Is the antihypertensive effect of captopril influenced by the dosage frequency? A study with ambulatory monitoring

When captopril was first introduced for the management of hypertension, its short plasma half-life led to its use as a thrice daily regimen. However, further experience suggests that the biological action is more prolonged than the plasma half-life might suggest. This study examined the effect of varying the frequency of administration (once, twice and three times daily) of a fixed daily dosage of 75 mg captopril on ambulatory BP in a double-blind cross-over study in 15 patients with mild to moderate hypertension. Each patient had six ambulatory BP recordings with placebo alternating with active phase. The three regimens (75 mg daily, 37.5 mg twice daily and 25 mg three times daily) reduced the daily mean BP equally and significantly compared with placebo. Three patients with very high pretreatment plasma renin values showed some loss of BP control immediately prior to the first dose in the morning in the 75 mg single dose phase (i.e. 24 hours post dose); but group analysis showed no difference in mean BP at this time point with the three treatment regimens. We conclude that in spite of its short plasma half-life, captopril can effectively control BP over the whole day with a once daily regimen.     

Comparison of different regimens of glucocorticoid replacement therapy in patients with hypoadrenalism

Since the optimal glucocorticoid replacement needs to avoid over and under treatment, the adequacy of different daily cortisone acetate (CA) doses was assessed in 34 patients with primary and central hypoadrenalism. The conventional twice CA 37.5 mg/day dose was administered to all patients (A regimen: 25 mg at 07:00 h, 12.5 mg at 15:00 h), while in 2 subgroups of 12 patients the dose was shifted on 2 thrice daily regimens (B: 25 mg at 07:00, 6.25 mg at 12: 00, 6.25 mg at 17:00; C: 12.5 mg, 12.5 mg, 12.5 mg). In other 12 patients the conventional dose was reduced to a thrice 25 mg/day administration (D regimen: 12.5 mg, 6.25 mg, 6.25 mg). In all patients, urinary free cortisol (UFC) excretion and cortisol day curves were evaluated. During the CA 37.5 mg administration, nadir cortisol levels were significantly higher with the thrice daily regimens (143 +/- 31 on B and 151 +/- 34 nmol/l on C) than with the conventional twice (85 +/- 16 nmol/l). Moreover, UFC, morning cortisol levels and mean cortisol day curves were similar in each group. Finally, during D regimen nadir cortisol levels were higher than in A and similar to B and C regimens. No difference in UFC and in cortisol day curves by reducing the CA dose was found. In conclusion, the thrice daily cortisone regimens, in which more physiological cortisol levels are achieved, perform better as replacement therapy. The administration of 25 mg/day CA confirms that replacement therapy is more adequate with a lower dose, particularly in patients with central hypoadrenalism.     

Verapamil 240 SR versus verapamil 120 SR in arterial hypertension. A randomized double-blind,placebo-controlled study with 24-hour ambulatory blood pressure monitoring

Summary Fifteen patients (6 males, 9 females), age range 36–70 years, were enrolled in a randomized, double-blind, placebo-controlled study according to a Latin-square design, with the aim of comparing 24-hour blood pressure profiles after three 15-day treatment periods with placebo, verapamil SR 120 mg (V120 SR) given twice daily (bid), and verapamil SR 240 mg (V240 SR) given once daily (od.) All of the patients were diagnosed as mild or moderate essential hypertensives on the basis of standard casual recordings. Noninvasive 24-hour ambulatory blood pressure (BP) monitoring was performed with an ICR Spacelab 5200 automatic device. In comparison with placebo, a clinically and statistically significant reduction in both systolic and diastolic BP over 24 hours was obtained with both active treatments. Comparison of the two active treatments shows that V240 SR led to a greater reduction in systolic and diastolic BP than V120 SR. No changes in heart rate were observed. Both treatments were well tolerated. In conclusion, both verapamil regimens proved to be effective and safe in treating essential hypertensives, with V240 SR giving better 24-hour BP control.     

An Assessment of Optimal Hydrocortisone Replacement Therapy

OBJECTIVE To assess the management of hydrocortisone replacement therapy in one institution, and derive recommendations for optimum starting and maintenance replacement therapy with hydrocortisone. DESIGN Retrospective survey of clinical management using a clinical information system and the patient case notes. PATIENTS Using the department’s clinical information system, 210 patients were identified who had been treated with hydrocortisone. Case notes were reviewed and 130 patients were identified whose records contained the results of at least one valid hydrocortisone day curve. Data on 174 day curves performed on these patients (65 on twice daily and 109 on thrice daily hydrocortisone regimes) formed the basis of this analysis. METHODS Hydrocortisone day curves had been performed as part of routine clinical management: patients collected a 24 h urine for free cortisol on the day prior to the test and took their morning hydrocortisone at the normal time, at home, on wakening. During a day-case attendance serum cortisol was then measured at 0900 h, 1230 h (prior to any lunchtime dose) and 1730 h (prior to the evening dose). ‘Optimal replacement’ was arbitrarily defined as that dose which achieved a UFC and 09:00h cortisol within the reference range for the normal population (to avoid over-replacement) combined with 1230 h and 1730 h cortisol above 50 nmol/l, and ideally above 100 nmol/l (to avoid under-replacement). Raw data from all hydrocortisone day curves was analysed in an Excel spreadsheet to determine the effect of different dose regimens on the percentage of patients achieving each and all of these 4 criteria, and on an overall ‘quality score’ (comprising 1 point for each of the 4 criteria attained). RESULTS Patients on twice daily hydrocortisone regimes achieved optimal replacement in 15% of cases compared to 60% on thrice daily regimes (P < 0.001 by χ²); mean overall ‘quality scores’ for these regimens were 2.72 and 3.49 respectively (P < 0.001 by t-test). Of individual dose regimens with sufficient cases for valid comparison, a dose of 10 mg/5 mg/5 mg (rising/lunch/evening) achieved optimal replacement in 66% and mean ‘quality score’ of 3.62 (n = 53), compared to 50% and 3.32 for 10 mg/10 mg/5 mg (n = 28) and 10% and 2.48 for 20 mg/–/10 mg (n =29). CONCLUSIONS The use of arbitrary, but logical, criteria to assess the quality of hydrocortisone replacement regimens indicates that optimal replacement is achieved with thrice daily hydrocortisone regimens, and that the traditional twice daily regime results in a 0900 h cortisol above normal in one-third, and late afternoon cortisol below 50 nmol/l in one-half of patients thus treated. An appropriate starting dose of hydrocortisone of 10 mg/5 mg/5 mg (rising/lunch/evening) is suggested, with subsequent individual adjustment based on simple hydrocortisone day curves.     

Comparison of adherence between twice- and thrice-daily regimens of oral amoxicillin/clavulanic acid

Background and objective: Few studies have analysed adherence with antibiotic treatment in patients with respiratory tract infections. The aim of this study was to compare the compliance of patients taking a pharmacokinetically enhanced formulation of amoxicillin/clavulanic acid twice daily with that of patients taking the standard formulation thrice daily. Methods: Patients with suspected bacterial lower respiratory tract infections, pharyngitis and dental infections were included. Adherence was assessed by electronic monitoring, which recorded every opening of the patient's bottle of pills. The outcome variables were compliance with taking the medication, taking the correct dose and with timing of the dose. Results: A total of 240 patients were enrolled (167 in the thrice‐daily group and 73 in the twice‐daily group). The percentage of doses taken was greater with the twice‐daily regimen (84.5 ± 22.8%) than with the thrice‐daily regimen (72.7 ± 20.1%; P < 0.001). Forty patients in the twice‐daily group opened the container every 12 ± 6 h during at least 80% of the course (54.8%), while only 19.6% of the patients assigned to the thrice‐daily formulation did so every 8 ± 4 h (P < 0.001). The percentage of patients who opened the container a satisfactory number of times per day was significantly higher among those taking the twice‐daily regimen on days three, four, five, six and seven. Moreover, the thrice‐daily group more frequently forgot to take the afternoon dose. Conclusions: The rate of compliance with amoxicillin/clavulanic acid therapy was very low. However, compliance with the new formulation that is taken twice‐daily was significantly better.     

Effects of metoprolol succinate extended release vs. amlodipine besylate on the blood pressure,heart rate,and the rate-pressure product in patients with hypertension

Ambulatory monitoring of the blood pressure (BP) and heart rate allows for the assessment of the 24-hour rate-pressure product (RPP), a close correlate of myocardial oxygen demand, both in the untreated state and while on antihypertensive therapy. To evaluate the clinical effects of metoprolol succinate extended release (ER) tablets (100 mg titrated to 200 mg for clinic BP >140/90 mm Hg) vs. amlodipine (5 mg titrated to 10 mg for clinic BP >140/90 mm Hg) on the 24-hour and early morning hemodynamic parameters, we performed a double-blind crossover trial that included 8 weeks of active treatment, 4 weeks of placebo washout, and 8 weeks of active crossover treatment using 24-hour ambulatory blood pressure (ABP) measurements. Patients were included if they were untreated, had hypertension based on both clinic (140 to 179/90 to 109 mm Hg) and ABP recordings (>135/85 mm Hg while awake), and were 18 to 65 years of age. Patients enrolled in the trial (n = 35) had a mean age of 55 ± 7 years, 24-hour mean BP of 148/91 ± 11/7 mm Hg, heart rate (HR) of 76 ± 10 beats/minute, and a RPP of 11,230 ± 1717 mm Hg·beats·minute). In the early morning period (6 am to 10 am), baseline BP was 155/98 ± 11/7 mm Hg and the RPP was 12,084 ± 1752 mm Hg·beats·minute. The 24-hour diastolic blood pressure (DBP), HR, and RPP were lowered to a greater extent by metoprolol succinate compared with amlodipine. Additionally, changes from baseline in early morning DBP, HF, and RPP were lowered to a significantly greater extent by metoprolol (mean dose, 124 ± 44 mg daily) compared with amlodipine (mean dose, 7.2 ± 2.5 mg daily) (P = .02 for DBP and P < .0001 for HR and the RPP). The incident rates of adverse events were low and similar for the two treatment groups. These data demonstrate that metoprolol succinate ER induced greater reductions in early morning BP, HR, and FPP than amlodipine in middle-aged patients with Stages 1 and 2 hypertension. These findings have clinical implications for patients with hypertension and coronary heart disease.     

Verapamil and 24-hour ambulatory blood pressure monitoring in essential hypertension

The antihypertensive effects of oral regular and slow-release verapamil, a calcium-channel blocking agent, were evaluated in 22 patients with mild to moderate hypertension (sitting diastolic blood pressure [DBP] 95 to 112 mm Hg). The dose required to control blood pressure varied from 80 to 120 mg, 3 times a day. All patients received regular verapamil for a further 3 to 4 months, when systolic blood pressure (SBP) and DBP had risen from the end of the open-label phase. During a double-blind phase patients were randomly assigned to continue the same dose of regular verapamil, 3 times a day, or an equivalent daily dose of sustained-release verapamil (240 to 360 mg once a day). Seven of the 11 patients on regular and 3 of the 11 on sustained-release verapamil were also taking diuretics. This antihypertensive program was continued for at least 4 weeks. During the efficacy period, 24-hour ambulatory blood pressure monitoring was carried out. Mean 24-hour SBP and DBP were 133 +/- 20 and 89 +/- 13 mm Hg, respectively, on regular and 131 +/- 22 and 87 +/- 12 mm Hg, respectively, on sustained-release verapamil. There were no statistically significant differences noted between the 2 groups. Mean SBP and DBP varied similarly during awake and sleep hours with both formulations of verapamil. With regular verapamil, SBP was 139 +/- 18 and 124 +/- 20 mm Hg and DBP 92 +/- 11 and 84 +/- 13 mm Hg during awake and sleep hours, respectively; with sustained release, SBP was 138 +/- 21 and 122 +/- 22 mm Hg and DBP 92 +/- 10 and 80 +/- 10 mm Hg during awake and sleep hours, respectively. Heart rate fell during the entry period and continued during the entire study period. No other adverse effects were noted during the double-blind phase. In summary, verapamil is an effective antihypertensive medication and can be administered once a day as a sustained-release preparation; it is most useful in patients in whom adrenergic blocking drugs are indicated.     

Efficacy of once-daily lisinopril monotherapy in systemic hypertension

Lisinopril is a new, long-acting angiotensin-converting enzyme inhibitor formulated for once-daily treatment of hypertension. This study assessed the 24-h efficacy and tolerability of lisinopril in Chinese patients with mild to moderate hypertension of World Health Organization Stages I to II. A total of 30 patients aged 30 to 60 years (mean 47 ± 9) entered a 2-week washout period. All patients had ambulatory diastolic blood pressure (BP) > 90 mmHg and were given active treatment with lisinopril for 4 to 7 weeks. The dose of lisinopril was titrated from 10 to 40 mg daily (at 8-9 A. M.). In each patient, 24-h ambulatory blood pressure (BP) monitoring (SpaceLabs 90202) was performed twice, once before and once following treatment. Mean 24-hour systolic/diastolic BPs after lisinopril were significantly decreased compared with baseline values (132 ± 12/86 ± 7 vs. 150 ± 11/98 ± 7 mmHg; p < 0.0005/ 0.0005). The average dose of lisinopril was 14.5 ± 5 mg daily after a titration period of 5 weeks of treatment. Mean daytime (6 A. M. to 6 P. M.) BP decreased from 152 ± 11/100 ± 8 to 134 ± 12/87 ± 8 mmHg (p < 0.0005/0.0005) and nighttime (6 P.M. to 6 A. M.) BP from 147 ± 14/95 ± 9 to 128 ± 14/83 ± 8 mmHg ( p < 0.0005/0.0005). BP reduction was more pronounced during the night. Before treatment, the circadian variation showed a peak BP at 11 A. M. and nadir at 3 P. M. After treatment, significant BP reduction (p < 0.0005/0.0005) was seen throughout the 24-h period. The circadian rhythm of BP was preserved as indicated by similar BP standard deviations (14 ± 3/11 ± 2 vs. 13 ± 3/10 ± 2 mmHg). Mean heart rate increased from 76 to 80 beats/min (p < 0.05). Four patients reported having a nonproductive cough. Thus, lisinopril administered as once-daily monotherapy provided effective BP control over a 24-h period with preserved circadian rhythm.     

Comparison of sustained-release formulations of nicardipine and verapamil for mild to moderate systemic hypertension.

In this double-blind, parallel, multicenter study, sustained-release (SR) preparations of 2 calcium antagonists, nicardipine and verapamil, were compared for the treatment of mild to moderate systemic hypertension. Two hundred eighteen patients with supine diastolic blood pressures (BP) 95 to 114 mm Hg were randomly assigned to receive nicardipine-SR 45 mg twice daily (n = 73), nicardipine-SR 60 mg twice daily (n = 73) or verapamil-SR 240 mg once daily in the morning (n = 72). All 3 regimens significantly reduced supine and sitting systolic and diastolic BPs compared with baseline values (p < 0.005). The efficacy of drugs became apparent after 2 weeks of therapy, and was sustained throughout the 12-week study. Reductions in sitting diastolic BP and supine and sitting systolic BPs were statistically greater with nicardipine-SR 60 mg twice daily compared with verapamil, and nicardipine-SR 45 mg twice daily was equivalent to verapamil. Asthenia and constipation occurred more frequently in patients treated with verapamil (9.7 and 11.1%, respectively, compared with 6.8 and 4.1% in either nicardipine group). Adverse events reported more frequently with nicardipine were headache (17.8% with nicardipine-SR 60 mg and 15.1% with nicardipine-SR 45 mg vs 13.9% with verapamil) and edema (15.1% in the nicardipine-SR 60 mg group, 8.2% with nicardipine-SR 45 mg vs 4.2% with verapamil). Verapamil, but not nicardipine, produced significant reductions in heart rate. SR preparations of calcium antagonists offer options for effective monotherapy of systemic hypertension. Side-effect profiles differ and may affect choice of therapy.     

Overnight metabolic fuel deficiency in patients treated conventionally for hypopituitarism

BACKGROUND Hormone replacement in hypopituitary adults attempts to reproduce normal physiology. Conventional regimens fail to mimic normal hormone profiles over 24 hours. OBJECTIVE To investigate the metabolic consequences of conventional hormone replacement in hypopituitary adults by measuring circulating levels of the major fuels, glucose, non-esterified fatty acids (NEFA), glycerol and 3-hydroxybutyrate (3-OHB) over 24 hours in hypopituitary subjects and controls. SUBJECTS Ten GH and adrenocorticotrophin deficient hypopituitary adults on conventional replacement and 13 controls matched for age, sex and body mass index were studied. The patients received replacement with hydrocortisone twice daily (at 0730 and 1730 h; mean (range) daily dose 22 (10–30) mg/24 h) but not with GH. Other hormones were replaced as clinically necessary. MEASUREMENTS Circulating glucose, NEFA, glycerol and 3-OHB levels were measured over 24 hours together with concentrations of cortisol (total and free), GH and insulin, and urinary free cortisol. RESULTS Levels of glucose, NEFA and 3-OHB were lower in patients than controls (mean ± SEM) (4.3 ± 0.1 vs 5.3 ± 0.1 mmol/l, P = 0.0001; 291 ± 46 vs 448 ± 48 μmol/l, P = 0.015; 78 ± 8 vs 136 ± 24 μmol/l, P = 0.035, respectively) before breakfast. This decrease in glucose, NEFA and 3-OHB was observed in the patient group throughout the night, from midnight to breakfast. For NEFA, the decrease persisted throughout the 24 hours. Glycerol did not differ significantly in patients and controls. Integrated levels of total and free plasma cortisol, and 24-hour urine cortisol excretion, were normal in patients but total and free plasma cortisol concentrations overnight were markedly decreased (overnight area under the curve (AUC) of total cortisol: 440 ± 154 vs 1593 ± 267 nmol/l h, P = 0.0024; overnight AUC of free cortisol: 24 ± 8 vs 161 ± 26 nmol/l h, P = 0.0001). GH levels were low throughout the whole 24 hours in the patient group (24-hour AUC: 10.6 ± 5.1 vs 74.6 ± 19.6 mU/l h, P = 0.008). CONCLUSIONS Hypopituitary adults on conventional hormone replacement regimens have low concentrations of metabolic fuels, glucose, non-esterified fatty acids and 3-hydroxybutyrate throughout the night, possibly related to GH deficiency or to decreased overnight circulating cortisol levels. This overnight fuel deficiency may underlie the mechanism for the non-specific symptoms, such as fatigue and headache in the early morning, which are frequent in this group of patients.     

Acetylsalicylic acid mitigates erythropoietin-associated blood pressure increase in nonuremic rats

Abstract

Background: Approximately 30% of the chronic kidney disease patients using recombinant human erythropoietin (rhuEPO) have an increase in blood pressure (BP). Its mechanism and whether it depends on renal function remain unclear. There is early evidence that acetylsalicylic acid (ASA) prevents the rhuEPO-induced increase in BP. This study aims to verify whether very high doses of rhuEPO can increase BP in nonuremic rats and whether the co-administration of ASA can prevent it. Methods: Forty male Wistar rats were divided into four groups: placebo/placebo; placebo/rhuEPO 200?UI/kg thrice weekly; placebo/ASA 50?mg/kg daily; rhuEPO 200?UI/kg thrice weekly/ASA 50?mg/kg daily. Hematocrit was measured before and after and systolic BP was measured weekly by tail-cuff technique. Direct measurement of the BP was obtained at the end. Results: The rhuEPO groups had higher final hematocrit (rhuEPO/placebo 56.7?±?7.6, rhuEPO/ASA 56.7?±?7.7; p?<?0.001 versus placebo/placebo, 42.2?±?4.7 and ASA/placebo 41.2?±?4.2); and also increase in systolic BP (rhuEPO/placebo 135.1?±?15.0, p?=?0.01 and rhuEPO/ASA 127.2?±?6.8, p?=?0.02), whereas BP in rats from placebo/placebo (120.9?±?5.0, p?=?0.18) and placebo/ASA (124.6?±?13.3, p?=?0.12) groups remained unchanged. By direct measurement, the final BP was higher in rhuEPO/placebo (DBP 123.1?±?12.0; SBP 157.4?±?12.5; MBP 139.8?±?11.9) than placebo/placebo (DBP 105.1?±?11.5; SBP 141.0?±?12.6; MBP 122.1?±?12.1) and placebo/ASA groups (DBP 106.6?±?8.1; SBP 141.5?±?8.4, MBP 122.1?±?7.2) (p?<?0.05 by post hoc Bonferroni test ANOVA). The rhuEPO/ASA group (PAD 115.1?±?11.4, PAS 147.4?±?9.1, MBP 130.1?±?10.3) was not different from other groups. Conclusions: The administration of very high doses of rhuEPO is associated with an increase in hematocrit and BP in nonuremic rats. The concomitant use of ASA mitigates the rhuEPO-associated BP increase.     

Experience With Ketanserin,A Serotonin (S2) Antagonist,in Longterm Treatment of Essential Hypertension

Ketanserin is a quinazoline derivative which acts selectively on serotonin (S₂) receptors. The compound has been shown to possess antihypertensive properties. BP and HR were measured blindly on 14 patients with essential hypertension during one year. Ketanserin 40 mg, once or twice daily, reduced BP (and HR to a slight extent) largely unchanged from 14 days after initiation of therapy. Response rate varied from 57–77% at the regular control visits. During the one year follow up period the reduction in supine SBP was 9±3% (p < 0.001) and DBP was 12±1% (p < 0.001) The only side effect was a slight sedation that passed with time.

It is concluded that ketanserin is effective in the chronic treatment of hypertension and may offer a new alternative to existing pharmacotherapy.     

Antihypertensive monotherapy with nisoldipine CC is superior to enalapril in black patients with severe hypertension

A single-center, prospective double-blind randomized trial was conducted to compare the efficacy and safety of the calcium channel blocker nisoldipine in a sustained release coat-core formulation (CC), titrated from 10 mg to 40 mg daily, with the angiotensin converting enzyme inhibitor enalapril, titrated from 10 to 40 mg daily, in the treatment of black South African patients with severe hypertension (sitting diastolic blood pressure [DBP] between 115 and 140 mm Hg, confirmed by 24-h ambulatory blood pressure monitoring). Treatment target was a sitting DBP < 95 mm Hg by the 9th week of treatment. This was followed by a 4-month open phase using nisoldipine CC 10 to 60 mg daily. Ninety-six patients had complete data at baseline, and at the end of the double-blind and open phases, and were included in this analysis.In both groups, all patients required titration up to the maximal dose of double-blind medication. Monotherapy with nisoldipine CC, but not enalapril, significantly reduced both sitting and 24-h ambulatory blood pressure (BP). Twenty-four–hour BP in the nisoldipine CC group decreased from 179 ± 14/118 ± 7 to 144 ± 16/94 ± 10 mm Hg (P < .0001) versus 181 ± 13/117 ± 5 to 171 ± 17/110 ± 11 mm Hg in the enalapril group (P = ns). The profound decrease in blood pressure achieved with nisoldipine CC was accompanied by a significant reduction in left ventricular [LV] mass index, observed after only 2 months of treatment (from 146 ± 40 to 129 ± 35 g/m², P = .05). In contrast, enalapril had no effect on LV mass (from 139 ± 36 to 142 ± 50 g/m², P = NS). The antihypertensive effect of nisoldipine CC was further demonstrated in the open phase, during which 24-h BP decreased from 180 ± 14/118 ± 6 mm Hg (at baseline) to 142 ± 16/92 ± 10 mm Hg at the end of the 16-week open phase (P < .0001). This effect was sustained with trough-to-peak ratio of 74% for systolic and 67% for diastolic BP, with further regression in LV mass. Reduction in 24-h systolic BP to < 135 mm Hg was associated with a greater degree of regression of LV mass index in patients treated with nisoldipine CC. The incidence of adverse events in both groups was low and both nisoldipine CC and enalapril were well tolerated. The incidence of significant ventricular arrhythmia was also low and did not change with treatment.In conclusion, our findings suggest that nisoldipine CC administered once daily could be considered as a suitable first-line antihypertensive agent in black patients with severe hypertension, based on its profound and sustained blood-pressure–lowering effect, associated with significant regression of left ventricular mass and its low side effect profile.     

A comparison of the safety of therapeutically equivalent doses of isradipine and diltiazem for treatment of essential hypertension.

We compared the safety of a new dihydropyridine calcium entry blocker, isradipine, with an equipotent dose of diltiazem in 174 mild hypertensives (diastolic blood pressure [DBP] 95 to 105 mm Hg). After appropriate washout and placebo periods, patients were randomly assigned to receive either 1.25 mg isradipine twice daily (Group I) or 40 mg diltiazem thrice daily (Group D). If DBP remained above 90 mm Hg, doses were increased to a maximum of 5 mg isradipine twice daily or 120 mg diltiazem thrice daily. Active therapy was given for a total of 12 weeks. Only 18 patients (nine from each group) did not complete the protocol. The patients were well-matched at baseline with a mean BP of 149/100 mm Hg for those who were randomized to isradipine and completed the protocol and 153/99 mm Hg for the diltiazem group. The responses to each drug were excellent with 72% of the isradipine patients and 73% of the diltiazem group having DBP less than 90 mm Hg at the completion of the study. Of the 156 patients who completed the protocol, only 18 patients (ten in Group I and eight in Group D) failed to respond. Both drugs were well-tolerated. No adverse reactions were reported by 68 percent of the patients in Group I and 65% of those in Group D. The most common side effect was headache (9.0% in Group I and 7.8% in Group D) followed by fatigue (5.2% in Group I and 3.9% in Group D). Age and race did not predict response to either agent but men responded slightly better to diltiazem than women. We conclude that isradipine and diltiazem are equally well tolerated and can be used successfully as a monotherapy to treat hypertension in a wide variety of patients.     

Blood Pressure-Lowering Efficacy of Amiloride versus Enalapril as Add-On Drugs in Patients with Uncontrolled Blood Pressure Receiving Hydrochlorothiazide

A large proportion of patients with hypertension need a second drug to reach satisfactory control of blood pressure (BP), but there are few well-designed controlled trials comparing the efficacy of drugs added as a second option. In a double-blind randomized clinical trial, 82 patients with uncontrolled BP, receiving hydrochlorothiazide 25 mg daily, were selected to receive amiloride 2.5–5 mg/day (n?=?39) or enalapril 10–20 mg/day (n?=?43). Ambulatory blood pressure monitoring (ABPM) was done before and after 12-weeks of treatment. Office BP was measured in the 4^th, 8^th, and 12^th weeks. The doses of amiloride and enalapril were doubled in the fourth week, and propranolol was added in the 8th week if office BP was above 140/90 mm Hg. There was a greater BP reduction in patients treated with enalapril. The ABPM δ values between the groups were 3.6?±?2.2, 3.9?±?2.2, and 1.1?±?2.7 mmHg for 24-h, daily, and nightly systolic blood pressure, respectively, favoring enalapril. For diastolic blood pressure (DBP), the deltas were 1.7?±?2.0, 3.2?±?1.5, and 1.2?±?1.9 mmHg, respectively (p?=?0.039 for daily DBP). Office SBP decreased more and sooner in patients allocated to enalapril (p?=?0.003). More patients taking amiloride required propranolol to control BP (p?=?0.035). Potassium increased 0.3 mEq/L on the average in both groups. Cough, albeit predominantly mild, was reported more frequently by participants treated with enalapril. We conclude that enalapril is more effective than amiloride to lower BP of patients on hydrochlorothiazide with uncontrolled BP.

Trial registration: ClinicalTrials.gov identifier: NCT00394394.     

Twice-daily administration of oral verapamil in the treatment of essential hypertension

The antihypertensive effect of twice-daily administration of verapamil hydrochloride was evaluated in 21 adult patients with mild to moderate essential hypertension. Following four weeks of placebo therapy, verapamil was given for four weeks with a treatment goal of sitting diastolic blood pressure (BP) of less than 90 mm Hg, or to a maximum dose of 160 mg twice daily. Sitting and standing BPs, heart rate, and verapamil plasma levels were determined weekly, ten to 12 hours post dose. At the maximal dose (mean, 154 +/- 19.2 mg), heart rate was not affected, side effects were minimal, and sitting diastolic BP was significantly reduced from placebo baseline, with 12 of 21 patients having a fall in sitting diastolic BP of 10 mm Hg or more or less than 90 mm Hg. A trough verapamil plasma level of greater than 80 ng/mL was associated with a good hypotensive response. These data indicate the safety and utility of twice-daily verapamil administration for the treatment of essential hypertension and suggest the value of obtaining verapamil plasma levels as a guide to dosage determination.     

Comparison of valsartan and amlodipine on ambulatory blood pressure variability in hypertensive patients

We tested the hypothesis that calcium channel blockers (CCBs: amlodipine group, n = 38)) are superior to angiotensin receptor blockers (ARBs: valsartan group, n = 38) against ambulatory blood pressure variability (BPV) in untreated Japanese hypertensive patients. Both drugs significantly reduced ambulatory systolic and diastolic BP values. With regard to BPV, standard deviation (SD) in SBP did not change with the administration of either drug, but the ARB significantly increased SD in awake DBP (12 ± 4–14 ± 4 mmHg). The ARB also significantly increased the coefficients of variation (CVs)in awake and 24-h SBP/DBP (all P < 0.05), but amlodipine did not change the CV. CCB significantly reduced the maximum values of awake SBP (193 ± 24–182 ± 27 mmHg, P = 0.02), sleep SBP (156 ± 18–139 ± 14 mmHg, P < 0 .001), and awake and sleep DBP (P < 0.01 in both cases), but the ARB did not change the maximum BP values. In conclusion, a once-daily morning dose of CCB amlodipine was more effective at controlling ambulatory BPV than ARB valsartan, especially in reducing maximum BP levels.     

Antiarrhythmic significance of dosing intervals in beta receptor blocking therapy of hypertension with acebutolol

Six hypertensive patients with daily ventricular arrhythmias underwent a double-blind crossover study to examine whether a once daily regimen of beta receptor blockade was equipotent in antihypertensive and antiarrhythmic activity to a twice daily regimen. Acebutolol, a relatively cardioselective beta blocking compound with intrinsic sympathomimetic properties, was given in two regimens: 200 mg twice daily or 400 mg once daily. Ventricular ectopic beats were analyzed both during physical exercise and with multiple 24 hour ambulatory electrocardiographic (Holter) recordings. Serum concentrations of acebutolol and its acetyl metabolite were determined using high pressure liquid chromatography. The two regimens of acebutolol were equally potent in reducing the blood pressure and heart rate at rest and during physical exertion. The hourly heart rates during 24 hours were reduced to the same extent by both regimens. The single daily 400 mg dose did not significantly reduce the incidence of arrhythmias, whereas 200 mg twice daily evoked a significant reduction during 24 hours. Serum concentrations of acebutolol were twice as great with the twice daily regimen as with the single dose. Both treatments significantly shortened the Q-Tc interval. The data suggest that, despite apparent beta receptor blockade and good blood pressure control, beta blocking agents with a relatively short plasma half-life lose their antiarrhythmic potency when administered on a once daily basis. This property seems to be more related to the plasma concentration of the compound than to the degree of clinically assessed beta receptor blockade.     

Comparison of aspirin and indobufen in healthy volunteers

The aim of this study is to quantify the extent and recovery of platelet inhibition after administration of indobufen and aspirin in healthy volunteers. Indobufen inhibits platelet aggregation by reversibly inhibiting the platelet cyclooxygenase enzyme, thereby suppressing thromboxane synthesis. Twenty healthy volunteers completed the study and received aspirin (200?mg/day for 2 weeks) followed by a 4-week washout period and then indobufen (200?mg twice a day for 2 weeks). The percent (%) inhibition of platelet aggregation (IPA) was assessed using arachidonic acid (0.5?mg/ml) and adenosine diphosphate (5?µM) at 4, 12, 24 and 48 hours after last dose of each drug. IPA assessed using arachidonic acid as the agonist was similar at 4 hours after the last dose of indobufen (81.07?±?9.36%) and aspirin (96.99?±?0.29%, p?=?0.10), but significantly lower at 12 hours (74.04?±?9.55% vs. 97.94?±?0.28%, p?=?0.02), 24 hours (33.39?±?11.13% vs. 97.48?±?0.32%, p?p?p?=?0.002). Indobufen (200?mg twice a day) caused equivalent initial inhibition of platelet aggregation to aspirin (200?mg daily), and the anti-aggregation effect diminished faster than after aspirin.     

Verapamil administered twice daily in stable angina pectoris

To assess whether verapamil taken orally twice daily (bd) was as effective as four times daily (qd) in patients with angina a placebo controlled double blind crossover trial was conducted in 12 patients. Each patient was randomized to verapamil, 160 mg bd, 80 mg qd, or corresponding placebo, each for three weeks. Patients were assessed subjectively and by treadmill exercise test. On both verapamil regimens, patients had less angina with delayed onset of ST segment depression during exercise compared to placebo, without any differences between the two regimens. On bd verapamil, patients could increase their exercise capacity as much as on qd without any increase in adverse effects. Angina threshold during exercise was increased by both regimens with a slightly higher threshold on qd verapamil compared to bd. Therefore, administration of verapamil twice daily is effective in patients with stable angina pectoris, with a similar efficacy to taking verapamil four times daily without any increase in adverse effects.