慢性B型肝炎的治療方式及藥物

慢性B型肝炎的治療方式及藥物
chronic hepatitis 

treatment
治療目標:
● 肝發炎指數AST(GOT)、ALT(GPT)恢復正常，避免肝臟持續處於發炎狀態，以免走向肝纖維化、肝硬化、肝癌。
● 血液中測不到B肝病毒量。

降血脂藥物對LDL-C 低密度膽固醇效果 Rosuvastatin 最強

Effect on LDL cholesterol

Potency — Aside from proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, statins are the most powerful drugs for lowering low-density lipoprotein (LDL) cholesterol, with reductions in the range of 30 to 63 percent (table 3) [6-10]. When switching between statin drugs, equipotent doses with regard to LDL cholesterol reduction can be found in the figure (figure 2).

Rosuvastatin 效果比 Atorvastatin 強

Rosuvastatin 和 Atorvastatin 兩者又比其他四種 statin 強 (simvastatin, lovastatin, pravastatin. fluvastatin) 

當使用至每種藥物各自的最大劑量, 降低 LDL-C 的效果, rosuvastatin 和 atorvastatin 比其他 statin 強

Rosuvastatin is somewhat more potent than atorvastatin [10,11], and both these agents are significantly more potent than simvastatin, lovastatin, pravastatin, and fluvastatin [11,12]. At maximal prescribed doses, LDL cholesterol reduction is greater with rosuvastatin and atorvastatin than with the other available statins (figure 2).

Fluvastatin 40mg QD 效果最弱. 但如果使用到 80mg QD 效果與其他三種(除Rosuvastatin 和 Atorvastatin外)降血脂藥物相近

At doses of up to 40 mg/day, fluvastatin is the least potent statin (figure 2). However, at doses of 80 mg/day, fluvastatin is as effective on lowering LDL cholesterol as most statins other than rosuvastatin and atorvastatin [13]. Fluvastatin, pitavastatin, and pravastatin are less likely to have drug interactions or produce muscle toxicity than some other statins. (See 'Side effects' below.)

Simvastatin 不建議使用至每天 80 mg. 雖然降血脂效果強, 但副作用例如橫紋肌溶解會增加

因此simvastatin 建議每天不要超過 40 mg. 此外, 若病患先前曾經服用 simvastatin 80mg 而無副作用, 仍建議換成其他種類statin, 因為如果之後持續服用 simvastatin 80 mg qd 會增加肌病變機率

高劑量 simvastatin 適合一小部分患者, 包括服用多年仍沒有不良反應, 或無法忍受其他降血脂藥物副作用. 

Although simvastatin 80 mg/day is a high-intensity dose of statin, given high rates of adverse muscle symptoms including rhabdomyolysis [14] and the availability of generic rosuvastatin and atorvastatin, we suggest not treating patients with doses of simvastatin above 40 mg/day. Additionally, clinicians should strongly consider switching even patients who are currently tolerating simvastatin 80 mg/day to one of these other statin options, since future medication therapy or illness could increase the risk for development of myopathy on high-dose simvastatin. High-dose simvastatin may be appropriate for a small number of patients who have tolerated it well for many years or who are intolerant of other high-potency statin options.

Statins類藥物與 bile acid sequestrant 或 cholesterol absorption inhinitor ezetimibe 合併使用有加成作用
There is an additive hypolipidemic effect when any of the statins is used in combination with a bile acid sequestrant (figure 3) [15-17], or the cholesterol absorption inhibitor ezetimibe.

兒童感染水痘需要使用抗病毒藥物嗎?

uptodate 對於抗病毒藥物的敘述.
對於健康成人或免疫功能不全的人, 抗病毒藥物治療水痘感染很有效.

ANTIVIRAL THERAPYAcyclovir and its analogues (valacyclovir, famciclovir) are effective for the treatment of primary varicella in both healthy and immunocompromised hosts [4-11]. Higher doses of acyclovir are used to treat VZV compared with herpes simplex virus (HSV). VZV is less susceptible to acyclovir, and 50 percent inhibition of VZV replication requires about 10-fold higher levels of acyclovir than those typically required for HSV [8,12]. Acyclovir and its analogues are dependent upon renal function for clearance and dose adjustment is needed in moderate to severe renal insufficiency.

成人口服抗病毒藥耐受性通常不錯. 

Oral agents are generally very well tolerated, especially in adults; however, gastrointestinal side effects or headache may occur. Acyclovir is also available in an intravenous form which can cause local reactions (phlebitis) and reversible acute kidney injury. Risk factors for acute kidney injury include dehydration, failure to dose adjust for reduced kidney function, and overly rapid infusion (eg, <1 hour) [13]. In addition, for obese adults, weight-based dosing should be scaled to ideal body weight (IBW) rather than actual body weight (ABW) to avoid an increased risk of toxicity (calculator 1).
Additional discussions on the use of acyclovir and its analogues are found in the Lexicomp drug information topics within UpToDate and within individual topic reviews.

全民健保對於抗病毒製劑的給付規定

降血脂藥物 statins 類早上或晚上服用?空腹或飯後服用?

有些 STATIN 建議空腹服用. 有些建議飯後服用.
.
人體的膽固醇, 80% 來自於體內合成, 通常是在晚上產生., 因此半衰期短的藥物建議晚上吃,

simvastatin 在傍晚服用的效果優於早上服用

半衰期長的藥物例如 atovastatin. 在早上或傍晚服用, 藥效沒有差異

Pitavastatin 和 Pravastatin 會因食物而減少吸收
Lovastatin 會因食物增加吸收率, 建議飯後服用.

至於服用時間應該挑早上還是晚上
Lovastatin IR 和 Fluvastatin IR 劑型建議與晚餐一起吃.
Lovastatin XR 和 Fluvastatin XR劑型則可以在任何時間服用.
其他的都可以在任何時間服用.

腎功能不良,. Atorvasatin 和 fluvastatin 不需調整劑量.

下面表格來自於 2014壢新藥訊: 降血脂藥物比較

但

Gemfibrozil和Fenofibrate的比較

臨床藥物治療學 102-03-13 高血脂症的防治觀念與用藥選擇
Gemfibrozil和Fenofibrate的比較

FDA 2016-04-19最新報告指出，從ACCORD study做出的結論，statins與fibrate並用，跟單純使用Statins相比，在糖尿病患中，兩者的心血管疾病發生並無不同。另外，根據AIM-HIGH study指出，statins與niacin併用與statins單獨使用相比，雖然可以改善HDL以及TG，但是對於心血管疾病和改善LDL並沒有明顯差別，而HPS2-THRIVE study也同樣指出statins與niacin同時使用，與單用statins相比，並不會更改善心血管疾病的發生，所以FDA取消了statins + fibrate
以及statin + niacin的合併劑型。

不建議併用 repaglinide (novonorm 諾和隆) 及 gemfibrozil， 此兩藥併用會增加低血糖風險，在歐洲是禁止同時使用這兩種藥物。如有需要使用 fibrate 類 藥物，可以選擇將 gemfibrozil 改為 fenofibrate。

三酸甘油酯的控制 Control of hyper-triglycemia

臨床藥物治療學 102-03-13 高血脂症的防治觀念與用藥選擇
Triglyceral TG 三酸甘油酯的控制
第2型糖尿病人最常見之血脂異常為：

1. 三酸甘油酯升高, 糖尿病造成的三酸甘油酯升高通常小於400 mg/dL，若大於400mg/dL應考慮其他次發的原因。
2. 高密度膽固醇下降。

對於糖尿病合併高三酸甘油酯患者
1、TG介於200~400 mg/dL 首要之治療方向為嚴格控制血糖，及飲食控制、減重、運動、減少酒精的攝食等。嚴格控制血糖對降TG非常有效，應先積極嘗試，單獨使用胰島素或併用胰島素增敏劑控制血糖對降TG也有效，如果效果不彰，才考慮使用降血脂藥物治療。

2、TG＞400 mg/dL應考慮同時使用降血脂藥物治療以降低併發急性胰臟炎之風險。

a.TG及LDL均高可單獨使用高劑量的Statins，因高劑量的Statins除了降LDL外，同時也可降TG達30 %以上。如果是使用Fibric acid類藥物，可嘗試單獨使用Fenofibrate，此藥對TG跟LDL同時有效，但不可單獨使用Gemfibrozil。
b.LDL不高且TG超過400 mg/dL，使用降TG類藥物（如Fibrate）會較有效，此時則建議使用Gemfibrozil。
3、病人TG嚴重升高：

>1,000 mg/dL：美國糖尿病學會定義標準，>500 mg/dL：美國NCEP-ATP-III及我國衛生署定義標準因有急性胰臟炎的風險，必須馬上使用F ibrate類降血脂藥物治療，Gemfibrozil為首選，同時施以嚴格之非藥物治療，包括低脂飲食（佔總熱量10%）、減重、及加強運動。三酸甘油酯的控制

各類藥物對於降血脂能力之比較

依據健保給付的規定，使用降血脂藥物的病人，第1年應每3-6個月抽血檢查1次，第2年以後應至少每6-12個月抽血檢查1次。
降低LDL-C效果以 rosuvastatin 最強

臨床藥物治療學 102-03-13 高血脂症的防治觀念與用藥選擇
Statin類. 

1. 慢性肝疾病患者：選用 pravastatin 或rosuvastatin (親水性)，並從低劑量開始

2. 嚴重腎功能不佳患者(Clcr <30 mL/min)：可選擇 atorvastatin 或fluvastatin (不需調整劑量)
3.代謝酵素：

(1) 經CYP3A4：Atorvastain、lovastatin、simvastatin；

(2) 經 CYP2C9：Fluvastatin、rosuvastatin；

(3) Pravastain 經硫化代謝

4.建議接受治療後3個月監測肝功能，之後應定期追蹤

5.懷孕分級：X

其他降血脂藥物能力比較

Pitavastatin 

酒精及藥物對於血脂肪的影響

臨床藥物治療學  2012-03-31 高血脂症的用藥觀念與防治選擇
酒精會增加TG, 但對LDL影響不大

老年人血壓 血脂肪 血糖控制目標

活動力佳的, 可以比照一般成人
活動力差的, 預期餘命短的, 不需要太積極

胸部X光診斷肺炎有時候不容易看出來

在祕密花園看到的, 連結裡面有連續的CT可以看.
.

70-year-old male with proven COVID-19. Imaging reveals bilateral areas of peripheral ground-glass opacity.

https://bit.ly/2WhZNwY
Case contributed by Dr Fabio Macori.

腎臟尿酸結石治療

避免腎臟發生尿酸結石的方法有三種

鹼化尿液

增加水分補充

減少尿酸生成

TREATMENT

Because alkalinization of the urine with medical therapy can lead to dissolution of pure uric acid stones, more invasive procedures (such as extracorporeal shock wave lithotripsy) are usually not required. The three treatments options to prevent recurrent uric acid nephrolithiasis include [3]:

●Alkalinization of the urine

●Increased fluid intake

●Reduction of uric acid production with reduced purine intake and xanthine oxidase inhibitors

尿酸腎結石病患都應該鹼化尿液及增加水分補充

Urinary alkalinization and increased fluid intake should be prescribed to almost all patients with uric acid stones. The indications for xanthine oxidase inhibitors to reduce uric acid production depend upon whether uric acid stones are recurrent despite alkalinization or when alkalinization cannot be used and also upon the presence or absence of gout:

Xanthine Oxidase  inhibitor  主要用於鹼化尿液和補充水分治療無效的病患, 尿酸生成過多 (每天超過 1000 mg) 的病患, 鹼化尿液和補充水分可能無效, 但尿酸排泄在正常範圍內的病患,  xanthine oxidase inhibitor 仍有效

●Recurrent uric acid stones – Xanthine oxidase inhibitors are usually reserved for patients who continue to have stones despite urinary alkalinization and a prescribed higher fluid intake. Recurrent uric acid stone formation despite urinary alkalinization and increased hydration usually occurs in patients with high urinary uric acid excretion (exceeding 1000 mg/day [6 mmol/day]). However, xanthine oxidase inhibitor therapy is warranted in recurrent uric acid stone formers even if urinary uric acid excretion is in the reference range.

●Patients with gout – Patients with uric acid stones who also have recurrent or tophaceous gouty arthritis should be treated with a xanthine oxidase inhibitor for long-term control of gouty manifestations; the primary indication in such patients is gout and not necessarily the prevention of kidney stones (see "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout"). Urate-lowering therapy for gout with uricosuric agents is not indicated as first-line therapy in gouty stone formers to prevent stone recurrence, as this will not lead to a long-term change in the amount of uric acid in the urine.

In a patient with a history of uric acid stones and gout but ≤1 flare of gouty arthritis per year, there may be no specific indication for xanthine oxidase inhibitor therapy. Rather, urinary alkalinization and increased hydration are the initial treatment option in such patients. If, however, the patient prefers a medication that could reduce both gout flare frequency and recurrence of uric acid stones, we would agree to prescribe treatment with a xanthine oxidase inhibitor (along with increased hydration but not necessarily urinary alkalinization).

Urinary alkalinization — The effect of increasing the urine pH on uric acid solubility can be appreciated from the Henderson-Hasselbalch equation for the relationship between soluble urate and insoluble uric acid, where 5.35 is functionally the pKa for this reaction under conditions existing in urine [31]:

pH = 5.35 + log ([urate] ÷ [uric acid])

At a urine pH of 6.75, more than 90 percent of the total urinary uric acid will be the more soluble urate salt, thereby minimizing the risk of uric acid precipitation.

There are no randomized trials that have evaluated the efficacy of urinary alkalinization on recurrence or dissolution of uric acid stones. However, alkalinization is associated with a remarkable reduction in recurrent stone episodes in observational studies. As an example, the mean rate of recurrent uric acid stones among 18 patients was reduced from 1.2 to 0.01 stones per patient per year with long-term treatment with potassium citrate [32]. Alkalinization can also dissolve existing uric acid calculi, as demonstrated in eight patients with recurrent uric acid stones who underwent serial ultrasound examinations after initiating potassium citrate or potassium bicarbonate [33].

鹼化尿液過度可能會造成磷酸鈣結石, 所以維持尿液 pH 6.5~7 即可, pH 超過 7 以上, 效果並沒有更好.
另外, 也不需要持續維持鹼化尿液, 一天一次或兩天一次, 將尿液pH提升超過 6.5 以上, 就可以預防尿酸結石產生. (不用 24 小時)

Alkalinization therapy should target a urine pH between 6.5 and 7. Achieving a urine pH higher than 7 will provide little if any further benefit on uric acid stone formation and may increase the risk of calcium phosphate stone formation (figure 1). An alkaline urine pH may not need to be maintained at all times since raising the urine pH to at least 6.5 once per day or every other day may prevent uric acid stone formation [34].

可給予重碳酸鉀 或檸檬酸鉀, 可將已經出現的腎結石溶解, 也可以預防腎結石生成, 使用鉀鹽比鈉鹽好. 因為檸檬酸鈉或重碳酸鈉會增加鈣的排泄(經腎臟), 在某些病患會引起鈣結石. 

應建議病患在家自己測尿液pH

Either potassium bicarbonate or potassium citrate can be given, with the typical dose being 40 to 80 mEq/day (table 2) [3,32]. This regimen can dissolve preexisting pure uric acid stones and prevent the formation of new stones. Alkalinization with potassium salts is preferable since the sodium load with sodium citrate or sodium bicarbonate may increase calcium excretion and promote the formation of calcium stones in some patients [32]. Patients should be instructed to check their urine pH at home; this will help guide the amount of alkali required.

飽和脂肪酸與反式脂肪會增加血中膽固醇濃度

國健署-膽固醇
cholesterol 膽固醇
high density lipoprotein 高密度膽固醇

low density lipoprotein 低密度膽固醇
食物中的飽和脂肪酸以及反式脂肪對膽固醇影響較大. 這兩類是身體合成膽固醇原料.

體檢報告上看到的膽固醇，其實不是膽固醇，而是「脂蛋白」

影響血液中膽固醇含量最大的因素是吃進去的『飽和脂肪酸』，而不是『膽固醇』。

我們體內膽固醇約有70-80%是內生性膽固醇，是自己身體從肝臟或小腸細胞合成的膽固醇，而剩餘的20-30％才是來自於飲食中，其中最主要引起膽固醇的是飽和脂肪酸，因此我們應該要更注意飽和脂肪酸的攝取，例如：五花肉、培根、奶精、烹調用豬油等。

107年最新版的「每日飲食指南」也將蛋白質食物來源的順序調整為豆>魚>蛋>肉類，因此適量吃海鮮與雞蛋是沒有問題的！

糖在體內會轉變成三酸甘油脂, 也會增加血中膽固醇濃度

飲食控制降低膽固醇效果有限, 通常需要藥物控制. 

食物的成分, 即使膽固醇含量低, 但飽和脂肪酸過高, 仍會增加血中膽固醇濃度, 例如奶精

反式脂肪酸, 會增加低密度膽固醇LDL濃度, 減少高密度膽固醇HDL濃度, 而 LDL

2015~2020 年最新美國飲食指南指出：「取消膽固醇攝取上限」。原因在 於飲食僅佔膽固醇生合成中 2~3 成的影響因素。許多報告發現飲食中的飽和及 反式脂肪酸會導致更多膽固醇生成且不易代謝。因此減少富含飽和及反式脂肪 的食物來源，例如高脂肉品(培根、熱狗等)、冰淇淋、奶精、使用棕櫚油或椰 子油或氫化植物油製作的餅乾、糕點等，對於降低膽固醇是首要之道。

DM病患應該多久回診一次

控制不佳的一個月回診一次
控制良好的三個月回診一次

開始胰島素注射, 或改變胰島素劑量, 每天回診一次
改變口服治療藥物, 每周回診一次

正常成人血糖值與糖尿病患血糖控制目標

糖尿病臨床照護指引摘要
降血脂的首要目標是降低 LDL.
慢性腎病的血壓要控制低一點
空腹血糖 80-130
飯後兩小時血糖 80-160

正常人, 飯前(空腹)血糖 < 110, 睡前血糖< 120
DM患者, 依照美國糖尿病學會建議, 制訂血糖控制目標：飯前血 糖介於 80-120 毫克/毫升，睡前血糖 100-140 毫克/毫升
Target of blood glucose
飯前血糖(空腹血糖)
睡前血糖

低血糖 HYPOGLYCEMIA

美國糖尿病學會ADA

Classification of hypoglycemia
Level 1 <70
Level 2 < 54
Level 3 神智改變或活動變差 A severe event characterized by altered mental and/or physical status requiring assistance

血糖<70建議給予GLUCOSE葡萄糖 15-20g
血糖<54如果無法口服碳水化合物, 可考慮給予昇糖素, 昇糖素並不限制醫護人員才能使用. 家人或學校人員或病患的照顧者都可以給.

6.10 Glucagon should be prescribed for all individuals at increased risk of level 2 hypoglycemia, defined as blood glucose <54 mg/dL (3.0 mmol/L), so it is available should it be needed. Caregivers, school personnel, or family members of these individuals should know where it is and when and how to administer it. Glucagon administration is not limited to health care professionals. E



Glucagon 昇糖素
The use of glucagon is indicated for the treatment of hypoglycemia in people unable or unwilling to consume carbohydrates by mouth. Those in close contact with, or having custodial care of, people with hypoglycemia-prone diabetes (family members, roommates, school personnel, child care providers, correctional institution staff, or coworkers) should be instructed on the use of glucagon kits, including where the kit is and when and how to administer glucagon. An individual does not need to be a health care professional to safely administer glucagon. Care should be taken to ensure that glucagon kits are not expired.

慢性腎病定期檢驗項目及處置建議~慢性腎病管理流程

台灣慢性腎臟病臨床診療指引_國家衛生研究院

慢性腎病定期檢驗項目及處置建議. 

GFR<30 轉介至腎臟科

GFR 30-44 每三個月測一次GFR. 每 3-6 個月測一次電解質. bicarbonate, hemoglobin. Ca. P/ parathyroid hormine. albumin. 體重. 

GFR 45-60 如果有非糖尿病引起的腎病變, 例如T1DM<10年. 腎臟超音波檢查異常. 難治療之高血壓, 快速GFR下降. 尿液沉渣檢查異常. 轉介至腎臟科

  考慮治療藥物是否需降低劑量

  每六個月測一次GFR

  每年測一次電解質. bicarbonate, hemoglobin. Ca. P/ parathyroid hormine. albumin. 體重. 

  確認vitamin D 足夠

  考慮骨密度檢查

  轉介營養師諮詢

全部病患, 每年測 Cr. urine protein. 血鉀. 

全民健保給付規定~血脂肪治療建議 hyperlipidemia treatment guideline

健保給付規定. 起始治療血脂值 

(糖尿病的其他治療指標)

糖尿病患 LDL > 100

心血管疾病 LDL > 100 

糖尿病 total Cholesterol > 160

心血管疾病 total cholesterol > 160
沒有危險因子. LDL > 190

沒有危險因子 TG > 500 

高血壓 目錄

ARB類藥物之比較

新診斷高血壓的檢查

共病症與高血壓藥物之選擇

台灣高血壓指引 2017 未完成

ARB 高血壓藥物之比較

參考資料 台中榮總藥訊
食物會影響吸收
肝腎功能有些會受影響.
diovan 特別加註 LV dysfunction.
Cozaar 特別加註 DM腎病變
Amoten Exforge:  AMLODIPINE 5MG + VALSARTAN 80mg
Co-Diovan: Hydrochlorothiazide 12.5 mg. Valsartan 80 mg

新診斷高血壓的患者可以安排哪些檢查

高血壓初診

例行檢查
血色素
血清肌酸酐 eGFR (每三年追蹤一次腎功能)
Na. K. Ca.
空腹血糖
總膽固醇. 低密度膽固醇, 高密度膽固醇, 三酸甘油脂
尿酸
EKG
UA
CXR

其他
如果空腹血糖超過 100, 加做 HbA1c
HS-CRP
眼底鏡
心臟超音波
頸動脈超音波
ABI 踝動脈壓與肱動脈壓比值

共病症與血壓藥物選擇

2014 藥學雜誌

antihypertensive agents and comorbility
參考資料: 2016 高血壓治療指引, 民眾版衛教手冊
一般而言, 降血壓藥物的好處, 來自於降壓幅度, 與藥物選擇關聯較小.
但不同的共病症仍有不同考量.

另外, 不同的藥物有不同的副作用, 有些疾病應避免選用特定藥物

高血壓藥物組合
1. ARB + Diuretic 優於 BB + Diuretic
2. CCB + ACEI 優於 BB + Diuretic
3. BB + Diuretic 相較於其他組合, 新診斷的DM個案較多.

Three large-scale RCTs have tested the superiority of one combination versus the other.242-244 In the LIFE trial, the combination of losartan (ARB) plus hydrochlorothiazide (diuretic) was compared with the combination of atenolol (beta-blocker) plus hydrochlorothiazide (diuretic), showing that ARB + diuretic combination was better than beta-blocker + diuretic combination in reducing CV endpoints, mainly stroke.242 The difference of achieved SBP was only 1.3 mmHg, lower in the ARB þ diuretic group. In the ASCOT trial, the combination of amlodipine + perindopril (CCB + ACE
inhibitor) was better than the combination of atenolol  + benzofluthiazide (beta-blockerþdiuretic) in reducing total mortality and other CV endpoints with a SBP difference of 2.7 mmHg, lower in the CCB + ACE inhibitor group.243 Besides, the risk of new-onset diabetes from the combination of
beta-blocker + diuretic was higher than other combinations.367 Therefore, the combination of beta-blocker + diuretic is inferior to the combination of ARB+ diuretic or CCB + ACE inhibitor combinations.

the ACCOMPLISH trial 比較不同藥物組合對 reducing CV endpoints 差異
ACEI + CCB 與 ACEI + Diuretic 比較. 因ACEI + CCB 壓倒性的優勢, 所以實驗提早終止
對於腎功能的影響. 也是 ACEI + CCB 較優
對於糖尿病患 subgroup 也是 ACEI + CCB 較優

哪些類型藥物可以兩種組合使用
Recommended 2-drug combinations include:
✓ ARB + CCB (A + C)
✓ ACE inhibitor + CCB (A + C)
✓ ARB + thiazide diuretic (A + D)
✓ ACE inhibitor + thiazide diuretic (A + D)
✓ CCB + beta-blocker (B + C)

三種以上的血壓藥物組合, 研究較少, 不過從學理上建議可選
ACE inhibitor (or ARB) + CCB + Thiazide diuretic (A + C + D) combination

不建議合併使用的藥物包括 Unfavorable or prohibited 2-drug combinations include:
Beta-blocker + diuretic (except in heart failure)
ACE inhibitor + ARB (兩種都是作用於RAA系統renin-angiotensin system)
(ACE inhibitor or ARB) + DRI (direct renin inhibitor)