RENAL EFFECTS OF 26-WEEK ADMINISTRATION OF OLMESARTAN MEDOXOMIL/HYDROCHLOROTHIAZIDE IN RATS
-
- OGATA Seiya
- Medicinal Safety Research Laboratories, Sankyo Co., Ltd.
-
- SHARYO Satoru
- Medicinal Safety Research Laboratories, Sankyo Co., Ltd.
-
- HINMAN Donald
- Clinical Development, Sankyo Pharma Development
-
- MANABE Sunao
- Medicinal Safety Research Laboratories, Sankyo Co., Ltd.
この論文をさがす
説明
The combination of an angiotensin II type 1 receptor blocker (ARB) and a diuretic is effective clinically in treatment of hypertension. As a non-clinical safety evaluation of a combination of the ARB olmesartan medoxomil (OM) and the diuretic hydrochlorothiazide (HCTZ), male and female normotensive rats were administered OM/HCTZ (fixed ratio of 8 : 5) orally by gavage for 26 weeks at dose levels of 0 , 4.88, 16.25, 48.75, 162.5, 487.5, or 1625 mg/kg/day. Additional groups were given 1000 mg/kg/day OM or 625 mg/kg/day HCTZ. Statistically significant and marked decreases in urinary protein excretion were observed in males and females given doses of 16.25 mg/kg/day or higher compared to vehicle-control groups. Increases in blood urinary nitrogen (BUN) were observed in males and females given doses of 16.25 and 162.5 mg/kg/day or higher, respectively. Increased incidence of chronic progressive nephropathy (CPN), a rat-specific spontaneous renal lesion, was observed in males and females given doses of 48.75 mg/kg/day or higher. An additional mechanistic study, consisting of male and female rats given 0, or 162.5 mg/kg/day OM/HCTZ, was conducted to clarify the toxicological significance of the increases in BUN and the increased incidence of CPN described above. This additional study clearly demonstrated that saline-supplementation through free access to saline in the drinking water ameliorated the elevation in BUN and also ameliorated the incidence of CPN. Consequently, the effects on BUN and CPN observed in the first study can be explained by the hemodynamic disturbances caused by the large doses and an exaggerated pharmacological action in volume-depleted normotensive animals. Importantly, the marked decreases in urinary protein were not affected by the saline-supplementation, and indicated that OM/HCTZ elicited a renoprotective effect, probably by an effect on the glomeruli. An additional toxicokinetic study revealed no drug interactions between OM and HCTZ. In conclusion, OM/HCTZ induced a renoprotective effect as well as changes probably attributed to the exaggerated pharmacological action of the ARB with diuretic in normotensive rats. These results suggest that OM/HCTZ may have renoprotective effects in clinical treatment of hypertensive patients.<br>
収録刊行物
-
- The Journal of Toxicological Sciences
-
The Journal of Toxicological Sciences 29 (1), 37-46, 2004
一般社団法人 日本毒性学会
- Tweet
キーワード
詳細情報 詳細情報について
-
- CRID
- 1390282679879639808
-
- NII論文ID
- 110001802916
-
- NII書誌ID
- AN00002808
-
- ISSN
- 18803989
- 03881350
-
- NDL書誌ID
- 6869078
-
- PubMed
- 15018153
-
- 本文言語コード
- en
-
- データソース種別
-
- JaLC
- NDL
- Crossref
- PubMed
- CiNii Articles
-
- 抄録ライセンスフラグ
- 使用不可