles. However, the power of the test using beagles was extremely low in comparison with that in the human study. Food enhanced the bioavailability of cyclandelate from the capsules having the highest and lowest bioavailability in the fasted state in beagles as observed in the human study previously. The bioinequivalence of the cyclandelate capsules detected in the fasted state disappeared in the fed state in the beagle dog study, while the bioinequivalence still remained in the non-fasted state in human subjects. Thus bioequivalence testing in the fed state led to different results in both species. The most poorly bioavailable capsule in both species in the fasted state showed a slow dissolution rate by several dissolution methods with moderate stirring. In order to obtain a good correlation with in vivo bioavailability, a large volume of test solution and addition of Tween 80 were required. Extensive growth of whiskers (needle-like crystals) was observed in the entire capsule mass having the lowest bioavailability.

Animals↗

PubMed1991

In vitro and in vivo correlation for controlled-release formulation of d-chlorpheniramine maleate.

Four commercial controlled-release tablets of d-chlorpheniramine maleate, which showed various drug release properties, were administered to beagle dogs, and the correlation between in vitro drug release and in vivo absorption was studied. The mean in vivo absorption amount-time profile for each product showed good accordance with the in vitro drug release profile until 2-3 h after administration. However, absorption of the drug in dogs terminated at about 3 h. This short absorption time may be due to a short intestinal residence time for these dosage forms in the dog. In the present study, the deconvolution method was proved to be useful for in vitro/in vivo comparison, which clarified the in vivo absorption of controlled-release dosage forms having various release profiles.

Animals↗

PubMed1990

Stimulation of the hypothalamic-pituitary-adrenal axis by epidermal growth factor.

The effects of mouse epidermal growth factor (mEGF) on the hypothalamic-pituitary-adrenocortical axis were studied in vivo in conscious male rats and in vitro with cultured anterior pituitary cells. Both intravenous (i.v.) and intracerebroventricular (i.c.v.) injections of mEGF (5-20 ng: 8.3-33.3 pmol) produced significant, dose-related increases in plasma ACTH and corticosterone concentrations. The potency of mEGF is 1/20-1/50 of that of rat corticotropin-releasing factor (rCRF), and pretreatment with 150 micrograms alpha-helical CRF (9-41) completely abolished the effects of the two peptides. mEGF in concentrations ranging from 10 pM to 10 nM did not significantly affect ACTH release from dispersed anterior pituitary cells. It also failed to alter ACTH secretion in response to rCRF. These results indicate that mEGF stimulates the pituitary-adrenocortical axis through a CRF-dependent mechanism.

Adrenocorticotropic Hormone↗

PubMed1990

Application of the NONMEM method to evaluation of the bioavailability of drug products.

The NONMEM method, one of the methods used for analysis of population pharmacokinetics, was applied to the evaluation of the relative bioavailability of drug products. The data of 2 x 2 crossover studies of several drugs and a 3 x 3 crossover study of phenytoin using healthy volunteers were analyzed by the NONMEM method, as well as by the confidence interval procedure, which is a standard approach to the bioequivalence test data using model-independent parameters. Very close confidence intervals for the relative difference in bioavailability were estimated by the NONMEM method and the standard approach, both in cases where products were bioequivalent and where they were not. The NONMEM method could also correctly estimate the relative bioavailability of the products using simulated clinical data obtained by randomly reducing the sampling points of the phenytoin data mentioned above, which cannot be analyzed by the standard approach. Thus, the usefulness of the NONMEM method was confirmed for evaluation of bioavailability using clinical or experimental data.

Administration, Oral↗

PubMed1990

Effects of food on bioavailability of two indomethacin capsules containing different sizes of particles.

Two different indomethacin capsules, a commercial one containing fine drug particles and an experimental capsule containing 125-177 microns particles, were employed in this study. The commercial preparation showed faster in vitro dissolution than the experimental one. When administered to humans having normal acidity of the gastric juices, the commercial capsule exhibited higher Cmax and smaller Tmax and mean residence time (MRT) than the experimental one both in fasting and nonfasting states, although the two capsules were equivalent in area under the serum concentration-time curve (AUC). The ingestion of a breakfast delayed the gastrointestinal absorption from both preparations, which resulted in larger Tmax's and MRT's and smaller Cmax's in the nonfasting state. Food, however, did not have any significant effect on the AUC's of the preparations.

Adult↗

PubMed1989

Power analyses of moment analysis parameter in bioequivalence tests.

Simulated and experimental data were used to evaluate the mean residence time (MRT) as a parameter for estimating the rate of bioavailability in bioequivalence tests and to compare MRT with tmax (the time of peak drug concentration), both pharmaceutically and statistically. Although the values of MRT were more dependent on the elimination rate constant than tmax, MRTs were sufficiently sensitive to variations in the absorption rate. The statistical power of MRT infinity obtained by an extrapolation method was lower (especially when the flip-flop phenomenon occurred) than that of MRTt (calculated using data from zero time through the last sampling time). However, the power of MRTt was shown to be comparable to or higher than that of either AUCt or Cmax (the peak drug concentration) from simulated data. These results were also confirmed experimentally using previously obtained data. The effect of variances of plasma concentrations on the power of these parameters was also studied using a simulation technique. Even large variances near the last sampling time did not substantially affect the power of MRTt. Thus MRTt can be used as a parameter for estimating the rate of bioavailability from dosage forms in place of tmax in bioequivalence tests.

Biological Availability↗

PubMed1989

Rerupture of intracranial aneurysms during angiography.

We analyzed 70 patients (64 from the literature and 6 of our own cases) who had suffered from rerupture of their aneurysms during angiography. When these cases are compared with those who had suffered rupture of their aneurysms only once and a rerupture, which did not coincide with angiography, they were clinically distinguished by a higher Hunt-Hess grade, a higher rate of IC aneurysms, less operability, far miserable outcome and concentration of aneurysmal rerupture within three hours after the initial subarachnoid haemorrhage. It is suggested waiting at least 3 hours after SAH before performing angiography and to use digital subtraction angiography in order to prevent aneurysmal rerupture during angiography.

Adult↗

PubMed1989

Normoreninemic hypoaldosteronism in a case of isolated ACTH deficiency.

This paper documents the rare and hitherto unreported association between isolated ACTH deficiency and normoreninemic hypoaldosteronism in a 63-year-old woman. Baseline plasma aldosterone and 18-hydroxycorticosterone were extremely low. Both steroids did not respond to exogenous angiotensin II infusion, whereas they were increased in parallel to ACTH stimulation. Thus, acquired dysfunction or congenital dysgenesis of the zona glomerulosa was suspected. The upright posture-furosemide test showed a subnormal but definite plasma aldosterone response coupled with a normal increase in plasma renin activity, indicating that there may be a yet unidentified mechanism(s) underlying the postural increase of aldosterone.

17-Hydroxycorticosteroids↗

PubMed1988

Gastric emptying rates of drug preparations. I. Effects of size of dosage forms, food and species on gastric emptying rates.

The gastric emptying rates of oral dosage forms of different sizes were studied in humans and beagle dogs measuring of marker drugs such as acetaminophen, aspirin and pyridoxal phosphate in plasma or urine. The marker drugs, except acetaminophen, were contained in enteric-coated granules or tablets which did not dissolve in the stomach but dissolved rapidly in the upper intestine. The gastric emptying rate of a dosage form of smaller size was faster than that of a larger size. The gastric emptying rates of dosage forms with different sizes did not correlate with each other inter-individually. The gastric emptying rates of dosage forms of any size were delayed when drugs were administered after taking a meal. The gastric emptying rates of dosage forms were extremely prolonged in beagle dogs after drug administration postprandially, and this restricted the use of beagle dogs as an animal model in bioavailability tests.

Acetaminophen↗

PubMed1988

Gastric emptying rates of drug preparations. II. Effects of size and density of enteric-coated drug preparations and food on gastric emptying rates in humans.

Enteric-coated granules with different densities and tablets of different sizes were prepared in order to study the effect of these physical properties of dosage forms on the gastric emptying rates in humans. The effect of food on the gastric emptying rate was also studied. Aspirin contained in an enteric-coated product as a marker drug was used to determine the gastric emptying rate by measuring salicylates excreted into the urine. The larger the size of the dosage form, the larger were the values of parameters for estimating the gastric emptying rate such as tlag, tmax and the mean absorption time. There was a significant correlation between the gastric emptying rates and sizes of dosage forms. On the other hand, no effects of density of enteric-coated granules on the gastric emptying rate were observed. The gastric emptying of dosage forms of various sizes or densities tested were prolonged by food. However, the gastric emptying rate of granules was less affected by food than that of tablets.

Aspirin↗

PubMed1988