Toshiji Igarashi

Chronic hypertension induced by streptozotocin in rats

SummaryAn intravenous injection of 40 or 65 mg/kg streptozotocin induced not only diabetes but also severe hypertension in rats. Whereas the hyperglycemia developed fully within a few days after the injection of streptozotocin, the hypertension progressively advanced and reached maximum level several weeks after the treatment and lasted more than 20 weeks. Twenty mg/kg streptozotocin did not induce hyperglycemia but significantly increased blood pressure several weeks after the treatment. Arrest of growth, polyuria, glycosuria, hyperlipemia and lenticular cataracts developed in the animals treated with 40 or 65 mg/kg streptozotocin, but in none of the animals treated with 20 mg/kg. In histological examinations in the 24th week after the treatment, degranulation and necrosis in the pancreatic β-cells, and vacuolization and deposition of PAS-positive materials in the renal proximal tubules were found in the animals treated with 40 or 65 mg/kg streptozotocin.

Effects of geranygeranylacetone on gastrointestinal secretion in rats

The effects of geranylgeranylacetone (GGA), a new acyclic polyisoprenoid with a novel antiulcer action on gastrointestinal secretion were studied in rats. Intraduodenal administration of GGA (1-30 mg/kg) dose-relatedly reduced the gastric acid secretion caused by pentagastrin, histamine or insulin. On the other hand, GGA (3-30 mg/kg i.d.) dose-relatedly increased pancreatic secretion but did not affect biliary secretion. The above-mentioned findings seem consistent with the further findings that GGA depressed a plasma gastrin level enhanced by insulin while in increased the basal level of plasma secretin. These pharmacological features found in the present studies may partially, at least, account for the mechanism of GGA antiulcer action.

Determination of inflamed paw surface temperature in rats

The surface temperature of a rats paw is greatly affected by heat transfer because of its contacts with the body, as well as several environmental conditions. To establish a methodology for determining the surface temperature of the inflamed rats paw, we devised an individual cage with a pair of rolling rods. The rods were set to protect contacts of paws with the body and were devised to roll easily when rats put their feet on the rods. When a rat was transferred to the individual cage with rolling rods from a group cage, the surface temperature of a normal or inflamed paw fell gradually and reached equilibrium within 10 minutes. The application of the rolling rods markedly narrowed the range of fluctuation of paw surface temperatures at the equilibrium, and increased the temperature difference between inflamed and noninflamed paws. We compared local hyperthermia and swelling of inflamed paws, and tested the effects of indomethacin. The results suggest that the local hyperthermia is a useful index of inflammation and a sensitive parameter for the pharmacological evaluation of antiinflammatory drugs.

The metabolism of phenyl o-(2-N-morpholinoethoxy)-phenyl ether hydrochloride in the rabbit and rat.

1. Urinary and faecal excretion of radioactivity in 120 h after oral administration of [U-14-C]phenyl o-(2-N-morpholinoethoxy)phenyl ether hydrochloride (200 mg/kg) were 92 and 3% dose in the rabbit, and 60 and 35% in the rat. 2. Urinary metabolites were produced by aromatic hydroxylation and aryl alkyl ether bond cleavage. Some evidence for formation of dioxomorpholino, oxohydroxymorpholino, and ethanolamino derivatives of the drug was obtained. 3. The aromatic hydroxylation product, p-hydroxyphenyl o-(2-N-morpholinoethoxy)phenyl ether hydrochloride had vasopressor activity comparable with the parent compound, but with shorter duration of action.

Update of general pharmacology/safety pharmacology studies in Japan

The General Pharmacology Working Group of the Japanese Pharmaceutical Manufacturers Association review the current status of safety pharmacology list procedures.

A Study on the Consistency between Flagging by Statistical Tests and Biological Evaluation

Statistical hypothesis tests are used as a flagging device to highlight differences worth further attention in the evaluation of repeated dose toxicity studies in the rat. Raw data of quantitative parameters of 19 regulatory toxicity studies were collected with their final interpretation of each study. An investigation was done on the consistency between flagging by statistical tests and biological significance by final interpretation. Williamss test at 2.5% of the significance level showed as much accuracy (correct results compared with the sum of false negative and false positive results) as the rate of Dunnetts test at the 5% significance level. Since a monotonic dose-response relationship is usually assumed in selection of dose levels, Williamss test with ordered alternative hypotheses is recommended as a routine procedure instead of the currently used Dunnetts test. A supplementary procedure, using Steels test, was shown to be effective for flagging unexpected ‘downturn’ dose response.

THE RATIONALE FOR USING LOGARITHMIC TRANSFORMATION OF CONCENTRATION DATA :A COMMENT ON STATISTICAL EVALUATION OF TOXICOKINETIC DATA

There are several papers describing the rationale for using logarithmic transformation on concentration-dependent pharmacokinetic parameters before examination by analysis of variance in bioequivalence studies (1, 2). This paper focuses on the necessity of logarithmic transformation of plasma concentration of toxicokinetic studies.

THE USE AND ABUSE OF TOXICOKINETICS : WHAT DOES ACTUAL DATA TELL RESEARCHERS ?

Pharmacokinetic data obtained in 71 toxicity studies on 38 compounds were investigated. Twenty-four studies (33%) were of “I-type” nonlinear kinetics where the plasma concentration did not increase as much as the dose increased, while 14 studies (20%) were of “S-type” nonlinear kinetics where the plasma concentration increased super-proportionally. Some marked increase in plasma concentrations during repeated administration occurred exclusively in “S-type” nonlinear kinetics cases, while decreases were found in some “I-type” kinetics cases. Plasma concentrations at dose levels which produced toxicity were less than the human therapeutic plasma concentrations in 6% of studies and in 18% for those compounds which did not produce toxicity. The intertest compounds difference in items investigated seemed to be much greater than the interstudies (animal species) difference. It should be stressed from these results that the well-designed assessment of systemic exposure in toxicity studies should be requested only in certain representative studies.