Biomedical subjects

M Tsunoo

Publications and source records attributed to M Tsunoo.

10 recordsLinked to original sources

PubMed2000

Exogenous 20K growth hormone (GH) suppresses endogenous 22K GH secretion in normal men.

The physiological and pharmacological functions of the 20-kDa human GH (20K-hGH) isoform are unknown. We conducted a pharmacokinetic study of recombinant 20K-hGH in human subjects (Phase I clinical trial). Placebo or 20K-hGH was administered sc to normal men (20-31 yr of age, n = 6-8 per group) at 2100 h. Serum 20K- and 22K-hGH levels were monitored every 30 min for 24 h by specific enzyme-linked immunosorbent assays. Serum free fatty acid, insulin-like growth factor I, insulin, and glucose levels were measured for 24 h. In the placebo group, the secretion profiles of endogenous 20K- and 22K-hGH were pulsatile and similar to each other. The proportion of 20K- to 22K-hGH was fairly constant. In the 20K-hGH-treated groups, serum 20K-hGH levels increased in a dose-dependent manner over the dose range of 0.01-0.1 mg/kg. Maximum serum 20K-hGH levels were reached at 3-4 h and decreased with half-lives of 2-3 h. Marked suppression of endogenous 22K-hGH secretion was observed in a time-dependent manner. Serum free fatty acid and insulin-like growth factor I levels were significantly elevated (P < 0.01) at 4, 8, and 12 h and at 8, 12, and 24 h after 20K-hGH administration, respectively. Serum insulin and glucose levels did not change significantly within 24 h. These results suggested that: 1) regulation of 20K-hGH secretion is physiologically the same as that of 22K-hGH; 2) the pharmacokinetics after sc injection of 20K-hGH are comparable with those of 22K-hGH; 3) 20K-hGH regulates hGH secretion through "GH-induced negative feedback mechanisms"; and 4) administration of 20K-hGH is expected to exert GH actions (growth-promoting activity and lipolytic activity). Monitoring of serum 20K- and 22K-hGH levels may be useful in evaluating the effects of administered GH isoforms on their own release from the pituitary.

Adult↗

PubMed1998

Pharmacokinetics and plasma protein binding of tamsulosin hydrochloride in rats, dogs, and humans.

The pharmacokinetics of tamsulosin hydrochloride, a selective alpha1-adrenoceptor antagonist, was investigated after single iv and oral dosing to rats and dogs, and oral dosing to healthy male volunteers. After iv dosing, plasma tamsulosin concentrations declined in an apparent biexponential manner with terminal half-lives of 0.32 hr in rats and 1.13 hr in dogs. Values for total blood clearance (CLB) were 6.57 l/hr/kg in rats and 1.61 l/hr/kg in dogs, suggesting "hepatic blood flow-limited" and "intermediate flow-dependent" clearance, respectively. After oral dosing, tamsulosin was rapidly absorbed and reached maximum levels within 1 hr in rats and dogs, and at 1.0-1.8 hr in humans. Values for oral clearance (CLoral) in rats, dogs, and humans were 34.5-113.6, 3.01-3. 99, and 0.031-0.041 l/hr/kg, respectively, showing wide variation among these species. The absolute bioavailability (F) increased with dose in rats (from 6.9% at 1 mg/kg to 22.8% at 10 mg/kg), but was almost constant in dogs (29.7-42.0% over the 0.3-3 mg/kg dose range). The plasma protein binding of 14C-tamsulosin in humans was much higher (98.9-99.1%) than that in rats and dogs (79.0-80.6% and 90. 2-90.3%, respectively). The ratio of blood to plasma concentrations (RB) value in rats, dogs, and humans decreased in this order (1.2, 0. 72, and 0.53, respectively), corresponding to the decrease in plasma unbound fraction (fu) in these species. These results imply that the large interspecies difference in CLoral is attributable to a difference not only in hepatic metabolism but also in protein binding among these species.

Administration, Oral↗

PubMed1997

Pharmacokinetic properties of YM17E, an inhibitor of acyl coenzyme A: cholesterol acyl transferase, and serum cholesterol levels in healthy volunteers.

We conducted a single and repeat oral dose study of YM17E, a novel inhibitor of acyl coenzyme A (CoA): cholesterol acyltransferase, in healthy male volunteers to evaluate the pharmacokinetic profile, tolerability and effect of the drug on serum cholesterol. In the single administration study, YM17E was administered after a meal to two groups of subjects (each containing six subjects taking the drug and three taking placebo) receiving 3, 60 and 300 mg or 15, 60 and 450 mg YM17E, respectively. Plasma concentrations of unchanged drug following single oral administration at 3-300 mg after a meal increased with increasing dose. In contrast, plasma concentrations after administration of 450 mg were almost the same as after 300 mg. Unchanged YM17E was not detected in urine after single administration, suggesting that it was excreted via the bile or urine after metabolism. Five active metabolites (M1, M2-a, M2-b, M3 and M4) were observed in plasma at concentrations comparable to those of unchanged YM17E. Their plasma concentrations increased in a slightly greater than dose-dependent manner from 3 to 300 mg. The effect of food was studied in an open crossover design with a 1-week washout period. Twelve subjects received 150 mg YM17E in both the fasted and post-prandial states. The AUC and Cmax after fasting were closely similar to those after a meal, showing that bioavailability was not affected by food intake. In the repeated oral dose study, the subjects received test drug at 150 mg or 300 mg (n = 6 each) or placebo (n = 3) twice a day (after breakfast and after dinner) for 7 days. On days 1 and 7, the subjects received YM17E once a day (after breakfast) for evaluation of pharmacokinetic properties. After repeated oral administration of 150 mg b.d., plasma concentrations reached steady state by day 5 (mean Cmin 48.6 ng.ml-1). After repeated administration of 300 mg b.d., plasma concentrations prior to each daily morning dose increased up to the 5th day (mean Cmin 166.6 ng.ml-1) and then tended to decrease until the 7th day. No significant signs, symptoms or changes in serum cholesterol levels were observed during the single and repeated oral dose studies at 150 mg b.d. Although statistical analysis was not conducted because of the small number of subjects, all subjects receiving repeated oral administration of 300 mg twice daily showed a 25% decrease in serum cholesterol level on day 7, but also the simultaneous occurrence of diarrhoea.

Administration, Oral↗

PubMed1986

Pharmacokinetics and protein binding of cefazolin and cephalothin in patients with cirrhosis.

The effects of liver disease on the pharmacokinetics and protein binding of cefazolin and cephalothin were studied in patients with cirrhosis, chronic active hepatitis or normal liver function. The T1/2 and mean residence time of cefazolin were significantly shorter in cirrhosis. Cephalothin clearance was decreased by cirrhosis. Plasma protein binding of cefazolin, but not cephalothin was significantly reduced in cirrhosis. It is suggested that no dose reduction is necessary for either drug in severe hepatic impairment.

Adult↗

PubMed1979

Changes in blood level of kininogen, prostaglandin E and hemodynamics during experimental acute myocardial ischemia with and without FOY-007.

Changes in kininogen, prostaglandin E and hemodynamics were studied during 2 hours after left anterior descending artery ligation in 19 anesthetized dogs with and without FOY-007, an inhibitor of kinin forming enzyme. Significant decrease in kininogen in aorta and great cardiac vein (aorta greater than great cardiac vein) and increase in prostaglandin E in great cardiac vein were observed after ligation, indicating release of kinin and prostaglandin E from ischemic area. Both kininogen and prostaglandin E changes were inhibited by FOY-007 but further decrease in cardiac output and increase in systemic vascular resistance were observed. In summary, myocardial release of both kinin and prostaglandin E was inhibited by FOY-007, with increase of afterload of the heart.

Animals↗

PubMed1969