Pharmacokinetic and pharmacologic properties of delapril, a lipophilic nonsulfhydryl angiotensin-converting enzyme inhibitor

Pharmacokinetic and Pharmacologic Properlies of Delapril, a Lipophihc Nonsulfhydryl Angiotensin-Converting Enzyme Inhibitor Roberta

Razzetti,

PhD, and Daniela

Acerbi,

PhD

Delapril is a carboxyl-alkyl-dipeptide mainly convetted in animals and humans to an active diacid derivative (M-l), which in turn is converted to an active 5-hydroxy-indane diacid (M-III). In humans these metabolites are excreted in the urine. The presence of the indanyl-glycine moiety gives delapril a high lipophilicity, greater than several other angiotensin-converting enzyme (ACE) inhibitors, such as captopril and enalapril. Due to its greater lipophilicity, delapril has been shown to exert a more effect’nre inhibition of vascular ACE than captopril and enalapril, both in vitro and in vivo. The act.tity of delapril on tissue ACE also lasts longer than on the circulating enzyme. At doses ranging from l-l 0 mg/kg omlly, delapril exerts a marked

and long-lasting antihypertensive action in various experimental models of hypertension. The blood pressure reduction has been shown to be accompanied by suppression of angiotensin II release from the vascular wall. In stroke-prone spontaneously hypertensive rats (SHR-SP) and in SHR with chronic renal failure, besides reducing hypertension, delapril significantly improves survival rate and prevents the development of stroke, cardiac hypertrophy, and renal sclerosis. The ability of delapril to reduce hypertrophy in vascular and cardiac tissue has been demonstrated in both in vitro and in vivo experiments. (Am J Cardioll995;75:7F-12F)

I

Delapril is a highly lipophilic carboxyl-alkyldipeptide with potent ACE inhibitory activity. It is a prodrug converted in vivo by esterolysis to an active diacid derivative (M-I), which is converted in turn to an active 5hydroxy-indane diacid (M-III). The pharmacokinetic and pharmacodynamic profile of this drug will be described in this article.

nhibition of the renin-angiotensin system (RAS) by angiotensin-converting enzyme (ACE) inhibitors is well established as a treatment not only for hypertension, but also for congestive heart failure. There is increasing evidence confirming their ability to improve symptoms, hemodynamics, exercise performance, and even to reduce mortality in patients with congestive heart failure.‘” The efficacy of ACE inhibitors in improving cardiac performance has been correlated with suppression of the production of both circulating and tissue angiotensin II. The existence of an autocrine-paracrine RAS in organs that play an important role in cardiovascular homeostasis-such as blood vessels, heart, and kidney-has been clearly demonstrated.&12 The pattern and degree of inhibition of tissue ACE by the various inhibitors may be dependent on their tissue bioavailability, which means the ability to penetrate into the tissue. Lipophilicity may thus be an important feature of these drugs; the more lipophilic ACE inhibitors may be more readily taken up by tissue to suppress the locally generated angiotensin II.8~9

From the Research and Development Department, tici, Parma, Italy. Address for reprints: Roberta Razzetti, PhD, S.p.A., Via Palermo 26a, 43100 Parma, Italy.

Chiesi Chiesi

FarmaceuFarmoceutici

LIPOPHILICITY Delapril is a nonsulfhydryl compound that also lacks the proline moiety present in captopril and enalapril. The indanyl-glycine moiety that substitutes the proline moiety in delapril affects the properties of delapril and its metabolite M-I (delaprilat) in several ways. As can be seen from a comparison of the log P values (Table I), delaprilat is more lipophilic than most other ACE inhibitors.13 As a prodrug, delapril is clearly more lipophilic than delaprilat: distribution coefficient data give a ratio of 2:1.14 This relatively high lipophilicity means not only that delapril will be more easily absorbed after oral administration, but also that delapril and delaprilat may be able to penetrate better into the various target organs such as heart, vessel wall, and kidney, and, subsequently, to inhibit the tissue membrane-bound ACE. In addition, Ranadive et alI5 suggested that lipophilicity may be involved in differentiating the ACE inhibitory activities of structurally similar A SYMPOSIUM:

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The pharmacokinetics of delapril has been widely investigated in several animal species.17-20 After oral administration of [14C]delapril 10 mg/kg to rats, 57% of the dose is absorbed mainly in the small intestine via the portal route and extensively metabolized by esterases to the diacid derivative M-I. Plasma levels of M-I peak within 0.4 hour of administration (maximum concentration [C,,] 1.23 pg/mL), then decline biphasically with half-lives of 0.6 and 9.1 hours. Excretion of radioactivity is almost complete within 48 hours of administration, mainly in feces (91.8%) and to a minor extent in urine (8%). In biliary cannulated rats given intraduodenally [14C]delapril, 65% of the dose is excreted in the bile over 24 hours and only partially reabsorbed via enterohepatic cycling, indicating that fecal excretion is mostly due to the biliary route and only partially to nonabsorbed drug. After oral administration of [14C]delapril to pregnant rats, radioactivity is detected in both fetal plasma and tissues, indicating that the drug or its metabolites cross the placenta. However, radioactivity is always higher in maternal plasma, followed in decreasing order by placenta, fetal plasma, fetal tissue, and amniotic fluid.

In dogs given 10 mg/kg of [14C]delapril, 72% of the dose is absorbed. Plasma levels of M-I peak within 0.4 hour of administration (C,, 0.9 Kg/ mL), then decline biphasically with half-lives of 0.3 and 2.8 hours. Excretion of radioactivity is almost complete within 48 hours of administration, mainly in feces (89.7%) and to a minor extent in urine (11%). In both rats and dogs the radioactivity is largely in the form of metabolites ( > 97%). Tissue distribution studies have been carried out in rats given single or repeated (once daily for 14 consecutive days) oral doses of 10 mg/kg [*4C]delapril. The highest concentrations of radioactivity are observed 30 minutes after single dosing. At this time, radioactivity is higher in the stomach and intestinal wall, followed in decreasing order by liver, kidney, plasma, lung, inferior vena cava, and abdominal aorta; the lowest concentration is observed in the brain. Radioactivity falls to very low levels within 24 hours. M-I is the predominant metabolite in most tissues, including the abdominal aorta and inferior vena cava. The tissue radioactivity 24 hours after the 4th and the 14th daily dose of [14C]delapril, clearly shows that no appreciable accumulation of the drug occurs after repeated administration. In vitro studies show that the protein binding of delapril and M-I is about 85% in rat plasma and 96% in dog plasma over the concentration range 0.1-10 kg/mL. The pharmacokinetics of delapril has been thoroughly investigated in healthy volunteers and patients. After single oral administration of increasing doses of delapril (3-60 mg) to healthy volunteers21 the drug is rapidly absorbed. There is a correlation between dose and blood levels (C,, and area under the curve [AUC]) of M-I. After administration of 60 mg to 6 volunteers,22 high plasma levels of M-I are observed, followed by the other active metabolite, M-III. Plasma levels of the inactive diketopiperazine metabolite M-II and unchanged delapril are low. C,, values of M-I and M-III are 1,200 and 430 ng/mL at 1.39 and 1.67 hours, respectively. Serum levels decline rapidly with elimination half-lives of 1.21 and 0.81 hours, respectively (Figure 1). Urinary excretion of delapril and its metabolites is 55.7% of the administered dose, mainly as M-I (21.4%) and M-III (30.4%). Food intake has no effect on the absorption of the drug. Serum levels of delapril and its metabolites as well as total urinary recovery have been determined after repeated administration of

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TABLE I Logarithm (Log

P) of Delaprilat

Angiotensin-Converting

of the 0ctanol:Water Partition Compared with That of Other Enzyme

Inhibitors

Compound

Log P

Fosinoprilot Deloprilot Qulnaprilat Romiprilat Captopril Perlndoprilot Enalaprilot Lisinoprll All the reported

Coefficient

>2 1.974 1.422 1.034 1.016 0.554 0.161 -2.439

v(~Iues refer to the active drug.‘3

molecules. When the lipophilicity of a molecule is increased by chemical substitution of the proline residue (delapril has a 2-indanyl substituent), the enzyme inhibitory activity is increased. It is believed that ACE and its inhibitors interact at several sites; interactions at some sites are ionic in nature (such as zinc binding), whereas at others, they may be of the van der Waals type.16 Therefore, the lipophilicity of delapril and delaprilat may be significant in determining the binding of inhibitors to ACE and also in determining the concentration of inhibitors in the lipophilic membrane environment of the enzyme.

ABSORPTION, DISTRIBUTION, EXCRETION, AND METABOLISM

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FIGURE 1. Mean serum levels (*SD) of delapril ((X-331 7) and its metabolites (I, II, Ill) after administration to fasting healthy male adults (dose level, 60 mg). (Reprinted with permission from Jpn Pharmacol Ther.22)

60 mg delapril once daily for 7 consecutive days in healthy volunteers. The results indicate that there is no accumulation of the drug or its metabolites in the body. Several studies have investigated the pharmacokinetics of delapril in patients with renal impairment.23-25 The results clearly show that renal impairment has no effect on the pharmacokinetics of the prodrug but does influence the plasma profiles of the 2 active metabolites. Plasma concentrations and AUC values of M-I and M-III are higher in patients with renal failure than in healthy volunteers, and there is a significant relationship between AUC and the reciprocal of creatinine clearance, suggesting that dosage adjustment is necessary in patients with marked renal impairment. Plasma profiles of delapril and metabolites are similar after both single and repeated administrations. In elderly patients with essential hypertension,26 repeated administration of 30 mg of delapril twice a day for 7 consecutive days results in increased plasma concentrations and AUCs compared with adult healthy volunteers, probably as a consequence of age-related reduced renal and hepatic

Ramipril (lo-‘M)

Cilazapril (10.‘M)

Delapril (10.‘M)

Captopril (10.‘Ml

FIGURE 2. Effects of delapril and other angiotensin-converting enzyme (ACE) inhibitors on immunoreactive angiotensin (Ang) II release from isolated perfused rabbit mesenteric arteries. The basal value represents the avemge of the basal values of each ACE inhibitor experiment. The values are expressed as mean f SEM. *p co.01 compared with the basal value. (Reprinted with permission from Hypertension.9)

function. Plasma levels of delapril and metabolites are similar after both single and repeated administrations.

PHARMACOLOGIC

ACTMTY

Delapril has been shown to exert potent ACE inhibitory activity in both in vitro and in vivo experiments. Its potency is about 15 times greater than captopril and almost equal to enalaprilat in inhibiting rabbit lung ACE activity in vitro27,28 and about 10 times greater than captopril in inhibiting angiotensin I-induced contraction in isolated tissue preparations, such as rat aortic rings and rat kidney.27 Higashimori et al9 recently reported that in isolated and perfused rabbit mesenteric arteries delapril is about as effective as cilazapril, but more potent than captopril and ramipril in reducing the baseline release rate of immunoreactive angiotensin II (Figure 2). Interestingly, ramipril, which has been reported to be more effective than captopril

A SYMPOSIUM:

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on rat plasma ACE,29 is equipotent with captopril in this study, confirming that membrane permeability may be an important feature in determining the effectiveness of ACE inhibitors on the vascular ACE. A similar suppression of angiotensin II release has been observed in isolated and perfused hind legs of normotensive30 and spontaneously hypertensive rats (SHR)31 and in human umbilical veins.lO Delapril is able to inhibit plasma and tissue ACE at doses 5-10 times lower than captopril and this has also been found in in vivo experiments.14,27,28,32 When delapril (3 mg/kg) is administered orally to SHR for 2 weeks, the tissue ACE inhibitory activity, especially on aortic wall vascular ACE, is more marked than captopril(30 mg/kg) and enalapril(3 mg/kg), whereas all inhibitors were about equally effective on plasma ACE 14,28(Figure 3). Moreover, the effect of delapril on tissue ACE lasts longer than on the circulatory system.

FIGURE 3. Effects of delapril and enalapril(3 mg/kg/day omlly for 14 days) on plasma and vascular angiotensin-converting enxyme (ACE) activity in spontaneously hypertensive rats. *p ~0.01. (Reprinted with permission from Am .I HypefTens.14)

The antihypertensive activity of delapril has been examined in various hypertensive animal models. At oral doses of l-10 mg/kg, delapril exerts marked and long-lasting antihypertensive action in RAS-dependent models of hypertension, such as 2-kidney, l-clip hypertensive rats and dogs33 and in SHR, where circulating renin is generally normal or even 1ow.27,28,32,33 The effect of delapril versus captopril and versus enalapril is shown in Figure 4. In SHR, the blood pressure lowering effect of delapril, but not of captopril, becomes more marked and longer lasting with repeated doses. Moreover, the antihypertensive effect of delapril persists when the plasma ACE activity returns to normal, whereas ACE in vascular wall and kidney is still inhibited.27,28 These findings agree well with the highly effective inhibition of tissue ACE produced by delapril. In support of this concept, Mizuno et a131,34and

FIGURE 4. Effects of delopril, enalapril, and captopril omlly administered to spontaneously hypetiensive rats for 1 week, on systolic blood pressure. The values are expressed as mean f SEM. *p do.05 compared with baseline. (Reprinted with permission from Am J Hypertens.J*)

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FIGURE 5. Effects of delapril(2 mg/kg/day orally) on systolic blood pressure, left ventricular weight, and heart weight in stroke-prone spontaneously hypertensive rats. The values are expressed as mean f SEM. *p cO.05; **p CO.01 compared with control (Student’s t test). (Reprinted with pennission from Drugs Exp Clin Res.37)

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Higashimori et aP2 have demonstrated that in SHR, where local RAS has been shown to be activated in the established phase of hypertension,34-36 the antihypertensive effect of delapril is accompanied by the unequivocal suppression of angiotensin II release from the hind legs and the mesenteric arteries. In these latter vessels delapril is again > 5 times more potent than captopril. In view of the greater lipophilicity of delapril compared with captopril, it can be argued that delapril is taken up readily by vascular tissue to suppress angiotensin II generated by an intracellular mechanism. A marked antihypertensive activity has been observed in stroke-prone SHR37 and in SHR with chronic renal failure.38 In these models delapril(l0 and 30 mg/kg/day orally for 32 and 28 days, respectively) is also able to improve survival rate significantly and prevent the development of symptoms of cardiac and renal injury, such as stroke, cardiac hypertrophy, and renal sclerosis. The inhibition of locally generated angiotensin II, rather than blood pressure reduction, seems to be involved in these effects. In fact, hydralazine, although effectively lowering blood pressure, does not affect the just-mentioned parameters.38 An increasing body of evidence is being collected regarding the ability of delapril to reduce vascular and cardiac hypertrophic tissues.3U1 Delapril has been shown to decrease heart weight, left ventricular weight (Figure 5), the wall to lumen ratio of small coronary arterioles, and thickness of the left ventricular wall in strokeprone SHR, 37 to reduce cardiac renin gene expression in SHR,36 and to protect perfused rat hearts

against ischemia-reperfusion injury.39 Cardioprotection is associated with a marked decrease in cardiac angiotensin II content. Since ACE also degrades bradykinin, ACE inhibitors induce an accumulation of this peptide. It is thought that some of the adverse reactions of ACE inhibitors, such as cough42 and angioneurotic edema,43 might be due to the action of bradykinin. In this regard, delapril seems to be somewhat selective for ACE. In fact, it is slightly less potent than captopril in augmenting both bradykinin-induced contraction of guinea pig ileum and hypotension in dogs;27 it also causes a lower incidence of citric acid-induced cough than captopril and enalapril in the guinea pig.44 In conclusion, the pharmacologic profile and lipophilic properties of delapril suggest that this non&‘hydryl ACE inhibitor may represent a promising drug for treatment of congestive heart failure. 1. Edwards CRW, Padfield PL. Angiotensin-converting enzyme inhibitors: past, present and bright future. Lancer 1985;i:3&34. 2. Gavras H. The place of angiotensin-converting enzyme inhibition in the treatment of cardiovascular diseases. N Engl .I Med 1988;319:1541-1543. 3. Davies MK. Congestive cardiac failure. J C[in Pham Ther 1989;14:1-19. 4. Armstrong PW, Moe GW. Medical advances in the treatment of congestive heart failure. Circulation 1994;88:294-2952. 5. Cleland JGF. The clinical course of heart failure and its modification by ACE inhibitors: insights from recent clinical trials. Ew Heun .I 1994;15:12.%130. 6. Campbell DJ. Circulating and tissue angiotensin systems. I Clin Invest 1987; 791-6. 7. Dzau VJ. Circulating versus local renin-angiotensin system in cardiovascular homeostasis. Ckculariwt 1988;77(supplI):4-13. 8. Minmo K, Nakamaru M, Higashimori K, Inagami T. Local generation and release of angiotensin II in peripheral vascular tissue. Hywtenxion 1988;11:223. .

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9. Higashimori K, Gante renin for local generation 10. Mknmo K, Niimura

J, Holzemann G, Inagami T. Significance of vascular of angiotensins. Hpzrtemion 1991;17:270-277. S, Tani M, Haga H, lnagami T, Fukuchi S. Direct

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proof for local generation and release of angiotensin II in peripheral human vascular tissue. Am J Hwens 1991;4:67s-729. 11. Grinstead WC, Young JB. The myocardial reniwangjotensin system: existence, importance, and clinical implications. Am Heart J 1992;123:1039-1045. 12. Hirsch AT, Talsness CE, Smith AD, Schunkert H, Ingeliinger JR, Dzau VJ. Differential effects of captopril and enalapril on tissue renin-angiotensin systems in experimental heart failure. Circulation 1992;86:156&1574. 13. Ondetti MA. Structural relationships of angiotensin-converting enzyme inhibitors to pharmacological activity. Circularion 1988;77(suppI 1):74-78. 14. Saruta T, Nishikawa K. Characteristics of a new angiotensin converting enzyme inhibitor: delapril. Am J Hypertens 1991;4:23S-Z&S. 15. Ranadive SA, Chen AX, Serajuddin ATM. Relative lipophilicities and structural-pharmac&gical considerations of various angiotensin-converting enzyme (ACE) inhibitors. I’hum fies 1992;9:1&1486. 16. Ondetti MA, Rubin B, Cushman DW. Design of specific inhibitors of angiotensin-converting enzyme; new class of 0raIIy active antihypertensive agents, science 1977;1%:44l-w. 17. Tanayama S. Disposition and metabolism of m-3317. Takeda Central Research Division, unpublished report no. C-24-144, 1983. 18. Tanayama S. Disposition and metabolism of delapril ((X-3317) in rats and dogs. Takeda Central Research Division, unpublished report no. C-24-516, 1987. 19. Tsukamoto T, Yoshida K, Mitsuya M, Torii H, Naeshiro I, Tanayama S. Metabolic fate of delapril hydrochloride ((X-3317), a new angiotensinconvetig enzyme inhibitor, in rats and dogs. Jpn Phamucol 7’hzr 1987;15:11671193. 20. Yoshida K, Tsukamoto T, Kobayashi T, Tanayama S. Pharmacokinetics and metabolism of alindapril hydrochloride (CV-3317), a new angiotensinconverting enzyme inhibitor, in rats and dogs. Jpn F’hmmzcol7lw 1985;13:71517165. 21. Ogihara T, Nakamaru M, Higaki J, Kumahara Y, Hamano Y, Minamino T, Nakamura N. Phase I study of a new orally active angiotensin-I-converting enzyme inhibitor, delapril. Cwr Ther Res 1987;41:-22, 22. Tateno M, Nakamura N. Clinical pharmacokinetics of (X-3317. Jpn Pharmacd Ther 1986;14:4225-4231. 23. Minamisawa K, Shionoiri H, Sugimoto K, Ueda S, Ashino K, Ebina T, Gotoh E, Ishii M. Depressor effects and pharmacokinetics of single and consecutive doses of delapril in hypertensive patients with normal or impaired renal function. Cardiowc Dmgv mr 1990,4:1417-1423. 24. Onoyama K, Nanishi F, Okuda S, 0 Y, Fujishima M, Omae T. Pharmacokinetics of delapril hydrochloride, angiotensin-I-converting enzyme inhibitor, in patients tith renal dysfunction. Clin Rep 1987;21:191’+1932. 25. Shionoiri H, Yasuda G, Abe Y, Yoshiiura H, Kaneko Y, Shindo Y. Pharmacokimetics and acute effect on the renin-angiotensin system of delapril in patients with chronic renal failure. C&t Nephrol 1987;27z65-70. 26. Portioli I. Studio farmacocinetico-farmacodinamico su delapriI somministrata a pazienti ipertesi anziani. Unpublished report, July 1, 1989. 27. Inada Y, Terashita Z, Imura Y, Tanabe M, Nishikawa K, Kikuchi S. Inhibition of angiotensin converting enzyme by (X-3317, a non-sulfhydryl compound. Jpn JPhamuzco11986;42:9!&108. 28. Inada Y, Nishikawa K. Antihypertensive action and tissue angiotensin converting enzyme inhibitory action of delapril, enalapril and captopril in spontaneously hypertensive rata. 3pn Phamuzcoi Z?ter 1989;17:4293-4301. 29. Unger T, Moursi M, Ganten D, Hermann K, Lang RE. Antihypertensive

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action of the converting enzyme inhibitor perindopril (S9490-3) in spontaneously hypertensive rats: comparison with enalapril (MK-421) and ramipriI (Hoe 498). J Cardiovasc Ph~nnacol1986;8:27&285 30. Mizuno K, Niimura S, Tani M, Fukuchi S, Inagami T. Effect of delapril hydrochloride on angiotensin II release from isolated rat hind legs. Ew J Phanz~~co11990;184:169-172. 31. Mizuno K, Tani M, Niimura S, Yamaguchi M, Inagami T, Fukuchi S. The antihypertensive mechanism of delapril, a newly developed converting enzyme inhibitor, is related to the suppression of vascular angiotensin II release in the spontaneously hypertensive rat. Am J H-m 1991;4:6OS66S. 32. Higashimori K, Nakamaru M, Tabuchi Y, Nagano M, Mikami H, Ogihara T, Inagami T. Angiotensin converting enzyme inhibitors suppress the vascular renti-angiotensin system of spontaneously hypertensive rats. Am J mm 1991;4:56S-5959s. 33. Inada Y, Tanabe M, Shibouta Y, Kawazae K, Nishikawa K, Kikuchi S. Antihypertensive action of a nonsulfhydryl angiotensin converting enzyme inhibitor (CV-3317) in various hypertensive models. Jpn J Phamtacol 1986;42: l-8. 34. Mizuno K, Tani M, Niimura S, Fukuchi S. Effect of delapril on the vascular angiotensin II release in isolated hind legs of the spontaneously hypertensive rat: evidence for potential relevance of vascular angiotensin II to the maintenance of hypertension. C&n Eip Pftarmacol Physioi 1991;18:619-625. 35. Assad MM, Antonaccio MJ. Vascular wall renin in spontaneously hypertensive rat: potential relevance to hypertension maintenance and antihypertensive effect of captopril. H~mnsion 1982;4:487-493. 36. Okura T, Kitami Y, Wakamiya R, Marumoto K, Iwata T, Hwada K Renal and extra-renal renin gene expression in spontaneously hypertensive rats. BIood tiesrum 1992;I(suppl3):~11. 37. Inada Y, Ojima M, Itoh K, Shine A, Nishikawa K. Effects of delapril on stroke, kidney dysfunction and cardiac hypertrophy in stroke-prone spontane ously hypertensive rats. Drugs &J Clin Res 1995;21:41-19. 38. Kohara K, Mikami H, Okuda N, Higaki J, Ogihara T. Angiotensin blcckade and the progression of renal damage in the spontaneously hypertensive rat. H~rtension 1993;21:975-979. 39. Yoshiyama M, Kim S, Yamagishi H, Omura T, Tani T, Yanagi S, Toda I, Teragaki M, Akioka K, Takeuchi K, Takeda T. Cardioprotective effect of the angiotensin II type 1 receptor antagonist TCV-116 on ischemia-repcrfusion injury. Am Heati J 1994;128:1+. 40. Morishita R, Higaki J, Nakamura F, Tomita N, Yu H, Nagano M, Mikami H, Ogihara T. Regression of hypertension-induced vascular hypxtrophy by an ACE inhibitor and calcium antagonist in the spontaneously hypertensive rat. Blwdpressure 1992;l(suppl 3):41-47. 41. Taguchi J, Abe J, Okazaki H, Ochiai M, Ohno M, Takuwa Y, Kurokawa K. Angiotensin converting enzyme inhibitors or DUF753 prevent neointimal formation following balloon injury with single topical or multiple systemic application. Biochem Biophys Res Common 1993;196:%+974. 42. Morice AH, Brown MJ, Higenbottam T. Cough association with angiotensin converting enzyme inhibition. J Canliovarc Phamwol 1989;13(suppl3):S5~ S62. 43. Becker RHA, Scholkens B. Ramipril: review of pharmacology. Am J Cardial 1987;59(suppl):3D-1lD. 44. Inada Y, Ojima M, Morimoto S, Saijo T, Kito G, Nishikawa K Comparison of cough-inducing action of angiotensin converting enzyme inhibitors. Jpn Phannacol7kr 1989;17:203!L24kt8.

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