Comparison of stable nitroxide, 3-substituted 2,2,5,5-tetramethylpyrrolidine-N-oxyls, with respect to protection from radiation, prevention of DNA damage, and distribution in mice.

We compared three 3-substituted 2,2,5,5-tetramethylpyrrolidine-N-oxyls (PROXYLs): carbamoyl-, methoxycarbonyl-, and hydroxymethyl-PROXYL (CM-, MC-, and HM-PROXYL, respectively) with respect to radioprotection, prevention of DNA damage, and in vivo distribution in mice. The PROXYLs provided protection to C3H mice against lethal X-irradiation (8 Gy) with the following order of magnitude, HM- > CM- approximately MC-PROXYL. In contrast, radioprotection at the cellular level assessed by the colony formation of leukemia cell line L5178Y showed no difference among them. The degree of protection from X ray-induced oxidation of DNA bases measured by the formation of 8-hydroxydeoxyguanosine in salmon DNA and the cleavage of DNA measured by electrophoresis of plasmid pBR322 DNA did not differ among the PROXYLs. Redox potentials were also similar for each. However, the blood concentration of the PROXYLs injected ip into the mice showed different maximum concentrations (HM- > CM- approximately MC-PROXYL), although all reached a maximum at around 5-10 min and gradually decreased thereafter. Their concentration in bone marrow showed a similar pattern, suggesting that the difference in in vivo radioprotection among the three PROXYLs is due to the difference in their distribution to bone marrow. In general, the radioprotection provided by stable nitroxides is affected not only by redox potential and reactivity in vitro but also by pharmacokinetics.

In vivo radioprotection of mice by 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone; Radicut), a clinical drug.

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one; Radicut) is a brain-protecting agent used clinically to treat acute ischemic stroke with a reaction mechanism of free radical scavenging. Since the initial stage of radiation damage involves the formation of free radicals, edaravone is expected to be effective in preventing lethal damage from ionizing radiation. In the present study, we used mice to examine in vivo the radioprotective effect of edaravone on whole body X-ray irradiation. A solution of edaravone was administered intraperitoneally to C3H mice (male, 10 weeks old), and they were irradiated with a total dose of 8.0 Gy. Edaravone exhibited dose-dependent and injection time-dependent radioprotection. When injected 30 min before the X-ray irradiation, it had the greatest radioprotective effect, whereas an injection after the irradiation showed no protective effect. The LD(50/30) was about 8.8 Gy for edaravone-injected mice and 6.6 Gy for control mice, yielding a DRF for edaravone (450 mg/kg bw) of 1.3. Edaravone decreased the body temperature transiently about 3-6C, but this did not seem to be responsible for the radioprotection. Since the radioprotection was observed only when the reagent was administered before the irradiation, the primary action of edaravone might be the quenching of free radicals with a short lifetime generated by the irradiation.

Current status of lipid management of hypertensive patients.

Hypertensives, in addition to requiring strict blood pressure control, need lipid management to prevent cardiovascular disease. To assess the current status of lipid management of hypertensives, we reviewed the profiles of 830 hypertensives. The quality of lipid management was assessed using the Japan Atherosclerosis Society (JAS) Guideline for Diagnosis and Treatment of Hyperlipidemia in Japanese Adults announced in 1997. Hyperlipidemia was diagnosed in 45.2% of hypertensives and in 56.6% of patients in category C (a group of patients with coronary heart disease). Lipid-lowering drugs were used in 63.5% of all hypercholesterolemic patients and in 78.1% of category C patients. Statins were administered to more than 80% of hypercholesterolemic patients. Only 39.4% of hypertensives achieved the target total cholesterol level and only a very small percentage (17.1%) of patients in category C reached the target levels. The elderly hypertensives were the single largest group (42.2% of all hypertensives) in this study population, and the target cholesterol level for this group has been elevated from 200 mg/dl to 220 mg/dl in the JAS Guidelines for Diagnosis and Treatment of Atherosclerotic Cardiovascular Diseases announced in 2002 (new guidelines). In conclusion, in hypertensives requiring lipid management, the lipid-lowering approach appeared insufficient, as the target achievement rate was relatively low despite a high treatment rate. This was most marked for patients in category C.

Effect of the angiotensin II receptor antagonist losartan on uric acid and oxypurine metabolism in healthy subjects.

OBJECTIVE: The acute effects of the angiotensin II receptor antagonist losartan on uric acid and oxypurine metabolism were evaluated. METHODS: Losartan (50 mg) was administered orally to 6 healthy males. Blood and urine samples for uric acid and oxypurine were collected before and up to 6 hours after losartan administration. The same examinations were performed later using enalapril (5 mg). RESULTS: Losartan decreased the serum uric acid concentration (from 5.9 +/- 0.9 to 5.2 +/- 1.0 mg/dl) and increased its fractional clearance, which reached a maximum after 2 hours, while enalapril did not. Losartan also induced an increase in the plasma concentration of hypoxanthine, peaking in the fourth hour, and a decrease in its urinary clearance, while the plasma xanthine concentration and its urinary clearance were unchanged. The extent of uric acid excretion was much greater than that of the oxypurines. CONCLUSIONS: Losartan, which has a high affinity for the urate/anion exchanger, has a transient uricosuric effect. Our data indicate that losartan induces a significant decrease in the urinary excretion of hypoxanthine without changes in xanthine.

The status of hypertension management in Japan in 2000.

To evaluate the current status of the management of hypertensive patients in Japan, we investigated 907 treated hypertensive patients (486 females and 421 males; mean age, 66.7 years) followed by cardiologists. According to the guidelines for the management of hypertensive patients in Japan in 2000 (JSH-2000), only 41.5% of the subjects achieved the target blood pressure, with a mean systolic blood pressure of 140.0+/-14.9 mmHg and a mean diastolic blood pressure of 80.0+/-10.7 mmHg. There were no differences between patients with and without concurrent disease or among age groups (<60, 60-69, 70-79, and 80 years and over) in systolic blood pressure levels achieved. However, the diastolic blood pressure decreased with age, indicating an increase of the pulse pressure. Overall, the prescription rates were: calcium channel blockers (CCBs), 73.0%; angiotensin converting enzyme inhibitors (ACE-inhibitors), 31.3%; angiotensin receptor blockers (ARBs), 18.9%; beta-blockers, 16.2%; and diuretics, 10.1%. Although some selection of antihypertensive drugs was based on evidence from previous trials on hypertensive patients with diabetes mellitus, chronic heart failure and renal insufficiency, overall, CCBs were selected in all age groups and in all comorbid conditions. In conclusion, Japanese cardiologists do not appear to consider age and comorbidity when choosing antihypertensive managements. Based on current evidence, the management of hypertension should be individualized, with the blood pressure target level and antihypertensive medications chosen on the basis of age and comorbidity.