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Purpose: To evaluate the inhibitory effect of aldose reductase inhibitor (ARI) for the accumulation of sugar alcohol and the enhanced proliferation of lens epithelial cells of rats fed a galactose diet., Methods: Sprague-Dawley rats were fed a diet containing 50% galactose with or without ARI (SNK-860). Histological changes in the lenses were observed by light microscopy, and the amount of galactitol accumulated in the lens epithelium was measured by liquid-gas chromatography. Immuno-histochemical staining of proliferating cell nuclear antigen (PCNA) in whole-mount preparations was performed to assay the proliferative ability of the lens epithelial cells., Results: The amount of galactitol in the lens epithelium and the number of PCNA positive cells in rats administered ARI were less than in rats fed the galactose diet. Multi-layered epithelium was observed in advanced cataract of rats fed the galactose diet, but not in the rats given ARI., Conclusion: The administration of ARI can prevent cataractous changes and aberrant proliferation of lens epithelial cells.

The current information regarding mechanistic understanding of atrial fibrillation(AF) and flutter(AFL) is reviewed, and the recent development in both pharmacological and non-pharmacological treatment for AF and AFL is also introduced. For the antiarrhythmic therapy, the effectiveness and safety of new class III drugs(ibutilide and azimilide) in the termination and prophylactic therapy are focused. In the non-pharmacological section, several ablative strategies including electrical isolation of PV-LA interface for focal AF, 'Ablate and Pace' therapy and AV nodal modification for drug-refractory tachycardic AF, and so-called 'Hybrid' therapy are introduced. It is emphasized that the newly developed 3-dimensional mapping system is useful to determine the appropriate target site of ablation for atypical AFL.

Changes in valvular function and blood pressure level during long-term pharmacological anti-hypertensive therapy were investigated in patients with mild to moderate essential hypertension. Sixty-seven patients with hypertension (mean [+/-SD] 60 +/- 10 years) were followed up for 5.4 +/- 1.6 years with antihypertensive medication. During the follow-up period, valvular dysfunction was assessed by color Doppler echocardiography. Increased mitral valve regurgitation > or = grade II and/or aortic valve regurgitation > or = grade II were aggravated in 17 patients, whereas the other 50 patients did not reveal any significant changes in valvular functions. Systolic blood pressure and end-systolic wall stress at the end of the follow-up period were higher in the aggravated group (156 +/- 30 mmHg and 79 +/- 23 dyne/cm2) than in the unchanged group (143 +/- 17 mmHg and 63 +/- 18 dyne/cm2). Dimensions of the left atrium and left ventricle at both systole and diastole were enlarged in the aggravated group (37 +/- 4 to 40 +/- 4, 31 +/- 4 to 33 +/- 4 and 48 +/- 3 to 51 +/- 3 mm, respectively), but not in the unchanged group. Nine patients in the aggravated group received additional treatment with imidapril hydrochloride over 6 months in an attempt to further reduce blood pressure levels, resulting in significant improvements in systolic blood pressure (151 +/- 12 to 129 +/- 7 mmHg), diastolic blood pressure (91 +/- 4 to 79 +/- 8 mmHg), left atrial dimension (41 +/- 3 to 39 +/- 3 mm) and left ventricular end-diastolic dimension (49 +/- 4 to 48 +/- 3 mm). Adequate pharmacological intervention can ameliorate valvular dysfunction, left ventricular enlargement and increased ventricular wall stress.

The antihypertensive mechanism of imidapril was investigated in relation to its inhibition of ACE activities in the serum, thoracic-abdominal aorta, lung, kidney, heart and brain from adult spontaneously hypertensive rats (SHRs). In comparison with normotensive rats (NTRs), the ACE activities in the aorta, heart, brain and lung were higher, while those in the serum and kidney were considerably lower. Imidapril (2 mg/kg) showed remarkable inhibitions within 6 hr in all tissues, except for the brain, after a single oral administration. Consecutive administration of imidapril (2 mg/kg/day) for 30 days produced inhibitions in all tissues. The inhibitions in the serum, aorta and lung were greater, and the duration of inhibition in the aorta, brain and lung were longer. Blood pressure declined gradually until 6 hr, and the reductions were significant at 24 hr after the single and chronic administrations. Imidapril (0.5 mg/kg, ineffective on normal blood pressure) inhibited ACE activities in NTRs similarly. Enalapril at the same dose exhibited less ACE inhibition and antihypertension. These results suggest that the ACE inhibition in the serum, lung and aorta by imidapril correlate with the antihypertension in SHRs; especially, the lung and vascular ACE inhibitions play an important role in the duration of antihypertension in SHRs.

Twenty seven patients with endocrine therapy relapsed prostate cancer were studied by measuring their prostatic acid phosphatase (PAP), prostate specific antigen (PSA), gamma-semino-protein (gamma-Sm) and alkaline phosphatase (ALP) serially before change of the treatment, and tumor marker doubling time was calculated. The exponential increase in PAP, PSA and gamma-Sm was observed in all patients and ALP showed a similar pattern in some. The values of PAP doubling time were the same as those of PSA, but gamma-Sm doubling time was slightly longer than the former ones. Tumor marker doubling time correlated with survival after the increase in markers, and also with time between the start of endocrine therapy and the increase in markers. Patients who showed either NC or PR to chemotherapy had a longer tumor marker doubling time than those with PD. In cases showing progression of bone metastasis, patients with exponential increase in ALP showed worse prognosis when compared with those showing other patterns. From these results, it was demonstrated that determination of tumor marker doubling time in patients with endocrine therapy relapsed prostate cancer was a valuable method to measure rate of regrowth, and to assess the prognosis after relapse.

Imidapril is a newly synthesized non-sulfhydryl-containing angiotensin I converting enzyme (ACE) inhibitor. The present study describes the inhibitory effects of imidapril and its active metabolite 6366A on ACEs from various tissues and compares its effects to those of captopril, enalapril and enalaprilat in vitro. 6366A inhibited swine renal and human serum ACEs with an inhibition constant (Ki) of 0.067 nM and 0.04 nM, respectively. These values were 3 to 18 times more potent than those of the other inhibitors. The kinetic study showed that 6366A exerted competitive type inhibition. The ACE inhibition (IC50 values) of 6366A, enalaprilat and the structurally related compounds (6366DM and 6366PY) were compared in homogenates of lung, aorta, heart, brain and kidney from spontaneously hypertensive rats (SHRs) and Wistar Kyoto rats (WKYs). The inhibitory effects of 6366A on all tissue ACEs from SHRs and WKYs were the most potent among these compounds. And the inhibitory potencies of these compounds were correlated with their chemical structure. The present results suggest that 6366A may show a strong inhibitory effect on ACEs from several tissues and species due to its chemical characteristics.

To investigate the efficacy and the safety of RU23908 for the treatment of prostatic cancer, an early phase 2 study with the oral administration of 150 or 300 mg daily was performed in 47 patients with stage C or D prostatic cancer at 15 institutions from April 1987 to June 1988. Forty patients were evaluable for efficacy. Concerning the effect on the object lesion, the results of the overall evaluation revealed that complete or partial response (CR + PR) was obtained in 34 of the 40 cases (85.0%). As to the effect classified by site, CR + PR were observed in 35 out of the 40 cases with primary lesion (87.5%), in 10 of the 22 cases with bone metastasis (45.5%), in 5 of the 6 cases with lymph node metastasis (83.3%) and CR was observed in one case with lung metastasis. In the PAP evaluation, 33 out of the 34 cases were judged to be CR + PR (97.1%). The improvement rate of clinical symptoms was 88.9% for bone pain, 83.3% for dysuria and 45.5% for performance status. Adverse reactions were observed in 29 of the 47 cases (61.7%) investigated and 7 cases (14.9%) were withdrawn. During the study period of 12 weeks and the subsequent period of continued administration, 6 cases (12.8%) and 2 possible cases of interstitial pneumonia were diagnosed. From the above results, the treatment of prostatic cancer with RU23908 150 mg/day or 300 mg/day in combination with surgical castration showed an excellent clinical effect compared to conventional endocrine therapy, but has a problem of safety. Therefore, this drug may be expected to be a highly useful therapeutic drug, if safely is improved in the future by reviewing the dose.