perindopril

Cardiovascular Drug Reviews Vol. 10. No. 4. pp. 446-471 0 1992 Neva Press, Branford, Connecticut

Perindopril

Jeffrey Atkinson

Loboratoire de Pharmacologie Cardiovasculaire. FacultP de Pharmacie, Nancy, France

Key Words: Angiotensin I converting enzyme inhibition-Perindopnl

The present review is intended to complement other excellent reviews on perindopril, such as that of Lees and Reid (92). It represents an update on certain aspects of fundamental and clinical pharmacology, with extended chapters on two specific subjects: toxicity and potential protection of target organs.

PHYSICOCHEMICAL PROPERTIES

Perindopril tert-butylamine ([2S, 3aS, 7aSl- 1 -{2-[ l-(ethoxycarbony1)-(S)-butyl- amino]-(S)-propionyl}-octahydroindole-2-carboxylic acid; S-9490-3; Fig. 1) is an angiotensin I-converting enzyme inhibitor (ACEI), developed by Servier Laboratories, Paris, France in the 1980s, for use in hypertension and heart failure (92). Perindopril tert-butylamine is moderately to freely soluble in water, methanol, ethanol, and chloro- form. The molecular weight of the tert-butylamine salt of perindopril is 442, and that of the free amino acid is 368. The molecule has two pKa values (3.0 and 5.7); the pH of an aqueous solution (1% w/v) is 8.

PHARMACOKINETICS

Perindopril and its diacid metabolite, perindoprilat, can be measured in biological samples, following ion exchange chromatography, by either enzyme inhibition (87,90) or radioimmunoassay (43,121,147). Pharmacokinetic studies in the rat, dog, and monkey, using ''[C]perindopril, revealed that the drug was rapidly absorbed following oral administration (61). Metabolic hydrolysis leads to the formation of the diacid, perindoprilat, which is 10oO times more active than perindopril; other metabolic pathways give inactive glucuronide and lactam derivatives (61). Extensive tissue binding may occur (20). Move- ment across the placenta appears negligible. In pregnant female rats, placental transfer of radioactivity following administration of I4[C]perindopril was less than 1 % of the dose (unpublished data).

In humans drug clearance is greatly affected by renal function (90) and it has been

Address correspondence and reprint requests to Dr. J . Atkinson at Labratoire de Pharmacologie Cardiovas- culaire, Facult6 de Pharmacie, 5 rue Albert kbrun, 54000 Nancy, France.

446

PERINDOPRIL 447

&COO. PERINDOPRIL

- H I oSC,cH -NH-cH-y,

A A CH3 COOGH,

PERINDOPRILAT

A COOH

A CH3

FIG. 1. Chemical structures of perindopril and its active diacid metabolite perindoprilat. Perindopril: S-9490 for free acid, S-9490-3 for ?err-butylamine salt; perindoprilat: S-9780.

recommended that dosage be lowered in patients with renal failure, in elderly patients, as well as in patients with chronic heart failure (121). Mild hepatic insufficiency, however, does not appear to significantly modify the pharmacokinetics of either perindopril or perindoprilat (145), and, therefore, would not appear to require a change of dose.

TOXICITY

The acute toxicity of perindopril was determined in several species and LD,, values for perindopril and perindoprilat are listed in Table 1. The figures given in this table, and in the following tables and paragraphs, are from the unpublished data of Servier Laborato- ries, Paris, France. The LD,, for perindopril is 75 to 175 times the intended human dose when given i.v., and at least 400 to 750 times when the drug is administered by the oral route. No major sex differences were observed. The metabolite perindoprilat produced no mortality, even at high doses (up to 2 g/kg i.v.).

The subchronic toxicity (1 to 3 months of treatment) of perindopril was also studied in several species. In Wistar rats at doses up to 5 mg/kg per day (P.o.), perindopril was well tolerated. At a higher dose of 30 mg/kg per day perindopril reduced growth rate and increased blood urea and creatinine levels. Tubular nephritis was observed in 4 of 20 animals. In Cynomolgus monkeys at doses of up to 10 mg/kg per day (p.0.) perindopril produced no overt signs of toxicity apart from a slight decrease in body weight at the highest dose used. In beagle dogs with i.v. administration perindoprilat at 80 mgkg per

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448 J . ATKINSON

TABLE 1 . Acute toxicity of perindopril and perindoprilat

Substance and administration

route Species Sex LD,, (mg/kg)

perindopril i . v

perindopril p.0.

perindoprilat i.v.

OF1 mice M F

Wistar rats M F

Swiss mice M a n d F Wistar rats M and F Beagle dogs M a n d F Swiss mice M a n d F Wistar rats M and F

704 619 323 423

>2,500 >3,000 > 1,600 >2,000 >2.000

Unpublished data from Servier Laboratories. Paris, France

day for 1 month produced slight renal toxicity in the form of an increase of blood urea and creatinine levels.

The chronic toxicity of perindopril was studied in the same species. The drug was given orally for periods of up to 18 months. In Wistar rats given perindopril at doses of 1, 3, and 12 mg/kg per day, for up to 6 months, and in Fischer rats given perindopril at doses of 0.75, 2, and 7.5 mg/kg for up to 18 months, an increase in kidney weight, and interstitial and tubular nephritis were observed at the highest dose used. Electron micros- copy revealed osmotic nephrosis at the level of the proximal tubules. In Wistar rats in which a recovery study was carried out, all changes in renal structure and function had disappeared 6 weeks after cessation of treatment. In beagles given perindopril(1, 5 , or 25 mg/kg p.0. for 6 months) a slight reduction in body weight was observed. There were no signs of renal toxicity even at these very high doses of perindopril, but a dose-related inhibition of angiotensin I-converting enzyme (ACE) was observed. In Cynomolgus monkeys given perindopril (1, 4, or 16 mg/kg P.o., per day, for 1 year) there was a slight reduction in body weight in males. There was no effect on the kidney, apart from medial hypertrophy of the afferent glomerular arterioles at the highest dose of perindopril given.

Further studies were performed in order to investigate the possible mechanisms of the renal toxicity of high doses of perindopril. Cynomolgus monkeys received increasing oral doses of perindopril starting at 100 mg/kg per day, and increasing up to a maximum of 450 mgkg per day. Treatment was discontinued when the increases in blood urea and creatinine exceeded 300% and 200%, respectively, or when no sign of renal failure was observed after 4 weeks of treatment with a daily dose of 450 mg/kg. An eight-week reversibility study was then carried out. Controls were given rert-butylamine hydrochlo- ride alone. The duration of administration varied from 27 to 63 days. Symptoms included gastrointestinal disorders, anorexia, weight loss due to dehydration, sedation, bradycardia, and hypotherrnia. There were also increases in blood potassium and slight reductions in blood sodium. Blood parameters returned to normal during the first week after cessation of treatment. Histopathological examination of biopsies performed upon cessation of treatment, showed osmotic lesions of the proximal tubules which were spontaneously and completely reversible 4 weeks after discontinuation of treatment. Tert-butylamine hydro- chloride induced no renal lesions. In summary, perindopril at high doses may produce reversible osmotic nephrosis.

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The influence of sodium intake on the adverse effects of perindopril was studied in male Wistar rats given increasing oral doses of 0.5 to 32 mgkg per day for 14 weeks. Animals were fed a low, normal, or high sodium diet; renal toxicity was greater on low sodium diets.

Drug interaction studies were performed in male Wistar rats given high doses of aspirin, amiloride, digoxin, etlunyloestradiol plus norethisterone, furosemide, hydrochlorothiazide, nifedipine, phenobarbital, phenylbutazone, or warfarin, orally for 5 days. Nifedipine increased the LD,, of perindopril; the other drugs had no effect. In Wistar rats given perindopril (1, 10, or 40 mg/kg per day), together with hydrochlorothiazide (10 mg/kg per day), and in Cynomolgus monkeys given perindopril (1, 20, or 60 mg/kg per day), together with hydrochlorothiazide (10 mg/kg per day), renal insufficiency was observed at the highest dose of perindopril used, and was amplified by the addition of hydrochlorothiazide. Yet again, the renal toxicity of high doses of perindopril appeared to be influenced by sodium balance.

In fertility studies in which Wistar rats were given perindopril before mating (males for 80 days, females for 14 days), and for 7 or 20 days during gestation, mortality of the Fl pups was increased at the highest dose used (10 mg/kg per day and 4 mg/kg per day, respectively); the growth of the survivors was retarded. These changes did not affect the reproductive capacity of the F l generation. The results of the embryotoxicity and teratogenicity studies in mice, rats, rabbits, and monkeys, are shown in Table 2. Generally, few adverse fetal effects were observed.

Pen- and postnatal toxicity studies were carried out in the Wistar rat. In the first study, pregnant rats received perindopril (1, 4, or 16 mgkg p.0. per day) from day 17 of gestation until day 21 after parturition. At the intermediate and high doses, maternal toxicity was observed at the end of gestation causing a reduction in food consumption and weight gain. Dystocia caused the death of four females during parturition at the high dose. There were significantly fewer neonates with all doses, although the average weight of the F1 pups was unchanged. During lactation, with the intermediate and high doses perindopril provoked a dose-related reduction in the weight gain of the FO dams and of the

TABLE 2. Embryotoxicity and teratogenicity studies

Dose Treatment Sacrifice Species (mgkg per day) (days) (Pc)

Mouse (NRMI) 1,4.5, or 20 6-15 18

Rat (Wistar) 1,4, or 16 6-17 20

Rabbit (New Zealand) 0.5,1.5, or 5 (plus 6-18 30 0.15 M NaCI)

Monkey (Cynomolgus) 1,4, or 16 20-50 99-101 gestation

CeSarian

Comments

no embryotoxicity or teratogenicity

dose-related hydronephrosis; delayed ossification at highest dose; no teratogenicity

plantation losses at highest dose

teratogenicity

slight increase in postim-

no embryotoxicity or

~~ ~

Unpublished data from Servier Laboratories, Paris, France. pc, postconception.

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450 J . ATKINSON

F1 pups. There was persistent anorexia and an increase in postnatal mortality. At the high dose perindopril caused delayed physical and behavioral development, reduced fertility, polyuria, and renal lesions in the F1 progeny; no adverse effects were seen in the F2 generation. In a further study pregnant rats were given perindopril (16 mgkg p.0. per day), and fed a diet with an elevated sodium content (equivalent to 1.9 g/kg per day). The toxicity of perindopril for the dams and their progeny was reduced.

In summary, although no embryotoxic or teratogenic effects were observed, at very high doses perindopril did have an impact on both mothers and their offspring. Thus, perindopril should not be given during pregnancy except if the potential benefit outweighs the potential risk.

In genetic toxicity testing, gene mutation assays, including the Ames test, were performed in seven strains of Salmonella. No mutagenicity was demonstrated. The mouse lymphoma test, performed in vitro with the mammalian cell line L5178Y, also demonstrated the lack of any mutagenic effect of perindopril. Clastogenicity tests were carried out in vitro using human lymphocytes, and in vivo using metaphase analysis of Chinese hamster bone marrow cells or the mice bone marrow micronucleus test. In the in vivo tests perindopril or perindoprilat were given either p.0. or i.p. No clastogenic effects were observed. Following intraperitoneal administration of perindoprilat, a slight increase in the number of Chinese hamster bone marrow cells with chromosomal abnormalities was observed. No effect was seen in the micronucleus test in the mouse, suggesting that the slight effect observed at high doses in the Chinese hamster was due to a cytotoxic and not a clastogenic effect. The gene conversion test using Saccharomyces cerevisae did not reveal any primary DNA damage. Carcinogenicity studies carried out in B6C3F1 mice and Fischer 344 rats, given perindopril in the drinking water (0.75, 2, or 7.5 mg/kg, per day) revealed no increase in the incidence of benign or malignant tumors.

In conclusion, the acute toxicity of perindopril appears to be very low. Following chronic administration of very high doses of perindopril, the main toxicity observed is renal.

ANIMAL STUDIES

Mechanism and Site of Action

In vitro studies in humans (74) and rat (75,81,146) showed that perindoprilat has an ICso./u of 2 nM for plasma ACE, and is significantly more potent than other ACEIs such as captopril and enalapril. In in vivo studies in normotensive rats (85), 2 kidney-1 clip renovascular hypertensive rats ( 10 1 ) or stroke-prone spontaneously hypertensive rats (SHRSP) (146), perindopril inhibited the pressor response to angiotension I (AI), decreased angiotensinogen, and, less consistently, decreased angiotensin I1 (AII) and aldosterone levels (28,146). Plasma ACE was maximally inhibited (>90%) by perindopril(1, 4, or 8 mgkg p.0.) 1 h following administration, then returned to control levels 24 h later (76). Compared to enalapril, perindopril was significantly more potent in vivo, both in terms of intensity and duration of action (42).

Recently the importance of local renin-angiotensin systems (RAS) of, for example, the kidney, heart, vascular wall, adrenal gland, and central nervous system in cardiovascular regulation has been ascertained (46). ACEIs may exert their beneficial cardiovascular effects by inhibiting the tissue RAS of such target organs. For example, cardiac ACE is

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inhibited by perindopril (41,82,146) and this effect might contribute to the structural and functional effects of perindopril on the heart.

The antihypertensive effects of ACEIs have a time course which is different from that of plasma ACE inhibition, and following long term ACEI, blood pressure remains lowered while plasma A11 levels tend to return to normal (28,76,146). Using quantitative autoradiographic techniques, the time course and degree of ACEI produced by perindopril (1 to 32 mgkg p.0.) with acute administration was shown to vary amongst different tissues (76,100,132,133). Two hours following administration, renal and plasma ACE were completely inhibited. ACEI in the lungs and in the aorta persisted after plasma ACE had returned to normal. Testicular ACE activity was not blocked by perindopril. ACE in brain circumventricular organs was inhibited at low doses (1 mg/kg); larger doses were required to inhibit ACE in other brain structures (1 32).

Following 15 days of treatment with perindopril(1 mgkg P.o.), renal and aortic ACE activities were persistently blocked (100). Furthermore, Johnston and coworkers showed that following such subchronic treatment ACE was inhibited by perindopril in brain areas inside the blood-brain barrier, suggesting that the chronic effects of perindopril may involve cerebral mechanisms (personal communication).

In summary, perindopril has been shown to block both plasma and tissue ACE. The degree and the evolution of ACE inhibition, and the relationship of these two factors to the dose of perindopril, vary within different tissues. Further studies are needed to dem- onstrate to what degree blockade of RAS in tissue is involved in the blood pressure- lowering effect and/or the protection of target organs afforded by ACEIs such as perindopril. In this respect it is interesting to note that with chronic treatment perindopril can have marked structural effects, especially in large arteries (see below) and that most of the ACE in large vessels is to be found in the nutrient vasa vasorum of the adventitia (130).

Vasodilation

In various hypertensive animal models (SHR, SHRSP, 2 kidney-1 clip renovascular hypertensive rats) perindopril induces dose-related and long-lasting decreases in blood pressure (12,42,45,146). The threshold oral dose is approximately 0.1 mg/kg depending on the activity of the RAS in the experimental model considered. As with other ACEIs the fall in blood pressure induced by perindopril is not accompanied by reflex tachycardia (12). ACEIs lower arterial pressure by decreasing total peripheral resistance. The regional vasodilatory profile of ACEIs is heterogeneous. Using radioactive microspheres, regional vascular resistances were shown to be decreased in the following order: kidney > spleen = liver > skin > muscle = brain (125,126). This rank order for ACEI-induced regional vasodilation mirrors the regional vasoconstriction profile of A11 (128). All ACEIs produce a sustained decrease in renal vascular resistance, and an increase in renal blood flow with some redistribution of cardiac output towards the renal bed (126,128). This property separates them from vasodilator antihypertensive drugs, such as hydralazine, which produce a global decrease in regional vascular resistances in SHR (140). When given in combination with nitrendipine, a dihydropyridine calcium antagonist, perindopril had an increased vasodilator effect in some beds such as skeletal muscle and liver (135). The enhanced antihypertensive effect of such an association was due to an enhanced vasodi- lating effect (135).

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452 J . ATKINSON

Other vasodilatory mechanisms also contribute to the effects of ACEIs, such as perindopril, on blood pressure; examples are facilitation of the release and/or action of bradykinin, endothelium-derived relaxing factor (EDRF), prostacyclin, etc. (84), and pre- and postsynaptic sympathoinhibitory effects ( 10,125).

In summary, perindopril is a powerful vasodilator, especially of the renal bed. Al- though one component of this vasodilatory action is presumably blockade of the generation of AII, other neurotransmitter and/or hormonal systems are probably involved. Furthermore, we are as yet uncertain as to which of the actions of AII-vasoconstrictor, trophic, modulator of sympathetic and/or endothelial function, etc.-is important. It is idiomatic that perindopril, like other cardiovascular drugs has more than one mechanism of action.

Vascular Structure

Perindopril and other ACEIs prevent the development of genetic hypertension. Inter- estingly, the antihypertensive effect persists after treatment has been stopped (27,33,63). In young SHR a short treatment period of 4 weeks with perindopril produces a significant, 25-30 mmHg reduction in blood pressure up to 15 weeks following treatment withdrawal (64). Using radioactive microspheres it was shown that the fall in blood pressure was due to reduced total peripheral resistance, yet plasma renin activity and A11 concentrations were no different from those of age-matched, untreated SHR (32,64). Christensen and coworkers proposed that during treatment, A11 levels, rather than blood pressure, were important. Concomittant A11 infusion during perindopril treatment prevented the post- treatment effects on blood pressure seen with perindopril alone (64). Several hypotheses have been proposed to explain the long-term effects of ACEIs on blood pressure, such as the correction of fundamental abnormalities in SHR involving renal function (63) and/or vascular structure (32,33,109).

Hypertension is characterized by arterial and arteriolar hypertrophy (or “remodeling,” see below), which may represent an adaptive process aimed at decreasing wall stress (50). It has also been argued that hypertension represents a vicious cycle in which elevated blood pressure increases vessel stiffness, thereby increasing pulse pressure and the rate of rise in pressure. These increased stresses produce further degeneration, dilatation, and stiffening.

In large arteries such a process leads to a decrease in compliance with a subsequent increase in left ventricular afterload and impeded diastolic outflow. The effect of ACEIs on large artery compliance has been investigated in several models. In the 2 kidney-1 clip rat model, hypertension is associated with a stiffer arterial wall, as shown by an increase in characteristic impedance of the aorta and a decrease in systemic arterial compliance and carotid compliance. With chronic treatment perindopril normalized blood pressure and vascular stiffness (93). Simultaneously, the increased medial thickness of the aorta was reversed. There was a reduction of smooth muscle cell hypertrophy, but no effect on elastin and collagen contents. The absence of any effect on collagen density may be due to the short (1 month) treatment period. Similar experiments were performed in SHR. Blood pressure was normalized by perindopril with chronic treatment (3 months). The medial thickness of the aorta was reduced and the elastidcollagen ratio was significantly increased following a reduction in collagen content (94). The effects of ACEIs on arterial


PERINDOPRIL 453

function and structure seemed to be dependent on the timing of the treatment and on the pathogenesis of the hypertension. Perindopril may act by blocking an abnormally high vasopressive signal (renovascular hypertension), or a normal signal in a hyperresponsive system (genetic hypertension).

Most of the experiments on the effects of perindopril on the structure and/or function of resistance arteries have been performed using mesenteric vessels (27,32,33,64). In 24-week-old SHR given various antihypertensive drugs for the previous 20 weeks, perindopril was found to produce the largest fall in blood pressure and medidlumen ratio. The latter effect was caused by an increase in the lumen diameter. Moreover, unlike other drugs such as captopril, perindopril also decreased medial thickness (33). The medial regression induced by perindopril was dose-dependent and correlated with the reduction in blood pressure (32). However, at any given blood pressure, the medidlumen ratio was greater than that to be expected from the relation between blood pressure and medidlumen ratio seen in untreated SHR and WKY. This emphasizes the fact that blood pressure can be more easily reduced than the medidlumen ratio (1,33,52,80).

Most of the above studies are concerned with the impact of ACEIs on the relationship between mean blood pressure and vascular hypertrophy as originally described by Folkow (50). More recently it has been suggested that hypertension may be associated with a reduction in the external diameter and vascular “remodeling” and that pulse pressure may be the important determinant of this process (14). As the determinants of hypertrophy and “remodeling” may not be the same, different antihypertensive drugs may have different effects. Treatment of SHR with hydralazine and ACEIs prevented hypertrophy of cerebral arterioles, but only ACEIs attenuated remodeling (62).

As previously mentioned, an original property of ACEIs appears to be their long-lasting antihypertensive effects following treatment withdrawal (27,33,64); this may be linked to their long-term effects on resistance vessel structure. Following withdrawal of perindopril treatment in SHR, the reduction in medidlumen ratio (and blood pressure) persisted for at least 12 weeks (33). However, in another rat model, the Milan genetic hypertensive rat, no persistent effect on blood pressure was observed after perindopril treatment withdrawal, despite a regression of vascular hypertrophy observed during ACE1 treatment (109).

Another potentially beneficial effect of ACEIs is the prevention of the myointimal proliferation following arterial lesions ( 1 19), and in this respect perindopril appears to be one of the most potent ACEIs (78). Perindopril was also shown to significantly reduce the rejection-induced intimal proliferation in a model of aortic allograft in rats. ACEIs had a greater effect on vascular smooth muscle cell trophicity and on collagen secretion than on vascular smooth muscle cell division (1 16).

In summary, an important aspect of chronic treatment with perindopril appears to be its effect on vascular structure. We are as yet uncertain as to whether perindopril acts directly or indirectly, via a reduction in wall stress. Several recent reports outline the contradic- tions still present in this area as to whether the blockade of the RAS (18) or the fall in blood pressure (65) is the most important factor. It has also been suggested that ACEIs may attenuate vascular smooth muscle proliferation by potentiation of bradykinin ( 19). Furthermore, it would be interesting to know whether perindopril acts mainly on smooth muscle (or other) cells or on the extracellular matrix (138).


454 J . ATKINSON

Endothelium

Although blockade of endothelial ACE is an important target of ACEIs, little is known of the effects of ACEIs on other endothelial cell functions. Endothelial cells play a major role in the vasodilator responses to a variety of neurohumoral mediators (5435,148). Perindoprilat, and other ACEIs, do not exert a direct relaxing effect on isolated vessel rings, with or without endothelium (149). Thus, ACEIs do not appear to directly interfere with release of EDRF from endothelial cells (84). They may, however, potentiate receptor-linked release of EDRF. This has been confirmed for muscarinic agonists in the hypertensive SS Dahl rat (Vanhoutte, unpublished data), and in a rat model of calcium vascular overload (69). Perindoprilat also potentiates the endothelium-dependent relaxations of canine coronary arteries produced by bradykinin; such responses are mediated by both endothelium-derived nitric oxide and endothelium-derived hyperpolarizing factor (EDHF) (84,104). This effect is presumably linked to the prevention by ACEIs of the degradation of bradykinin. Finally in isolated perfused vessels, perindoprilat potentiated the flow-induced release of EDRF and this effect was blocked by a B, kinin receptor antagonist (103).

On the whole, the data suggest that the protection of locally generated kinins by ACEIs may enhance the production of endothelial nitric oxide and EDHF, and that this may contribute to the vasodilator and cardioprotective effects of these compounds.

Heart

ACE is present in the heart (48), the highest activity being found in the valves and coronary arteries, with a lower activity in the atria, and a very low activity in ventricular myocardial cells (154). Perindopril can prevent or reverse cardiac hypertrophy in the hypertensive rat, with regression of the left ventricular to body weight ratio towards normotensive values (27,45,48,93). Prevention of cardiac hypertrophy may occur inde- pendently of the fall in blood pressure as recently observed in reduced renal mass hypertensive rats ( 1 10). In SHR, regression of cardiac hypertrophy was still present 7 weeks after treatment withdrawal (27), and even with very short treatment (4 weeks) perindopril prevented cardiac hypertrophy for at least 15 weeks (64). Perindopril-induced regression of cardiac hypertrophy was associated with a reversion of the hypertrophic isoenzyme profile of cardiac myosin, a biochemical marker of cardiac contractility and energetic efficiency (45,95). Such a beneficial effect was not observed with antihypertensive triple therapy (clonidine, dihydralazine, furosemide; 45). Finally, perindopril treatment normalized coronary vascular reserve and papillary muscle contractility in hypertensive rats (59).

Chronic hypertension results in a resetting and reduction in slope of the baroreceptor heart rate reflex due to a reduction in the cardiac vagal component (66). The degree of cardiac hypertrophy seems to determine the level of vagal reflex deficit. With chronic treatment of young or adult SHR perindopril shifted the baroreflex curves back towards normotensive curves, and restored the baroreflex vagal deficit (67,68).

Cardioprotective effects of perindopril have also been demonstrated in experimental models of heart failure and myocardial ischemia. In the rat cardiac hypertrophy following coronary artery ligation can be prevented or reversed by perindopril with long-term

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treatment (72,73,102,141). There was also a partial, but significant, prevention of the shift in the isomyosin profile (102). The increase in collagen density, associated with cardiac arrhythmia and reduced ventricular compliance, can also be reversed by perindopril (102). Furthermore, in the noninfarcted part of the myocardium, in which elec- trophysiological changes are observed, perindopril normalized the duration of the repo- larization phase of the action potential (141). This improvement of cardiac electrogenesis may be linked to a reduction of cardiac sympathetic hyperreactivity normally associated with coronary artery ligation (72,73,124). This could also explain the improvement of contractile function seen with perindopril in the same model (34). Perindopril also prevented the alterations of myocardial contraction and energetics in Bio 53.58 cardiomyopathic Syrian hamsters (31).

By intravenous injection prior to coronary artery ligation perindopril has been shown to exert antiarrhythmic effects during the early postinfarction period, reducing the duration of ventricular fibrillation and preventing mortality (123). In isolated rat hearts subjected to coronary ligation, perfusion with perindopril or captopril exerted a protective effect on reperfusion-induced cardiac arrhythmia, but did not modify the release of norepinephrine following reperfusion (129). Finally, the antiarrhythrnic potential of perindopril has been recently confirmed in a pig model of acute myocardial ischemia, where the drug was shown to prevent the reduction in ventricular fibrillation threshold following coronary artery ligation (107). Such an effect may be important in the improved survival in pigs subjected to acute myocardial ischemia and treated with perindopril (144,150). Several hypotheses have been put forward to explain such antiarrthymic effects: improvement of hemodynamics, sympatholytic effects (107,124), or a direct action on the electrophysi- ological properties of the cardiac myocytes (47).

In summary, perindopril appears to possess cardioprotective effects on both the structure and function of pathological and nonpathological myocardium. One interesting, but as yet unexplained, property is the antiarrhythmic effect of perindopril.

Kidney

Renal tissue is the second major source of ACE, after the pulmonary endothelium. The kidney constitutes one of the main target organs of ACEIs. With four weeks of treatment perindopril led to a 96% inhibition of renal ACE; this was the highest degree of inhibition observed in any tissue (146). 3[H]perindopril binding follows the same distribution pattern as ACE within the kidney (21,30,106).

Changes in renal hemodynamics following acute or chronic administration of perindopril have been studied in normotensive and hypertensive animals. With a single dose perindopril decreased renal vascular resistance, increasing renal blood flow, whatever the blood pressure level or the sodium balance (37,63,128,136). In the normotensive rat, perindopril (0.1 mg/kg p.0.) produced renal vasodilation without impairing natriuretic adaptation to sodium restriction (83). Unfortunately, no correlation between the hemodynamic effects and tissue ACE inhibition was possible in this study, since only plasma ACE was measured. In anesthetized rats submitted to a sequential reduction of renal perfusion pressure, captopril was shown to alter the autoregulation of glomerular filtration rate, whereas perindopril had no effect (1 15).

Repeated administration of perindopril in SHR from the ages of 4-16 weeks was

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accompanied by an increase in glomerular filtration rate and renal blood flow. Moreover, 12 weeks after cessation of such treatment renal blood flow was still markedly increased. The persistence of both the antihypertensive activity and the renal hemodynamic effects suggest that perindopril acts by modifying a renal vascular abnormality which may contribute to the onset and/or maintenance of hypertension (63). Finally in the 2 kidney-1 clip model, hypertensive microangiopathy was found to be a prominent feature of the un- clipped kidney of untreated hypertensive rats. These lesions were totally prevented by perindopril but not by antihypertensive triple therapy (101).

The effects of perindopril on renal hyperfiltration, which leads progressively to renal autodestruction and insufficiency, have been studied in different experimental models. Hyperfiltration, associated with feeding, aging, or renal mass ablation, was shown to be prevented by perindopril (38,39). In 14-month-old Sprague-Dawley rats, in which proteinuria is already present, perindopril (for 4 months) reduced proteinuria and partially protected the kidney against the development of glomerulosclerosis (155). It is possible that perindopril protected the rats against the development of glomerulosclerosis by di- minishing glomerular ultrafiltration, as described recently for another ACE inhibitor ( 1 20). Finally in normotensive or spontaneously hypertensive rats made diabetic using streptozotocin, with chronic treatment perindopril prevented development of albuminuria (36).

In summary, as with the heart, perindopril appears to possess renal protective properties. It is as yet uncertain, however, whether with chronic treatment perindopril would alter the outcome of the development of hypertension-linked renal failure.

Brain

All components of the RAS have been found in the brain (56,114). The cerebral RAS is independent of the peripheral system, the two being separated by the blood-brain barrier. As mentioned previously, although at lower doses perindopril inhibits ACE activity only in circumventricular organs where the blood-brain barrier is deficient, larger doses do cross the blood-brain barrier (132). The involvement of cerebral ACE1 in the extracerebral hemodynamic effects of perindopril is as yet uncertain.

Hypertension increases the frequency and severity of cerebral ischemic accidents in humans (153). Similar results have been obtained in several animal models. In a model of global cerebral ischemia performed in 2 kidney-1 clip hypertensive rats, mortality following ischemia was higher than in normotensive rats and was lowered by perindopril following chronic treatment, suggesting a cerebroprotective effect of the drug (16).

The cerebroprotective effect of perindopril may be partially explained by the effects of the drug on the regulation of cerebral blood flow. In chronic hypertension the autoregu- latory curve is shifted to higher blood pressure levels, leaving the brain less tolerant to acute reductions in blood pressure (1 3,53,95). With chronic treatment perindopril normalized the blood pressure of 2 kidney-1 clip hypertensive rats and caused a shift in the lower limit of cerebral blood flow autoregulation towards the value observed in normotensive rats (108). There was also a concomitant reduction of cerebrovascular resistance (Table 3).

Acute drug-induced falls in blood pressure may lower cerebral blood flow in hypertensive patients and animals whose lower limit of autoregulation has been shifted to a

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TABLE 3. Effect of chronic treatment with perindopril on cerebral blood flow autoregulation in 2 kidney-I clip hypertensive rats

Renovascular hypertension Normotension

Control Perindopril Control Perindopril

Mean arterial pressure

Cerebrovascular (MAP; mmHg) 154 t 6 113 t 2 108 t 2 89 T 3

resistance (mmHglm1 per 100 g per min) 1.88 f 0.06 1.33 f 0.04 1.26 f 0.04 0.86 2 0.03

limit of CBFAR 150 90 70 70 Lower pressure

Security margin (%) 3 20 35 21

CBFAR, cerebral blood flow autoregulation. Security margin = ([CBFAR-MAP]/MAP) X 100; index of the extent to which blood pressure may fall

Adapted from ref. 108. before cerebral blood flow starts to fall.

higher pressure level. In SHR the fall in blood pressure following acute treatment with antihypertensive drugs, such as prazosin, was accompanied by a fall in cerebral blood flow, whereas this was not the case following acute perindopril treatment (23). Mecha- nisms involved are still unclear but different hypotheses may be drawn such as: (1) abolition of AII-induced tone in large extraparenchymal cerebral arteries followed by an increase in pial artery pressure and an enhanced ability to dilate at low systemic pressures (1 1 1,112), (2) a change in sympathetic activity, (3) a change in pCO,, or (4) changes in cardiac output.

In summary, with both acute and chronic treatment perindopril appears to be without risk to cerebral circulation and may even have a beneficial effect, possibly via restoration of the security margin of the lower limit of cerebral blood flow autoregulation (Table 3). As the results of all the clinical trials are in agreement as to the beneficial effect of antihypertensive treatment on stroke, other aspects of the potential cerebroprotective effects of ACEIs such as perindopril merit further attention.

Finally, several recent studies have outlined the psychopharmacological actions of ACEIs and it is interesting to note that perindopril has an antidepressant-like action in animals (97).

CLINICAL PHARMACOLOGY

Clinical data corroborated the animal studies, showing a dose-dependent inhibition of ACE in man (6,26,88,89,117,142). Following a single oral administration the maximal inhibition of plasma ACE activity was obtained with 8-16 mg of perindopril (26,88,151). ACEI was detected as soon as the first hour following administration, was maximal at 4 to 8 h, and lasted 24 h (6,26,88,89,117,127,142,151). ACEI was maintained after repeated, once daily administration (89,15 l ) , and was accompanied by a fall in plasma AII, and an increase in plasma renin activity and A1 level. Plasma aldosterone was slightly decreased.

Blockade of the RAS accounts for most of the effects of perindopril, the stimulation of


458 J . ATKINSON

prostaglandin synthesis playing a minor role in the antihypertensive action of perindopril in humans. In a double-blind, cross-over study, 10 hypertensive patients treated with perindopril received indomethacin (50 mg b.i.d.). Indomethacin significantly lowered serum thromboxane B, and urinary thromboxane B,, 6-keto PGF,,, and PGE,, but did not modify perindopril-induced ACEI or the antihypertensive effect of perindopril (2). Moreover, no change in plasma levels of epinephrine or norepinephrine were found after oral administration of perindopril to normal volunteers (88), hypertensive patients (89), or patients with congestive heart failure ( 142).

There is some evidence showing that the absence of tachycardia in response to perindopril-induced blood pressure reduction may be due, at least in part, to an increase in parasympathetic tone. In healthy subjects perindopril (8 mg) with a single dose enhanced the vagally mediated heart rate variation produced by deep breathing, whereas there was no change in the response to bicycle exercise, isometric handgrip, cold pressure test, or Valsalva’s maneuver (4). Studies on changes in parasympathetic tone produced by facial immersion-induced bradycardia (1 52) confirmed these results in essential hypertensive patients treated during 6 weeks by perindopril (8 mg) in a placebo-controlled study.

In summary, studies on the clinical pharmacology of perindopril have not revealed any fundamental difference with the results of the pharmacological studies performed in animals. One interesting aspect, also seen in animal studies (67,68), is the possibility that perindopril potentiates vagal, parasympathetic tone.

ANTIHYPERTENSIVE EFFECTS IN HUMANS

With single and repeated oral administration to healthy, normotensive volunteers perindopril (1-16 mg/day) did not cause a marked reduction in blood pressure (17,26,88, 127); nor was heart rate modified in these studies.

In essential hypertensive patients blood pressure was significantly reduced by perindopril ( 3 4 mg daily) following both acute (89,117) or repeated oral administration (8, 86,89,96,105,113). Perindopril did not produce marked, sustained reductions in blood pressure at lower doses (96,113). A dose-response relationship has been demonstrated using automatic blood pressure recording (96). After a 2-week placebo run-in period, 40 patients with essential hypertension were treated with placebo or 2, 4, or 8 mg perindopril once daily for I month. There was a significant dose-response relationship for both the fall in diastolic blood pressure and the percentage of patients having achieved the goal of a fall in the diastolic blood pressure to G95 mmHg.

In a double-blind, placebo-controlled study including 32 patients, the same blood pressure reduction was observed in patients with high or low sodium intakes, after 4 weeks of perindopril treatment (105). Thus, the antihypertensive effect of perindopril did not appear to depend on salt intake. Using three different techniques (measurement of blood pressure 24 h after the last drug intake, 24-h ambulatory blood pressure measurement, and peak/trough evaluation), it was shown that the reduction in systolic and diastolic blood pressures was significant over 24 h (9,71,86,113,118,134). These results show that satisfactory blood pressure control can be obtained with perindopril by a once daily administration.

Three double-blind, pivotal trials were performed comparing perindopril with either hydrochlorothiazide plus amiloride (3, atenolol (143), or captopril, another ACEI (91).

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PERINDOPRIL 459

A similar design was used for the three studies. After a one-month placebo run-in period, patients were randomly allocated to either perindopril (4 mg) or the reference antihypertensive drug (hydrochlorothiazide plus amiloride (50 mg + 5 mg, atenolol 50 mg, or captopril25 mg b.i.d.). Patients were treated for 3 months with the possibility of monthly titration. If diastolic blood pressure remained above 90 mmHg the initial dose could be doubled, and an additional drug could be prescribed if necessary: atenolol in the diuretic study, hydrochlorothiazide in the other two studies. The results of these studies are reported in Table 4. The reduction in supine blood pressure with perindopril or the reference drug was significant as early as the first month of treatment. After 3 months of treatment the efficiency of perindopril was similar to the other antihypertensive treat- ments. There was a similar percentage of patients treated by monotherapy in each group who achieved a diastolic blood pressure equal or less than 90 mmHg (“normalized patients,” Table 4). The majority of perindopril-treated patients received 4 mg, a dose of 8 mg increased control by 15%. In the atenolol and captopril trials, adding hydrochlorothiazide to perindopril increased the percentage of patients normalized by + 23% and + 26% respectively, leading to a significant difference between the two groups. On the contrary, the addition of atenolol to patients poorly controlled with perindopril had no significant effect.

The additive antihypertensive effect of the combination perindopril plus hydrochloro-

TABLE 4. Mean reduction in blood pressure after 3 months of treatment with perindopril in mild to moderate hypertension

~ ~ ~

Change in blood pressure ( d g )

Reference drug Perindopril

Reference drug Systolic Diastolic Systolic Diastolic

HCTZ-A -24.6 -18.1 -26.5 -19.1 n = 165 (5) Atenolol -20.6 -15.1 -26.5* -17.4 n = 173 (143)

n = 165 (91) Captopril -18.9 -11.7 -26.5* -18.1*

Percentage of normalized patients after 3 months of treatment with perindopril in mild to moderate hypertension

Monotherapy Mono- and Bitherapy

Reference Reference Reference drug Perindopril drug Perindopril

HCTZ-A 72 n = 165 (5) Atenolol 55 n = 173 (143) Captopril 49 n = 165 (91)

72 78 84

48 78* 58

49 75* 57

* p < 0.05 vs. reference drug. HCTZ-A, Hydrochlorothiazide + Amiloride. “normalized” = diastolic blood pressure d 90 d g .

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460 J . ATKINSON

thiazide was confirmed in a double-blind, placebo-controlled study (25). Forty mild to moderate hypertensive patients received either placebo, perindopril (4 mg), hydrochlorothiazide (25 mg), or combination of the two drugs. After 4 weeks of treatment, blood pressure was measured 24 h following the last drug intake. Perindopril and hydrochlorothiazide produced significant and similar reductions in systolic ( - 1 1 .O and - 11.3 mmHg, respectively) and diastolic ( - 7.4 and - 7.6 mmHg, respectively) blood pressures. The combination of perindopril and hydrochlorothiazide showed an additive effect on diastolic ( - 12.6 mmHg), and a synergistic effect on systolic ( - 24.5 mmHg), blood pressures.

In another study comparing perindopril with captopril, 108 hypertensive patients received similar doses following a design similar to the three pivotal studies described above (3). At the end of the study 67% of the patients in the perindopril group and 47% in the captopril group were normalized (p < 0.01). Absolute reductions in blood pressure were - 17.8/ - 14.0 mmHg in the perindopril group, and - 15.9/ - 13.5 mmHg in the captopril group. The percentage of patients who required the addition of a diuretic was significantly lower in the perindopril group (27% versus 41%, p < 0.05). A subgroup of the population (n = 38) underwent an echocardiography study. After 3 months of treatment, left ventricular mass index significantly decreased in both groups (p < 0.01) from 123.5 * 9.3 g/m2 to 106.2 5 7.4 g/m2 in the perindopril group, and from 117.5 * 6.0 g/m2 to 101.9 * 5.1 g/m2 in the captopril group. This reduction was linked to a decrease in septa1 and posterior wall thickness. No significant change was observed in shortening fraction or in systolic stress.

Forty patients with essential hypertension and left ventricular hypertrophy received either perindopril (4 mg) or nifedipine (20 mg b.i.d.) (137). Titration was possible by doubling doses and then adding hydrochlorothiazide in poorly controlled patients. After 24 weeks blood pressure decreased similarly in both groups and there was a parallel reduction of left ventricular hypertrophy (perindopril 148 to 127 g/m2, nifedipine 140 to 118 g/m2).

In summary, good blood pressure control can be easily achieved with perindopril. It appears unlikely, however, that there is any marked difference between perindopril and other ACEIs as far as their effects on blood pressure are concerned. Possible differences in their capacity to protect organs in spite of similar pressure profiles, should be further investigated.

ARTERIAL HEMODYNAMICS Six healthy volunteers were enrolled in a double-blind, latin-square design study, and

were given in a random order placebo and perindopril 4, 8, or 16 mg, as a single oral administration at weekly intervals (127). Despite a lack of blood pressure reduction or of change in heart rate, perindopril caused a dose-dependent increase in brachial and carotid artery diameter, and in blood flow measured by a pulsed-doppler system, with a decrease in forearm vascular resistance. Peak effects occurred 2-4 h after drug intake. Arterial vasodilation in the absence of any significant reduction in blood pressure suggests that perindopril increases arterial compliance.

Arterial compliance is significantly reduced in hypertensive patients ( 13 l) , possibly reflecting intrinsic abnormalities in the viscoelastic properties of the arterial wall. The acute effects of perindoprilat on brachial artery hemodynamics and aortic distensibility

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PERINDOPRIL 461

were compared with those of dihydralazine, in 21 mild to moderate hypertensive patients (15). Perindoprilat was administered intravenously at 1 or 2.5 kg/kg/min, and dihydralazine at 4 kg/kg/min. Brachial hemodynamics and aortic distensibility were assessed noninvasively (pulsed-doppler system and carotid-femoral pulse wave velocity). Identical falls in blood pressure were observed in the three groups. A significant increase (10%) in brachial artery diameter was observed with the higher dose of perindoprilat. Moreover a positive correlation between the decrease in blood pressure and the fall in pulse wave velocity was observed with dihydralazine, whereas no such correlation was found with perindoprilat. These results suggest that, unlike dihydralazine, perindopril acts on aortic distensibility through mechanisms independent of blood pressure.

The effect of perindopril on arterial stiffness was confirmed in 16 essential hypertensive patients treated with 2-8 mg of perindopril daily for 3 months (8). A significant decrease in blood pressure was achieved at the end of the study. Using a pulsed-doppler flowmeter it was shown that perindopril significantly increased brachial blood flow (63%), with an increase in blood flow velocity (35%) and arterial diameter (9%). During a 5-min period of wrist occlusion, blood flow velocity was reduced to a greater extent in the perindopril- treated group, whereas the reduction in arterial diameter was similar to that obtained with placebo. Thus, the increase in arterial diameter produced by perindopril could not entirely be explained by flow-dependent dilation, suggesting that drug-induced relaxation of arterial smooth muscle was involved. In addition, during active treatment, pulse wave velocity decreased ( - 13%) and arterial compliance increased (+43%). In another study (7), the beneficial effects of perindopril on arterial hemodynamics remained significant after 1 year of treatment. In this study, it was shown that perindopril treatment produced a reduction of left ventricular hypertrophy, thus confirming previous studies (see above and 60).

In summary, hemodynamic studies in humans point to an interesting effect of perindopril on large artery compliance. However, as many of the in vivo indices of arterial compliance are closely coupled to blood pressure, both acutely and chronically, it is difficult to ascertain whether perindopril has an additional, pressure-independent effect on arterial compliance, and whether it is unique in this respect. Finally, the importance of a drug-induced reduction in arterial stiffness as an independent variable in regression of phenomena such as cardiac hypertrophy following antihypertensive therapy is far from established and merits further investigation.

CONGESTIVE HEART FAILURE

In recent years ACEIs have emerged as an important class of therapeutical agents not only for hypertension but also for congestive heart failure. The principal drawback in the treatment of congestive heart failure by ACEIs is the fall in blood pressure in response to the first dose of the drug. Responses to the first low dose of 3 ACEIs (captopril, enalapril, and perindopril) were compared in 48 elderly patients with stable, chronic heart failure (98). All patients were symptomatic and received diuretic treatment which was withdrawn 48 h before the study. Four groups were given captopril 6.25 mg, enalapril 2.5 mg, perindopril 2 mg, or placebo. Captopril produced a significant early (1.5 h) brief fall in blood pressure. The blood pressure fall with enalapril was observed later (4-10 h), was longer lasting, and was associated with a significant slowing of supine heart rate. The


462 J . ATKINSON

blood pressure changes produced by perindopril were similar to those produced by placebo, though the degree of inhibition of plasma ACE was similar to that produced by enalapril. These differences may reflect different effects of the drugs on local tissue A11 generation.

The acute hemodynamic effects of perindopril with a single oral dose, 2 mg (6), or 4 mg (49,142), have been measured following right heart catheterization in different types of heart failure (NYHA class I1 to IV). The results are summarized in Table 5. Both preload and afterload were improved after administration of perindopril. Following the decrease in systemic vascular resistance, blood flow was increased to a greater extent in territories whose vascular resistance were the most augmented before therapy, i.e., the kidneys and the limbs (142). The maximal effect was obtained about 4 h after treatment (142) and was maintained for at least 24 h (49,142). These beneficial hemodynamic effects were maintained in patients who continued treatment for 1 year (49).

As stated previously, since the results of the CONSENSUS and SOLVD studies (35,139), ACEIs represent an excellent form of treatment for congestive heart failure, whatever its severity (NYHA class 11, 111 or IV), with an improvement in mortality. A double-blind, parallel group study compared perindopril to placebo after 3 months of treatment (22). One hundred and three patients entered this study after a 2-week prein- clusion period. All had chronic congestive heart failure (NYHA class I1 to 111) and were stable under diuretic plus digitalis treatment. Forty-six patients completed the 3-month study in each group. At inclusion, in spite of (or because of) randomization, the ratio NYHA IYIII was significantly different between the two groups (perindopril 22/28, placebo 37/16, p = 0.008) and the heart failure symptom score tended to be higher in the perindopril group than in the placebo group (5.5 vs. 4.3; p = 0.072). Perindopril was given at dose of 2 mg at inclusion, and then 4 mg if systolic blood pressure remained above 100 mmHg. At the end of the study, 40 patients received 4 mg, and 6 patients received 2 mg. After 3 months of perindopril treatment all indices of cardiac failure improved significantly. Results are summarized in the Table 6. NYHA class improved significantly with perindopril(63.3% success rate vs. 32.7%, p = 0.002). Tolerance was very good during this study and subgroup analysis of a long-term study indicated that good tolerance is to be found with elderly patients (57) and patients with impaired renal function (58).

In summary, perindopril, like other ACEIs, would appear to be a useful drug in the therapy of congestive heart failure. At the present time it is impossible to state whether the

TABLE 5 . Acute hemodynamic eflects of perindopril in patients with congestive heart failure (NYHA class 11 to IV)

% maximum change from baseline Dose

Ref. n (mg) MAP HR CI SVR PCWP RAP PAP

- 11* + 19* -32* -54* - - 26*

142 10 4 -13* -I* + 12* - 18* - 44* - 60* - 28*

6 14 2 -15* - + 16* -21* - - - - 49 14 4

MAP, mean arterial pressure; HR, heart rate; CI, cardiac index; SVR, systemic vascular resistance; PCWP,

* Statistically significant from baseline (JJ < 0.05). pulmonary capillary wedge pressure; RAP, right atrial pressure; PAP, pulmonary artery pressure.

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PENNDOPRIL 463

TABLE 6. Congestive heart failure: results of a 3-month study of perindopril versus placebo

Month 0 Month 1 Month 3

Parameter Per Placebo Per Placebo Per Placebo

Increase in exercise test duration 0 0 79* 65* 124*t 45*

HF score 5.6 4.3 3.0* 3.4* 2 S * t 3.5 Cardiothoracic

ratio 0.584 0.573 - - 0.554*t 0.566

HF score, heart failure system score (0-17). Per, perindopril treatment. * p C 0.05 versus baseline (intragroup analysis). t p < 0.05 versus placebo (intergroup analysis). Adapted from ref. 22.

apparent hemodynamic specificity of perindopril would confer any long-term advantage over other ACEIs.

ELDERLY PATIENTS

Two studies have been performed in elderly hypertensive patients (5 1). A double-blind, placebo-controlled study was performed in 34 patients with a mean age of 84 years. Systolic and diastolic blood pressures decreased significantly in the perindopril group by 10% and 9%, respectively, in the placebo group the reductions observed were 5% and 4%, respectively. The difference between the two groups was not significant because of the small number of patients. There was a significant increase in serum potassium but it remained within normal limits. Another open study was conducted in 91 patients with a mean age of 79.1 years. Results showed the excellent tolerability of perindopril, and, after 6 months of treatment blood pressure was controlled in 92.5% of the patients.

IMPAIRED RENAL FUNCTION

By a single oral dose perindopril(8 mg) increased the urinary excretion of sodium and chloride, and their renal clearances, 6 and 24 h after dosing, in 11 healthy volunteers (122). This increase in sodium excretion rate was confirmed in 8 hypertensive patients after administration of perindopril(8 mg daily for 5 days; 29). In this study there was no statistically significant change in renal blood flow or glomerular filtration rate, but there was a significant decrease in renal vascular resistance and filtration fraction. In summary, the little data available confirm the results previously obtained in animals on the renal effects of perindopril. It would be interesting to have more data, however, on the effect of chronic treatment with perindopril on the development of renal failure in hypertensive patients.

The efficacy of perindopril was assessed in 36 patients with hypertension associated with impaired renal function who entered a long-term period of treatment (44). The initial dose of perindopril was chosen on the basis of the degree of renal failure. Twenty-nine patients received 4 mg (mean creatinine clearance 47.2 f 3.2 ml/min) and seven received 2 mg (creatinine clearance 22.3 f 3.1 mllmin). These doses were eventually doubled,

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464 J . ATKINSON

then additional antihypertensive therapy was added according to the response to treatment. The mean duration of treatment was 10.2 months (3 to 12 months). Baseline and final creatinine (223.7 2 22.7 vs. 234.7 & 28.5 pmoV1) and creatinine clearance (42.5 k 3.2 vs. 45.7 2 4.6 ml/min) values were not statistically different. Proteinuria decreased significantly (1.88 f 0.56 versus 0.86 2 0.23 g/24 h, p < 0.01). Potassium levels remained stable during the study, and only minor complaints were recorded. Thus perindopril appeared safe and efficient in hypertensive patients with renal failure.

DIABETIC PATIENTS

Long-term acceptability of perindopril in 18 type I1 diabetic patients with hypertension was recently reported (77). Blood pressure reduction was obtained by the end of the first month of treatment and remained stable throughout the year of the study. Blood pressure was normalized in 83% of patients. Similar results were obtained in 39 hypertensive patients with insulin-treated diabetes mellitus, 29 being treated for at least 9 months (24) and 23 for 3 years (70). In these open studies the clinical tolerance was good and there was no change in glycemic control, renal function, or lipid metabolism. In the latter study, patients were divided into 3 groups according to their albumin excretion rate: 11 normoalbuminuric patients, 8 microalbuminuric patients (15 C albumin excretion rate < 150 mg/24 h), and 4 macroalbuminuric patients (albumin excretion rate > 150 mg/24 h). A reduction in microalbuminuria appeared after 1 month of perindopril treatment (20.5 k 7.6 to 12.4 * 7.4 mg/24 h) and persisted throughout the 3 years. This reduction reached statistical significance when normoalbuminuric and microalbuminuric groups were considered together. Macroalbuminuria remained stable in the third group for 3 years. This effect on microalbuminuria has been confirmed (99).

Hypertension and non-insulin dependent diabetes may be manifestations of the insulin- resistance syndrome with glucose intolerance, hyperinsulinemia, increased plasma triglycerides decreased plasma high-density lipoprotein cholesterol (HDLc), and hypertension. ACEIs are thought to be at least neutral on insulin sensitivity and lipid metabolism, contrary to thiazide or beta-blockers. A double-blind, placebo-controlled, cross-over study in 11 non-insulin dependent diabetic hypertensive patients was performed (1 1). After each period of 6 weeks, patients were examined under fasting conditions and were given an oral glucose tolerance test, and an intravenous insulin tolerance test. Insulin sensitivity was expressed as the rate constant for plasma glucose disappearance. Glycemic control (hemoglobin Alc), lipid parameters (total cholesterol, HDLc, triglycerides), oral glucose tolerance curves, and insulin sensitivity were similar in the perindopril-treated and placebo groups.

In summary, perindopril would appear to be safe in diabetic patients with hypertension.

SAFETY

A large multicenter study including 856 patients with mild to severe hypertension investigated the safety of perindopril treatment (40). Treatment started with a dose of 4 mg once daily and increased when necessary to 8 mg; hydrochlorothiazide and eventually a third drug could be added. Seven hundred and ten patients were treated for at least 1 year and 215 patients were treated for 3 years. After 1 year, supine and diastolic blood


PERINDOPRIL 465

TABLE 7 . Incidence of symptoms occurring in 1% or more of patients of a long-term open study on perindopril treatment

~

Withdrawal incidence Overall incidence

(n) ( n ) (%)

Cough Headache Asthenia Mood and/or sleep disturbance Dizziness Muscular cramps Dry mouth Sexual problems Cutaneous signs Tinnitus Nausea Orthostatic discomfort

19 3 1 2 4 1

3 4

3 3

-

-

2.2 0.4 0.1 0.3 0.5 0.1

0.4 0.5

0.4 0.4

-

-

60 48 44 44 27 27 16 15 15 11 9 9

7.0 5.6 5.1 5. I 3.2 3.2 1.9 1.8 1.6 1.3 1.1 1 . 1

Adapted from ref. 40.

pressures were reduced by 29/19 mmHg, and after 3 years by 31/21 mmHg (p < 0.001). After 1 and 3 years respectively, 55% and 56% of the patients were controlled by monotherapy, 19% and 25% by addition of a diuretic. Eight deaths occurred during the study but none was considered to be drug-related (myocardial infarctions, cerebral hem- orrhages). A total of 10 severe adverse events were reported which did not appear to be caused by perindopril treatment: 3 myocardial infarctions, 4 cases of angina pectoris, 3 strokes. The symptoms occurring in 1% or more of patients are reported in Table 7. The most frequent complaint was cough (7%) which lead to interruption of treatment in 2.2% of patients. Cough was predominantly nocturnal, irritative, laryngeal with occasional sore throat, and mainly reported by women. No clinically relevant changes were observed in hemoglobin, white cells and platelets, sodium, potassium, glucose, creatinine, uric acid, total cholesterol, or triglycerides.

In conclusion, while extravagant panacean claims should be avoided, it would appear that the ACE1 perindopril is a relatively safe cardiovascular drug, which, at least on the basis of experimental evidence, seems to afford a certain degree of protection of target organs.

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