Antihypertensive effect of diltiazem administered once and twice daily

This study was undertaken to compare the antihypertensive effect of diltiazem administered once or twice daily. After a two week wash-out period, eight hypertensive patients were treated for two consecutive four week phases with 180 mg once daily or 90 mg twice daily of a sustained-release formulation of diltiazem. The sequence of the treatments was randomised and the trial carried out in a double-blind fashion. Ambulatory daytime BP profiles were obtained using a portable BP recorder (Remler M2000). The average of all BP readings taken during the monitoring period was 159/104 +/- 21/10 mgHg (mean +/- SD) at the end of the wash-out period and 145/90 +/- 20/12 and 148/95 +/- 21/11 mmHg under treatment with diltiazem 180 mg once daily and 90 mg twice daily, respectively. These data indicate that 180 mg of a slow-release formulation of diltiazem are as effective in lowering the BP of hypertensive patients when administered daily in a single dose as when divided into two doses.     

Antihypertensive effect of isradipine administered once or twice daily on ambulatory blood pressure

The antihypertensive efficacy of sustained-release isradipine administered once daily compared to the immediate-release formulation administered twice daily was assessed by ambulatory blood pressure (BP) monitoring in a double-blind randomized crossover study in 76 mild-to-moderate hypertensive patients. Conventional BP and heart rate parameters were evaluated after a 4-week placebo period and patients qualified for entry if sitting diastolic BP was between 95 and 114 mm Hg. Ambulatory BP monitoring was measured at baseline and after active treatment with both formulations. The 2 regimens induced a significant and almost identical reduction (p less than 0.001) in the mean 24-hour BP without affecting heart rate. Isradipine was more effective in patients whose clinical hypertension was confirmed by ambulatory BP monitoring (35) than in patients who remained normotensive by ambulatory BP monitoring criteria (41). The isradipine-treated ambulatory hypertensive group experienced significantly greater decreases in BP during 24-hour, work, awake and sleep periods than did the ambulatory normotensive group. These data suggest that sustained-release isradipine has a sustained antihypertensive effect throughout 24 hours comparable to that of isradipine given twice daily and may improve compliance with long-term treatment. In addition, the results confirm the usefulness of ambulatory BP monitoring in determining truly hypertensive patients likely to respond to drug administration.     

Effects of vildagliptin twice daily vs. sitagliptin once daily on 24-hour acute glucose fluctuations

There is increasing evidence that glycemic disorders such as rapid glucose fluctuations over a daily period might play an important role on diabetic complications. We evaluated the efficacy of sitagliptin 100 mg once daily vs. vildagliptin 50 mg twice daily on daily blood glucose fluctuations in patients with type 2 diabetes that was inadequately controlled by metformin.Forty-eight-hour continuous subcutaneous glucose monitoring (CSGM) was performed in patients treated with metformin plus vildagliptin (n=18) or sitagliptin (n=20) over a period of 3 months. The mean amplitude of glycemic excursions (MAGE) was used for assessing glucose fluctuations during the day. During a standardized meal, glucagon-like peptide-1 (GLP-1), glucagon, and insulin were measured.CSGM shows large MAGE decrements in the vildagliptin group compared with the sitagliptin group (P<.01). A marked increase in GLP-1 occurred during interprandial period in vildagliptin bid-treated toward sitagliptin 100 mg once daily (P<.01). Glucagon was more suppressed during interprandial period in subjects receiving vildagliptin compared to those receiving sitagliptin (P<.01). Since MAGE is associated with an activation of oxidative stress, our data suggest that dipeptidyl peptidase IV inhibition therapy should target not only reducing HbA_1c but also flattening acute glucose fluctuations over a daily period.     

24-hour blood pressure profiles in hypertensive patients administered ramipril or placebo once daily: magnitude and duration of antihypertensive effects. Ramipril Multicenter Study Group.

Ramipril is a new, potent nonsulfhydryl inhibitor of angiotensin converting enzyme. The magnitude and duration of its antihypertensive effect were evaluated in a multicenter, placebo-controlled, randomized clinical trial conducted in 100 patients with mild to moderate essential hypertension. Ramipril significantly reduced both supine and standing blood pressures measured 24 h after dosing. Automated blood pressure monitoring showed that ramipril significantly reduced systolic and diastolic pressures for 24 h after dosing. The peak effect occurred between 3 and 6 h after dosing, with approximately 50% of this effect retained after 24 h. Ramipril was well tolerated; there was no significant difference between active drug and placebo in the overall incidence of side effects. Ramipril is an effective and well-tolerated antihypertensive agent, which reduces both supine and standing blood pressure over the entire 24-h period after dosing.     

Metabolic effects of growth hormone administered subcutaneously once or twice daily to growth hormone deficient adults

OBJECTIVE The aim of this study was to compare the metabolic effects of GH administered subcutaneously either once or twice daily. The actions of GH might depend upon a pulsatlle pattern of serum GH. Pulsatile and continuous intravenous delivery of GH, however, induce similar short-term metabolic effects in GH deficient patients. An improved growth response is obtained in GH deficient children when a fixed weekly GH dose Is administered by dally subcutaneous injections instead of twice or thrice-weekly intramuscular injections. A more pulsatile pattern and serum GH levels above zero might be achieved by further increasing the Injection frequency. Increased daytime GH levels might, however, adversely affect the circadian patterns of metabolic indices, whlch have been demonstrated to be more successfully reproduced by evening compared with morning GH administration. DESIGN AND MEASUREMENTS In a cross-over study, 8 GH deficient patients (age 16–43 years) were treated with 3IU/m²/24h of human GH. The dose was injected in the evening for 4 weeks and for another 4 weeks two-thirds was injected in the evening and one-third in the morning. At the end of each period the patients were admitted to the hospital for 37 hours. Steady-state profiles of GH, IGF-I, IGF binding proteins 1 and 3, Insulin, glucose, lipid Intermediates and metabolites were obtained following administration of 3IU/m² of GH (at 1900 h (one injection) and at 1900 and 0800 h (two injections). RESULTS Similar mean integrated levels of serum GH (mUII) were obtained (7·46 ± 0·84 (one injection) vs 6·46 ±0·62 (two Injections) (P = 0·15). Mean levels ± SEM of serum IGF-I (μg/I) were significantly increased (P < 0·01) following two daily GH Injections (330·3±48·1 (one Injection) vs 399·1±53·0 (two injections). Serum IGFBP-3 levels were not signlflcantly different on the two occasions, while levels of the GH Independent IGFBP-1 (μg/l) were slightly but significantly lower following twice-dally GH injections (1·61±0·42 vs 1·13 ±0·56, respectively (P < 0·04). The pattern of IGFBP-1 was opposite to that of insulin. Similar levels of insulin and glucose were obtained with both GH regimens, while levels of non-esterlfied fatty acids were significantly higher following once-dally GH injection (P < 0·001). CONCLUSIONS Twice-dally GH injections, apart from producing a more physiological serum GH profile, were superior to one Injection in increasing serum IGF-I and decreasing IGFBP-1 levels. Both of these changes tend to amplify the effects of the administered GH. Twice-daily Injections, however, resulted Ln lower night-time levels of lipid Intermediates.     

Comparison of dilevalol and enalapril administered once daily for mild hypertension

This was a multicenter, randomized, double-blind, parallel-group study of the efficacy and safety of dilevalol, 200 mg (n = 86), compared with enalapril, 20 mg (n = 92), administered once daily to patients with mild hypertension. Three weeks of placebo washout were followed by 4 weeks of comparative treatment. Beginning with the first week of treatment, both drugs substantially decreased blood pressure from baselines of approximately 160/100 mm Hg. Decreases in systolic pressure were comparable throughout treatment, but dilevalol tended to have a greater effect on diastolic pressure. At the end of double-blind treatment, average decreases in blood pressure with dilevalol and enalapril were 16/13 and 16/11 mm Hg supine and 15/13 and 15/10 mm Hg standing (p = 0.03 for between-group comparisons of standing diastolic pressure). More dilevalol- than enalapril-treated patients achieved a diastolic pressure less than 90 mm Hg; 73 vs 55% (p = 0.02) supine, and 69 vs 43% (p less than 0.01) standing. The safety profiles of the 2 drugs were comparable. The incidence of adverse effects was low, and few patients discontinued treatment. Headache and gastrointestinal discomfort were reported in both groups. Average postural changes in blood pressure were similar to baseline. Electrocardiographic changes were rare and not treatment related. Changes in laboratory test results were minor. Heart rate decreased modestly with dilevalol relative to enalapril (6 vs 2 to 3 beats/min; p less than 0.01), but no bradycardia was observed.     

Comparative efficacy of two different beta-blockers on 24-hour blood pressure control.

Atenolol and metoprolol succinate, dosed once daily, have different pharmacokinetic profiles. This study tests the hypothesis that differences that are especially noted in the early morning period, when cardiovascular risk is highest, in 24-hour blood pressure (BP) control exist between these 2 beta-blockers. This was a small, randomized open-label study with blinded end point evaluation in 36 hypertensive patients. All participants received hydrochlorothiazide 12.5 mg for 2 weeks before randomization to either 50 mg atenolol or metoprolol succinate given every morning; both treatments were force-titrated to 100 mg/d at 4 weeks. The primary end point was the change in early morning ambulatory systolic BP. Early morning (12 AM-6 AM) systolic BP differences were 3+/-14 mm Hg with atenolol vs -7+/-8 mm Hg with metoprolol succinate (P=.03). The overall 24-hour changes in systolic BP were 1+/-15 mm Hg with atenolol vs -9+/-11 mm Hg with metoprolol (P=.03). In conclusion, metoprolol succinate was more effective in sustaining 24-hour and early morning BP reductions compared with atenolol in a small group of hypertensive patients also treated with once-daily low-dose hydrochlorothiazide. It is possible that differences in outcome between atenolol-based and other therapies may be the result of inadequate dosing of atenolol, a medication that may not be effective for the entire 24-hour period.     

Antihypertensive efficacy of once daily MK-521, a new nonsulfhydryl angiotensin-converting enzyme inhibitor

The effects of the new nonsulfhydryl-containing oral converting-enzyme inhibitor MK-521 on blood pressure, heart rate, angiotensin-converting enzyme activity, plasma renin activity and plasma aldosterone concentration were assessed in 10 hypertensive patients. After a 2-week no-treatment period, patients received placebo and then 14 days each: MK-521 20 mg once daily, hydrochlorothiazide 50 mg once daily and the latter 2 in combination. During the last day of each treatment, the mean (+/- standard deviation) time-averaged (1- to 12-hour) standing diastolic blood pressure decreased from 106 +/- 8 (placebo) to 95 +/- 10 mm Hg with MK-521, 95 +/- 13 mm Hg with hydrochlorothiazide (p less than 0.05 vs placebo) and 88 +/- 11 mm Hg with the combination (p less than 0.05 vs all other treatments). The antihypertensive effect of MK-521 was maintained 24 hours after dosing. Heart rate did not change significantly after MK-521 treatment. MK-521 caused a marked suppression of converting enzyme activity for over 24 hours; plasma renin activity increased significantly after each active treatment and MK-521 significantly decreased the hydrochlorothiazide-induced elevation of plasma aldosterone concentration. In this short-term trial, MK-521 was well tolerated.     

Pharmacotherapy in congestive heart failure: Cardiopulmonary effects of ophthalmically administered beta-blockers

Early clinical studies reported that timolol and other topical beta-blockers were effective in reducing intraocular pressure, without the side effects associated with other antiglaucoma agents. However, because people with cardiovascular or respiratory diseases were generally excluded from many of these early studies, the risk of serious cardiovascular and respiratory side effects was seriously underestimated. Once these drugs were made available to the general population, reports of systemic side effects began to proliferate. Very quickly adverse effects from topical beta-blockade became "old news." Despite this new found recognition, many treating physicians still remained unaware of the potential for systemic beta-blockade from topical applied beta-blockers. A significant portion of a topically administered dose of a beta-blocker can be absorbed and thereby effect systemic beta-blockade. Sensitivity to systemic beta-blockade can be quite dramatic in certain highly susceptible patients, particularly those with either cardiac or pulmonary abnormalities. Careful review of patients' medications will generally lessen, but not completely eliminate, the risk of undesired complications attributable to topical beta-blockade.     

Continuous 24-hour registration of intra-arterial pressure in basal states and during therapy with a fixed slow-release oxprenolol-chlorthalidone combination, administered once a day

Intra-arterial 24 hour blood pressure (BP) recording (OXFORD MEDILOG) was carried out in 10 patients with essential hypertension, 6 males and 4 females, aged between 41 and 58 years, 3 at WHO stage 1 and 7 at stage 2, in basal conditions and after 6 weeks of treatment with a fixed combination of 160 mg of slow-release oxprenolol and 20 mg of chlorthalidone per tablet (tb). The fixed combination was given once daily, in the morning, at the dosage of 1 tb, which was increased to 2 tbs o.d. after the first 2 weeks in 6 patients. Computer calculated mean BP and heart rate (HR) values from each consecutive hour of the day were obtained in all patients. Hourly trend of BP and HR were plotted and circadian variations were thus determined. Treatment with fixed combination o.d. significantly reduced systolic and diastolic BP, compared to pretreatment values, throughout of the 24 hours (p less than 0.01; p less than 0.001), without altering the circadian rhythm. Before and after 6 weeks of treatment, a bicycle exercise test was performed in 8 patients, who reached 85% of the maximal predicted HR. Pretreatment resting mean BP (+/- SD) was 190 +/- 31/108 +/- 10 mmHg (HR: 68 +/- 9 b/min) and those during the last minute of exercise 242 +/- 29/125 +/- 5 mmHg (HR: 147 +/- 13 b/min); posttreatment resting BP was 161 +/- 20/88 +/- 7 mmHg (HR: 58 +/- 7 b/min) and at peak exercise, 212 +/- 16/106 +/- 7 mmHg (p less than 0.025 for the systolic pressure; p less than 0.001 for the diastolic pressure).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects on 24-hour intragastric pH: a comparison of lansoprazole administered nasogastrically in apple juice and pantoprazole administered intravenously

OBJECTIVE: To compare the 24-h intragastric pH effects of lansoprazole, 30 mg administered nasogastrically, with pantoprazole, 40 mg administered i.v. METHODS: Healthy adults were enrolled in an open label, two-way crossover, single-center study. Thirty milligrams of lansoprazole (administered nasogastrically in apple juice) or pantoprazole (i.v.) were administered once daily at 8:00 AM for 5 consecutive days with at least a 2-wk washout period between the regimens. Ambulatory 24-h intragastric pH was monitored at baseline and on days 1 and 5 of each treatment period. Blood specimens were collected on days I and 5 for pharmacokinetic parameter determinations. RESULTS: Thirty-three adults completed both crossover periods, with the exception of one patient with a zero lansoprazole plasma concentration on day 1 of period 2. Lansoprazole, 30 mg per nasogastric tube, produced significantly higher mean 24-h intragastric pH values relative to pantoprazole, 40 mg i.v., on both day 1 (3.05 vs 2.76, p < 0.002) and day 5 (3.65 vs 3.45, p = 0.024). Lansoprazole sustained the intragastric pH above 3 (days 1 and 5), 4, and 5 (day 1) significantly longer relative to pantoprazole. Lansoprazole's time to the maximum observed concentration and area under the plasma concentration-time curve over the 24-h time interval increased significantly from day I to day 5 (1.7 h vs 2.0 h and 1865 ng x h/ml vs 2091 ng x h/ml, respectively), and a significant increase in half-life relative to day 1 (0.96 h) was observed on day 5 (1.03 h) during pantoprazole treatment. CONCLUSION: Lansoprazole, 30 mg administered nasogastrically, effectively controls intragastric pH and is an alternative to i.v. pantoprazole in patients who are unable to swallow solid dosage formulations.     

Transient S-T elevation detected by 24-hour ECG monitoring during normal daily activity

Seven out of 174 patients subjected to continuous 24-hour ECG monitoring because of atypical chest pain and/or palpitations were found to have transient S-T elevation. Two were diagnosed as suffering from neurocirculatory asthenia, three had myocardial infarction, and two suffered, most probably, from Prinzmetal's variant angina pectoris. We believe that the finding of transient S-T elevation is of special significance, because of the pathological and therapeutic implications, and that continuous ECG monitoring during unrestricted daily activities provides a unique opportunity to detect this condition more frequently.     

Efficacy and safety of fluticasone propionate/salmeterol 250/50 mcg Diskus administered once daily

BACKGROUND: The twice daily administration of an inhaled corticosteroid (ICS) and long-acting beta(2)-agonist (LABA) has been shown to be effective in achieving asthma control. The once daily administration of an ICS/LABA may be a treatment option for some patients. OBJECTIVE: To assess the effectiveness of fluticasone propionate (FP)/salmeterol via a single inhaler (FSC) administered once daily compared with FP once daily, FSC twice daily, or placebo. METHODS: A 12-week, randomized, double-blind multicenter study conducted in 844 patients > or = 12 years of age who were symptomatic while using a short-acting beta(2)-agonist alone. Blinded treatments included: FSC 250/50 mcg once daily in the evening (FSC 250/50 QD), FP 250 mcg once daily in the evening (FP 250 QD), FSC 100/50 mcg twice daily (FSC 100/50 mcg BID), or placebo. All treatments were delivered via the Diskus device. RESULTS: All treatments demonstrated greater improvements in efficacy measures compared with placebo. Overall, the greatest improvements were observed in the patients receiving FSC, either once or twice daily, compared with the FP 250 QD group. The two FSC treatments were similar except that QD dosing did not maintain improvements in lung function for 24h compared with twice daily dosing. All treatments were well tolerated. No suppression of HPA axis, as assessed by 24-h urinary cortisol excretion, was observed in any of the active treatment groups. CONCLUSION: In patients symptomatic on a short-acting beta(2)-agonist alone, FSC 100/50 mcg BID was shown to provide better efficacy than a higher strength (FSC 250/50 mcg) administered once daily. However, a once daily regimen was effective and may be a valuable treatment option for some patients. Registered at (http://ctr.gsk.co.uk/welcome.asp) (SAS30022).     

Usefulness of low dose guanfacine, once a day, for 24-hour control of essential hypertension

The 24-hour duration of the antihypertensive effect of guanfacine, a centrally acting alpha 2-adrenoceptor agonist administered once a day, was demonstrated in a 12-week, multicenter, double-blind, placebo-controlled study. Two hundred and forty-nine patients who remained mildly to moderately hypertensive following a 5-week period, during which they had been weaned from previous antihypertensive medications and stabilized on 25-mg chlorthalidone taken once a day, were involved. Of the 249 patients, 126 received guanfacine as a step-2 agent and 123 received placebo. Both groups were further subdivided so that blood pressure (BP) measurements were determined either 12 or 24 hours after dosing. The initial dose of guanfacine was 1 mg/day, which could be raised 1 mg at 2-week intervals to a maximum daily dose of 3 mg/day at the discretion of each investigator. The daily dose could also be lowered by 1 mg at 2-week intervals, depending on patient response. The mean 24-hour reductions with guanfacine in sitting diastolic BP (-11 mm Hg), systolic BP (-14 mm Hg) and mean arterial pressure (-12 mm Hg) were statistically significant (p less than 0.01) compared with the reductions in BP with placebo. Heart rate also decreased with guanfacine, but no clinically relevant bradycardia (less than 60 beats/min) was observed. Dry mouth (47%), constipation (16%), fatigue (12%) and drowsiness (4%) were the most frequently reported side effects. The highly acceptable side-effects profile of guanfacine was also indicated by the small percentage of patients (7%) who prematurely left the study because of adverse reactions.     

Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD.

This study compared the bronchodilator effects of tiotropium, formoterol and both combined in chronic obstructive pulmonary disease (COPD). A total of 71 COPD patients (mean forced expiratory volume in one second (FEV1) 37% predicted) participated in a randomised, double-blind, three-way, crossover study and received tiotropium 18 microg q.d., formoterol 12 microg b.i.d. or both combined q.d. for three 6-week periods. The end-points were 24-h spirometry (FEV1, forced vital capacity (FVC)) at the end of each treatment, rescue salbutamol and safety. Compared with baseline (FEV1 prior to the first dose in the first period), tiotropium produced a significantly greater improvement in average daytime FEV1 (0-12 h) than formoterol (127 versus 86 mL), while average night-time FEV1 (12-24 h) was not different (tiotropium 43 mL, formoterol 38 mL). The most pronounced effects were provided by combination therapy (daytime 234 mL, night-time 86 mL); both differed significantly from single-agent therapies. Changes in FVC mirrored the FEV1 results. Compared with both single agents, daytime salbutamol use was significantly lower during combination therapy (tiotropium plus formoterol 1.81 puffs.day(-1), tiotropium 2.41 puffs x day(-1), formoterol 2.37 puffs x day(-1)). All treatments were well tolerated. In conclusion, in chronic obstructive pulmonary disease patients, tiotropium q.d. achieved a greater improvement in daytime and comparable improvement in night-time lung function compared with formoterol b.i.d. A combination of both drugs q.d. was most effective and provided an additive effect throughout the 24-h dosing interval.     

24 h anti-anginal and anti-ischaemic effects with once daily felodipine: A double-blind comparison with nifedipine, twice daily, and placebo in patients with stable exercise induced angina pectoris

The effects, as monotherapy, of felodipine ER 10 mg o.m. andnifedipine SR 20 mg b.d. were compared in a double-blind, randomized,placebo-controlled, three-way cross-over trial in 43 patientswith stable exercise-induced angina pectoris. The exercise testswere performed at the end of dosage interval (i.e. 24 h afterfelodipine ER, 12 h after nifedipine SR) and at the expectedpeak time of 3 h post dose. Felodipine and nifedipine improved exercise duration by 66 and50 s, respectively, (P<0.001) compared with placebo at theend of the dosing interval. Time to the end of exercise showedno statistically significant difference between the two calciumantagonists. The onset of anginal pain and time to 1 mm ST depressionwere significantly more delayed by felodipine ER than nifedipineSR (22 s and 19 s, respectively, P<0.05). Both felodipineand nifedipine decreased the pain score and rate pressure productat the highest comparable work load. Overall tolerability wasgood for both drugs.