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Biomedical subjects

K Iseki

Publications and source records attributed to K Iseki.

At least 163 records · Page 9Linked to original sources
PubMed1991

Role of calcium supplementation in patients with mild renal failure.

A low-protein diet has been shown to be effective in the prevention of progression of renal failure. However, the role of protein and that of phosphate intake have not been definitely separated. To determine the use of calcium (CaCO3) as a phosphate binder and a possible hypotensive agent, we performed a prospective, double-blind study of oral calcium in patients with mild-to-moderate renal failure (SCr less than 5.0 mg/dl). Thirty-six patients (20 m, 16 f) were studied. After a 2-month control period, either CaCO3 (6 g/day, 12 Cap) or placebo was given for 3 months. There was no significant difference in BUN, S-Sr, S-Ca, S-Pi, 24-hour Ccr, and blood pressure during the study period both in the genuine and the placebo group. Urine phosphate was decreased by about 50% in the CaCO3 group. Calcium carbonate is feasible as a phosphate binder for patients with mild-to-moderate renal failure.

Adult↗
PubMed1991

A simple method for the simulation of unbound serum disopyramide concentration in patients.

There were remarkable differences in the serum total and unbound concentrations of disopyramide (DP) and mono-N-dealkyldisopyramide (MND), the major metabolite of DP, among patients with arrhythmias. Serum levels of alpha 1-acid glycoprotein (AAG) also varied among the same patients. To predict the unbound DP concentrations, we have obtained the serum concentration-time curves of unbound DP in these patients by means of total DP concentration, DP pharmacokinetic parameters, AAG levels and dissociation constants of DP and MND at specific AAG binding sites. In patients with normal AAG levels, the theoretical values of unbound DP were in good agreement with the measured concentrations. On the other hand, in patients with high AAG levels, the theoretical values could be obtained by correcting the calculated values using both AAG levels of each patient and the equation correlating the unbound DP fraction to AAG concentrations. These findings indicate that patient AAG levels can provide valuable information permitting the rapid estimation of unbound DP concentrations, the pharmacologically active fraction, and the development of effective DP dosage regimens.

Disopyramide↗
PubMed1991

Improvement of dissolution and bioavailability for mebendazole, an agent for human echinococcosis, by preparing solid dispersion with polyethylene glycol.

The solid dispersion of mebendazole was prepared with polyethylene glycol (PEG) to enhance the dissolution rate of mebendazole, an agent for the chemotherapy of human echinococcosis. The dissolution rate of the solid dispersion increased compared with the physical mixture, and also increased with the incorporation of an increasing amount of PEG-6000. An extensive improvement of the dissolution rate was observed when the ratio of the solid dispersion of mebendazole to PEG-6000 was more than 1: 2. Furthermore, greater bioavailability in rabbits was obtained after oral administration of the solid dispersion compared with the physical mixture.

Animals↗
PubMed1991

[Pharmacokinetic and clinical studies of cefdinir in the pediatric field. Pediatric Study Group of Cefdinir].

We studied pharmacokinetics and clinical effects of 5% and 10% fine granules of cefdinir (FK 482, CFDN), a new oral cephalosporin, in the pediatric field and the following results were obtained. 1. Pharmacokinetics (blood concentration and urinary excretion) Pharmacokinetics of CFDN in 163 children was investigated. Cmax and T 1/2 were 0.92 +/- 0.45 micrograms/ml and 1.95 +/- 1.06 hours, respectively, in the fasting state, and were 0.63 +/- 0.29 micrograms/ml and 2.26 +/- 0.65 hours, respectively, in the non-fasting state, at a dose level of 3 mg (potency)/kg. At a dose level of 6 mg (potency)/kg, Cmax and T 1/2 were 1.29 +/- 0.49 micrograms/ml and 2.11 +/- 1.85 hours, respectively, in the fasting state and were 1.28 +/- 0.48 micrograms/ml and 2.01 +/- 0.84 hours, respectively, in the non-fasting state. Data of Cmax and AUC showed that blood concentration of the drug depended on dose levels. Urinary recovery rates in the first 8 hours were 20.5 +/- 8.8% in the fasting state and 14.8 +/- 5.9% in the non-fasting at a dose level of 3 mg (potency)/kg and 16.5 +/- 6.7% and 17.8 +/- 2.4%, respectively, at 6 mg (potency)/kg. 2. Clinical effects Clinical effects of CFDN on various infections were studied in 612 children who were treated with 5% fine granules of CFDN (5% granule group) and in 208 with 10% fine granules of CFDN (10% granule group). CFDN granules were administered mainly at daily doses of 9.0-18.0 mg (potency)/kg in 3 divided portions. Clinical efficacy rates in 428 children of the 5% granule group and in 159 of the 10% granule group from whom causative bacteria were isolated, were 94.9% and 96.2%, respectively. The clinical efficacy rates for patients who were responsive to previous antibiotic therapy were 91.2% in the 5% granule group and 100% in the 10% granule group. Bacteriological eradication rate was 82.1% for 491 strains in the 5% granule group, and was 84.0% for 175 strains in the 10% granule group. The incidences of side effects were 3.9% (24/608) in the 5% fine granule group and 5.8% (12/206) in the 10% granule group. All of the side effects were slight gastrointestinal disorders, and no serious side effects were found. As for clinical laboratory test results, slight elevations of eosinophile, platelet or transaminase were observed. Based on the above results, it is considered that the appropriate dose levels of CFDN for pediatric infections ranged from 9.0 to 18.0 mg (potency)/kg a day, divided into 3 portions.

Administration, Oral↗
PubMed1991

Effect of different doses of aluminium hydroxide on renal deterioration and nutritional state in experimental chronic renal failure.

To investigate the effects of aluminium hydroxide (AH), a phosphate binder, on the progress of chronic renal diseases, high doses (9.6 g/kg/day, group ADR-H), moderate doses (2.4 g/kg/day, group ADR-M), and low doses (1.2 g/kg/day, group ADR-L) of the compound, were orally administered for 34 weeks to rats with Adriamycin (ADR)-induced focal glomerular sclerosis. Serum creatinine and blood urea nitrogen were significantly lower in either group ADR-H or ADR-M than in group ADR at week 34. Urinary protein excretion was significantly lower in group ADR-H than in group ADR in all observation periods and was also lower in group ADR-M than in group ADR at weeks 28 and 32. Both glomerular sclerosis and tubular change were significantly less severe in group ADR-H, while tubular change was less marked in group ADR-M than in group ADR. These results revealed that phosphate depletion was induced, and progressive renal failure was ameliorated in proportion to the dosing of AH. On the other hand, body weight was significantly smaller in group ADR-H than in group ADR in more than half of the observation period. In conclusion, a high dose of AH may adversely affect the nutritional state irrespective of having an extremely protective effect on progress of renal dysfunction. Appropriate doses of AH should be used to prevent the renal deterioration.

Administration, Oral↗
PubMed1990

Mechanism of nasal absorption of drugs. III: Nasal absorption of leucine enkephalin.

The nasal absorption of a model peptide, leucine enkephalin (LE), was studied in rats using an in situ technique in which 4 mL of perfusion solution was circulated. Leucine enkephalin (LE) was found to undergo hydrolysis to its major metabolite des-tyrosine leucine enkephalin (DTLE). The addition of 1% sodium glycocholate (SGC) to the perfusion solution resulted in an increase in the overall rate of disappearance of LE and a decrease in the rate of formation of DTLE. When LE was added to nasal washings (i.e., Ringer's buffer that was precirculated through the nasal cavity to extract enzymes), LE was found to form DTLE. When SGC or puromycin was added to the nasal washings prior to the addition of LE, the rate of conversion of LE to DTLE was significantly reduced, suggesting that these two agents can inhibit peptidase enzyme activity in the nasal cavity. Since the volume of the solution has been shown to influence the kinetics of absorption of drugs administered nasally, a new experimental technique, the in vivo-in situ technique, which utilizes small volumes of solution and simulates realistic use of nose drops, was employed to further examine the mechanism of absorption and hydrolysis of LE in rats. Leucine enkephalin (LE) dissolved in 100 microL of Ringer's buffer was placed in the isolated nasal cavities of rats. The disappearance of LE and the appearance of DTLE were followed by rinsing the nasal cavity with fresh buffer. Disappearance of LE was always accompanied by appearance of DTLE, and the fraction of LE converted to DTLE decreased as the concentration of LE increased, suggesting a saturable enzymatic process.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1990

Mechanism of nasal absorption of drugs. IV: Plasma levels of radioactivity following intranasal administration of [3H]leucine enkephalin.

To study the factors influencing nasal absorption of a model pentapeptide, plasma levels of total radioactivity were determined following the administration of [3H]tyr-leucine enkephalin to rats intravenously, intranasally alone, and intranasally in the presence of puromycin. The major pathway for transport of radioactivity into the blood from the nasal cavity appeared to be hydrolysis of [3H]tyr-leucine enkephalin to [3H]L-tyrosine, followed by absorption of [3H]L-tyrosine. When puromycin was added to the nasal solution in concentrations at which the in vitro hydrolysis of leucine enkephalin was completely inhibited, the appearance of radioactivity in the plasma was slowed, but plasma concentrations of radioactivity eventually reached levels comparable to those observed in the absence of puromycin. In view of the inhibitory effect of puromycin on the hydrolysis of leucine enkephalin, it was assumed that a significant fraction of the [3H]tyr-leucine enkephalin was absorbed intact in the presence of this substance. However, an assay method for intact leucine enkephalin in plasma is needed to confirm these preliminary observations.

Administration, Intranasal↗
PubMed1990

Parathyroid hormone and the vascular response to norepinephrine.

Norepinephrine blood pressure reactivity is reduced in uremia, an effect attributed to excess parathyroid hormone (PTH). Most, but not all, animal and human studies support the theory that high PTH levels diminish the pressor response to norepinephrine. In hemodialysis patients in whom norepinephrine infusion tests were performed to determine the effect of parathyroidectomy on vascular responsiveness, the vascular response to norepinephrine (100 ng/kg/min) improved significantly (11.3 +/- 1.3 mm Hg before and 17.5 +/- 2.4 mm Hg after parathyroidectomy; P less than .01). Excess parathyroid hormone appears to play an active role in reduced vascular responsiveness to norepinephrine, although the mechanisms of this effect are unknown.

Animals↗
PubMed1990

Correlation between structures of organic cations and their binding behaviours to brush border membrane isolated from rat small intestine.

We have investigated the correlation between the molecular structures of various organic cations and their binding to rat small intestinal brush border membrane. The binding of small quaternary ammonium compounds such as tetramethylammonium and choline to brush border membrane was not sufficient to inhibit methylchlorpromazine binding. However, lauryltrimethylammonium and cetyltrimethylammonium, both quaternary amines with a long carbon chain, inhibited binding significantly. The inhibition was competitive. When the unbranched hydrocarbon chain of the quaternary amines was extended in steps from C1 (methyl) to C16 (cetyl), the inhibitory effect increased sharply with length from C7 (heptyl) to C16. These results suggest that the size of the hydrophobic part of the molecule is an important factor in binding of quaternary ammonium compounds to the brush border membrane. The structure of the hydrophilic part was another factor. In imipramine-related compounds, the order of binding was N-didesmethylimipramine (primary amine) greater than desipramine (secondary) greater than imipramine (tertiary) greater than methylimipramine (quaternary). However, with the small molecular ethylamine-related compounds, binding properties did not reflect differences in the hydrophilic component. Therefore, the effect of the hydrophilic part may be secondary and may depend on the size of the hydrophobic part. We suggest that organic cations which are amphiphilic can bind to a common binding site on brush border membrane through hydrophobic and/or hydrophilic interactions.

Animals↗
PubMed1990

Contribution of passive transport mechanisms to the intestinal absorption of beta-lactam antibiotics.

The transport characteristics of aminopenicillins (ampicillin and amoxicillin), aminocephalosporins (cephalexin, cephradine and cefadroxil) and cefazolin have been compared with those of an actively transported substance (D-glucose) and a passively transported substance (L-glucose). Although the initial uptake of the aminocephalosporins was stimulated in the presence of an inward H+ gradient, there was no overshoot in the uptake of any of the drugs tested, even in the presence of an H+ gradient. Also, the time course and the degree of uptake of these drugs were similar to those of L-glucose, especially in the absence of an H+ gradient. These results suggest that the beta-lactam antibiotics tested, like L-glucose, pass through the rat intestinal brush border membrane mainly by passive diffusion. However, the differences in absorption between these drugs, like the differences in their disappearance from a proximal loop of rat intestine, cannot be explained by a simple permeation process alone.

Animals↗
PubMed1990

[Intestinal absorption and urinary excretion of triethylenetetramine for Wilson's disease in rat].

Triethylenetetramine.2.HCl (trientine, TE) is an orphan drug for the treatment of Wilson's disease. There has been no reports regarding the absorption, distribution, metabolism, and excretion in the body. In the current study, the absorption and excretion of TE in rats were examined. The observed mean percentage amount of TE absorbed at the jejunum and ileum with the loop method for 1 h was 42.0% and 22.5%, respectively. Tight junction blocking agent inhibited the absorption of TE from the jejunum loop with 27%, but the absorption of TE from the ileum loop was not affected by this blocking agent. Therefore, the main absorption route for TE might be permeation across the plasma membrane of intestinal epithelial cells. TE and amikacin, a polycationic compound like TE, bound to the brush border membrane (BBM) of rat small intestine in the absence of inorganic ions such as Na+, K+, Ca2+, Mg2+ and Cu2+. But the binding of TE to BBM was inhibited markedly under the physiological concentration of these ions. The bioavailability of TE was below 10% and the plasma levels of TE in non-fasted rats were significantly lower than that observed in fasted rats. The urinary excretion of unchanged TE during 24 h was only 3.5% of the orally administered dose. However, the urinary excretion of total TE including metabolites, though they have not been identified, was 35.7%. These results suggest that low bioavailability of TE might be due to the rapid metabolism in the body after absorption from the gastrointestinal tract.

Administration, Oral↗
PubMed1990

Antithrombotic effects of KP-10614, a novel and stable prostacyclin (PGI2) analog.

A chemically stable prostacyclin analog, KP-10614 [(4z,16s)-4,5,18,18,19,19-hexadehydro-16,20-dimethyl-delta 6(9;alpha)-9(o)- methano-PGI1], has been compared with two other prostacyclin derivatives (Iloprost and TEI-7165) and one prostaglandin E1 derivative (OP-1206) with respect to ADP-induced in vitro aggregation of human platelets and ex vivo platelet aggregation in rats and dogs, given by bolus injection and i.v. infusion. These compounds were also tested on the systemic arterial blood pressure of rats and dogs. KP-10614 was the most potent inhibitor of in vitro platelet aggregation induced by ADP with IC50 of 1 nM among the compounds studied in this report, and it also showed ex vivo effectiveness at doses much lower than the other three compounds. KP-10614 was also orally active. At oral doses of 25, 50 and 100 micrograms/kg, this new compound caused a dose-dependent inhibition of ex vivo platelet aggregation in rats, whereas the other three compounds were effective only at 500 micrograms/kg or more. In addition, KP-10614 showed definite antithrombotic effects at a dose range of 0.1 to 1 microgram/kg i.v. in various thrombosis models in which platelet aggregation was mainly involved. These results indicate that KP-10614 possesses therapeutic potential in thrombotic diseases.

Administration, Oral↗
PubMed1990

[Clinical and pharmacokinetic evaluation of cefdinir in children].

Thirty children were treated with cefdinir (CFDN) for the evaluation of its clinical efficacy and side effects. Their ages ranged from 1 to 9 years. The dosage of CFDN ranged from 8.1 to 15.9 mg/kg/day with the treatment continued for 2 to 10 days. Twenty-eight of the 30 patients were evaluated for clinical efficacy; 10 patients with tonsillitis, 3 with scarlet fever, 4 with lower respiratory infections, 2 with otitis media, 2 with cervical lymphadenitis, 3 with urinary tract infections and 4 with skin and soft tissue infections. The remaining 2 patients who had viral diseases were included in the evaluation for side effects. Clinical responses were excellent in 14 patients, good in 12, fair in 1 and poor in 1 with an efficacy rate of 92.9%. Diarrhea was noted in one of the 30 patients. A pharmacokinetic study on CFDN was performed in 8 fasting patients whose ages ranged from 3 to 7 years. Serum concentrations of CFDN peaked at 0.59 to 1.76 micrograms/ml (mean 1.13 microgram/ml) at 2 hours after dosing of 3 mg/kg in 4 patients, and 0.89 to 2.49 micrograms/ml (mean 1.49 micrograms/ml) 2 or 3 hours after dosing of 6 mg/kg in the other 4 patients. The 8-hour urinary excretion rates were 16.0% to 21.3% (mean 17.4%) in 4 patients given a dose of 3 mg/kg and 10.9 to 21.1% (mean 15.5%) in 4 patients given a dose of 6 mg/kg.

Administration, Oral↗
PubMed1990

Hemodynamic and volume changes by recombinant human erythropoietin (rHuEPO) in the treatment of anemic hemodialysis patients.

Hemodynamic and volume changes induced by recombinant human erythropoietin (rHuEPO) treatment were investigated in 12 chronic hemodialysis patients with refractory anemia. After rHuEPO administration for 49 to 151 days, hematocrit (Ht) significantly improved from 19.4 +/- 2.3 to 30.1 +/- 1.1% (Mean +/- SD). Mean blood pressure (MBP) increased slightly but significantly from 78.8 +/- 13.2 to 88.9 +/- 16.9 mmHg. Hemodynamically, total peripheral resistance index (TPRI) increased significantly from 1,444 +/- 367 to 2,146 +/- 470 dynes.sec.cm-5.m2, while cardiac index (CI) decreased significantly from 4.49 +/- 0.85 to 3.37 +/- 0.60 l/min/m2. Both pulse rate (PR) and stroke volume index (SVI) also decreased significantly, but blood volume (BV) remained unchanged. Plasma renin activity and plasma norepinephrine decreased significantly. There were positive correlations between the change of MBP and that of CI, and between the change in CI and that of BV, respectively (p less than 0.05 or less). In conclusion the improvement of anemia using rHuEPO is hemodynamically associated with an increase in TPRI and a decrease in CI as well. Blood pressure elevation seems to be caused by an inappropriately minor reduction of CI. The contribution of humoral factors is not suggested.

Adult↗
PubMed1989

Transport characteristics of [3H]-chlorpromazine across rat small intestinal brush border membrane.

The transport mechanism of chlorpromazine, a tertiary amine, has been investigated using brush border membrane vesicles isolated from rat small intestine. Chlorpromazine was taken up rapidly by the vesicles the uptake being mainly due to binding to the membrane. The transport of chlorpromazine into the intravesicular space was facilitated by the transmembrane electrical potential difference (inside negative) induced by valinomycin or sodium thiocyanate. This facilitating effect was observed only when the transmembrane electrical potential difference was induced after chlorpromazine uptake had reached a steady state. In the initial phase of chlorpromazine uptake, there was no effect. Therefore, it is suggested that both rapid binding to brush border membrane and transmembrane electrical potential difference (inside negative) across the membrane plays a significant role in the transport processes of chlorpromazine through the intestinal epithelium.

Animals↗