Characterization of the High Sensitivity of Rabbits to the Effects of TCV-116, an Angiotensin II Receptor Antagonist

A high incidence of maternal toxicity in rabbits characterizedby uremia and death was observed when TCV-116, a novel angiotensinII subtype-1 (AT1) receptor antagonist, was orally administeredto pregnant rabbits at dosage levels of 3 mg/kg/day or more.The effects of TCV-116 on blood pressure in nonpregnant or malerabbits and rats and on blood chemistry, renal circulation,and plasma renin activity in nonpregnant or male rabbits wereexamined to characterize the toxicity in rabbits. In a 2-weekrepeated dose study, most nonpregnant female rabbits receiving3 or 100 mg/kg/day died or were sacrificed in a moribund state,indicating that toxicity could be caused independently of pregnancy.When these rabbits became moribund, marked hypotension, accompaniedby increases in plasma concentrations of urea nitrogen, creatinine,and potassium, was observed, suggesting uremia. In a singledosestudy, blood pressure in rabbits was decreased after administrationof 10 or 100 mg/kg of TCV-116, and the hypotension was moremarked and sustained than that in rats, as was the case with30 mg/kg of enalapril. The sustained pharmacological effectin rabbits was also confirmed with regard to decreases in effectiverenal plasma flow and the glomerular filtration rate and increasedplasma renin activity. Species differences in the hypotensiveeffect and mortality could not be explained by toxicokineticdata for the active metabolite of TCV-116 in various species,which supported a possibility that the differences in toxicitymay be related to the species difference in sensitivity to thepharmacological effect of TCV-116. We conclude that the specificmaternal toxicity of TCV-116 in rabbits may be mainly due tothe higher sensitivity of rabbits to the pharmacological effectsand is caused by marked and sustained hypotension resultingin the decrease in glomerular filtration rate, uremia, and death.     

Regional cerebral blood flow abnormalities in late-life depression:Relation to refractoriness and chronification

Abstract We examined patterns of regional cerebral blood flow (rCBF) abnormalities in 18 patients with major depressive disorder in late life using single photon emission computed tomography (SPECT) and (^99mTc-hexamethyl-propylenamine oxime (^99mTc-HMPAO). Compared with 13 age-matched controls, relative rCBF was significantly decreased bilaterally in the anterior cingulate gyrus, the prefrontal cortex, the temporal cortex, the parietal cortex, the hippocampus and the caudate nucleus. However, it was not correlated with the severity of depression or global cognitive dysfunction. In 10 patients with a prolonged depressive episode or prolonged residual symptoms (the refractory subgroup), robust and extensive decreases in rCBF were found compared with controls and the rCBF decreased significantly in the anterior cingulate gyrus and the prefrontal cortex compared with that in the non-refractory subgroup. In the non-refractory subgroup, rCBF decreased significandy in the caudate nucleus and tended to decrease in the anterior cingulate gyrus compared with controls. These findings indicate that dysfunction of the limbic system, the cerebral association cortex and the caudate nucleus may be implicated in late-life depression and that robust and extensive hypoperfusion, especially in the anterior cingulate and the prefrontal regions, may relate to refractoriness or chronification of depression.     

CALCINOSIS AND THE ANTICENTROMERE ANTIBODY: ITS CLINICAL, RADIOLOGICAL AND IMMUNOGENETIC ASPECTS

The relationship between calcinosis and the anticentromere antibody(ACA) was studied from a clinical, radiological and immunogeneticstandpoint. Ten ACA-positive scleroderma patients, 34 ACA-negativescleroderma patients, 31 ACA-positive patients without sclerodermatousskin changes and 140 ACA-negative patients with various rheumaticdiseases were compared with regard to the incidence of calcinosisas measured by radiographs of hand and/or foot. Calcinosis wasfound in 10(100%), 12(35%), 13(42%) and eight(6%) patients ineach group respectively. Frequent sites for calcinosis in theACA-positive patients were foot (24%), hand (21%) and leg(19%).The forearm was not usually involved (6%). During the follow-upterm (1.0–9.5 years; mean 4.5 years) of 11 ACA-positivepatients without calcinosis, four (36%) developed new calcinosisand this incidence was significantly higher (P<0.02) thanthat in the ACA-negative control group (2/42; 4.8%). As a whole,23(59%) of 39 patients with ACA showed calcinosis. In the ACA-positivepatients with calcinosis, sclerodactyly (P<0.005) and CRESTsyndrome (P<0.001) were found more frequently than in ACA-positivepatients without calcinosis. HLA-A2 was found more frequently(67%) in the ACA-positive patients with calcinosis when comparedto normal subjects (41%) (P<0.02). We concluded that calcinosisseems closely related to scleroderma, especi ally those withACA, and that the development of calcinosis requires a certaingenetic background. KEY WORDS: Calcinosis, Anticentromere antibodies, Scleroderma     

Laparoscopic Findings of Asymptomatic Primary Biliary Cirrhosis —Particular investigation in early PBC—

Abstract: of 17 cases of asymptomatic primary biliary cirrhosis (PBC), seven cases whose ALP (alkaline phosphatase) was less than twice the upper limit of the normal range were defined as being “early PBC”, and ten cases whose ALP was more than twice the upper limit of the normal range were defined as being “classical PBC” in order to investigate their clinical pictures and laparoscopic findings. There were no significant differences between early PBC and classical PBC in terms of sex differences, age, a positive rate of antimitochondrial antibody and histological findings. On the other hand, apart from IgM being as high as 86%, laboratory studies indicated that early PBC cases showed relatively low abnormal levels of GOT (29%), ALP (43%), γ-GTP (57%), and erythrocyte sedimentation rate (ESR) (57%). Classical PBC cases exhibited almost 100% abnormal values. Laparoscopic examination of all the classical PBC cases revealed such specific characteristics of PBC as reddish patches, protuberance formations and mesh-like white markings. Early cases revealed one of the following nonspecific findings: proliferation of the portal veins, irregularity of the liver surface, dullness of the liver edge and enlargement of the liver. However, in terms of the specific findings, none of the patients had reddish patches, and half of the patients demonstrated protuberance formations and mesh-like white markings in part of the liver.     

Colonoscopic Follow-up Study after Polypectomy

One hundred and forty-seven patients with colonic adenoma and early cancer were followed by one or more total colonoscopies. A very precisely planned colonoscopic follow-up schedule for the polypectomized patients was then assessed. In patients who received a single follow-up examination, the incidence of developing new polyps was 46.7% (1 year), 53.9% (2 years) and 73.3% (3 years or more). Patients who received multiple follow-up examinations showed an average incidence of developing new polyps (polyp positive examinations/total examinations) of 46.9%. With regards to the location and histology of the polyps, there was no difference found between the initial and new polyps. Seventeen colon cancers (14 mucosal, 2 early invasive, 1 advanced) were detected in 16 patients in the follow-up examinations. The time elapsed from a diagnosis of ‘clean colon’ to a new cancer developing was 1.9±1.0 years. The rate of new pedunculated polyps was found to be significantly low (p <0.01), and their size was significantly smaller (p<0.01) when compared with polyps in the initial early colon cancer. Follow-up examinations every two years are recommended     

Anti-HBs responses after combined injection of recombinant yeast and plasma-derived hepatitis B vaccines

Anti-HBs responses to a combined injection of recombinant yeast and plasma-derived hepatitis B vaccines were evaluated in 119 healthy members of medical staff. They were divided into three age- and sex-matched groups. Group I (YHB-YHB-YHB) were given recombinant yeast vaccine at 0, 1 and 6 months, group II (PHB-YHB-YHB) were given plasma-derived vaccine at 0 month, and then recombinant yeast vaccine at 1 and 6 months, and group III (YHB-YHB-PHB) were given recombinant yeast vaccine at 0 and 1 month and then plasma-derived vaccine at 6 months.
The seroconversion rate in each group at 7 months were similar (group I: 91.2%, group II: 88.5%, and group III: 94.1%). Acquired antibody titre (S/N ratio) was higher, however, in group II than in group I (group I: 37.6 ± 29.1 versus group II: 57.4 ± 44.9).
The present study indicated that in this combined injection method, cross antigenicity was observed between plasma-derived vaccine and recombinant yeast vaccine and that high antibody titres could be obtained by a combined injection of a recombinant yeast vaccine and a plasma-derived vaccine when compared with the recombinant vaccine alone. Accordingly, this combined vaccination method is recommended because of its easy availability.