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DRUG EVALUATION Drugs 1996 May; 51 (5): 820-845 0012 -6667/96/0005 0820/$26 00/0 © Adis International Limited, All rights reserved. Losartan Potassium A Review of its Pharmacology, Clinical Efficacy and Tolerability in the Management of Hypertension Karen L, Gon and Antona J. Wagstaff Adis International Limited, Auckland, New Zealand Various sections of the manuscript reviewed by: J. Chan, Department of Clinical Pharmacology, The Chinese University of Hong Kong, Hong Kong; NL. Gilchrist, Older Persons Health Division, The Princess Margaret Hospital, Christchurch, New Zealand; E, Grossman, Hypertension Unit, Chaim Sheba Medical Center, Tel-Hashomer, Israel; A. Himmelmarn, Department of Clinical Pharmacology, Sahlgrenska University Hospital, Goteborg, Sweden; S.E, Kjeldsen, Department of Internal Medicine, Ullevaal University Hospital, Oslo, Norway; Y. Lacourcière, Hypertension Research Unit, Centre Hospitalier de 1'Université Laval, Sante-Foy, Quebec, Canada; J. Lefebvre, Hypertension Research Unit, Centre Hospitalier de 1'Universite Laval, Sante-Foy, Québec, Canada; M. Nakashima, Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu City Japan; J.H. Pratt, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA; L. Ramsay, University Department of Medicine and Pharmacology Royal Hallamshire Hospital, Sheffield, England; JM. Ritter, Department of Clinical Pharmacology, Guy's Hospital, London, England; C.T. Stier Jr, Department of Pharmacology, New York Medical College, Valhalla, New York, USA; K. Sugimoto, Department of Clinical Pharmacology, Jichi Medical School, Tochigi, Japan; K. Yoshinaga, Tohuku Rosai Hospital, Sendai, Japan. Contents Summary .............. ... .................................................................................................................... 821 1. Role of the Renin-Angiotensin System (RAS) in Hypertension ........................................................... 824 2. Pharmacodynamic Properties ...................................................................................................... 826 2.1 inhibition of Angiotensin II (All) Activity .................................................................................... 826 2.1.1 Inhibition of Receptor Binding . ..................................................................................... 826 2.1.2 Functional Antagonism of All Activity ......................................................................... 826 2.2 Effects on the RAS ................. . . . .......................................................................................... 827 2.3 Haemodynamic and Cardiovascular Effects .......................................................................... 827 2.3.1 EFfects on Left Ventricular Hypertrophy ...................................................................... 828 2.3.2 Other Effects ............ . ................................................................................................... 828 2.4 Effects on Renal Haemodynamics and Function ....................................................................829 2.5 Effects on Bradykinin . ....................................................................................................... ..…829 2.6 Metabolic and Neuroendocrine Effects ................................................................................. 829 3. Pharmacokinetic Properties .................................................................... ....................................... 830 3.1 Absorption and Distribution .................................................................................................... 830 3.2 Metabolism and Elimination .................................................................................................... 830 3.3 Drug Interactions ..................................................................................................................... . 831 4. Clinical Efficacy of Losartan Potassium in Hypertension .................................................................. . 831 4.1 Losartan Potassium Monotherapy ........................................................................................... . 833 4.1.1 Dose-Finding Studies ..................................................................................................... . 833 4.1.2 Comparisons with Other Antihypertensive Drugs ..................................................... ..… 833 4.2 Losartan Potassium plus Hydrochlorothiazide ......................................................................... . 834 4.2.1 Noncomparative Studies .............................................................................................. . 834 Losartan Potassium: Use in Hypertension 821 4.2.2 Dose-Finding and Comparative Trials ............................................................................ 834 4.3 Special Patient Groups ............................................................................................................ 836 4.4 Long Term Efficacy ................................................................................................................ . 836 5. Tolerabllity Profile ............................................................................................... . .................... ....... 836 5.1 Losartan Potassium Monotherapy. ....................................................................................... .. 836 5.1.1 Compared with Other Antihypertensive Drugs ................. . ......................................... 838 5.2 Losartan Potassium Plus Hydrochlorothiazide ......................... ……………………………………839 6. Dosage and Administration ............................................................................................................. 839 7. Place of Losartan Potassium in the Management of Hypertension ............. ................................... 840 Summary Synopsis Losartan potassium is an orally active, nonpeptide angiotensin II (AII) receptor antagonist. It is the first of a new class of drugs to be introduced for clinical use in hypertension. This novel agent binds competitively and selectively to the AII subtype 1 (AT1) receptor, thereby blocking AII-induced physiological effects. An active metabolite, E3174, contributes substantially to its antihypertensive effect, which persists throughout 24 hours after once-daily administration. In patients with mild to moderate hypertension, losartan potassium 50 to 100mg once daily as monotherapy lowers blood pressure to a similar degree to enalapril, atenolol and felodipine extended release (ER). Losartan potassium combined with hydrochlorothiazide reduces blood pressure further than either drug given separately. About one-third of patients with severe hypertension have responded to the combination product. Losartan potassium appears to be effective in elderly patients. Losartan potassium is very well tolerated. In clinical trials, dizziness was the only drug-related event reported more frequently with losartan potassium monotherapy than with placebo. First-dose hypotension is uncommon. An aspect of the drug's tolerability profile which may prove to be particularly advantageous is that it is associated with a similar incidence of cough to placebo in patients with a history of ACE inhibitor-related cough. Additionally, clinically relevant adverse metabolic effects or laboratory abnormalities have not been documented during losartan potassium therapy and renal function is preserved in patients with or without renal insufficiency. The adverse effect profile of the losartan potassium-hydrochlorothiazide combination resembles those for losartan potassium monotherapy and. placebo. Long term tolerability data are limited (<2 years) but support the very good tolerebility profile in shorter studies. Elements of the drug's profile yet to be assessed or reported fully in the literature include long term efficacy, potential to favourably influence cardiovascular and renovascular systems (and ultimately mortality) in patients with hypertension and, lastly, cost effectiveness and influence on quality of life. In summary, losartan potassium is the first AT1 receptor antagonist to become available for the management of hypertension and, as such, it is an important new antihypertensive agent. Pending long term data as outlined above, it is likely to find initial use in patients with mild to severe hypertension who are unresponsive to, or intolerant of, their current therapy. However, with its novel mechanism of action, good efficacy and favourable tolerability profile, losartan potassium is well placed to claim a prominent position in the management of patients with essential hypertension in the future. © Adis International Limited. All rights reserved. Drugs 1996 May; 51 (5) Goa & Wagstaff 822 Pharmacodynamic Properties Pharmacokinetic Properties The action of angiotensin II (AII) at the AII subtype 1 receptor (AT1) is critical to cardiovascular homeostasis: physiological consequences pertinent to hypertension include vasoconstriction, sodium/fluid retention, increased sympathetic activity and cellular growth. Losartan potassium binds selectively, competitively and with high affinity to the AT1 receptor, thereby blocking the activity of AII. It has no clinically relevant affinity for any other pharmacological receptor at the concentrations tested. The active metabolite E3174 is a noncompelitive antagonist which binds to the AT1 receptor with 10-fold greater affinity than its parent compound. E3174 is about 15 to 20 times more potent in inhibiting All-induced pressor and contactile responses, as shown in vitro and in vivo. Neither losartan potassium nor E3174 possess any agonist activity at the AT1 receptor. In patients with hypertension, losartan potassium increases plasma renin act i vi t y and plasma AII levels and appears to decrease plasma levels of aldosterone, at least in the short term. Forearm vasodilator responses to bradykinin are not altered by losartan potassium. Blood pressure decreases produced by once-daily losartan potassium persist throughout 24 hours and heart rate is unchanged. Single doses of losartan potassium and captopril (both 50mg) yielded similar quantitative effects on blood pressure, although the onset was slower in the first 3 hours with losartan potassium. The influence of pretreatment plasma renin activity on the antihypertensive effect of losartan potassium has not been determined, and its influence on other haemodynamic or cardiac indices in patients with hypertension has not been well reported. Preliminary data obtained in a few patients and evidence from numerous animal studies suggest that losartan potassium causes regression of left ventricular hypertrophy (LVH); a large clinical study using losartan potassium is under way to determine whether any clinical benefits are associated with LVH regression. Losartan potassium improved mortality rates in animals prone to stroke and prevented librinoid necrosis of other end organs, including the heart, in various animal models. Renal function is preserved during losartan potassium administration in patients with hypertension with or without renal dysfunction. A uricosuric effect for losartan potassium demonstrable in healthy individuals has been observed in some but not all studies of patients with hypertension. Losartan potassium decreased proteinuria [including that associated with renal failure or with noninsulin-dependent diabetes mellitus (NIDDM)] in limited investigations. Plasma levels of lipids/lipoproteins and prostaglandins are unchanged during losartan potassium administration in patients without other concomitant diseases, as are plasma norepinephrine levels and insulin sensitivity in patients without NIDDM. The bioavailability of losartan potassium is about 33%, indicating a considerable first-pass effect, and is not altered significantly by the presence of food. In most patients about 14% of an oral dose of losartan potassium is metabolised via hepatic carboxylation to the active metabolite E3174. However, in a very small proportion of patients (< 1 %), enzymes responsible for metabolism to E3174 are deficient (< 1 % of a dose is converted). Time, to achieve peak plasma concentration is about 1 hour for losartan potassium and 3 to 4 hours for E3174. Blockade of pressor response correlates more closely with plasma concentrations of the metabolite than with those of the parent drug. The volume of distribution is about 34L for losartan potassium and 12L for E3174: both compounds are >98% bound © Adis International Limited. All rights reserved. Drugs 1996 May; 51 (5) Losartan Potassium: Use in Hypertension 823 to plasma proteins. The kinetics of losarlan potassium and E3174 are not influenced by multiple-dose administration. At about 4 hours (in Japanese) and 6 hours (in Western individuals), the terminal elimination half-life of E3174 is longer than that of losartan potassium (2 hours). The pharmacokinetic properties of losartan potassium and E3174 are not affected by renal dysfunction to any clinically important extent. In contrast, in patients with hepatic dysfunction, plasma drug concentration of both agents is increased and plasma clearance is reduced, necessitating dosage adjustment. Pharmacokinetic studies using cimetidine and ketoconazole suggest that clinically significant interactions with losartan potassium and cytochrome P450 (CYP) 34A inhibitors are unlikely to eventuate. However, drugs that induce CYP systems may hasten the metabolism of losartan potassium. No significant drug interactions occur between losartan potassium and warfarin, digoxin or hydrochlorothiazide. Clinical Efficacy Tolerability Losartan potassium is an effective treatment for hypertension. Large dose-finding trials have shown losartan potassium 50mg daily as monotherapy to be superior to placebo and indistinguishable from the l00mg dose. The drug has reduced diastolic blood pressure (DBP) by about 8 to 13mm Hg in patients with mild to moderate hypertension, as shown by several well-designed comparative trials lasting 8 to 12 weeks. Antihypertensive efficacy as determined by trough blood pressure values and percentage responders has not differed significantly between losartan potassium and enalapril, atenolol or felodipine extended release (ER) in comparative trials. Blood pressure lowering is evident within 1 week of initiating losartan potassium therapy and is maximal by 6 weeks. Approximately 30% of patients with severe hypertension have had their condition managed with losartan potassium plus hydrochlorothiazide 12.5 or 25mg during 12-week noncomparative trials, with another 22% maintained on losartan potassium monotherapy in 1 trial and the remainder requiring the addition of atenolol and/or a calcium channel blocker. Overall decreases in DBP for regimens containing losartan potassium were in the magnitude of 18mm Hg in this population. Compared with losartan potassium or hydrochlorothiazide monotherapy, losartan potassium plus hydrochlcrothiazide reduced DBP by an additional 4 to 6mm Hg. Polydrug regimens incorporating losartan potassium were as effective as similar strategies using enalapril. Elderly patients have responded as well to losartan potassium as to felodipine ER. Published evidence for the efficacy of losartan potassium in other special patient groups is scant, as are long term efficacy data. Results from double-blind trials involving a total of >2800 patients with hypertension who received losartan potassium indicate that the drug is very well tolerated. Although headache (14.1%), upper respiratory tract infections (6.5%), dizziness (4.1%), asthenia/fatigue (3.8%) and cough (3.1%) have been reported during administration of losartan potassium monotherapy, these are 'all events' regardless of causality. Dizziness was found to be the only drug-related event documented more often with losartan potassium than with placebo in the clinical trials database. Orthostatic effects and first-dose hypotension are uncommon (0.5% with 50mg). There have been rare reports of patients developing angioedema, migraine or ageusia during losartan potassium therapy. Cough, which can limit treatment with ACE inhibitors, is seldom experienced during losartan potassium therapy and its incidence is similar to that for placebo. Adis International Limited, All rights reserved. Drugs 1996 May; 51 (5) Goa & Wagstaff 824 Dosage and Administration Spontaneous reports of cough occurred at a frequency of 3,1% for losartan potassium vs 2.6% for placebo. In trials conducted specifically in patients with a history of ACE inhibitor-related cough, its incidence was similar for losartan potassium (17 to 29%), placebo (35%) and hydrochlorothiazide (25 to 34%) but was much less than with lisinopril (62 to 72%). Comparisons without a placebo control showed that oedema was more common with felodipine ER (14%) and dizziness (7.4%) and insomnia (4.4%) were more frequent with atenolol compared with losartan potassium. Liver enzyme levels have risen to a minor extent in a few losartan potassium-treated patients, but this rarely necessitates treatment withdrawal. The incidence of drug-related adverse events and drug withdrawal using losartan potassium plus hydrochlorothiazide resembled that for losartan potassium alone and for placebo in clinical trials. The recommended initial and maintenance dosage of losartan potassium as monotherapy in patients with essential hypertension is 50mg once daily. Some patients may benefit from 100 mg/day. Losartan potassium may be given with or without food. In patients at high risk of hypotension or volume depletion and those with hepatic dysfunction, the initial dose should be 25mg. No dosage adjustment is needed for the elderly or patients with renal impairment. Losartan potassium is not recommended for use in pregnant women because of the risk of fetal morbidity/mortality. Japanese patients may receive losartan potassium 25mg daily. The combination product containing losartan potassium and hydrochlorothiazide is started at a dosage of 50mg/12.5mg which can be doubled if the result is unsatisfactory. This therapy is not recommended for use as initial treatment when monotherapy would suffice, for patients with hepatic impairment or for those with creatinine clearance 1.8 L/h (30 ml/min). Losartan potassium (fig. 1) is an orally administered nonpeptide angiotensin II (AII) receptor antagonist. It is the first of a new class of antihypertensive drugs which act by directly blocking AII subtype 1 (AT1) receptors. This novel action is the basis for its application in patients with hypertension. An active metabolite, E3174, is largely responsible for the antihypertensive effect of the drug. Losartan potassium is the prototype nonpeptide AT1 receptor antagonist. As such, it has found considerable use as a pharmacological tool for investigation of the role of AII and its receptors in cardiovascular disorders. However, this review concentrates on its clinical use in patients with hypertension when given as monotherapy or in combination with hydrochlorothiazide. Preclinical and clinical evidence to date (reviewed by Smith et al. [1] ) indicates that losartan potassium is also © Adis International Limited, All rights reserved likely to be beneficial in patients with congestive heart failure (CHF), but as yet too few data exist to confirm its role in this indication. 1. Role of the Renin-Angiotensin System (RAS) in Hypertension The renin-angiotensin system (RAS) is central to blood pressure regulation, fluid volume homeostasis and electrolyte balance. Figure 2 depicts the major elements of the renin-angiotensin cascade: the following discussion provides a simplified overview of its physiological importance in cardiovascular disorders. Briefly, renin is synthesised by the kidney and secreted into the systemic circulation. Renin acts on the substrate angiotensinogen to produce angiotensin I (AI), a decapeptide. AI is conyerted by ACE and other enzymes such as chymases to the Drugs 1996 May; 51 (5) Losartan Potassium: Use in Hypertension 825 active hormone AII, which in turn is hydrolysed to angiotensin III, another active substance, and to other fragments including angiotensin IV. The heart, vasculature and kidney are important sites for the local production of AII AII is the primary mediator of the RAS. It binds to receptors located in virtually every tissue (see section 2.1.1). The principal actions of AII critical in maintaining normal blood pressure control are: • direct and intense vasoconstriction of the smooth muscle of the arterioles; • release of aldosterone (and cortisol) from the adrenal cortex; • a direct antinatriuretic effect on the kidney to increase proximal tubular reabsorption of so dium, resulting in sodium and fluid retention. Among other actions, AII may cause positive inotropic effects and influences left ventricular function. It also facilitates norepinephrine release, Physiological effects Fig. 2. Site of action of losartan potassium. Simplified schematic representation of the renin-angiotensin system and its interaction with bradykinin, highlighting site of action of losartan potassium and ACE inhibitors. Fig. 1. Structural formulae of losartan potassium and its active metabolite E3174. © Adis International Limited. All rights reserved and thus sympathetic activity, and induces cellular growth possibly implicated in left ventricular hypertrophy (LVH).[2, 4] The exact role of the RAS in hypertension is complex and incompletely understood, although it is established that small increases in plasma levels of AII elevate blood pressure.[3] Inhibition of AII has little effect on blood pressure in normotensive sodium-replete individuals, whereas in sodium-depleted individuals the RAS is activated and blood pressure drops markedly upon AII blockade. Compensatory rises in plasma renin occur in response to decreased plasma AII levels.[4] ACE inhibitors are unable to block the effects of AII produced locally by systems other than the RAS or to prevent formation of AII by enzymes Drugs 1996 May; 51 (5) Goa & Wagstaff 826 other than ACE, including endopeptidase and chymases.[5] The rationale for developing specific AII receptor inhibitors is, therefore, to antagonise the activity of this crucial effector hormone independently of its source. 2, Pharmacodynamic Properties 2.1 Inhibition of Angiotensin II (All) Activity 2.1.1 Inhibition of Receptor Binding Two distinct types of AII receptor, subtype 1 (AT1) and subtype 2 (AT2), were first identified in rats[6,7] and are now known to exist in humans.[8,9] Further receptor subtypes (AT1A and AT 1B) have been discovered in rodent, but not in human, tissue.[10,11] AT1 receptors are located primarily in vascular and cardiac tissue but also in the brain, kidney and adrenal gland, notably in the aldosterone-secreting tissue of the zona glomerulosa. The function of the AT2 receptor, which is present in brain, kidney and adrenal medullary tissue, is poorly delineated. This receptor is not thought to contribute to cardiovascular haemostasis,[2, 4,12] although a role has recently been proposed in renal haemodynamics[13] and in smooth muscle cell proliferation.[ 1 4 ] The part played by AT1 receptors in mediating the complex effects of AII (including those briefly outlined in section 1), and thus in the pathogenesis of various cardiovascular disorders, is comprehensively reviewed elsewhere.[2,12,15] Losartan potassium is highly and specifically bound to AT1 receptors. It is 10 000 times more selective for the AT1 than the AT2 receptor.[16] In rats, losartan potassium l0mg/kg/day significantly (p < 0.05) reduced the density of AT receptors from baseline in the liver, kidney and adrenal cortex, sites of the AT1 receptor, but not in the adrenal medulla, where AT2 receptors predominate.[17] The drug inhibits the specific binding of [125I]AII to the AT 1 receptor site in a monophasic, concentrationdependent fashion, yielding an IC50 (concentration inhibiting 50% of binding) of 1 to 2 x 10-8 mol/L in isolated rat adrenal cortical microsomes and aortic smooth muscle cells.[18,19] This contrasts with © Adis International Limited. All rights reserved, the IC50 of 10-4 mol/L estimated for losartan potassium at the AT2 receptor site.[16] E3174 has 10-fold greater affinity than the parent drug for AT1 receptors, as shown by an ICso value of 1.1 x 10-9 mol/L in rat aortic smooth muscle cells. [19] In concentrations of up to 10-5 mol/L losartan potassium has no affinity for any other receptor types in rat tissue, e.g. -adrenoceptors in rat brain and Ca++ receptors in rat cardiac ventricle, or for other receptors (e.g. neurotensin, glycine, opioid, muscarinic, dopaminergic, serotoninergic) in various isolated tissue preparations.[18,20,21] 2.1.2 Functional Antagonism of All Activity Functional antagonism of AII activity, reflecting AT 1 blockade, has been demonstrated for losartan potassium in vitro, in vivo and in healthy volunteers. In Vitro and In Vivo Binding of losartan potassium to the AT1 receptor is saturable, reversible, and competitive.[22] In concentrations of 10-8 to 10-7 mol/L losartan potassium caused parallel shifts to the right of the concentration-contractile response or pressor response curve to AII The drug competitively blocked AII-induced contraction of rabbit aorta [percentage of maximal AII response (pA2) = 8.48],[18] guinea-pig ileum and rat uterus (pA2 = 8.5 for both)[23] and All-induced pressor response in conscious[24] or spinally pithed[25] rats. In none of these test systems did the drug display any AII agonist effects in the concentrations tested (up to 10-5 mol/L),[18,23,25] and it had no effects on the enzymes of the RAS.[18] E3174 is also devoid of agonist activity, as shown in similar experiments.[26] However, in contrast to losartan potassium, the metabolite is a noncompetitive antagonist, causing nonparallel shifts to the right of the concentration-contractile response curve and displaying a pA2 value of 10.09 in isolated rabbit aorta.[26] E3174 is estimated to be approximately 15 to 20 times more potent than losartan potassium. This is based on ED30 values (intravenous dose required to decrease mean arterial pressure by 30mm Hg) of 0.04 mg/kg for E3174[26] vs 0.78 mg/kg for losartan potassium[27] Drugs 1996 May; 51 (5) Losartan Potassium: Use in Hypertension 827 Table I. Effects of losartan potassium on the renin-angiotensin system. Mean changes in plasma hormones of the renin-angiotensin system in patients with hypertension 4 hours after the first dose and after 6 weeks' daily administration of losartan potassium 100mg (n = 13) or enalapril 20mg (n = 12)[36] First dose Mean plasma renin activitya losartan enalapril Week 6 1 .54 1.89 1.73 2.75* 2.03* 0.28* 2.45 0.23* Mean plasma angiotensin II levela losartan enalapril Mean plasma aldosterone levelb losartan enalapril . -3.6* -4.5* -7.6* -4.6* a Ratio of change compared with baseline value. b Mean change from baseline (ng/dl). Symbol: * p < 0.05 vs placebo (placebo values not shown). in renal hypertensive rats and on IC50 values for inhibition of AII-induced cell growth and increase in intracellular Ca++ levels in vitro.[19] In Healthy Volunteers In single oral doses of 20 and l00mg[28,29] losartan potassium blocked the vasoconstrictor response to exogenous AI and AII in healthy individuals, as measured by forearm blood flow[28] and change in dorsal hand vein diameter.[29] In contrast, enalapril l0mg was effective only against AI.[28,29] Similarly, the pressor response to exogenous AI and AII was inhibited by up to 95% in a doserelated fashion by single and multiple oral doses of losartan potassium 10 to 120mg.[30,31] With doses 40mg and higher this effect persisted for at least 24 hours.[31] 2.2 Effects on the RAS Effects of losartan potassium on the RAS are consistent with inhibition of AII activity (section 1). In healthy volunteers, losartan potassium 100mg in single[30,32,33] or multiple[30,34,35] doses increased plasma renin activity[30,32-35] and plasma AII levels[30,32,34] but produced inconsistent effects on plasma aldosterone levels, compared with placebo.[30,32,34,35] © Adis International Limited. All rights reserved. These close-dependent effects are also apparent during several weeks' therapy with losartan potassium in patients with essential hypertension (table I),[36] with the exception that plasma aldosterone levels appear to decrease, at least temporarily, during prolonged therapy. Plasma aldosterone levels fell by 74% after 6 weeks' therapy with the 100 mg/day dosage[36] and by 17%[37] and 47%[38] after a month with losartan potassium 50 mg/day. Increases in plasma renin activity and plasma AII levels peaked at about 2 weeks and declined thereafter in 1 study,[36] whereas plasma renin activity remained elevated at the end of 4 weeks' therapy in patients with low baseline values.[38] Plasma renin activity continued to rise over 12 months while plasma aldosterone levels returned to normal in another trial in which some patients also received diuretics.[37] There was no significant change in the proportion of active or inactive plasma renin glycoforms following 6 weeks of losartan potassium therapy.[39] Whether pretreatment plasma renin activity is related to the antihypertensive effect of losartan potassium is unknown. In hypertensive patients, Goldberg et al.[36] found these changes in RAS parameters to be smaller than those previously observed in healthy volunteers, who have more responsive negative feedback systems which are better able to inhibit renin release. Decreases in mean arterial pressure have been correlated with baseline levels of, and changes in, plasma renin activity in a small study in patients with hypertension.[37] Animal models showed that losartan potassium did not decrease blood pressure in low renin models of hypertension such as deoxycorticosterone acetate salt-hypertensive rats[27] and the bilateral nephrectomised rat.[40] 2.3 Haemodynamic and Cardiovascular Effects Losartan potassium reduces systolic and diastolic blood pressure (SBP; DBP) in patients with essential hypertension (section 4). Placebo-adjusted trough to peak ratios in patients with hypertension were calculated as 60% for the 50mg dose, 72% for Drugs 1996 May; 51 (5) Goa & Wagstaff 828 the l00mg dose[41] and 62 lo 85% for losartan potassium 50mg plus hydrochiorothiazide 6,25 or 12.5mg.[42] A ratio of 50% is considered indicative of a duration of activity permitting once-daily dosages, although the validity of this index has been questioned.[43] This aside, the effects of losartan potassium on blood pressure have been shown to extend throughout a 24-hour period[44,45] (see also section 4). 24hour ambulatory blood pressure monitoring in 14 patients given iosartsn potassium 50 to 100mg for 12 weeks demonstrated mean DB'P decreases of 8mm Hg during the day (0700 to 1900) and 6.8mm Hg at night (1900 to 0700).[45] Heart rate did not change substantially in healthy individuals[34,35] or in patients with hypertension (section 5). The blood pressure-lowering effects of single doses of losartan potassium 50mg and captopril 50mg were similar in sodium-depleted normotensive male volunteers and were additive when the drugs were combined.[33] In hypertensive patients receiving thiazides, the onset of action for a single dose of losartan potassium 50mg was slower in the first 3 hours than for captoprif 25mg. The magnitude of the effect on DBF was smaller with losartan potassium but not significantly so.[46] The influence of losartan potassium on other haemodynamic parameters in patients with essential hypertension is not fully reported in the literature. Cardiac output, left ventricular ejection fraction and circulatory blood volume remained unchanged and peripheral vascular resistance decreased in 10 Japanese patients treated with losartan potassium 50 to l00mg for up to 10 weeks.[47] In spontaneously hypertensive rats with pressure overload left ventricular dysfunction, long term (12 weeks') administration of oral losartan potassium 30 mg/kg/day decreased systemic arterial resistance, mean aortic pressure, myocardial contractility and left ventricular end diastolic pressure, and increased stroke volume and volumetric aortic flow, compared with placebo.[48] Losartan potassium enhanced the elasticity of a medium-sized artery in 20 patients with essential hypertension. Compliance of the radial artery, but © Adis International Limited. All rights reserved, not of the common carotid or femoral artery, increased by 50% after therapy with losartan potassium 50mg daily for 4 weeks (p = 0.02 vs placebo).[49] 2.3.1 Effects on Left Ventricular Hypertrophy In patients with hypertension, development of LVH amplifies the risk of end-organ damage and associated morbidity (e.g. myocardial infarction, stroke and heart or renal failure). Preliminary data suggest losartan potassium administration is associated with regression of LVH, Losartan potassium 50 to l00mg administered daily to 15 patients for 12 weeks of a 16-week study reduced left ventricular mass (LVM) from 196 to 191.5g and produced small decreases (0.2mm) in interventricular septal thickness and posterior wall thickness. In contrast, atenolol in the same dosage increased LVM, although not significantly, and other parameters were virtually unchanged.[50] The vast majority of studies using animal models,[51-59] including those for low renin (renal aortic coarction)[60] and high renin (2-kidney 1-clip renal hypertensive rats) hypertension,[61-63] have demonstrated either a preventative or a regressive effect of losartan potassium against cardiac hypertrophy when the drug was administered in dosages of 0.5 to 40 mg/kg/day for 2 to 16 weeks. 2.3.2 Other Effects Losartan potassium has improved survival and prevented the development of cerebrovascular infarcts and cardiovascular and renovascular fibrinoid lesions in stroke-prone spontaneously hypertensive rats[64-66] and salt-loaded Dahl S rats.[67] The drug was administered orally or by gavage in dosages of 1 to 30 mg/kg/day for 8 to 20 weeks. The effect was evident during losartan potassium administration and persisted for 8 weeks after drug discontinuation.[64] Losartan potassium (10 mg/kg/ day) reduced the collagen fibre content and thus myocardial fibrosis in the 2-kidney, 1-clip hypertensive model.[63] In other studies in rats, the drug inhibited the incorporation of human low density lipoprotein (LDL) into the hearts of normotensive animals[68] Drugs 1996 May; 51 (5) Losartan Potassium: Use in Hypertension and decreased ADP-induced platelet aggregation and thrombus weight.[69] 2.4 Effects on Renal Haemodynamics and Function Renal function is preserved during losartan potassium administration. Glomerular filtration rate, renal blood flow, urine volume or other renal parameters were unchanged in healthy volunteers following a single l00mg dose[32] and in patients with hypertension given losartan potassium 50mg daily for periods of 7 days to 1 year.[47,70-73] In patients with renal insufficiency, creatinine clearance was unaffected during losartan potassium therapy for 1[75] to 12 weeks.[138] Excretion of urinary electrolytes (including sodium and potassium) in healthy individuals on a low-salt diet was either increased[32] or unaltered.[35] Hyperkalaemia has been reported infrequently in clinical trials (section 5). Uricosuria demonstrated in normal, [74] saltloaded[32] and salt-depleted[32] volunteers who received single[32,74] or multiple[74] doses of losartan potassium 100mg was also observed in some[38,70] but not other[37,71] trials in patients with hyperten- sion. The mechanism of this effect is unknown. An albumin-sparing effect (lowering of proteinuria) in otherwise healthy patients with hypertension [72] has also occurred in the presence of renal dysfunction[75,76] (including nondiabetic patients with proteinuria >2 g/day)[76] and in elderly patients with or without non-insulin-dependent diabetes mellitus (NIDDM) [73] receiving losartan potassium. 2.5 Effects on Bradykinin Degradation of the potent vasodilator bradykinin, and of substance P, is prevented by ACE inhibitors. The subsequent accumulation of bradykinin may contribute to the mechanism of their antihypertensive action. Because losartan potassium does not inhibit ACE (fig. 2), it would not be expected to produce elevated levels of bradykinin which are also implicated in ACE inhibitor-induced cough (section 5). © Adis International Limited. All rights reserved. 829 This expectation is borne out by evidence to date. Losartan potassium in single oral doses of 20 and 100mg did not affect forearm vasodilation induced by exogenous bradykinin infusion in healthy volunteers, in contrast to enalapril l0mg. which potentiated this effect.[28] Eight-day administration of losartan potassium 10 mg/kg every 12 hours intraperitoneally to. rats decreased blood levels of bradykinin-(l-8) and renal levels of bradykinin(1-9) and bradykinin-(l-7),[77] suggesting that increased bradykinin levels are not contributory to the drug's hypotensive action. 2.6 Metabolic and Neuroendocrine Effects Serum levels of lipids or lipoproteins [total cholesterol, high density lipoprotein (HDL) cholesterol and triglycerides] have remained unchanged during losartan potassium treatment for 4 weeks in patients with mild hypertension but without NIDDM.[78] In contrast, in a small sample of 8 patients, including 4 with NIDDM, serum cholesterol levels dropped by 18% and LDL cholesterol levels fell by 28%.[79] Serum total cholesterol levels were also reduced by 8.8% among 11 patients with nephrotic syndrome who received losartan potassium 50 to 100mg daily for 1 month.[80] The results of a small pilot study (n = 5) showed improved insulin sensitivity and a 40% decrease in plasma norepinephrine levels during treatment with losartan potassium (50 mg/day for 6 weeks) in patients with severe hypertension. [81] These findings were not corroborated in larger placebocontrolled[36,78] or placebo run-in[37] trials which found no significant change in insulin sensitivity in patients with mild hypertension who were not diabetic,[78] nor any reduction in plasma norepinephrine levels in patients with mild to moderate hypertension.[36,37] The possible influence of disease severity, prior therapy or duration of therapy on these results is unknown. In vitro, losartan potassium 100 nmol/L stimulated prostaglandin (PG) I2 release in human saphenous vein during exposure to AII.[82] However, losartan potassium 50mg daily for 4 weeks did not Drugs 1996 May; 51 (5) 830 Goa & Wagstaff Table II. Pharmacokinetics of losartan potassium. Mean pharmacokinetic parameters of losartan potassium and its active metabolite E3174 after administration of a single 50mg dose of losartan potassium to healthy Western [86] or Japanese[87] volunteers Parameter Losartan potassium E3174 Western[86] Japanese[87] Western[86] Japanese[87] 0.19 0.25 0.46 0.29 Cmax (g/L) 1.3 4.1 3.0 tmax (h) 1.0 0.48 0.35 1.9 2.65 AUCo (g/L • h) 2.1 1.7 6.4 3.75 t1/2 (h) 4.2 3.2 6.1 6.9 Ae (% of dose) CLR(L/h) 4.3 5.6 1.6 1.5 Abbreviations: Ae =fraction excreted in urine; AUG, = area under the plasma concentration-time curve from 0 to infinity; CLR = renal clearance; Cmaxmaximurn plasma concentration; tmax = time to Cmax; t1/2 = terminal elimination half-life. alter renal or extrarenal PG synthesis in postmenopausal women with hypertension.[38] Lastly, losartan potassium 50 mg/day for 9 days did not affect adrenal function, as measured by adrenal steroid biosynthesis, in patients with hypertension.[83] 3. Pharmacokinetic Properties Hepatic oxidation of losartan potassium yields the pharmacologically active carboxylic acid metabolite E3174. [26, 84] The pharmacokinetics of both Iosartan potassium and E3174 have been determined in healthy volunteers and in patients with renal impairment, using high performance liquid chromatography assay methods.[85] The major results in healthy Western[86] and Japanese[87] volunteers are summarised in table II. The manufacturer's prescribing information is cited in the text where other sources are lacking. 3.1 Absorption and Distribution Oral bioavailability of Losartan potassium is approximately 33%[86] because of first-pass metabolism and is largely unaffected by food.[88] Peak plasma concentrations (Cmax) of a single close of losartan potassium are dose-proportional within the range 25 to 200mg.[87] Time to achieve Cmax is about 1 hour for Losartan potassium and 3 to 4 hours for E3174 (table II). The area under the plasma concentration-time curve (AUC) for 113174 is about 4-fold[86] to 8-fold[87] greater than for losartan potassium. Multiple-dose (up to 6 weeks) ad© Adis International Limited. All rights reserved. ministration does not significantly alter the pharmacokinetics of losartan potassium or E3174.[36,87] Losartan potassium was undetectable in plasma at 10 hours post-dose whereas E3174 was measurable at 24 hours.[87] Plasma concentrations of E3174 in healthy volunteers correlated more closely with blockade of the pressor response than did those of the parent compound.[3 1 ] Inhibition of All-induced pressor effects was dose-dependent within the range 40 to 120mg and reached a plateau at E3174 concentrations of about 200 g/L.[3l] Both compounds are >98% plasma protein bound (98.7% for losartan potassium vs 99.8% for E3174).[89] The volume of distribution is 34L for losartan potassium[86] and 12L for the metabolite.[88] In rats, losartan potassium crossed the blood-brain barrier after a single intravenous dose (3 mg/kg)|[90] but, of more clinical importance, not after single (10 mg/kg)[91] or multiple (3 mg/kg for 3 days)[92] oral doses. Following a single oral dose, tissue losartan potassium concentrations in the rat were highest in liver and the intestine but were un-detectable in muscle or fat.[9] The drug did not cross the placenta in sheep,[93] but this model may not be applicable to humans. Because of the risk of fetal abnormalities losartan potassium is not recommended in pregnancy (section 6). 3.2 Metabolism and Elimination Tests in rats demonstrate a significant first-pass effect for losartan potassium and indicate that E3174 is formed during uptake from the intestinal luDrugs 1996 May; 51 (5) Losartan Potassium: Use in Hypertension men.[91] About 14% of a dose (8% presystemic, 6% systemic) is converted to this metabolite in most individuals,[86] and several inactive metabolites are also produced.[88] In a very small proportion of patients (< 1 %), enzymes necessary for metabolism to E3174 are deficient (section 3.3). The terminal elimination half-life (t1/2) is longer for E3174 (about 4 hours in Japanese and 6 hours in Western individuals) than for losartan potassium (about 2 hours) [table II]. Renal clearance is 4.3[86] to 5.6[87] L/h for losartan potassium 50mg and about 1.5 L/h for its metabolite.[86,87] About 35% of a radiolabelled oral dose is recovered in the urine and 65% in the faeces.[88] Less than 5% of a losartan potassium dose is excreted unchanged renally in patients with normal renal function.[94] Clinically relevant effects of renal impairment on the pharmacokinetics of losartan potassium would therefore be expected to be minimal. This has been confirmed in patients with varying degrees of renal insufficiency given losartan potassium l00mg daily for 7 days. Renal clearance of losartan potassium and E3174 decreased significantly in the group with the greatest degree of renal dysfunction; however, AUC did not change. Furthermore, decreases in the percentage of losartan potassium excreted in the urine over 24 hours at steady state in patients with creatinine clearance <1.8 L/h (30 ml/min) and increases in t1/2(from 2.1 to 3.2 hours for losartan potassium and from 10 to 13 hours for the metabolite) were not considered to be important.[94] On the other hand, in patients with mild, to moderate alcoholic cirrhosis plasma concentrations of losartan potassium and E3174 increased 5-fold and 1.7-fold, respectively, oral bioavailability was doubled and total plasma clearance was halved.[88] Dosage adjustment is therefore required in this population (section 6). 3.3 Drug Interactions The major oxidative enzyme pathway responsible for the biotransformation of losartan potassium is the cytochrome P450 (CYP) system, predominantly CYP2C9[95] although CYP3A(4) has also © Adis International Limited. All rights reserved. 831 been shown to catalyse the reaction in vitro.[95, 96] Studies in healthy volunteers showed that pretreatment with cimetidine increased AUC values for losartan potassium (by about 20%) but did not affect the AUC for E3174 or Cmax for either compound.[97] Likewise, ketoconazole had no influence on the systemic conversion of losartan potassium to E3 1 74 or on their plasma clearance.[98] This suggests that significant drug interactions with other CYP34A inhibitors are unlikely. Conversely, the CYP inducer phenobarbital (phenobarbitone) modestly but significantly reduced the AUC for both losartan potassium and E3174.[99] The magnitude of change in this study was too small to be clinically relevant, but it was proposed that a more potent inducer might cause a significant interaction. [99] Conversion of losartan potassium to E3174 was markedly deficient in <1% of participants in clinical trials. Two individuals with this rare defect who converted <1 % of the parent drug to the metabolite (compared with 14% in the general population, section 3.2) were found to be homozygous for a mutation in CYP2C9.[100] Other work indicates that multiple phenotypic expressions exist for the defect in cytochrome enzymes.[101] In healthy volunteers, losartan potassium did not alter the pharmacokinetics of single-dose warfarin[102] or intravenous or oral digoxin.[103] Hydrochlorothiazide had no effect on losartan potassium pharmacokinetics and vice versa [104] 4. Clinical Efficacy of Losartan Potassium in Hypertension Losartan potassium has been investigated both as monotherapy and in combination with hydrochlorothiazide in randomised double-blind multicentre clinical trials, usually of 8 to 12 weeks' duration, involving a total of approximately 3700 patients. All comparative investigations included a placebo washout or active control run-in period and a placebo or active control during the main body of the study. The drug was administered orally and, almost invariably, once daily. Drugs 1996 May; 51 (5) Goa & Wagstaff 832 Table III. Efficacy of losartan potassium (L) in dose-finding studies and comparisons with other antihypertensive drugs in patients with mild to moderate hypertension; all trials were randomised, double-blind and multicentre in design a Defined as trough DBF <90mm Hg or DBP 90mm Hg but a decrease of 10mm Hg at study end. b 24h ambulatory measurements. c Abstract. Patients were hospitalised. d For per protocol analysis (blood pressure measured at trough). Abbreviations and symbols: ATE = atenolol; bid = twice daily; C = captopril; DBP = diastolic blood pressure; E = enalapril; FELER = felodipine extended release; SBP = systolic blood pressure; wk = weeks; y = years; = decrease; * p < 0.05, ** p < 0.01 vs placebo;†p < 0.05, †† p < 0,01 vs active comparator; > indicates superior efficacy for L or E based on statistical differences for UBP and percentage responders where available, p 0.05; ≡ indicates equivalent efficacy. Participants were diagnosed with mild, mode-ate or severe disease; the proportion of patients in each category was not described in some trials. With one exception,[105] all studies were conducted © Adis International Limited. All rights reserved. in outpatients. The primary efficacy measure was mean absolute change from baseline in trough supine or sitting DBP and SBP. The percentage of patients rated as 'responders' (trough DBP<90mm Drugs 1996 May; 51 (5) Losartan Potassium: Use in Hypertension Hg or DBF 90mm Hg but reduced by 10mm Hg) has been assessed in some instances. 4.1 Losartan Potassium Monotherapy 4. 1. 1 Dose-Finding Studies Nelson et al.[105] first reported the efficacy of losartan potassium in dosages 50mg daily in hospitalised patients. Subsequently, losartan potassium in the 50 mg/day dosage has proved to be efficacious and superior to placebo in large placebo-controlled dose-finding trials in outpatients (table III). Benefits of the 100mg daily dosage were similar to those of 50 mg/day.[41,44] This latter regimen has been adopted as the usual starting and maintenance dosage in patients with mild to moderate hypertension (see section 6). Significantly more losartan potassium recipients (41 to 54%) than placebo recipients (10%) were classified as responders at the end of 4 weeks' therapy in 1 trial.[44] Although some patients with severe hypertension have been maintained with losartan potassium monotherapy after 12 weeks[110] most require addition of a diuretic with or without other antihypertensivc agents (section 4.2). 833 Percentage responders did not differ significantly between the losartan potassium group (69%) or the felodipine group (76%)[109] or an atenolol group (50 vs 65%).[108] The latter 2 drugs were similarly effective when patients were stratified according to disease severity (fig. 3). There has been one comparison with captopril which was given in a once-daily regimen.[107] Losartan potassium produced a significantly larger decrease in DBP but not SBP at weeks 6 and 12. At week 12, the percentage of responders for losartan potassium (50%) was nearly twice that for captopril (29%) [table III]. These results are, however, unconvincing given that the dosage regimens used are not considered therapeutically equivalent: indeed, 82% of captopril recipients (vs 60% with losartan potassium, p = 0.001) required titration to a higher dose. A comparison is ongoing of losartan potassium once daily versus captopril administered in the more usual regimen of twice daily. Although losartan potassium appeared to be less effective than enalapril according to an 'all patients treated' analysis in a large trial of nearly 400 patients,[106] measurement of trough blood 4.1.2 Comparisons with Other Antihypertensive Drugs Losartan potassium reduces trough blood pressure in patients with mild to moderate hypertension to a similar extent to the standard antihypertensive agents with which it has been compared [enalapril, atenolol, felodipine extended release (ER)] (table III). Supine or sitting DBP fell by a mean of about 8 to 13mm Hg during 8 to 12 weeks' treatment with Josartan potassium 50 to l00mg daily, compared with 10 to 14mm Hg for the other drugs (table III). The largest mean decrease in DBP by losartan potassium (13.2mm Hg) occurred in a study of 132 elderly patients: felodipine ER caused a reduction of 14mm Hg.[109] A significant difference in DBP favouring felodipine at week 6 disappeared at week 12. Dosage titration was needed at week 6 in 62% of losartan potassium recipients and 51% of patients given felodipine ER. © Adis International Limited. All rights reserved. Fig. 3. Clinical efficacy of losartan potassium vs atenolol. Mean reduction from baseline in diastolic blood pressure at week 6 and week 12 in patients with mild or moderate hypertension given losartan potassium 50mg (n = 132 in total) or atenolol 50mg (n = 66 in total) once daily for 12 weeks.[108] Drugs 1996 May; 51 (5) Goa & Wagstaff 834 Table IV. Noncomparative trials of losartan potassium (L) plus hydrochlorothiazide (HCT) in patients with severe hypertension (DBP 115rnm Hg) Reference Dunlay et al.[110] Velivis et al.[111]a Dosage (once daily) [mg] L 50-100 ± HCT 1 2.5-25 ± ATE, CCB L/HCTb 50-100/12.5-25 ± FEL5-10, ATE 50-100 No. of evaluable patients Mean decrease in trough sitting SBP/DBP (mm Hg) 179 131 26*/19* NR/18 a Abstract. b Fixed combination tablet. Abbreviations and symbol: ATE = atenolol; CCB = calcium channel blocker; DBP = diastolic blood pressure; FEL = felodipine; NR = not reported; SBP = systolic blood pressure; * p < 0.001 vs baseline. pressure values using a per protocol analysis showed no differences in blood pressure reductions or percentage responders between the 2 drugs (table III). The antihypertensive effect of losartan potassium, like that of enalapril, is evident within 1 week of starting treatment. In a large comparison in 526 patients,[41] clinically relevant reductions were manifest within 1 to 2 weeks of starting therapy with losartan potassium 50 to 150mg daily or enalapril 20mg daily and were maximal at 3 to 6 weeks after treatment initiation. Similarly, Dahlöf et al.[l08] found that antihypertensive efficacy reached a plateau at 6 weeks, with no further reduction discernable at 12 weeks. 4.2 Losartan Potassium plus Hydrochlorothiazide 4.2.1 Noncomparative Studies Table IV summarises noncomparative trials of losartan potassium plus hydrochlorothiazide in patients with severe hypertension. This approach has provided a satisfactory response in about one-third of patients. Among 179 participants in the Losartan Severe Hypertension Study[11O] who began therapy with losartan potassium 50mg, 22% continued with losartan potassium monotherapy at week 12, 30% received losartan potassium plus hydrochlorothiazide 12.5 to 25 mg/day and 46% received this last regimen plus a dihydropyridine calcium channel blocker or atenolol or both. The remaining. 2% were prescribed regimens outside the protocol. The overall decrease in blood pressure of 26/19mm Hg for all patients in this trial[110] resem© Adis International Limited. All rights reserved. bled the reduction of 18.4mm Hg in DBP documented in a similar 12-week study[111] of 131 patients (31% Black). This latter result was obtained using a regimen containing a tablet specifically formulated to contain losartan potassium 50mg/hydrochlorothiazide 12.5mg, with provision for the doubling of dose plus addition of felodipine and/or atenolol. Approximately one-third of patients (data from graph) were controlled with the combination tablets only, but most also received felodipine.[111] 4.2.2 Dose-Finding and Comparative Trials Weber et al.[44] found that the addition of hydrochorothiazide 12.5mg daily for 2 weeks in patients unresponsive to losartan potassium lowered DBP by a further 6.1 to 7.8mm Hg, similar to the decrease of 6.4mm Hg in the placebo plus hydrochlorothiazide group. Adding hydrochlorothiazide in doses 12.5mg to losartan potassium 50mg reduces DBP by an additional 4 to 6mm Hg versus monotherapy with losartan potassium 50mg[112,113] or with hydrochlorothiazide 12.5mg[1l3] or 25mg[114] (table V). For example, DBP was decreased by 13.2mm Hg with losartan potassium 50mg plus hydrochlorothiazide 12.5mg versus 8,8mm Hg with losartan potassium and 7.2mm Hg with hydrochlorothiazide.[113] Efficacy for the combination, as for losartan potassium monotherapy (section 4.1.2), was seen after 1 week and reached a maximum at 3 to 6 weeks.[114] The percentage of patients responding in this trial was greatest for losartan potassium plus hydrochlorothiazide 12.5mg (78%), similar for losartan potassium plus hydrochlorothiazide 6.25mg (60%) and for losartan potassium Drugs 1996 May; 51 (5) Losartan Potassium: Use in Hypertension alone (56%), and least for hydrochlorothiazide (47%).[113] As for monotherapy (section 4.1), regimens containing losartan potassium produce equivalent antihypertensive effects to those containing enalapril in direct comparisons (table V). Hydrochlorothiazide was added in 53% of 132 patients with mild to moderate hypertension who initially received losartan potassium and in 47% of an enalapril l0mg group (n = 136).[1I5] Decreases in DBP were significantly larger in the losartan po- 835 tassium group at 4 weeks, but not at study end, and response rates did not differ (68% vs 60%). Similarly, in patients with severe hypertension, DBP fell by 27.7mm Hg with losartan potassium plus one or more other drugs (hydrochlorothiazide ± calcium channel blockers ± atenolol) and by 30.9mm Hg with a comparable regimen containing enalapril.[116] None of the reductions in DBP differed between groups at any of the measured intervals (weeks 1, 4 and 12).[116] At study end, 94% of 50 losartan potassium and 83% of 25 enalapril re- Table V. Efficacy of losartan potassium (L) plus hydrochlorothiazide (HCT) in dose-finding and comparative studies with an active treatment phase of 12 weeks in patients with mild to severe hypertension; all comparative studies were randomised, double-blind and multicentre in design a Abstract. Abbreviations and symbols: ATE = atenolol; CCB = calcium channel blocker; DBP = diastolic blood pressure; E = enalapril; od = once daily; SBP = systolic blood pressure; wk = weeks; = decrease; ** p < 0.01 vs placebo or placebo-containing groups; > indicates significantly greater efficacy for L groups, p < 0.05; ≡ indicates equivalent efficacy. © Adis International Limited. All rights reserved. Drugs 1996 May; 51 (5) Goa & Wagstaff 836 cipients were receiving either drug plus hydrochlorothiazide and one other antihypertensive drug. 4.3 Special Patient Groups Elderly patients have responded well to losartan potassium. Blood pressure reductions were similar for losartan potassium and felodipine ER in a study conducted specifically in elderly patients (see section 4.1.2), and response did not differ between patients older or younger than 75 years,[109] Among 29 individuals (18% of total) aged 65 years in a comparison with captopril,[107] age did not influence the antihypertensive effect of either treatment. Dahlof et al.[108] also found no differences in response to losartan potassium between younger and elderly patients (>65 years) nor between male and female patients (no quantitative data were presented). Patients 65 years or older showed a larger mean reduction in DBP at 12 weeks with losartan potassium (n = 25) than with enalapril (n = 30) [12.7 vs 8.7mm Hg, p = 0.03], but the percentage of responders was similar.[115] This was also the case for the Black patients . analysed in this study (losartan potassium = 32; enalapril = 33). The DBP reduction was slightly but significantly greater in the losartan group (10 vs 8mm Hg, p = 0.02)[115] The number of Black patients enrolled in other clinical trials (e.g. 12%[117] and 19%[110]) has been too few to permit subgroup analysis. Blood pressure decreased significantly from baseline (from 161/100 to 144/87mm Hg) in 89 patients with hypertension and various degrees of renal failure who had received losartan potassium 50 to l00mg daily for 12 weeks.[138] Similar results were earlier reported in 24 such patients treated for 7 days.[75] Compared with enalapril, losartan produced very similar effects on mean arterial pressure in 11 patients with moderate renal dysfunction.[118] Experience with losartan potassium is limited inother special groups such as those with NIDDM. In a small trial in 8 patients (4 with NIDDM), losartan potassium 50 mg/day with (6 patients) or without (2 patients) atenolol 100 mg/day was effective over a 12-week period.[79] © Adis International Limited, All rights reserved. 4.4 Long Term Efficacy In a noncomparative trial, the antihypertensive effects of losartan potassium persisted in the long term. 70.7% (41 of 58) of a losartan potassium monotherapy group (25 to l00mg daily) and 86.7% (26 of 30) of those receiving concomitant thiazide diuretics showed similar decreases in blood pressure at the end of a 52-week period to those recorded during the initial 8- to 10-week study.[l19] Extended clinical experience will assist in establishing the long term profile of losartan potassium; several such trials are underway (section 7). 5. Tolerability Profile The following discussion is largely extracted from a recent overview[120] of data obtained in clinical trials of >3800 patients with mild, moderate or severe hypertension. Of these, more than 2800 received losartan potassium with or without hydrochlorothiazide in double-blind comparisons with placebo or with other antihypertensive drugs. The major findings are illustrated in figure 4. No statistical analysis or methodological details of data collection were provided in the overview. Data from separate comparative clinical trials are also included where contributory. Dose,[41] age, gender or race[120] are reported to have no influence on the tolerability profile of losartan potassium; quantitative data for betweengroup comparisons are unavailable. 5.1 Losartan Potassium Monotherapy As shown in double-blind trials, losartan potassium is very well tolerated. Among 2085 losartan potassium and 535 placebo recipients usually treated for 8 to 12 weeks, losartan potassium monotherapy produced a similar incidence of drugrelated overall events (15.3 vs 15.5%) and patient withdrawal (2.3 vs 3.7%) to placebo. Drug-related events experienced most frequently with losartan potassium were headache (4.2%), asthenia/fatigue (2%) and also dizziness, which was the only drugrelated event reported more frequently with losartan potassium than with placebo (2.4 vs. 1.3%). Drugs 1996 May; 51 (5) Losartan Potassium: Use in Hypertension 837 Fig. 4. Tolerability of losartan potassium. Percentage of patients with adverse events during therapy with losart an potassium (n = 2085), placebo (n = 535), ACE inhibitors (captopril, enalapril or lisinopril; n = 239) or losartan potassium plus hydrochloro thiazide (HCT) [n = 858] in controlled trials of 8 to 12 weeks' duration. [120] Abbreviations: AE = adverse event; DRAE = drug-related adverse event; URTI = upper respiratory tract infection. When a causal relationship of events to treatment was not considered (fig. 4), the most commonly reported unwanted events in patients receiving losartan potassium monotherapy were headache (14.1%), upper respiratory tract infection (6.5%), dizziness (4.1%), and asthenia/fatigue (3.8%). Cough was reported in 3.1 % of the losartan potassium group;[120] this adverse event is discussed more thoroughly in section 5.1.1. The incidence of oedema with both losartan potassium and ACE inhibitors was 1.7%, a rate similar to that for placebo (1.9%). Orthostatic effects and first-dose hypotension appear uncommon, occurring in 0.5% of losartan potassium 25 to 50mg and 2.2% of l00mg recipients.[120] One report has described classic migraine in a patient without a previous history of migraine.[121] Symptoms developed within 6 hours of the losartan potassium 50mg dose and were confirmed on rechallenge.[121] Reversible ageusia also occurred in 1 patient receiving losartan potassium 25 mg/day: this symptom appeared within 3 weeks of commencing ther© Adis International Limited. All rights reserved, apy and resolved within 2 to 3 weeks of treatment discontinuation.[122] To date there have also been 2 reports of angioedema during losartan potassium therapy. A patient who was hypersensitive to penicillin and aspirin developed facial rash and swelling considered by the investigator to be angioedema.[88] Facial swelling and flushing without dyspnoea occurred within 30 minutes of ingesting a 50mg dose of losartan potassium in another patient with glomerulosclerosis and no history of angioedema, who had discontinued captopril because of cough. [123] During long term losartan potassium treatment (1 year) in 306 patients, headache (3.6%), dizziness (2.9%) and asthenia/fatigue (2.6%) were the most common complaints.[120] Rebound hypertension has not been reported in clinical trials which continued patient follow-up after abrupt losartan potassium withdrawal.[107, 108, 120] Levels of liver enzymes, usually alanine aminotransferase, have occasionally been elevated transiently during losartan potassium therapy (1.9%)[120] Drugs 1996 May; 51 (5) 838 and these increases necessitated drug withdrawal in one patient.[88] Hyperkalaemia (serum potassium 5.5 mmol/L) was documented in 1.5% of patients receiving losartan potassium vs 1.3% of those given ACE inhibitors but did not result in any patient being discontinued.[120] Apart from these alterations, no other changes in laboratory indices were reported in the clinical trials database.[120] There were no changes in haematological or haemorrheological indices in 7 elderly patients treated with losartan potassium 50 to 100 mg/day for 52 weeks.[124] Losartan potassium did not reduce heart rate in healthy individuals (section 2.3) or in patients involved in the clinical trials discussed in section 4 which measured this parameter. 5.1.1 Compared with Other Antihypertensive Drugs Cough Accumulation of bradykinin and substance P via inhibition of ACE is thought to increase bronchial reactivity and produce cough.[125,126] ACE inhibitorinduced cough can be sufficiently severe to limit treatment.[126,127] Several 8-week double-blind trials were designed specifically to assess the incidence and severity of cough associated with losartan potassium compared with hydrochlorothi-azide, placebo or the ACE inhibitor lisinopril in patients with a history of cough during ACE inhibitor therapy.[128,129] In the first study, involving 135 patients, cough was documented in 71.7% of lisinopril patients versus 29.2% of losartan potassium recipients (p < 0.01) and 34.1% of the hydrochlorothiazide group (p< 0.01) [fig. 5]. The relative risk of developing cough in the losartan group was 0.407 vs lisinopril and 0.854 vs hydrochlorothiazide. A visual analogue scale (VAS) confirmed that patients receiving lisinopril perceived cough to be more frequent: VAS scores increased by 3cm with lisinopril compared with 0.9cm for losartan potassium and 1.2cm for hydrochlorothiazide (p < 0.01 for both). Significantly more women than men reported cough, as has been observed by others.[126,127] © Adis International Limited. All rights reserved. Goa & Wagstaff As well as being more frequent, cough was also more severe with lisinopril, as evidenced by the Symptom Assessment Questionnaire. Furthermore, treatment duration was 18.6 days longer with losartan potassium and 13.2 days longer with hydrochlorothiazide than with lisinopril (p < 0.01). This reflects the delay in onset to cough with these drugs compared with the ACE inhibitor.[128] Two additional studies, as yet not fully published, have shown similar results in patients with ACE inhibitor-induced cough.[l29] In one, the percentage of patients experiencing cough was 17% for the lisinopril group, 25% for hydrochlorothiazide recipients and 69% for those given lisinopril. In the other, the percentages of patients with cough in losartan potassium, placebo and lisinopril groups were 29%, 35% and 62%.[129] Losartan potassium therefore was associated with an overall incidence of cough (17 to 29%) similar to that of placebo (35%) and hydrochlorothiazide (25 to 34%) and Fig. 5. Losartan potassium and incidence of cough. Percentage of patients with hypertension and a history of ACE inhibitorinduced cough who developed cough during daily therapy with losartan potassium 50 mg (n = 48), hydrochlorothiazide 25mg (n = 41) or lisinopril 20mg (n = 46).(128] * p < 0.01 vs other drugs. Drugs 1996 May; 51 (5) Losartan Potassium: Use in Hypertension demonstrably less than with lisinopril (62 to 72%) in patients with a history of ACE inhibitor-related cough. The high rate of cough in these studies is attributable to the selection of a cough-sensitive cohort. Spontaneously reported cough is much less frequent: its incidence was 3.1% during treatment with losartan potassium (n = 2085), 8.8% for ACE inhibitors (enalapril, captopril or lisinopril; n = 239) and 2.6% for placebo (n = 535) in clinical trials of up to 12 weeks' duration (no statistics given).[201] Therefore, as in the above-mentioned trials in patients predisposed to ACE inhibitor cough, the incidence of cough in this overview of clinical trials was similar for losartan potassium and placebo. Other Events Asthenia/fatigue appears to be more frequent with ACE inhibitors (6.7%) than with losartan potassium (3.8%) or placebo (3.9%) whereas the reverse is true for headache (14.1% for losartan potassium vs 10.9% for ACE inhibitors, but 17% for placebo).[120] Direct single-study comparisons with antihypertensive agents other than ACE inhibitors demonstrated that, in the elderly, headache and oedema were more common with felodipine ER (14% for each) than with losartan potassium (9 and 6.7%) but asthenia was more common with losartan potassium (8 vs <1%).[109] It was not stated whether the difference was statistically significant. Similarly, although the overall incidence of adverse events for losartan potassium (49%) resembled that for atenolol (57%), more events in the atenolol group (27%) than in the losartan potassium group (17%) were considered drug-related and caused treatment discontinuation (6.9 vs 2.2%, p < 0,05).[108] Headache was the most common event for both drugs (16% with losartan potassium and 19% with atenolol), but sweating and nausea were significantly more frequent with atenolol (p < 0.05).[108] It should be noted that these studies lacked a placebo arm. Compared with losartan potassium therapy, dizziness (7.4 vs 4.1%) and insomnia (4.4 vs 1.1%) were more frequent with at© Adis International Limited. All rights reserved, 839 enolol and oedema/swelling (14 vs 1.7%) was more common with felodipine in the overview of double-blind trials.[120] 5.2 Losartan Potassium plus Hydrochlorothiazide With losartan potassium plus hydrochlorothiazide, the incidence of any drug-related adverse event (14.8%) or event causing drug withdrawal (2.8%) is similar to that for losartan potassium alone and for placebo (fig. 4).[120] The tolerability of the combination is difficult to assess when it is used with other drugs. In noncomparative studies, 23% of 131 patients who received losartan potassium plus hydrochlorothiazide with or without atenolol and felodipine had a drug-related adverse event.[111] Similarly, headache occurred in 26% of 180 patients with severe disease receiving polytherapy with losartan potassium plus hydrochlorothiazide with or without atenolol and a dihydropyridine calcium channel blocker.[110] One trial comparing losartan potassium and enalapril, both plus hydrochlorothrazide and other drugs, found no differences in tolerability between the 2 approaches, [116] but no quantitative values were given. The rates of increased serum uric acid levels (3.5%) and decreased serum potassium levels (3.2%) with losartan potassium plus hydrochlorothiazide approximated those for the diuretic alone (3.9 and 4.3%) when overviewed in all clinical trials.[120] 6. Dosage and Administration The recommended starting and maintenance dosage of losartan potassium as, monotherapy in patients with essential hypertension is 50mg once daily. Some patients may benefit from receiving l00mg once daily. A dosage of 25mg once daily should be given to patients with hepatic impairment or volume depletion or who are otherwise at high risk of hypotension. Hydrochlorothiazide 12.5mg daily may be added in patients not responding completely to losartan potassium.[88] Drugs 1996 May; 51 (5) 840 In Japanese studies, the initial dosage of losartan potassium for mild to moderate hypertension has been 25mg daily. No initial dosage adjustment is necessary for elderly patients or those with renal impairment, including patients undergoing dialysis. However, in patients whose renal function may depend on an intact RAS, losartan potassium may be expected to be associated with worsening renal impairment. Losartan potassium may be given with or without food and with other antihypertensive agents.[88] Losartan potassium is not recommended in pregnant women because of the risk of fetal and neonatal morbidity and death.[88] The combination of losartan potassium and hydrochlorothiazide is initiated at a dosage of 50mg/12.5mg daily (1 tablet). The dosage can be doubled to 2 tablets daily (the recommended maximum). The product is not recommended for initial therapy in patients with hypertension when monotherapy is the usual starting point, for patients with hepatic impairment or for use in patients with creatinine clearance 1 .8 L/h (30 ml/min), who should receive loop diuretics rather than hydrochlorothiaInformation regarding losartan potassium overdosage is limited. Supportive treatment should be instituted if symptomatic hypotension occurs. Losartan potassium and E3 174 are not removed by dialysis.[88] 7. Place of Losartan Potassium in the Management of Hypertension Until recently, no new, classes of antihypertensive drugs had been introduced into clinical practice since the advent of ACE inhibitors in the late 1970s. Saralasin, the peptide prototype of a new class, the AII receptor antagonists, was first synthesised and developed as a potential antihypertensive agent earlier in that decade. This agent was investigated on the premise that blocking the AII receptor rather than inhibiting ACE would be expected to impede the physiological actions of AII regardless of source and might also prevent associated unwanted effects, such as bradykinin accumula© Adis International Limited. All rights reserved. Goa & Wagstaff tion.[4] However, its partial agonist activity, short duration of activity and lack of oral bioavailability precluded its clinical use.[4, 131] The shortcomings of saralasin have now been circumvented with the development of nonpeptide AT1 receptor antagonists. Losartan potassium is the first orally active member of this class to become available for clinical use in hypertension. It, is marketed alone and, in some countries, in fixed combination with hydrochlorothiazide, Losartan potassium is highly and selectively bound to the AT1 receptor, possesses no agonist activity, and is metabolised to an active metabolite, E3174, which contributes substantially to its antihypertensive effect. Its duration of activity persists throughout a 24-hour period, as evidenced by 24hour ambulatory monitoring. Adverse metabolic effects have not been documented and renal function is preserved during losartan potassium therapy. The drug has exerted a uricosuric effect in some patients and in preliminary investigations has decreased proteinuria. Losartan potassium is also currently undergoing investigation in phase III trials for CHF,[1] including the Evaluation of Losartan in the Elderly (ELITE) trial.[132] Losartan potassium is an effective therapy for hypertension. Data from well designed comparative studies of 8 to 12 weeks' duration in patients with mild to moderate hypertension demonstrate that the blood pressure-lowering effects of losartan potassium 50 to l00mg once daily as monotherapy are similar to those for the well-established agents enalapril, atenolol and felodipine ER. A comparison with captopril once daily showed more favourable results for losartan potassium once daily; however, dosages used were not therapeutically equivalent. A trial of losartan potassium once daily vs captopril in the more common twice-daily regimen is currently underway. The combination of losartan potassium plus hydrochlorothiazide produces larger reductions than are seen with either drug alone and, in noncomparative 12-week clinical trials, about 30% of patients with severe disease have been managed with this combination. However, as is usual with Drugs 1996 May; 51 (5) Losartan Potassium: Use in Hypertension patients in this category,[133,134] most require polytherapy (addition of a ( -blocker and/or calcium channel blocker) to control blood pressure. Losartan potassium appears beneficial in elderly patients, as evidenced by its similar efficacy to felodipine ER in a large trial. Its role in the treatment of other special groups (Blacks or patients with renal dysfunction or NIDDM) awaits definition by more thorough investigation and/or fuller publication of preliminary study results. Adverse effects commonly associated with ACE inhibitors are cough, dizziness, first-dose hypotension, rash and fatigue. The tolerability of losartan potassium has been assessed against this established profile and those of other antihypertensive drugs. Data from >2800 patients given losartan potassium with or without hydrochlorothiazide in controlled clinical trials of up to 12 weeks' duration demonstrate that the drug is very well tolerated. Dizziness was the only drug-related adverse event reported more frequently with losartan potassium than with placebo. First-dose hypotension has seldom been reported. There have been rare instances of angioedema, severe migraine and reversible ageusia developing during losartan potassium therapy. ACE inhibitor-related cough is a class-specific effect which can be sufficiently annoying to cause treatment discontinuation in as many as half of patients developing this symptom.[127] The incidence of cough varies according to the reporting method used: it has been reported to occur in about 5 to 15% of all patients who receive ACE inhibitors[125,126] and has been documented in up to 20% of patients in controlled trials.[126] Pulmonary accumulation of bradykinin subsequent to ACE inhibition is thought to be a main aetological factor in cough development[126] Clinical experience thus far has validated the expectation that, because losartan potassium lacks apparent effects on bradykinin, it would be associated with minimal cough. The incidence of cough in trials specifically designed to assess this parameter in patients with a history of ACE inhibitorrelated cough was similar for losartan potassium © Adis International Limited. All rights reserved. 841 (17 to 29%), hydrochlorothiazide (25 to 34%) and placebo (35%) but, as expected, was greater for lisinopril (62 to 72%). Spontaneously reported cough among the general population was also documented at a similar frequency in losartan potassium and placebo groups. This property is likely to be advantageous in patients at risk of developing ACE inhibitor cough. Guidelines for the pharmacological management of hypertension in the US[134] and the UK[133] recommend initiation of therapy with diuretics or -blockers - agents proven to reduce cardiovascular morbidity and mortality. ACE inhibitors, 1blockcrs and calcium channel blockers are positioned as 'alternative first-line' strategies in patients in whom diuretics and -blockers are ineffective, contraindicated or poorly tolerated. However, other factors, such as concomitant disease, potential for drug interaction, tolerability of the agent and cost of treatment, should also be considered when initiating antihypertensive therapy[134] and there is some controversy regarding the restrictiveness of these guidelines.[135,136] Predictably, the ultimate position of losartan potassium among the plethora of drugs available for the management of hypertension awaits clarification by long term efficacy data. At present, limited long term tolerability data (<2 years) are available but the results support the very good tolerability demonstrated in 12-week trials. Several other important features of the profile of losartan potassium requiring determination in future investigations arc: (i) its effects, if any, on mortality in patients with hypertension; (ii) the potential for cardiac and renal benefits, vis-a-vis diabetic nephropathy, renal glomerular hypertension, cardiac hypertrophy and left ventricular function, as implied by animal studies; (iii) whether long term unopposed AII blockade, which exposes other angiotensin receptors to increased circulatory AII, will produce unwanted consequences; (iv) its effects on quality of life and cost effectiveness. This last issue is being addressed by the Trial for Usual Care for Hypertension (TOUCH),[137] a 6month multicentre study designed to assess qualDrugs 1996 May; 51 (5) Goa & Wagstaff 842 ity of life and cost parameters as well as the long term efficacy of losartan potassium. Another recently-instigated trial, the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, seeks to evaluate whether any clinical benefits are associated with regression of LVH. The trial, which compares losartan potassium with atenolol, is to be conducted in patients with hypertension and LVH. It aims to enrol 8300 patients and will continue for at least 4 years or until 1040 pa-tients have experienced myocardial infarction, stroke or cardiovascular death.[129] In summary, losartan potassium is the first of a new class of drugs, the AT1 receptor antagonists, to be introduced for the treatment of hypertension. As such it is an important new agent. Pending long term efficacy and mortality data the drug is likely to find initial use in patients who are not well managed with, or are intolerant of, their current therapy. However, with its novel mechanism of action, good efficacy and favourable tolerability profile, losartan potassium is poised to claim a prominent position in the management of patients with mild to severe essential hypertension. References 1.Smith RD, Sweet CS, Goldberg A, et al. Losartan potassium (Cozaar™): a nonpeptide antagonist of angiotensin II. Drugs Today 1995; 31 (7): 463-98 2. Timmermans PB, Wong PC, Chiu AT, et al. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 1993 Jun; 45; 205-51 3. Garrison JC, Peach MJ. Chapter 31. Renin and angiotensin. in: Gilman AG et al., editors. The pharmacological basis of therapeutics. New York: McGraw Hill Inc., 1992: 749-58 4. Cody RJ. The clinical potential of renin inhibitors and angiotensin antagonists. Drugs 1994 Apr; 47: 586-98 5. Timmermans PBMWM, Wong PC, Chiu AT, et al. The preclinical basis of the therapeutic evaluation of losartan. J Hypertens 1995; 13 Suppl. 1:S1-13 6. 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Drug Metab Dispos 1995 Feb; 23: 285-9 Goldberg MR, Lo M-W, Bradstrect TE, et al. Effects of cimetidine on pharmacokinelics and pharmacodynamics of losartan, an ATi-seleclive non-peptide angiotensin H receptor antagonist. Eur J Clin Pharmacol 1995; 49: 115-9 McCrea JB, Lo M-W, Furtek CI, et al. Ketoconazole does not affect the systemic conversion of losartan to E-3174 [abstract]. Clin Pharmacol Ther In press Goldberg MR, Lo M-W, Deulsch PJ, el al. Phenobarbital minimally alters plasma concentrations of losartan and its active metabolite E-3174. Clin Pharmacol Ther In press; 59 Spielberg S, McCrea J, Cribb A, et al. A mutation in CYP2C9 is responsible for decreased metabolism of losartan [abstract]. Clin Pharmacol Ther In press McCrea J, Lo M-W, Kong T, et al. A rare deficiency of the conversion of losartan to its active metabolite, E3174 [abstract]. Clin Pharmacol Ther In press Kong A-NT, Tomasko L, Waldman SA, et al. 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Edelman JM, Gazdick LP, Epstein RS, et al. Trial of Usual Care for Hypertension (TOUCH): an effectiveness study of newly treated hypertension comparing losartan potassium and usual care in a managed care setting. Am J Hypertens 1995 Apr: 8 (Pt 2): 79 138. Shaw W, Suavely D. Safety and efficacy of losartan (DuP 753, MK 954) in hypertensive patients with renal impairment [abstract]. J Am Soc Nephrol 1994; 5: 567 Correspondence: Karen L, Goa, Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand. Drugs 1996 May; 51 (5) Donahue et al. 540 60. Winward KE, Plugfelder SC, Flynn HW, et al. Postoperative Propionibacterium endpphthalmitis. Ophthalmology 1993; 100:447-51 61. Doft BH, Barza M, Ceftazidine or Amikacin. Choice of intravitreal antimicrobials in the treatment of postoperative endophthlamitis. Arch Ophthalmol 1994; 112: 178 62. Campochiaro PA, Lim Jl. Aminoglycoside toxicily in the treatment of endophthalmitis. Arch Ophthalmol 1994; 112: 48-53 63. Conway BP, Campoehiaro PA. Macular infarction after endophihalmitis treated with vitreclomy and intravitreal gentamicin, Arch Ophthalmol 1986; 104; 367-71 64. Donahue SP, Kowalski RP, Eller AW, et al. Empiric treatment of endophthalmitis; are aminoglycosides necessary? Arch Ophthalmol 1994; 112:45-7 65. Aaberg TM, Flynn HW, Murray TG. Intraocular ceftazidime as an alternative to the aminoglycosides in the treatment of endophthalmitis. Arch Ophthalmol 1994;112:18-19 66. Forster RK. Endophthalmitis. In: Tasman W, editor. Duane's clinical ophthalmology. Vol. 4. Chap. 24. Philadelphia: Lippincott-Raven, 1995; 15 Correspondence and reprints: Dr Sean P. Donahue, 8015 Medical Center liast, Vanderbilt University Eye Center, Nashville, T'N 37232-8808, USA. E-mail: [email protected] Errata Vol. 46, No. 3, page 387: In table II, the half-life of pergolide should read 75-42 (mean 27) hours. [Montastruc JL, Rascol O, Senard JM. Current status of dopamine agonists in Parkinson's disease. Drugs 1993 Sep; 46 (3): 384-93] Vol. 51, No. 5, page 838: In the fifth paragraph of section 5 .1.1, the second sentence should read, '. . . 17% for the losartan potassium group…..’ page 845: In reference no. 106, the journal name should read J Hypertens. [Goa KL, Wagstaff AJ, Losartan potassium: a review of its pharmacology, clinical efficacy and tolerability in the management of hypertension. Drugs 1996 May; 51 (5): 820-45] © Adis International Limited, All rights reserved. Drugs l996 Oct;52(4)