Charles S. Sweet

Safety and tolerability of losartan potassium, an angiotensin II receptor antagonist, compared with hydrochlorothiazide, atenolol, felodipne ER, and angiotensin-converting enzyme inhibitors for the treatment of systemic hypertension

This report presents data on the safety and tolerability of losartan potassium (losartan), a selective antagonist of the angiotensin II AT-1 receptor, in approximately 2,900 hypertensive patients treated in double-blind clinical trials. In these studies, headache (14.1%), upper respiratory infection (6.5%), dizziness (14.1%), asthenia/fatigue (3.8%), and cough (3.1%) were the clinical adverse experiences most often reported in patients treated with losartan. These adverse experiences were also frequently reported in patients receiving placebo: 17.2%, 5.6%, 2.4%, 3.9%, and 2.6%, respectively. Dry cough as an adverse event was reported in 8.8% of patients treated with angiotensin-converting enzyme inhibitors, and in 3.1% and 2.6% of patients treated with losartan or placebo, respectively. Only dizziness was considered drug-related more often in losartan-treated (2.4%) than placebo-treated (1.3%) patients. In controlled clinical trials, losartan was better tolerated than other antihypertensive agents as determined by the incidence of patients reporting any drug-related adverse experiences. Rates of discontinuation due to clinical adverse experiences in patients who received losartan monotherapy or losartan+hydrochlorothiazide were 2.3% and 2.8%, respectively, compared with placebo (3.7%). No laboratory adverse experiences were unexpected or of clinical importance. First-dose hypotension rarely occurred with losartan or with losartan plus hydrochlorothiazide, and withdrawal effects such as rebound hypertension were not observed in clinical trials. There were no clinically important differences in the clinical or laboratory safety profiles in the demographic subgroups for age, gender, or race. In controlled clinical trials, losartan demonstrated an excellent tolerability profile.

Efficacy and tolerability of losartan potassium and atenolol in patients with mild to moderate essential hypertension

The objective of this study was to compare the antihypertensive efficacy and tolerability of losartan potassium (losartan) and atenolol in patients with mild-to-moderate essential hypertension. This was a multinational, prospective, randomized, 12-week double-blind parallel study with a follow-up of 4 to 10 days posttreatment to assess any adverse effects of abrupt therapy withdrawal. Two hundred two patients were randomized (2:1) to treatment with losartan or atenolol, 50 mg once daily. Patients were titrated after 6 weeks to 100 mg once daily if their blood pressure was uncontrolled (sitting diastolic blood pressure > or = 90 mm Hg). Trough sitting diastolic blood pressure reductions at weeks 6 and 12 were similar in both the losartan (-9.2 mm Hg and -8.3 mm Hg) and atenolol (-10.8 mm Hg and -10.1 mm Hg) groups and a similar percentage of patients responded to each drug. Both agents were generally well tolerated, although eight patients (two patients taking losartan, and six taking atenolol) were withdrawn because of clinical adverse events (P < or = .05). Reduction in pulse rate from baseline averaged 10 beats/min in the atenolol group with no pulse rate reduction observed in the losartan group (P < .01). No evidence of rebound hypertension was observed in either group. In conclusion, losartan was as efficacious as atenolol in blood pressure reduction, and was at least as well tolerated.

Pilot study of combined blockade of the renin–angiotensin system in essential hypertensive patients

Background Additive hemodynamic effects of combined blockade of the renin–angiotensin system by an angiotensin I converting enzyme inhibitor and an angiotensin II antagonist have been observed in sodium-depleted normotensive volunteers and in patients with congestive heart failure. Objective To investigate whether the same additive hemodynamic effects occur in patients with hypertension and to verify the safety of such an approach. Design Multicenter, randomized, double-blind, parallel-group, pilot study. Patients 177 patients with mild-to-moderate hypertension [diastolic blood pressure (DBP): 95–115 mmHg after a 4-week placebo run-in period] were included in the study. Intervention Combination therapy consisting of 50 mg losartan daily and 10 mg enalapril daily was administered for 6 weeks. The effects of this therapeutic regimen was compared with similar groups of patients who received either 50 mg losartan daily or 10 mg enalapril daily Main outcome measures 24-hour ambulatory mean DBP and clinic DBP measured at trough after 6 weeks of treatment. Results 24-hour ambulatory mean DBP did not significantly differ between treatment groups although the combination tended to lower BP more. The combination therapy was more effective on clinic DBP measured at trough than was losartan by 3.2 mmHg [confidence interval (95%, CI) 0.7–5.7 mmHg, P = 0.012], and more effective than enalapril by 4.0 mmHg (95% CI, 1.5–6.4 mmHg, P = 0.002). In a subgroup of 28 patients, higher plasma active renin and angiotensin I levels during blockade by the combination therapy were observed. This finding confirmed that the combination of the two agents inhibited the renin–angiotensin system to a greater extent than did either agent alone. Conclusion A combination of 10 mg enalapril daily and 50 mg losartan daily safely induces a supplementary, although modest, fall in clinic DBP in patients with mild-to-moderate essential hypertension.

Controlled Trial of Losartan Given Concomitantly with Different Doses of Hydrochlorothiazide in Hypertensive Patients

The purpose of this trial was to evaluate the antihypertensive efficacy of the concomitant administration of selected doses of hydrochlorothiazide (HCTZ) on a background of losartan potassium (losartan) 50 mg, a selective angiotensin II receptor antagonist. Patients with essential hypertension ( > or = 95 mmHg inclusion criteria) with a mean sitting diastolic blood pressure (SiDBP) of 105 +/- 0.4 (S.E.) mmHg entered a 4-week, single-blind monotherapy period of losartan 50 mg once daily. At the end of the monotherapy period, patients whose blood pressure was adequately controlled were discontinued. Patients whose blood pressure was partially controlled based on a SiDBP > 92 mmHg entered a 12 week double-blind period and were randomly assigned to either receive placebo (n = 80), HCTZ 6.25 mg (n = 80), HCTZ 12.5 mg (n = 72) or HCTZ 25 mg (n = 80) in addition to losartan 50 mg. During the losartan monotherapy period, there was a 4 mmHg fall in SiDBP with a further fall of 5 mmHg after 12 weeks of double-blind therapy in the losartan/placebo control group. Based on the between group differences in BP change from the end of the losartan monotherapy period (baseline) to end of 12 weeks of double-blind, the concomitant administration of a very low dose of HCTZ (6.25 mg) with losartan did not significantly decrease SiDBP compared with the fall in blood pressure in the losartan/placebo control group (diff. between groups = -2 (95% C.I.[-4.1, +0.9] mmHg)). However, the concomitant administration of HCTZ 12.5 or 25 mg with losartan 50 mg resulted in significantly different (p < or = 0.05) reductions in diastolic blood pressure compared to the losartan/placebo group (diff. between groups = -4 (95% C.I. [-6.3, -1.1] mmHg) for 12.5mg combination group; -6 (95% C.I. [-8.3, -3.3]) mmHg for the HCTZ 25 mg combination group). The proportions of patients treated with losartan plus HCTZ 12.5 mg or 25 mg that achieved a trough SiDBP < 88 mmHg or a trough SiDBP > or = 88 mmHg but with a decrease of at least 5 mmHg were 71% and 83%, respectively. The percentage of clinical adverse experiences that were considered drug-related as assessed by the investigator were generally similar across all treatment groups. There were no reports of orthostatic hypotension in any of the treatment groups. Changes in serum glucose, potassium and uric acid were not appreciably different amongst the treatment groups. In summary, in patients with predominantly moderate to severe essential hypertension, the addition of HCTZ 12.5 mg or 25 mg to losartan 50 mg produced effective control of blood pressure in a substantial majority of patients who only partially responded to losartan monotherapy. There were no differences amongst the treatment groups with respect to drug-related adverse experiences in this trial.

Increased survival in rats with congestive heart failure treated with enalapril.

Summary: Vasodilating drugs such as angiotensin converting enzyme (ACE) inhibitors may extend life expectancy in patients with congestive heart failure (CHF). The purpose of this study was to evaluate whether long-term therapy (365 days) with enalapril (ENAL, an ACE inhibitor), would prolong life in rats with a healed myocardial infarction (MI), an experimental model with hemodynamic characteristics of CHF. Seven days after sham or coronary ligation, when the healing phase of MI was well underway. 132 rats (75 sham. 57 Ml) were randomized to receive either enalapril in the drinking water (17–25 mg/L, approximately 1.0 mg/kg/day) or tap water. The date of spontaneous death was recorded, and heart weight and MI size (by planimetry) were determined. Serum ENAL. total ACE concentration, and angiotensin and methoxamine pressor responses were quantified in 12 survivors. Long-term enalapril prolonged survival (p = 0.014) with a median 50% survival of 164 (164–165) days, compared to 84 (64–104) days in rats receiving tap water. There were twice as many MI rats alive at the end of one year on angiotensin converting enzyme inhibition (ACEI) therapy as compared to the untreated group. The average MI size (39–40%) was not different between groups, and there was a significant inverse correlation between date of death and MI size (r = 0.7–0.8) in both treatment groups. Cardiac hypertrophy was evident in all MI rats. Serum ENAL levels, after one year, were at the clinically relevant concentration (2.3 ng/ml) and total serum ACE (inhibitor removed) doubled to 4,300 nmol/h/ ml. The depressor response to bradykinin was enhanced, and the ratio of the pressor responses to angiotensin I/an-giotensin II were reduced, reflecting chronic ACE inhibition. This study demonstrates that long-term ACEI therapy prolongs survival in rats with chronic congestive heart failure

Comparative Antihypertensive Effects of Losartan 50 mg and Losartan 50 mg Titrated to 100 mg in Patients with Essential Hypertension

The antihypertensive activity of losartan potassium (losartan, Cozaar), an angiotensin II receptor antagonist, was evaluated in a parallel 12-week, double-blind, placebo-controlled trial in hypertensive patients with mild-to-moderate hypertension. After a 4-week, single-blind, placebo lead-in period, which included monitoring of baseline variables, 366 patients with a group mean sitting diastolic blood pressure of 101 +/- 5 (s.d.) mmHg were assigned randomly to one of three treatment groups: placebo, losartan 50 mg, or losartan 50 mg with the option to titrate to 100 mg after the first 6 weeks if the target sitting diastolic blood pressure (< 90 mmHg) was not reached. To assess the potential blood pressure response associated with the act of titration, patients in the placebo and losartan 50 mg treatment groups with a sitting diastolic blood pressure of > or = 90 mmHg at week 6 were mock titrated (changed to a new tablet containing the same study medication and dose). Sitting diastolic blood pressure was also evaluated at the end of the trial during a 1-week off-drug period to assess for rebound hypertension. At week 6, patients in the active-drug-treatment arms experienced significantly greater peak (6 h post-dose) and trough (24 h post-dose) reduction in systolic and diastolic sitting blood pressures compared with placebo (p < or = 0.01). Based on trough blood pressures at week 12, active drug (both arms) was more effective than placebo in lowering sitting diastolic blood pressure, with a very small additional benefit associated with increasing the dose of losartan to 100 mg in patients who did not reach the target blood pressure after the first 6 weeks on losartan 50 mg. There was no evidence of rebound hypertension during 1 week after withdrawal of losartan. The correlation between baseline plasma renin activity and reduction in peak and trough blood pressure at week 12, although statistically significant, was generally poor in the active treatment groups. In this trial, losartan was efficacious and well tolerated, and was similar to placebo with regard to adverse-experience profile. Adverse experiences that could reasonably be related to excessive lowering of blood pressure were not common and there was no evidence of rebound hypertension.

Three Candidate Genes and Angiotensin-Converting Enzyme Inhibitor–Related Cough A Pharmacogenetic Analysis

Unexplained, persistent cough limits the use of angiotensin-converting enzyme (ACE) inhibitors in a significant number of patients. It has been speculated that occurrence of this adverse effect is genetically predetermined; in particular, variants of the genes encoding ACE, chymase, and B2-bradykinin receptor have been implicated. To investigate this question, we determined genotypes for common polymorphisms for these three genes in subjects with a history of ACE inhibitor-related cough. Specificity of the adverse effect was confirmed by a blinded, double-crossover design protocol in which subjects were rechallenged with either lisinopril or placebo. In 99 case subjects and 70 control subjects (who failed to develop cough on rechallenge with ACE inhibitor) thus selected, frequencies for the ACE D and I alleles were 0.56 and 0.44 (cases) and 0.56 and 0.44 (controls), respectively; frequencies for chymase A and B alleles (absence/presence of BstXI site) were 0.56 and 0.44 (cases) and 0.46 and 0.54 (controls), respectively; frequencies for B2-bradykinin receptor + and - alleles (presence/absence of a 21 to 29 nonanucleotide sequence) were 0.52 and 0.48 (cases) and 0.53 and 0.47 (controls), respectively. All observed genotype frequencies were in Hardy-Weinberg equilibrium. There was no evidence for association between genotype at either gene examined and cough (adjusted for gender and age). Our data indicate that common genetic variants of ACE, chymase, and B2-bradykinin receptor do not explain the occurrence of ACE inhibitor-related cough.

Beta 1-selective adrenoceptor antagonists: examples of the 2-[4-[3-(substituted-amino)-2-hydroxypropoxy]phenyl]imidazole class.

A series of 2-[4-[3-(substituted-amino)-2-hydroxypropoxy]phenyl]imidazoles is described. The compounds were investigated in vitro for beta-adrenoceptor antagonism, and several examples were found to be selective for the beta 1-adrenoceptor. The structure--activity relationship exhibited by this series of compounds is discussed. (S)-2-[p-[3-[[2-(3,4-dimethoxyphenyl)ethyl]amino]-2-hydroxypropoxy]phenyl]-4-(2 -thienyl)imidazole [(S)-13] was over 100 times more selective than atenolol for the beta 1-adrenergic receptor and has been selected for in-depth studies.

Dose-ranging study of the angiotensin type I receptor antagonist losartan (DuP753/MK954), in salt-deplete normal man.

In a dose-ranging study, the angiotensin type I receptor antagonist losartan (DuP753/MK954) was administered orally to normal volunteers in whom the renin-angiotensin system (RAS) had been activated by a low sodium diet (40 mmol) and frusemide (40 mg twice daily) for 3 days before study. On the fourth day, subjects (n = 12) received placebo and three active doses (5, 10, 25, 50, or 100 mg) in a randomized, double-blind, three-panel, dose-ranging design. On the study day, 24-h urinary sodium excretion was 10–20 mmol Na, with an increase in renin and aldosterone levels at baseline. Dose-dependent decreases in supine and erect blood pressures (BP) were statistically significant for 50 and 100 mg and were associated with a modest increase in supine heart rate (HR) at the higher dose. The peak BP decreases observed suggested that the highest dose studied (100 mg) was not necessarily the maximal response. Active treatments caused no increase in the sodium loss on the study day. Renin was significantly increased by doses >10 mg in a dose-dependent fashion but there was little change in plasma aldosterone profile. Increase in renin was evident at doses (10 mg) below those significantly affecting overall BP (50 mg). Adverse symptoms were uncommon and limited to postural lightheadedness which was largely dose related. Our results indicate a BP and plasma renin dose-response relation for the orally active angiotensin II (AII) receptor blocker losartan in normotensive subjects with an activated RAS.

Some cardiovascular effects of ST-91 and clonidine☆

St-91, 2(2,6-diethylphenylamino)-2-imidazoline, is a clonidine derivative which does not penetrate the blood-brain barrier. In spontaneously hypertensive (SH) rats is acutely increased arterial pressure and reduced heart rate while at 8 to 12 h after oral administration, it slightly lowered arterial pressure. In contrast, clonidine had acute antihypertensive activity at all doses used. By intracerebroventricular administration to SH rats, both drugs (St-91 and clonidine) reduced arterial pressure and heart rate; in this respect, clonidine was more potent then St-91. Cardiac acceleration induced by low frequency electrical stimulation of right cardiac sympathetic nerves in anesthetized and vagotomized dogs was reduced by St-91 at the same doses by clonidine. Phenoxybenzamine, phentolamine and desipramine antagonized the inhibitory effects of St-91 on electrically induced cardiac acceleration. It was concluded that St-91, like clonidine, stimulates inhibitory alpha-adrenergic receptors at the sympathetic nerve endings but, unlike clonidine, is substantially devoid of acute antihypertensive activity. This suggests that stimulation of peripheral presynaptic inhibitory alpha-adrenergic receptors is not likely to represent the sole mechanism of antihypertensive action of clonidine.