Revista Latinoamericana de Hipertensión ISSN: 1856-4550 [email protected] Sociedad Latinoamericana de Hipertensión Organismo Internacional
Israili, Zafar H. Renin inhibitors as antihypertensive agents Revista Latinoamericana de Hipertensión, vol. 3, núm. 4, mayo-junio, 2008, pp. 98-112 Sociedad Latinoamericana de Hipertensión Caracas, Organismo Internacional
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enin inhibitors as antihypertensive agents
Zafar H. Israili, Department ofMedicine, Emory University School ofMedicine, Atlanta, Georgia USA [email protected]
Recibido: 15/06/2008 Aceptado: 07/07/2008
espite numerous advances in the phar Food reduces peak levels by 81 % and area under the macologic treatment of high blood curve by 62%, but inhibition of plasma renin activ pressure (BP) and the availability of ity is not affected; absorption is further reduced by seven c1asses of antihypertensive drugs, a significant high-fat mea!. The protein binding is about 50% and proportion of treated hypertensive patients still have the apparent volume of distribution is 135 L. The ter uncontrolled high Bp, and thus, face serious morbidity minal T'12 is about 24 hr (range 16-40 hr), suggest and mortality. Therefore, new therapeutic modalities ing 2- to 3-fold accumulation after multiple dosing; have to be developed to achieve optimum BP control steady-state is reached in 7 days of repeated dosing. as well as treat all the cardiovascular (CV) risk factors, Aliskiren does not have pharmacokinetic interactions, prevent end-organ damage and other hypertension when co-administered with allopurinol, celecoxib, ci (HTN) related pathologies. The renin-angiotensin-al metidine, lovastatin, atenolol, or warfarin. dosterone system (RAAS) is a major physiological reg ulator of body fluid volume, electrolyte balance, arte In patients with HTN, aliskiren produces dose-de rial Bp, and adrenal functions. Dysregulation of RAAS pendent BP reduction and 24-hr BP control up to a has been shown to be a major underlying cause of maximum dose of 300 mg given once daily; at this HTN, heart failure, renal disease, and related CV dis dose, aliskiren shows placebo-Iike tolerability. Its orders. Increasing evidence indicates that inhibition of antihypertensive potency is approximately equiva the RAAS is an effective way to control high BP and lent to that of ACE inhibitors, ARBs, calcium chan intervene in the pathogenesis of CV disorders, dia nel blockers, or diuretics. No dosage adjustment is betic kidney disease and atherogenesis. Blockade of necessary in the elderly or in patients with hepatic the RAAS with angiotensin converting enzyme (ACE) dysfunction or with mild-to-moderate renal impair inhibitors, angiotensin 11 AT, receptor blockers (ARBs) ment. However, the dose in patients with severe re does not result in complete suppression of RAAS. nal impairment has not been established. Aliskiren Blockade of renin at the initial, rate-limiting step in has favorable effect on left ventricular hypertrophy the renin cascade would favor more complete block and proteinuria. No ethnic difference was observed ade of the system, and may be more effective in af in the efficacy and tolerability of aliskiren. The drug fording greater protection from complications of high can be safely administered to obese, diabetic and/ BP. In that respect, orally active direct renin inhibitors, or elderly patients. In combination therapy, aliskiren such as aliskiren, ciprokiren, enalkiren, remikiren, ter further decreases BP when combined with either hy lakiren, zernikiren, etc., have been developed. Only drochlorothiazide, amlodipine, irbesartan or ramipril, Aliskiren has been approved for the treatment of possibly by a synergistic action both in terms of ef HTN. The renin inhibitors bind to the active site of re ficacy and tolerability. nin resulting in the inhibition of conversion of angio The major adverse effects (in 1% to 10% of patients), tensinogen to angiotensin I (Ang which results in 1), include malaise, palpitation, dizziness, rash, hyperkale the suppression of plasma renin activity (PRA), levels mia, diarrhea, nocturia, and increase in creatinine. Hy of Ang 1. Ang 11, and aldosterone. potension may also occur in patients with an activat ed RAAS, such as in volume or salt depleted patients, The renin inhibitors have low oral bioavailabilty, and such as in patients on diuretics. It is contraindicated most have short half life (T'I2)' Aliskiren has a bio in patients with a history of idiopathic or hereditary availability of 2.6%; peak levels are achieved in 1 angioedema, or ACE inhibitor- related angioedema, 4 hr following oral administration. Single oral doses bilateral renal artery stenosis, and pregnancy. of aliskiren (160 mg) produce plasma concentrations (24 ± 7 ng/mL) greater than 50 times the reported Renin inhibition has potential therapeutic benefit in 50% inhibitory concentration value for human renin. the treatment of renovascular HTN and congestive heart failure. These drugs may prevent end organ Renin-angiotensin-aldosterone system damage, especially the kidney and the heart, or at The renin-angiotensin-aldosterone system (RAAS) least slow the progression of damage. These drugs (Figure 1) is a major physiological regulator of body may also be useful in conditions such as stroke, myo fluid volume, electrolyte balance, arterial blood pres cardial infarction, scleroderma, renal trauma, and sure, tissue perfusion, and adrenal functions. How acute c10sure of renal artery grafts, which are associ ever, dysregulation of RAAS, such as by chronic RAAS ated with high plasma renin levels. activation, has been shown to be a major underly ing cause of hypertension, heart failure, renal dis Potential limitations of renin inhibitors include mod ease, and related CV disorders. Increasing evidence est levels of BP reduction that are equivalent to but indicates that inhibition of the RAAS is an effective not greater than produced by ARBs or ACE inhibi way to control high BP and intervene in the patho tors, flat-dose-response curve, reduced gastrointes genesis of CV disorders, diabetic kidney disease and tinal absorption with a high-fat meal, considerable atherogenesis (Dzau, 2005; Sepehrdad et aL, 2007). first-pass effect limiting oral bioavailability, short Although, blockade of the RAAS with angiotensin plasma T'12 and duration of action for most renin in converting enzyme (ACE) inhibitors, angiotensin 11 hibitors, and the large reactive increases in renin se AT1 receptor blockers (ARBs) or a combination of cretion. Furthermore, development of tolerance, due these drugs has become one of the most success to renin hypersecretion, may result in the reduction fui therapeutic approaches in medicine (Wuerzner in the antihypertensive effect of some renin inhibi and Azizi, 2008), the ACE inhibitors and ARBs do tors, especially in salt-replete hypertensive patients. not completely suppress the RAAS, beca use of the In addition, combination therapy (renin inhibitors compensatory rise in plasma renin activity (Li et aL, with ARBs or ACE inhibitors) is expected to increase 2007). Based on studies using very high-dose ARB the incidence of si de effects, such as hyperkalemia or combination therapy with ACE inhibitor and ARB, and acute renal insufficiency. it has been suggested that more complete blockade In conclusion, despite some reservations, renin inhib would lead to improved c1inical outcomes (Hollen itors may be a useful addition to the armamentarium berg, 2008). Blockade of renin, the most upstream of antihypertensive agents, especially when used in point of RAAS, that is, at the initial, rate-limiting step combination with other antihypertensive agents, in the renin cascade would also favor more complete such as diuretics, ACE inhibitors, ARBs or calcium blockade of the system than with the existing agents, channel, blockers. and therefore, may be more effective in affording Key words: Antihypertensive agents; Renin inhibi greater protection from hypertensive complications (Hollenberg, 2007; Shafiq et aL, 2008). tors; Renin-Angiotensin-Aldosterone System; Aliski ren; Pharmacokinetics; Pharmacodynamics Figure 1. Renin-angiotensin-aldosterone system
______~idnev Angiotensinogen l¡l- 1 I I 1 Adrenergic 1 ...... 1 blockers 1 1 Reninq~~~ Cathepsin o, Tonins ~ .. ~~~.~~~~~.¡.~...J r---- I Renin L_Inhibltors I ypertension, a serious disease affect ing almost a billion people (25% of adults) worldwide, is a major modi fiable risk factor for cardiovascular (CV) and renal disease (Kearney et aL, 2005). Despite numerous advances in the pharmacologic treatment of high blood pressure (BP) and availability of seven c1asses of antihypertensive drugs to treat hypertension, a significant proportion of treated hypertensive pa tients still have uncontrolled high Bp, and thus, face serious morbidity and mortality. Furthermore, it is • Smoot1l mu,c;." ¡;ontn~n c.asoeon&triction) ·Atter-.d"I\II~mb 'Mocl"lItlonof not sufficient to aim for optimum BP control, but to IdecrNMCI blOGd fIow. iIIR,t1'.IIC4IlIul ... inc,..Md ,(MI um uptllka' m¡¡tTb: treat all CV risk factors, protect end-organ damage, • Vascular remod.ling • C.llul.ar ICJlrc;jl. hy~op"Y) c;llff.,.ntb"on prevent progression of disease, as well as to prevent • Vascular Imooth musdlt • Neuronal PfOII1....IItlon Ae
Renin (EC 3.4.99.19; also known as angiotensinoge Iimited oral activity. The strategy for producing orally nase), a circulating enzyme belonging to the aspar active inhibitors of renin is aimed at developing com tic proteinase family (340 amino acids; molecular pounds that are smaller and less peptidic in nature, weight = 40,000 Dalton), synthesized and secreted thus, reducing problems of poor absorption, proteo by the kidneys from specialized juxtaglomerular cells Iytic degradation and rapid biliary extraction. Such of the afferent arterioles, controls the first rate-Iimit attempts have been successful in the development ing step of the RAAS (Figure 1) by c1eaving angio of direct renin inhibitors, such as aliskiren. tensinogen to the inactive decapeptide angiotensin A number of low molecular weight renin inhibitors 1. The enzyme ACE c1eaves angiotensin I to form the (peptidomimetic compounds and non-peptides) active octapeptide angiotensin 11, which in turn acts have been synthesized, which display excellent spec via angiotensin 11 type 1 (AT ) receptors to increase a) 1 ificity toward human renin (Maibaum and Feldman, atrial tone, b) secretion of aldosterone from adrenals, 2003; Sueiras-Diaz et al. 1997a; Sueiras-Diaz et al., c) renal reabsorption of sodium, d) sympathetic neu 1997b; Azizi et al., 2006). Some of the renin inhibi rotransmission, and e) cellular growth (Dzau, 2005). tors include: Angiotensin 11 plays an important physiological role in the regulation of Bp, but excessive activation of the Peptidomimetic inhibitors: (Figure 2) RAAS leads to increase in BP and end-organ dam Ditekren (U 71038); enalkiren (A 64662), terlaki age. Renin secretion is suppressed by ~-adrenergic ren (CP 80794); A 62198; BW 175, BW 633C; CGP blockers, but the blockade is incomplete. Since, nei 29287; CGP 44099; CGP 60536; CI 992; CP 71362; ther ACE inhibitors nor ARBs alone can completely CP-72,647; CP-80,794, CP81282; EMD 51921; EMD suppress RAAS activity, direct inhibition of renin was 52297; EMD 56133; EMD 58265; ES 1005; ES 6864; attempted to completely inhibit RAAS at the first ES-8891; FK 906; H-77; H-77-77; H 142; H-142-08; rate-Iimiting step. The effect of various agents inter H-261; KR 1314, KRI 1177; L 363714; PD 132002; rupting the RAAS at different sites on the compo RI 78; R-PEP-27; S 2864; SC 46944; SC 56525; SQ nents of the RAAS is presented in Table 1. 32970; pepstatin A (SR 42128); SR 43845; YM 21095; YM-26365 Table 1. Effect of blockers of RAAS on the components of RAAS RAAS Ang I Ang 11 Plasma Plasma Plasma! Non-ACE Aldo- Non-peptide inhibitors: blocker level level renin renin lissue production slerone Aliskiren (SPP-100; formerly CGP-60536; CGP conc. acllvity bradykinin of Ang 11 60536B,Tekturna); ciprokiren (Ro 44-9375); remiki
ACE-I + + + + + Not + ren (Ro 42-5892); zankiren (A 72517); Ro 44-9378; blocked A 65317; A 74273; BILA 2157 BS; BW 175; CGP ARB + + + + NC Blocked + 38560A; H 189; S 2864; SQ 33800. Renin·1 t t + t NC Not Cyclic analogs: cyclothiazomycin (macrocyclic thio blocked • peptide antibiotic) and other cyclic analogs, such as ACE-I ++ +/NC ++ ++ + t +ARB PD-129,541 Renin·1 t/NC •• ++ t + ++ Renin binding protein: N-acetyl-D-glucosamine-2 +ACEI epi merase enzyme Renin inhibitory peptide, statine; Renin·1 t/NC t/NC ++ t NC ++ pepstatins. +ARB
Ang I = angiotensin 1. Ang 11 = angiotensin 11; ACE-I angiotensin converting enzyme Figure 2. Molecular structures of renin inhibitors inhibitor; ARB = angiotensin 11 Al1 receptor blocker; renin-I = renin inhibitor; NC = no AIIsIt"n change (Adapted from Azizi et al., 2006; Staessen et al., 2006)
Renin inhibitors Early attempts by using immunologic inhibitors of renin (antisera, monoclonal antibodies and Fab frag brl\l~hn ments), fragments of the prorenin sequence and compounds related to pepstatin (a potent penta peptide inhibitor of pepsin and less potent inhibitor of renin), and angiotensinogen analogs, but none of these attempts proved feasible for a variety of reasons including poor absorption, short duration terlakiren of action and weak activity. Synthesis of compounds mimicking the enzyme transition state, the condi ()• tion of greatest binding affinity, has resulted in renin HNAo inhibitors with potencies in the nanomolar range, which have shown hypotensive activity. These com pounds contain at least one peptide bond and have Mechanism of action of renin inhibitors inhibitors is dependent on pretreatment renal tone, The direct renin inhibitors bind to the active site of the since, single as well as multiple doses of remikiren, renin molecule resulting in the blockade of the con significantly correlated with pretreatment renal vas version of angiotensinogen to angiotensin I (Figure cular tone [estimated from free fraction and renal 1). Angiotensin I suppression decreases the formation vascular cresistance, but not with remikiren-induced of the pharmacologically active angiotensin 11 and, in changes in renal hemodynamics or in hormonal pa effect inhibits the actions of angiotensin 11 (Figure 1). rameters (van Paassen et aL, 1999). Since angiotensin 11 also functions within the RAAS as a negative inhibitory feedback mediator in the renal Effect of renin inhibitors on plasma renin levels parenchyma to suppress the further release of renin, The in vitro inhibition (IC so values) of human renin by the reduction in angiotensin 11 levels suppresses this various renin inhibitors is shown in Table 2. The IC feedback loop, leading to further increase in plasma values are higher in plasma than in buffer beca use Jf renin concentrations (PRC) and subsequent activity the binding of the renin inhibitors to plasma proteins. (plasma renin activity; PRA). This disinhibitory effect When administered to humans, renin inhibitors, such can be potentially problematic for ACE inhibitor and as aliskiren suppresse PRA (dose-dependently) when ARB therapy because increased PRA could partially given either as monotherapy or in combination with overcome the pharmacologic inhibition of the RAAS. ARBs or ACE inhibitors (Stanton et aL, 2003; Oparil But for direct renin inhibitors, blunting of PRA despite et aL, 2007; Nussberger et aL, 2007; Gradman et aL, the increased PRC (from 1055 of the negative feed 2008). Actually, aliskiren suppresses the compensato back) may be c1inically advantageous. The biochemi ry rise in PRA stimulated by a diuretic, an ACE inhibitor cal consequences of renin inhibition differ from those or an ARB, when given in combination (O'Brien et aL, of ACE inhibition and AT, receptor antagonism, par 2007). However, it causes much greater reactive rise ticularly in terms of angiotensin profile (Table 1) and in plasma renin concentration (PRC) than does any interactions with the bradykinin-nitric oxide-cyclic other antihypertensive c1ass tested (Sealy and Laragh, guanosine monophosphate pathway and possibly 2007). The renin inhibitors, similar to ACE inhibitors the (pro)renin receptor (see below) and ARBs, only blocks 90% to 95% of plasma renin, but the pressor consequences of the greater reactive A prorenin/renin receptor has been identified in me rise in PRC appear to offset the net ability of renin in sangial cells, to which prorenin/renin binds with high hibitors to lower Bp, especially at higher doses (Sealy affinity (Kd = 400 pmol/I); the receptor, acting as a and Laragh, 2007). cofactor, mediates the intracellular effects of renin and prorenin by increasing their enzymatic activ Table 2. Inhibtion of human renin by some renin inhibitors leso (nmoI/L)* ity on the cell-surface. It is not known whether the binding of prorenin to its receptor is attenuated by Ali~kir"n (P100) O.n CP-il1,1~R 10.0 Ciprokiren (Ro 44-9375) 0.07-005 CP-S1282 5.0 the addition of a renin inhibitor. The binding of renin Enalkiren (1164-662) 0.6-14.0 ES-8891 0.7 Remikiren (A 42-5892) 0.8-L7 FK-90S 0.6 to this receptor also elicits an increase in plasmino T8rlakiren (CP 60794) 1.1 H-14-1IH-14-2 10.0 gen activator inhibitor-1 antigen and an increase in Zankiren (A 72517) 0.6-1.1 PO '133,4-50 0.1 SQ 33800 0.35 [3H]-thymidine incorporation, without cell prolifera A-74273 3.1-4.3 tion. Renin binding to the receptor in mesangial cells BW 175 3.3 SR 42128 0.03-0.35 CGP-29,287 1.0 Dilek.ren CUl1 038) 0.4- is not attenuated by the addition of a renin inhibitor, CGP 38560 0.7-1.0 KR1-1314 4-.7 CGP-44099A 0.3 GR 70982 6.9 indicating that the renin catalytic site is distinct from CP-72,647 5.0 R042~o;892 0.5 the receptor binding site. Once bound, renin induces ES 6864 7.3 H-77 1.0 SR 43845 0.1 YM-21 095 047 a series of intracellular events, including the activa YM-26365 2.9 CI-992 0.58 tion of the mitogen activated extracellular signal leso is the concentration needed for SO% inhibition of human renin regulated protein kinases, ERK1 and ERK2 (Nguyen * the renin inhibitors show higher potency in inhibiting renin in in vitro (at pH 7.4 bu and Contrepas, 2008); these effects which are not ffer) than in plasma because of protein binding in the latter. attributable to the generation of angiotensin 11, are not blocked by the renin inhibitor aliskiren (Feldt et Effect of renin inhibitors on the normal circa aL, 2008). Renin inhibitors cause compensatory in dian rhythm of blood pressure crease in both prorenin and renin, but the angioten Aliskiren had no effect on the circadian rhythm of BP sin-independent actions of these molecules at the (O'Brien et aL, 2007; Oparil et aL, 2007). renin receptor are not known. Potential advantages and disadvantages of re Endocrine effects of renin inhibitors nin inhibitors In normotensive human beings, renin inhibitors given The advantages of direct renin inhibitors include intravenouslyor orally lead to acute and dose-depen possible greater protection from hypertensive com dent decreases in PRA, angiotensin 1, angiotensin 11, plieations, additional BP reduction when used in aldosterone (Table 1) and Bp, without inducing reflex combination therapy, a placebo-like side-effect pro tachycardia (Azizi et aL., 2004; Azizi et aL, 2007; file, avid renal concentration, and long duration of Oparil et aL, 2007). The natriuretic response to renin action for some compounds (for example, aliskiren). Revista Latinoamericana de Hipertensión. Vol. 3 N° 4, 2008
The renin inhibitors may prevent end organ damage, Aliskiren especially in the kidney and heart, or at least slow the Aliskiren has good water solubility and low lipophi progression of the damage. Since PRA is a risk fac Iicity, but its bioavailability after oral administration tor for myocardial infarction (Alderman et aL, 1997), is quite low (2.6%). Peak plasma levels (C ma) are and renin inhibitors decrease it, these agents may be achieved in 1-4 hr (t ) following oral administration. cardioprotective. The Aliskiren Observation of Heart In healthy voluntee~~ single oral doses of aliskiren Failure Treatment (ALOFD trial showed that the addi (160 mg) produced Cm (24.2 ± 6.79 ng/mL) greater tion of the aliskiren to an ACE inhibitor or ARB and a than SO times the repcfrted ICso values for inhibition l3-blocker leads to favorable effects on neurohormonal of renin (Table 3). Administration of aliskiren (1S0 mg) actions (reduction in plasma brain natriuretic peptide) with food reduces C by 81 % and area under the in heart failure (Recio-Mayoral et aL, 2007). Compared plasma level-time cu~~ (AUC) by 62%, but inhibition to the ACE inhibitors, the renin inhibitors have fewer of plasma renin activity is not affected (Azizi et aL, side effects (Maibaum and Feldman, 2003). The renin m2006). Absorption is further reduced by high-fat inhibitors may find a place as adjunctive therapy, in meaL Aliskiren binds moderately strongly to plasma combinations with ACE inhibitors or ARBs, or in pa proteins: the mean protein-binding is 49.5%, which tients intolerant to these drugs (Segall et aL, 2007). is independent of concentration over the range Potentiallimitations include modest levels of BP reduc 10-S00 ng/mL. The extent of metabolism of aliski tion that are not greater than produced by ARBs or ren is not known, but a small fraction of the dose ACE inhibitors (Hershy et aL, 200S), reduced gastro is metabolized by cytochrome P4S0CYP3A4; hepatic intestinal absorption with a high-fat meal, consider metabolism is not significantly affected by changes able first-pass effect limiting oral bioavailability, short in CYP4S0 activity. Following oral administration plasma T112 and duration of action (for some renin of radioactively labeled drug, 91 % of aliskiren was inhibitors), and large reactive increases in renin se eliminated unchanged in the feces, 1.4% as oxidized cretion. Furthermore, development of tolerance may metabolites, and 0.6% (one-fourth of the absorbed result in the reduction in the antihypertensive effect dose) was eliminated in the urine (Nussberger et aL, of some renin inhibitors, such as remikiren, in salt 2002), suggesting significant involvement of hepato replete hypertensive patients by repeated administra biliary c1earance. The terminal T112 aliskiren is about 24 tion (Rongen et aL, 1995). In addition, combination hr (range 16-40 hr), suggesting a two- to-three-fold therapy (renin inhibitors with ARBs or ACE inhibitors) accumulation in steady-state plasma concentration, is expected to increase the incidence of side effects, achieved after 7 days of once-daily dosing. In one such as hyperkalemia and acute renal insufficiency. study, the reported aliskiren troughlpeak ratio was Pharmacokinetics of renin inhibitors 64% and 98% with once-daily doses of 1S0 mg and Some of the pharmacokinetic parameters of renin 300 mg, respectively, indicating that aliskiren main inhibitors are presented in Table 3. The oral bioavail tains significant plasma concentrations throughout ability of most of the renin inhibitors is very low. The the 24 hour dosing intervaL T is rather short, except for aliskiren. Maximum In healthy male volunteers, single and multiple pl~sma levels (C ) achieved after oral administration dose-r~r~ted, dose pharmacokinetic studies of oral aliskiren (dose is usually however, there is considerable range 40-1800 mg), indicate that plasma concen variation in the reported values between studies. trations of the drug peak (tma) between 2 and 4 h Table 3. Pharmacokinetic parameters of some renin inhibitors after administration and mean plasma T'12 of 23-36 after oral administration h after the administration of multiple doses. Aliski ~ Bioavail QI.:!m Plasma ~ ~ ren pharmacokinetics deviate from dose linearity, (mg) % nglmL 11/2 h l:!;SD) Binding (%) as indicated by the results obtained for single and Aliskiren 2.7 23·36 50 CGP 38560 200 ~1.0 -9 -1 de Gasparo. 1989 multiple once-daily administrations over 1 week. In Ciprokiren 0.07-0.65 the dose range of aliskiren investigated in healthy Enalkiren 16!;0.4 89-94 Glassman el al., 1990 Enalkiren 40 0.5 37 Kleinert el al., 1990 male subjects (40-1800 mg), C 'C ' AUCo-¡infinityj ES-8891 240 42 Kokubu el al., 1991 max maxss Remikiren <1.0 9.4!: 4.1 and AUC increase over-proportional1y with doses Remikiren 200 4-6 Weber el al.. 1993 aboye 80 t~g; between-subject variability in C and Remikiren 300 23-27 Weber el al., 1993 max Remikiren 400 0.2 4 Kleinbloesem el al .. 1995 AUC is on average, 32-70% for the dose range of Remikiren 600 65·83 Weber el al., 1993 Remikiren 600 83 Weber el al.• 1993 40-1800 mg. Consistent with a T1/2 of approximately Remikiren 600 68 McFadyen el al., 1995 30 h, exposure to aliskiren increases following mul Remikiren BOa 47-4B Weber el al., 1993 Remikiren BOa 0.3 16 Kleinbloesem el al., 1995 tiple once-daily administration (24-h intervals), with Remikiren 1600 0.3 38 Kleinbloesem el al., 1995 Remikiren 1000 137 McFadyen el al., 1995 steady state reached after approximately 7 days, and YM-21095 400 167 Anonymous, 1993 aliskiren accumulates (accumulation ratio of 1.4 Zankiren 50 29 Ménard el al., 1995 Zankiren 125 47 Ménard el al .. 1995 3.9), especially at higher doses. Zankiren 250 407 Ménard el al .. 1995 Zankiren 125 430 Bogerelal.. 1993a After the administration of a single intravenous infu Glassman HN, Kleinert HD, Boger RS, Moyse DM, Griffiths AN, Luther RR. Cllnical sion of 20 mg aliskiren over 20 min in healthy male pharmacology of enalkiren, anovel, dipeptide renin inhibitor. J Cardiovasc Pharmacol. 1990;16 5uppl 4:576-81 subjects, plasma c1earance was found to be approxi- mately 9 Uh, the hepatic extraction ratio was ap ment on non-renal drug disposition (Vaidyanathan proximately 10%, and steady-state volume of distri et aL, 2007a). However, no initial dose adjustment bution (Vd) was approximately 135 L. should be needed in patients with mi Id to moderate renal dysfunction. Ethnic differences: aliskiren in Japanese and Caucasian subjects Hepatic dysfunction In Japanese (n = 19) and Caucasian (n = 19) healthy A pharmacokinetic study in patients with mild, young male subjects, given a single oral dose of 300 moderate and severe hepatic function after a single mg of aliskiren (day 1) and then daily on days 4-10, 300 mg, showed that there was no significant dif the pharmacokinetic parameters were comparable: ference in AUC or Cmax in patients as compared to for the single dose the ratio of geometric means: Cmax healthy subjects, suggesting that dosage adjustment 1.12; AUC _ h 1.19, and at steady state mean ratio: is unlikely to be needed in patients with liver disease a 72 Cmax 1.30; AUC a_tau 1.16. There was no difference in (Vaidyanathan et aL, 2007c). the plasma T'12 of aliskiren between the two ethnic groups (29.7 +10.2 h and 32.0 + 6.6 h, respectively). Pharmacokinetic drug interactions with aliskiren A single oral dose of aliskiren significantly reduced Aliskiren is metabolized by cytochrome P450 only to PRA to a similar extent in Japanese and Caucasian a minimal extent and it does not inhibit CYP isoen subjects (by 87.5% and 85.7%, respectively, com zymes. In vitro inhibition data for specific cytochrome pared with baseline; P< 0.01). At steady state, peak P450 enzyme activities in human liver microsomes PRC level and AUC for the concentration-time plot indicate that interactions between aliskiren and its were not significantly different between Japanese metabolites and drugs metabolically c1eared by hu and Caucasian subjects (Vaidyanathan et aL, BrJCP man cytochromes are unlikely. In a multiple-dose 2006;62:690). study, aliskiren showed no c1inically relevant phar macokinetic interactions when co-administered with Effect of age: aliskiran in the elderly allopurinol, celecoxib or cimetidine in healthy sub After a single oral dose of 300-mg aliskiren in 29 el jects (Ayalasomayajula et aL, 2008). In healthy indi derly compared with 28 young subjects, the AUC _ _ viduals, single doses of aliskiren did not exhibit c1ini a in finitY, was 57% higher and Cmax was 28% higher in the cally important pharmacokinetic interactions with elderly. Other parameters, including t max and Vd/F, lovastatin, atenolol, celecoxib or cimetidine (Dieterle were similar between the two age groups. No differ et aL, 2005), or warfarin (Dieterle et aL, 2004). In ences in aliskiren exposure were observed between hypertensive patients, co-administration of hydro subjects ages 65 to 74 years (n=16) and >75 years chlorothiazide (25 mg), irbesartan (150-300 mg) or (n=13). However, aliskiren exposure is modestly in ramipril (5 mg) daily for 6 weeks had no significant creased in elderly subjects as compared to the young effect on plasma levels of aliskiren (300 mg) (O'Brein subjects. Based on its wide therapeutic index and et aL, 2007 Vaidyanathan et aL, 2007). Aliskiren shallow dose response for Bp, no initial dose adjust may negligibly reduce the bioavailablity of digoxin. ment should be needed for elderly patients (Vaidya Atorvastatin may increase the level/effect of aliski nathan et aL, 2007b). ren, hence BP should be checked. Co-adminstra
tion of ketoconazole results in increases in Cmax of Effect of disease on the pharmacokinetics aliskiren by a factor of 1.8. When administered con of aliskiren comitantly with furosemide, the AUC of furosemide Diabetes was decreased; consequently, it is recommended to Aliskiren showed a similar pharmacokinetic profile monitor furosemide effects when given in a single 300 mg oral dose to diabetics Remikiren (n = 30) and healthy individuals (n = 30): Cmax 394 ng/mL versus 348 ng/mL, t 1.25 hr versus 1.0 hr, After oral administration of remikiren in doses rang max ing from 30 mg to 1600 mg, bioavailability is only and T112 39 hr versus 41 hr (Zhao et aL, 2006). 0.2-0.3 %, and plasma Cmax and AUC are highly Renal dysfunction variable, and not proportional to the dose (Boger, In a study in patients (n = 17 males) with mild, moder 1993a; Boger 1993b; Kleinbloesem, 1993; Weber et ate or severe renal impairment and healthy subjects ( aL, 1993; MacFadyden, 1995; Ménard, 1995). The n= 17 males), oral administration of 300 mg aliskiren drug is rapidly absorbed with a t max of 0.9-1.6 hr; daily for 7 days, the renal c1earance decreased with plasma T112 after an oral dose is about 7 hr, and after the degree of renal impairment [1280 +/- 500 mUhr intravenous dose it is 5.2-8.2 hr, with biphasic elimi (mean +/- SD) in healthy subjects versus 243 + 186 nation (Kleinbloesem et aL, 1993). The drug does mUhr to 559 +/- 220 mUhr in patients with renal not accumulate after multiple dosing. dysfunctionl, but the changes in exposure (measured by AUC) and drug accumulation, which increased Enalkiren with renal dysfunction, did not correlate with renal After oral administration of remikiren (40 mg), the bioavailability is very low (0.5%) and plasma C is c1earance, consistent with an effect of renal impair- max Revista Latinoamericana de Hipertensión. Vol. 3 N° 4, 2008
37 + 14 ng/mL (Kleinert, 1990). After intravenous Table 5. A comparison of the efficacy of aliskiren and hydrochloro administration, plasma T112 was 1.60±0.43 hr (Dela thiazide in hypertensive patients bays et aL, 1989). Wk 26 endpoint ALlS# HCTZ # Other renin inhibitors Dose (mg) 150 12.5 N= The bioavailability of an oral dose of 200 mg of CGP 459 444 Change in SBP (mm Hg) - 20.3 - 18.6 38,560 is <1 % with Cmax of 9 ng/mL, and a T'12 of about 1 hr (de Gasparo, 1989). The oral bioavailabili Change in DBP (mm Hg) - 14.2 -13.0 ty of ES-8891 (240 mg) and FK 906 (400 mg) are very low, and plasma C of 42.4 + 7.6 ng/mL and 167 max Wk 52 endpoint ALlS# HCTZ# nglmL, respectively, are achieved (Kokubo, 1991). Dose (mg) 300 25.0 Clinical studies of renin inhibitors N= 438 459 The effect of orally administered renin inhibitors on Change in SBP (mm Hg) - 22.1 - 21.2 BP is presented in Table 4 y 5. Aliskiren appears to Change in DBP (mm Hg) - 16.0 - 15.0 be the more potent of the group. For some, such as remikiren (600 mg/day), there was no significant * p<0.05 ALlS versus HCTZ at both endpoints effect on BP even after 8 days of continuous admin * p
Wk 6 endpoint RAM RAM/ALlS up to adose of approximately 300 mg once daily; N= 21 21 at these doses, aliskiren is very well tolerated (Grad Dose (mg) 5 5/150 man et aL, 2005; Widimsky, 2007). Its antihyperten Change in daytime ABPM systolicldiastolic (mm Hg) - 6/-6 - 14"/-9' sive potency is approximately equivalent to that of Change in night-time ABPM ACE inhibitors or ARBs, and diuretics. After abrupt systolicldiastolic (mm Hg) - 3/-1 - 10*/-7* withdrawal, persistent BP reduction and prolonged suppression of PRA is observed (Gradman and Kad, * p<0.05 RAM versus combination .. p<0.001 RAM versus combination 2008). The initial dose of aliskiren for hypertension Aliskiren ! irbesartan is 150 mg once daily, which then can be increased
Wk 6 endpoint IRB IRB/ALlS to 300 mg once daily (maximum dose). Aliskiren can N- 23 23 be effectively combined with the majority of other Dose (mg) 150 150/150 antihypertensive agents (hydrochlorothiazide, amlo Change in daytime ABPM dipine, ramipril, valsartan). The dose may be taken systolicldiastolic (mm Hg) -12/-7 - 14/- 7 Change in night-time ABPM with or without meals (except high fat meals). It is systolicldiastolic (mm Hg) - 9/-4 - 14*/-7* recommended that hypovolemia be corrected prior to initiation of therapy, and volume status should be , p
@BP control was defined as trough mean sitting diastolie BP<90 mm Hg and trough (17.9 versus 15.2 mmHg, P = 0.0036) and diastolic mean sitting systolic BP<140 mm Hg at end point. Data are presented as the mean ± SD; BP (13.2 versus 12.0 mmHg, P = 0.025), and higher * p
TableS et aL, 994). In sodium replete normotensive individu dverse Events Placebo Aliskiren Valsartan Aliskiren + als, the effect of intravenous drug administration on Valsartan BP is minimal (Cordero et aL, 1991). However, in so Headache 9% 3% 5% 4% dium-depleted volunteers, the BP is decreased (Cor Nasopharyngitis 2% 4% 4% 3% dero et aL, 1991), and in some there may be a sharp Dizziness 2% 2% 2% 2% Fatigue 1% 1% 2% 2% drop in BP and bradycardia (Webb et aL, 1989). In Nausea 2% 1% 2% 2% Any adverse evenl 37% 34% 37% 35% hypertensive patients, intravenous administration of Any serious adverse event 1% 2% 1% 0.7% some renin inhibitors reduces Bp, for example, CGP Discontinuation rate due to adverse effects was between 2-3% 38560A (Jeunemaitre et aL, 1989), enalkiren (Ander son et aL, 1990; Boger et aL, 1990; Bursztyn et aL, Combination of aliskiren with other antihyper 1990; Glassman et aL, 1990; Griffith et aL, 1990; tensive drugs Webb et aL, 1990; Weber et aL, 1990; Neutel et aL, In combination therapy, aliskiren further decreases 1991), remikiren (Azizi et aL, 1994?), RO 42-5892 BP when combined with either hydrochlorothiazide (Van den Meiracker et aL, 1990), SR 43845 (Denolle (HCTZ), amlodipine, irbesartan or ramipril, possibly et aL, 1993). The hypotensive effect of intravenously by a synergistic action both in terms of efficacy and administered renin inhibitors is enhanced by sodium tolerability (Wuerzner and Azizi, 2008). depletion (Webb et aL, 1990; Denolle et aL, 1993) Renin inhibitor + diuretic with low sodium diet or pretreatment with a diuretic (Weber et aL, 1990; Denolle et aL, 1993). Aliskiren in combination with HCTZ appeared to low Ethnic differences in efficacy and tolerability er BP more than the combination with an ARB (aliski Aliskiren in Japanese hypertensives ren + ARB), but still failed to control BP «140/<90) Aliskiren for 8 weeks at doses of 75, 150 or 300 mg in 50% of the patients (Sealy and Laragh, 2007). or placebo produced significant, dose-dependent re Renin inhibitor + ARB ductions in mean sitting diastolic BP (p<0.0005 ver sus placebo for each dose) and mean sitting systolic When given with an ARB, aliskiren produces sig BP (p<0.001 versus placebo for each dose). The pla nificant additional BP reduction indicative of com cebo-corrected reductions in mean sitting systoliddi plimentary pharmacology and more complete RAAS astolic BP were 5.7/4.0,5.9/4.5 and 11.2n.5 mmHg blockade. In 569 hypertensive patients, aliskiren in the aliskiren 75, 150 and 300 mg groups, respec (150-600 mg/day) significantly decreased systolic BP tively. After 8 wks of treatment, 47.8%, 48.2% and in a dose-dependent way; the decrease in BP with 63.7% of patients in the aliskiren 75, 150 and 300 300 mg aliskiren was similar to that produced by mg groups, respectively, (placebo = 27.8%) achieved 150 mg of irbesartan (Nussberger et aL, 2007). In a a successful treatment response (diastolic BP <90 randomized, double-blind, placebo-controlled study, mmHg and/or reduced by > or =10 mmHg from 1797 patients with stage 1-2 diastolic hypertension baseline; p<0.005 versus placebo for each dose). (mean sitting diastolic BP = 95-109 mm Hg) were Aliskiren treatment was well tolerated; the incidence randomized to receive aliskiren + valsartan (150/160 of adverse events in the active treatment groups (53 mg), 150 mg aliskiren, 160 mg valsartan or placebo 55%) was similar to that in the placebo group (50%). for 4 weeks, followed by 4 week on double dose (Kushiro et aL, Hypertens Res Clin Exp 2006;20:587 regimen. At 8 weeks, the combination was supe 597. Aliskiren was well tolerated by both Japanese rior (Table 5) to single doses of the drugs or placebo and Caucasian healthy subjects (Vaidyanathan et aL, in reducing both systolic and diastolic BP (Oparil et BrJCP 2006;62:690) aL, 2007). The rates of adverse events were similar (34%-37%), with headache being most common Aliskerin in obese hypertensives (Oparil et aL, 2007). However, Hyperkalemia was The renin system is activated in obesity-associated significantly more common in patients who received arterial hypertension. Obese hypertensive patients (n both valsartan and aliskiren . = 489), who had not responded to 4 weeks of treat ment with HCTZ 25 mg were randomized to receive Hemodynamic effects of renin inhibitors daily aliskiren (150 mg), irbesartan (150 mg), amlo Intravenous administration dipine (5 mg), or placebo for 4 weeks (added to 25 Although, the renin inhibitors have been developed mg HCTZ), followed by 8 weeks on double the ini for oral dosing, many renin inhibitors have been tial doses of aliskiren, irbesartan, or amlodipine. The tested for their BP lowering effect in healthy volun combination aliskiren/HCTZ lowered BP by 15.8/11.9 teers when given by the intravenous route, for ex mm Hg, significantly more (P<0.0001) than placebo/ ample, enalkiren (Delabays et aL, 1989; Cordero et HCTZ (n = 500) (8.6n.9 mm Hg), but similar to that aL, 1991), CGP 38560A (Jeunemaitre et aL, 1989; with the combination of irbesartan/HCTZ (15.4/11.3 Nussberger et aL, 1989), H 142 (Webb et aL, 1987; mm Hg) or amlodipine/HCTZ (13.6/10.3 mm Hg). Webb et aL, 1989), remikiren (Camenzind et aL, The tolerability was similar in all groups, except for 1991; Viskoper et aL, 1994), and R-PEP-27 (Zusman peripheral edema, which was highest with amlo- 2 dipine/HCTZ (11.1 % versus 0.8% to 1.6% in other dex (from 26 + 3 to 34 +4 mUm ) and decreases in groups). The investigators concluded that the com left ventricular filling pressure (from 31 + 3 to 25 bination of aliskiren/HCTZ is a good therapeutic op + 3 mm Hg), mean right atrial pressure (from 15 + tion in obese patients who fail to achieve BP control 1 to 13 + 2 mm Hg), heart rate (from 78 + 5 to with HCTZ alone (Jordan et aL, HTN 2007;20:587). 72 + 6 beats/min) and systemic vascular resistance (from 2,199 +/- 594 to 1,339 +/- 230 dynes.s.cm-5) Aliskerin in diabetic hypertensives (all p < 0.01-0.05). These observations indicate that Aliskiren appears to be a better agent than ramipril renin inhibition produces hemodynamic benefits in in controlling high BP in diabetic patients with hy patients with chronic CHF and could potentially pro pertension (Taylor et aL, 2006; Uresin et aL, 2006); vide a novel approach to interfering with the RAAS a combination of aliskiren with ramipril was more in patients with this disorder (Neuberg et aL, 1991). effective (Taylor et aL, 2006). In a double-blind trial by Kiowski and co-workers Aliskiran in the elderly (1994), 36 patients with chronic heart failure (New Aliskiren is well tolerated by tolerated by patients of all York Heart Association Class 2 or 3) were given intra age groups, including the very elderly (Vaidyanathan venous remikiren, enalaprilat, or their combination. et aL, 2007b). Based on pharmacokinetic data, no Remikiren and enalaprilat were associated with simi initial dose adjustment of aliskiren should be needed lar rapid reductions in systemic vascular resistance and for elderly patients (Vaidyanathan et aL, 2007b). BP. These hemodynamic changes were proportional Cardio-renoprotective effect of renin inhibitors to the baseline PRA. Both drugs also equally lowered BP in the right atrium and pulmonary artery as well as Besides their utility as antihypertensives, the ability to the pulmonary-capillary wedge pressure. During exer decrease renin concentration and PRA, the more com cise, remikiren and enalaprilat similarly increased the plete inhibition of the RAAS, the expected limitation stroke volume index and reduced pulmonary-capillary of angiotensin 11 and aldosterone escape phenomena, wedge pressure. The combination of both drugs did and the prevention of possible direct damaging ef not induce additive hemodynamic changes. fects of renin on the kidney make the renin inhibitors useful in patients with cardiac and renal dysfunction. Remikiren increased renal blood flow and decreased In a study in spontaneously hypertensive rats, given RVR in healthy and hypertensive sodium-depleted an ACE inhibitor, ARB, renin inhibitor, or the combi men, who received angiotensin 11 infusion (Fisher nation of hydralazine and HCTZ for 7 days to obtain et aL, 1994). Similarly, in 14 hypertensive patients the same decrease in Bp, the effects of blockade of with normal or impaired renal function, remikiren the RAAS at three different sites on regression of given once daily at adose of 600 mg reduced mean left ventricular hypertrophy (LVH) were investigated. arterial pressure from baseline by 11.2% at peak Treatment with the ACE inhibitor, ARB or renin inhib plasma concentration and by 6·0% at trough levels itor significantly decreased LV mass, but hydralazine (van Paassen et aL, 2000). In this study, glomerular (plus HCTZ) had no effect. These findings indicated filtration rate (GFR) remained stable, whereas effec that blockade of the RAAS regressed LVH irrespec tive renal plasma flow increased, and FF and RVR tive of the site of the blockade and independent of decreased by 15% and 10%, respectively; remikiren hemodynamic changes. Even though the study is of also reduced proteinurea by 27%, indicating and a a short duration, the trend is positive. In humans, reduction in glomerular protein leakage. In this study, aliskiren has also been shown to have an favorable remikiren induced a cumulated sodium 1055 of -82 + influence on the regression of cardiac hypertrophy 22 mmol and a positive potassium balance of 49 + 9 as shown in the Aliskiren in Left-Ventricular Hyper mmol (both P< 0.01). These data are consistent with trophy trial (ALLAY) (Horky, 2007). a renoprotective potential of renin inhibition. (Van Paasesn et aL, 2000). The Aliskiren Observation of Heart Failure Treatment (ALOFT) trial showed that the addition of the aliskiren The apparent renoprotective effect of the 8-day to an ACE inhibitor or ARB and a ~-blocker leads to course of remikiren contrasted with its weak blood favorable effects on neurohormonal actions (reduc pressure-Iowering activity and probably reflected spe tion in plasma brain natriuretic peptide) in heart fail cific uptake of the drug by the kidney (Richter et aL, ure (Recio-Mayoral et aL, 2007).; aliskiren was well 1996). Enalkiren was more effective than captopril in tolerated in patients with heart failure receiving ACE causing renal vasodilation O, Zankiren also induced a inhibitors or ARBs, although the study was not pow large renal vasodilator response in normal volunteers ered to show c1inical benefit (Cleland et aL, 2007). on low sodium diet (Fisher and Hollenberg, 2005).
In patients with chronic congestive heart disease (n The renoprotective effect of renin inhibitor was =9), intravenous administration of enalkiren (1.0 mg/ similar to that of an ACE inhibitor, as shown by a kg) produced increases in cardiac index (from 2.0 + study (Buter et aL, 1997) in which six hospitalized 2 0.3 to 2.3 + 0.1 liter/min/m ) and stroke volume in- patients (proteinuria 5.8 + 2.9 g/day) were treated Revista Latinoamericana de Hipertensión. Vol. 3 N° 4, 2008 with remikiren (600 mg per day for 8 days), and or ARB lowered BP to a greater extent than aliskiren eight ambulant patients (proteinuria 7.5 + 2.7 g/day) alone, yet, BP control was achieved in less than were treated for 6 weeks with trandolapril (4 mg per 50% of patients; d) aliskiren stimulates kidney renin day). Although, both drugs decreased BP significant secretion to a greater degree than do ACE inhibitors Iy during the day and during the night, the decrease or ARBs, its antihypertensive capabilities can be in proteinuria was significant only during the day: counteracted by large reactive increases in renin from 0.29 + 0.15 to 0.22 + 0.11 g/h (P < 0.05) with secretion, especially at higher dosage; e) the high remikiren, and from 0.33 + 0.14 to 0.16 + 0.08 g/h cost of medication, continuing problems with oral (P < 0.05) with trandolapriLNight-time proteinuria bioavailability, Laragh and co-workers (2007) have decreased but not significantly: from 0.23 + 0.11 to recommended that in most patients, treatment of 0.19 + 0.11 g/h (P = NS) with remikiren, and from hypertension should be carried out with safe and 0.29 + 0.17 to 0.20 + 0.12 g/h (P =NS) with trandol less expensive, equally effective and widely available apriL In patients with diabetic nephropathy, addi generic ACE inhibitors or ARBs (Sealy and Laragh, tion of aliskiren to losartan resulted in a 20% greater 2007). The drug has not been tested in renovascu reduction in proteinuria (Gradman et aL, 2008). lar hypertension or severe hypertension. In addition, the overall adverse effect profile of aliskiren does not In animal experiments, aliskiren attenuated renal seem to be any better than that of other antihyper damage (Pool, 2007). In transgenic rats, aliskiren at tensive drugs, as aliskiren contributes to the onset of antihypertensive doses, attenuated end-organ (renal angioedema, cough, diarrhoea and abdominal pain, and cardiac) damage, similar to that produced by hyperuricaemia, gout attacks, kidney stones and skin valsartan (Pilz et aL, 2005). rash. Hence it has been suggested that,"ln practice, Adverse effects of renin inhibitors: it is better not to use aliskiren to treat hypertensive The major adverse effects (in 1% to 10% of pa patients beca use better-assessed antihypertensive drugs with longer follow-up are available," (Anon, tients), include malaise, palpitation, dizziness (2%), 2008). Furthermore, long-term renin inhibition ther rash (1 %), hyperkalemia (monotherapy < 1%; con apy may induce pharmacologic tolerance with renin current with ACE inhibitors in patients with diabetes hypersecretion, as well as the phenomenon of re or renal dysfunction, and those on potassium sup plements 6%), diarrhea (1 % to 2%), nocturia, in bound hypertension after abrupt cessation of chron crease in creatinine kinase (>300% in 1%), increase ic therapy. This hypersecretion also would result in an increased release of prorenin, which might have in blood urea nitrogen and serum creatinine «7%), and cough (1 %). (Un and Frishman, 1996; Horky, unknown effects on local tissue RAAS. In addition, excessive levels of prorenin, with its localized vasodi 2007). Other adverse effects «5) include angio latory potential, also may predispose to hypoperfu neurotic edema, abdominal pain, anemia, angina, sion injury in various tissues, especially in patients gastroesophageal reflux, gout, myositis, renal stone with diabetes mellitus (Un and Frishman, 1996) formation, rhabdomyolysis, seizure, hyperuricemia. Hypotension may also occur in patients with an ac Figure 3. Evolution of antihypertensive agents tivated RAAS, such as in volume or salt depleted pa tients, such as patients on diuretics. Contraindica 19500 196110 19700 19800 19900 20000 tions: hypersensitivity to aliskiren or any component of the formulation; history of idiopathic or heredi i Oiree' Central0:l tary angioedema; history of ACE inhibitor- or ARB vasodilatorsi 1 agonists related angioedema; bilateral renal artery stenosis; Thlazide Non-OHP OH? calcium Renln dlurelles ealcium channel blockers Inhíbltors pregnancy (Horky, 2007) channet In one of the large studies, sponsored by the drug bIockers industry, the reported adverse effect profile has been ll-blockers c1aimed to be similar to that of placebo or valsartan. On the other hand, in the opinion of Fisher and Ho The future of renin inhibitors as antihyperten lIenberg (2005) the potential of renin inhibition in sive agents (Figure 3) human therapy has been underestimated and in deed shows substantial promise, thus prompting There are two opposing views about the future of the search for a better orally acting renin inhibitor. renin inhibitors. In addition, the role of prorenin in the pathogenesis Based upon the following observations, a) analysis of microvascular injury is beginning to unravel, as a of the c1inical trials involving over 5000 hypertensive number of studies have shown that the onset of mi patients show that aliskiren is not more effective as crovascular disease (nephropathy and retinopathy) in an antihypertensive agent than ACE inhibitors, ARBs, diabetic and hypertensive patients coincides with el diuretics or calcium channel blockers; b) aliskiren has evated plasma levels of prorenin (Misbin et aL, 1987; a shallow antihypertensive dose response curve; c) Luetscher et aL, 1989; Franken et aL, 1990; Skinner, the combination of aliskiren with an ACE inhibitor 1993; Ichihara et aL, 2008). If renin inhibitors block the binding of prorenin to the renin receptor, these pressure response to enalkiren, the novel dipeptide renin inhibitor, in agents may be valuable in controlling the microvas essential hypertension. Hypertension 1990; 15:835-840. cular disease, especially in the kidney and eye (Fisher Booz Gw. Devising new drugs for the treatment of hyperten and Hollenberg, 2005). sion--"novel drugs targeting hypertension: renin inhibitors and beyond".[comment]. J Cardiovasc PharmacoI2007;50:1-2.
In addition, renin inhibition has potential therapeutic Bursztyn M, Gavras 1, Tifft Cp, Luther R, Boger R, Gavras H. Effects of efficacy in the treatment of renovascular and cardio a novel renin inhibitor in patients with essential hypertension. Am J vascular disease (see earlier). Renin inhibition mayalso Cardiovasc PharmacoI1990;15:493-500. have c1inical utility in stroke, myocardial infarction, Buter H., Hemmelder M.H., Van Paassen P., Navis G., De Zeeuw D., scleroderma, renal trauma, and acute c10sure of renal De Jong P.E. Is the antiproteinuric response to inhibition of the renin artery grafts, since all of these pathologies are associ angiotensin system less effective during the night? Nephrol Dialysis ated with high plasma renin levels. The demonstration Transplant 1997;12(Suppl. 2):53-56. of reduction of intraocular pressure in unanesthesized Camenzind E, Nussberger J, Juillerat L, Munafo A, Fischli W, Coassolo rabbits and anesthesized monkeys by topical applica P, Van Brummelen P, Kleinbloesem CH., Waeber B, Brunner HR. Effect tion of enalkiren suggests a possible functional role of the renin response during renin inhibition: Oral Ro 42-5892 in nor of RAAS in modulation of intraocular pressure and mal humans. J Cardiovasc PharmacoI1991;18:299-307. the potential c1inical utility of renin inhibitors as ocu Chrysant SG. Aliskiren-hydrochlorothiazide combination for the treat lar pressure-Iowering agents (Giardina et al., 1990). ment of hypertension. Expert Rev Cardiovasc Therap 2008;6:305-314. Finally, Renin inhibitors are promising drugs for com Cleland JGF, Abdellah AT, Khaleva O, Coletta AP, Clark AL. 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