Effects of treatment withdrawal on brachial and central aortic pressure after direct renin inhibition or angiotensin receptor blockade.

INTRODUCTION: Whilst sustained lowering of brachial systolic blood pressure (Br-SBP) and central aortic systolic pressure (CASP) have been demonstrated in patients with hypertension, effects of treatment withdrawal on these parameters have not been investigated. The ASSERTIVE study previously reported more sustained control of Br-SBP with aliskiren versus telmisartan in patients with hypertension, following 7-days treatment withdrawal. In this ASSERTIVE sub-study, we hypothesised that aliskiren would similarly exert more sustained control of CASP than telmisartan during treatment withdrawal. METHODS: We investigated the effects of treatment withdrawal on both Br-SBP and CASP following 12-weeks treatment with either aliskiren (300 mg) or telmisartan (80 mg). Br-SBP and CASP were measured at the end of treatment, and at days 2 and 7 following treatment withdrawal in 303 patients (CASP randomised set). RESULTS: Of the CASP randomised set, 94 patients completed CASP measurements at all time points (CASP completer set). After 7 days of treatment withdrawal, aliskiren demonstrated lesser increases in both Br-SBP and CASP than telmisartan; Br-SBP change: -2.0±1.6 vs. +5.6±1.7 mmHg, p = 0.001; CASP change: -0.4±1.6 vs. +4.6±1.7 mmHg, p = 0.041, n = 94. Similar findings were obtained for the CASP randomised set. CONCLUSIONS: Following treatment withdrawal, aliskiren demonstrated more sustained control of both brachial and central SBP than telmisartan.

Effects of exercise on central aortic pressure before and after treatment with renin-angiotensin system blockade in patients with hypertension.

INTRODUCTION: Brachial blood pressure increases with exercise and an excessive rise predicts increased cardiovascular risk. Measurement of brachial blood pressure alone may exaggerate the true blood pressure elevation due to exercise-induced change to pressure amplification. Whether blood pressure-lowering treatment modulates pressure amplification during exercise is unknown. METHODS: Thirty-two participants with stage 1-2 hypertension (mean age 59.2 years) received eight weeks' blood pressure lowering with either aliskiren (300mg, n=16) or valsartan (320mg, n=16). Brachial and central aortic pressure (CASP) were measured non-invasively during treadmill exercise (Bruce protocol) at baseline, after eight weeks' treatment and 48 hours following treatment withdrawal. RESULTS: The rise in brachial blood pressure with exercise exceeded the rise in CASP, indicative of enhanced pressure amplification. Eight weeks' treatment elicited similar reductions in brachial blood pressure and CASP which did not differ between rest and peak exercise (p>0.05). The exercise-induced increase in systolic pressure amplification did not differ between baseline and following eight weeks' treatment (p>0.05). These effects remained unchanged following treatment withdrawal. CONCLUSION: Blood pressure lowering does not directly influence the relationship between aortic and brachial pressure either at rest or during exercise in patients with hypertension, other than through proportionate lowering of both pressures. These effects remained unchanged 48 hours after a simulated missed medication dose.

Effects of aliskiren- and ramipril-based treatment on central aortic blood pressure in elderly with systolic hypertension: a substudy of AGELESS.

BACKGROUND: Systolic hypertension is the most common form of hypertension in elderly patients. There is increasing evidence that measurement of central aortic pressure (CAP) better accounts for cardiovascular risk than brachial blood pressure (BP). The Aliskiren for GEriatric LowEring of SyStolic hypertension (AGELESS) study in elderly patients with systolic hypertension showed that aliskiren-based therapy provided greater reductions in peripheral BP than ramipril-based therapy over 12 and 36 weeks of treatment. Here, we present CAP results in a substudy of elderly patients from the AGELESS study. METHODS: This was a post hoc analysis of a 36-week, randomized, double-blind, parallel-group, active-controlled, optional-titration study in patients ≥65 years of age with systolic BP ≥140 mmHg. Changes in both central and peripheral BP and pulse pressure (PP) and changes in systolic and PP amplification ratios from baseline to the week 36 end point with aliskiren-based versus ramipril-based therapy were analyzed. RESULTS: Of the 901 patients randomized in the overall study, 154 patients (aliskiren, n=78; ramipril, n=76) had CAP data. Numerically comparable reductions were seen for central aortic systolic pressure (CASP) in aliskiren-based therapy (baseline: 143.7±15.0; week 36: -20.3±16.2) compared with ramipril-based therapy (baseline: 147.9±11.9; week 36: -20.7±14.6). However, for the change in central aortic diastolic pressure, the least squares mean between-treatment difference (-3.6 mmHg [95% confidence interval, -6.76, -0.43; P=0.0263]) was in favor of aliskiren, while the other changes were comparable between the two groups with a trend in favor of aliskiren for CASP as well (-2.6 mmHg [95% confidence interval, -7.38, 2.19; P=0.2855)]. Correlation coefficients for change from baseline between CASP and systolic BP and between central aortic pulse pressure and PP (r=0.8, P<0.0001) were highly significant. CONCLUSION: Aliskiren-based therapy provides comparable reductions in CASP to ramipril-based therapy. Although the results did not reach statistical significance, these findings, when coupled with those of the main study, suggest that aliskiren may offer effective control of central BP in elderly patients with systolic hypertension and may be a good alternative to ramipril.

Site selection in global clinical trials in patients hospitalized for heart failure: perceived problems and potential solutions.

There are over 1 million hospitalizations for heart failure (HF) annually in the United States alone, and a similar number has been reported in Europe. Recent clinical trials investigating novel therapies in patients with hospitalized HF (HHF) have been negative, and the post-discharge event rate remains unacceptably high. The lack of success with HHF trials stem from problems with understanding the study drug, matching the drug to the appropriate HF subgroup, and study execution. Related to the concept of study execution is the importance of including appropriate study sites in HHF trials. Often overlooked issues include consideration of the geographic region and the number of patients enrolled at each study center. Marked differences in baseline patient co-morbidities, serum biomarkers, treatment utilization and outcomes have been demonstrated across geographic regions. Furthermore, patients from sites with low recruitment may have worse outcomes compared to sites with higher enrollment patterns. Consequently, sites with poor trial enrollment may influence key patient end points and likely do not justify the costs of site training and maintenance. Accordingly, there is an unmet need to develop strategies to identify the right study sites that have acceptable patient quantity and quality. Potential approaches include, but are not limited to, establishing a pre-trial registry, developing site performance metrics, identifying a local regionally involved leader and bolstering recruitment incentives. This manuscript summarizes the roundtable discussion hosted by the Food and Drug Administration between members of academia, the National Institutes of Health, industry partners, contract research organizations and academic research organizations on the importance of selecting optimal sites for successful trials in HHF.

Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial.

AIMS: The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM). METHODS AND RESULTS: ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64-0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P = 0.07 for interaction). CONCLUSION: This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without DM.

Novel description of the 24-hour circadian rhythms of brachial versus central aortic blood pressure and the impact of blood pressure treatment in a randomized controlled clinical trial: The Ambulatory Central Aortic Pressure (AmCAP) Study.

Elevated brachial blood pressure (BP) is associated with increased cardiovascular risk and predicts morbidity and mortality in humans. Recently, 24-hour ambulatory BP monitoring and assessment of central aortic BP have been introduced to improve BP phenotyping. The Ambulatory Central Aortic Pressure (AmCAP) study combines these approaches and describes, for the first time, the diurnal patterns of simultaneously measured 24-hour ambulatory brachial and central pressures in a prespecified substudy embedded within a clinical trial of BP lowering in patients with hypertension. Twenty-four-hour ambulatory brachial and central pressure measurements were acquired using a tonometer mounted into the articulating strap of a wristwatch-like device (BPro) in 171 participants with hypertension recruited into the ASSERTIVE (AliSkiren Study of profound antihypERtensive efficacy in hyperTensIVE patients) trial. Participants were randomly assigned to BP lowering with either aliskiren 300 mg QD or telmisartan 80 mg QD for 12 weeks. Ambulatory brachial and central BP was measured in all participants both at baseline and at study end. Brachial and central BP both demonstrated typical diurnal patterns with lower pressures at night. However, night time was associated with smaller reductions in central relative to brachial pressure and decreased pulse pressure amplification (P<0.0001 for both). These effects were not modulated after BP lowering and were maintained after adjustment for day and night-time BP and heart rate (P=0.02). This study demonstrates that brachial and central pressure show different diurnal patterns, which are not modulated by BP-lowering therapy, with relatively higher night-time central pressures. These novel data indicate that night-time central BP may provide prognostic importance and warrants further investigation. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00865020.

Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: the ASTRONAUT randomized trial.

IMPORTANCE: Hospitalizations for heart failure (HHF) represent a major health burden, with high rates of early postdischarge rehospitalization and mortality. OBJECTIVE: To investigate whether aliskiren, a direct renin inhibitor, when added to standard therapy, would reduce the rate of cardiovascular (CV) death or HF rehospitalization among HHF patients. DESIGN, SETTING, AND PARTICIPANTS: International, double-blind, placebo-controlled study that randomized hemodynamically stable HHF patients a median 5 days after admission. Eligible patients were 18 years or older with left ventricular ejection fraction (LVEF) 40% or less, elevated natriuretic peptides (brain natriuretic peptide [BNP] ≥ 400 pg/mL or N -terminal pro-BNP [NT-proBNP] ≥ 1600 pg/mL), and signs and symptoms of fluid overload. Patients were recruited from 316 sites across North and South America, Europe, and Asia between May 2009 and December 2011. The follow-up period ended in July 2012. INTERVENTION: All patients received 150 mg (increased to 300 mg as tolerated) of aliskiren or placebo daily, in addition to standard therapy. The study drug was continued after discharge for a median 11.3 months. MAIN OUTCOME MEASURES Cardiovascular death or HF rehospitalization at 6 months and 12 months. RESULTS: In total, 1639 patients were randomized, with 1615 patients included in the final efficacy analysis cohort (808 aliskiren, 807 placebo). Mean age was 65 years; mean LVEF, 28%; 41% of patients had diabetes mellitus, mean estimated glomerular filtration rate, 67 mL/min/1.73 m2. At admission and randomization, median NT-proBNP levels were 4239 pg/mL and 2718 pg/mL, respectively. At randomization, patients were receiving diuretics (95.9%), ß-blockers (82.5%), angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (84.2%), and mineralocorticoid receptor antagonists (57.0%). In total, 24.9% of patients receiving aliskiren (77 CV deaths, 153 HF rehospitalizations) and 26.5% of patients receiving placebo (85 CV deaths, 166 HF rehospitalizations) experienced the primary end point at 6 months (hazard ratio [HR], 0.92; 95% CI, 0.76-1.12; P = .41). At 12 months, the event rates were 35.0% for the aliskiren group (126 CV deaths, 212 HF rehospitalizations) and 37.3% for the placebo group (137 CV deaths, 224 HF rehospitalizations; HR, 0.93; 95% CI, 0.79-1.09; P = .36). The rates of hyperkalemia, hypotension, and renal impairment/renal failure were higher in the aliskiren group compared with placebo. CONCLUSION AND RELEVANCE: Among patients hospitalized for HF with reduced LVEF, initiation of aliskiren in addition to standard therapy did not reduce CV death or HF rehospitalization at 6 months or 12 months after discharge. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00894387.

Exercise testing in hypertensive patients for assessing the cardiovascular protective potential of antihypertensive drugs.

Exercise testing is an established noninvasive tool in cardiology used to diagnose and guide treatment in individuals with suspected or confirmed coronary artery disease. Owing to the wealth of information it provides, exercise testing is also being utilized to evaluate prehypertensive stages, characterize hypertension, assess tolerance to exercise and the efficacy of antihypertensive therapies, and predict target organ damage and cardiovascular risk. The literature on exercise tolerance tests is relatively limited since these studies are difficult to conduct although they represent a valuable test for evaluating the benefits of antihypertensive therapies beyond their blood-pressure-lowering efficacy at rest or during exercise. Such a setting can be immensely useful for the evaluation and for the differentiation of treatments, especially in patients with evident rises in systolic blood pressure and with concomitant diseases, who are at higher risk of stroke. Exercise-induced increase in systolic blood pressure from rest to peak exercise should therefore be used as the primary efficacy variable. There is growing evidence that central pressure is a better predictor for cardiovascular risk than peripheral blood pressure, since this variable takes into account the overall effect of vascular aging and increased arterial stiffness that age and other concomitant diseases may induce. It is also important to include central aortic blood pressure and biomarkers of hypertension and cardiac disease in the overall assessment.

Sustained blood pressure-lowering effect of aliskiren compared with telmisartan after a single missed dose.

Poor adherence to antihypertensive drug treatment is common and is often associated with marked prolongations of the dosing interval. Hence, selecting a treatment that has the potential to provide a sustained blood pressure (BP)-lowering effect is important. The objective of this analysis is to compare the sustained efficacy of aliskiren with telmisartan after a single missed dose. This is part of a 12-week double-blind study conducted in patients with mild to moderate hypertension randomized to once-daily aliskiren 150 mg or telmisartan 40 mg for 2 weeks, force-titrated to double the doses for 10 weeks, followed by placebo for 1 week. The changes in BP from the end of active treatment (EOA) to 48 hours after treatment withdrawal (day 2) were analyzed. Demographic and baseline characteristics were comparable between the treatment groups. Aliskiren continued to show significantly greater reductions in mean sitting systolic BP (-0.7 vs +1.3 mm Hg; P<.05), 24-hour mean ambulatory systolic BP (-3.6 vs +2.6 mm Hg; P<.01), and 24-hour mean ambulatory diastolic BP (-3.7 vs +0.4 mm Hg; P<.01) compared with telmisartan from EOA to day 2, despite the similar BP reductions from randomization to EOA. In conclusion, aliskiren sustained the BP-lowering efficacy better than telmisartan after a single missed dose.

Blood pressure and plasma renin activity responses to different strategies to inhibit the renin-angiotensin-aldosterone system during exercise.

OBJECTIVE: The effect of two different strategies for renin-angiotensin-aldosterone system (RAAS) blockade; direct renin inhibition (DRI) versus angiotensin receptor blockade (ARB) on blood pressure (BP) and plasma renin activity (PRA) was compared during exercise. METHODS: Hypertensive adults were randomised to aliskiren (300 mg once daily, n=33) or valsartan (320 mg once daily, n=35). BP and PRA were measured during treadmill exercise (Bruce protocol), at baseline, end of treatment (eight weeks), and after treatment withdrawal (48 hours after last dose). RESULTS: After eight weeks treatment, Aliskiren inhibited PRA (>80%) at rest and during exercise, with inhibition remaining undiminished 48 hours after treatment withdrawal. In contrast, valsartan increased PRA at rest, and more-so during exercise (>400%). Angiotensin receptor blockade, as indicated by PRA increase, was reduced, 48 hours after valsartan treatment withdrawal, suggesting more sustained RAAS blockade with aliskiren. Despite divergent effects on PRA, similar exercise-induced changes in BP were seen. The primary outcome, the rise in systolic BP from rest to peak exercise (baseline to after treatment withdrawal) did not differ between treatments (p=0.25). CONCLUSION: Measurement of PRA is a more sensitive index of RAAS blockade than the BP response during exercise. Furthermore, after treatment withdrawal, aliskiren provides more sustained RAAS inhibition than valsartan at rest and during exercise.

Aliskiren alone or in combination with hydrochlorothiazide in Hispanic/Latino patients with systolic blood pressure 160 mm Hg to <180 mm Hg (Aliskiren Alone or in Combination with Hydrochlorothiazide in Patients with Stage 2 Hypertension to Provide Quick Intensive Control of Blood Pressure [ACQUIRE] substudy).

In a prespecified subgroup analysis of a 12-week multinational, randomized, double-blind, parallel-group trial, self-identified Hispanic/Latino adult men and women with systolic blood pressure 160 mm Hg to 179 mm Hg received combination aliskiren/hydrochlorothiazide (HCT) 150/12.5 mg or aliskiren 150 mg (force-titrated to 300/25 mg and 300 mg, respectively, at week 1). At week 12, combination aliskiren/HCT provided greater reduction in mean sitting systolic blood pressure from baseline, the primary efficacy variable, compared with aliskiren monotherapy (-32.6 mm Hg vs -19.6 mm Hg; P<.0001). Differences in mean sitting diastolic blood pressure reductions followed a similar pattern (-13.5 mm Hg vs -7.1 mm Hg; P<.0001). Notable blood pressure reductions were evident at week 1 in both treatment groups, with near-maximal effects reached by week 8. Results were consistent regardless of country of residence. Both treatments were well tolerated. Aliskiren alone or in combination with HCT is safe and effective in Hispanic/Latino patients with stage 2 hypertension. Combination aliskiren/HCT produced greater blood pressure reductions than aliskiren monotherapy.

Sustained decrease in blood pressure following missed doses of aliskiren or telmisartan: the ASSERTIVE double-blind, randomized study.

OBJECTIVES: The AliSkiren Study of profound antihypERtensive efficacy in hyperTensIVE patients (ASSERTIVE) study was designed to assess the sustained blood pressure (BP)-lowering effect of aliskiren vs. telmisartan after a 7-day treatment withdrawal in patients with hypertension. METHODS: Patients were randomized to once-daily aliskiren 150  mg (N = 414) or telmisartan 40  mg (N = 408). After 2 weeks, all patients were uptitrated to double the initial dose for 10 weeks; subsequently, all patients were treated with placebo to simulate a 7-day treatment withdrawal. RESULTS: At the end of active treatment (EoA), similar decreases in mean ambulatory BP were observed with aliskiren and telmisartan. From EoA to day 7 of treatment withdrawal (end of withdrawal, EoW), the least squares mean increase in 24-h mean ambulatory SBP was smaller for aliskiren (2.7 mmHg) vs. telmisartan (6.5  mmHg). Between-treatment difference was significant in favour of aliskiren (-3.8  mmHg; P < 0.0001). Similar effects were observed for the increase in 24-h mean ambulatory DBP after EoW (-2.1 mmHg; P < 0.0001). Mean sitting SBP and DBP were also significantly lower with aliskiren than telmisartan after EoW with SBP (2.0  mmHg) and DBP (1.1  mmHg) differences in favour of aliskiren, already evident on day 2 after a single 'missed dose'. CONCLUSION: Aliskiren showed a greater and more sustained BP-lowering effect than telmisartan during a 7-day treatment withdrawal. Aliskiren may provide sustained BP lowering during 1 day or more missed dose.

Aliskiren alone or in combination with hydrochlorothiazide in patients with the lower ranges of stage 2 hypertension: The ACQUIRE randomized double-blind study.

Patients with stage 2 hypertension (systolic blood pressure [SBP] ≥160mm Hg and/or diastolic blood pressure [DBP] ≥100mm Hg) are at high cardiovascular risk and require intensive blood pressure (BP)-lowering therapy. This randomized double-blind study is the first prospective trial specifically designed to evaluate the direct renin inhibitor aliskiren in patients with a mean sitting SBP ≥160 mm Hg and <180mm Hg (the lower ranges of stage 2 systolic hypertension). After a 2- to 4-week washout period, 688 patients were randomized to once-daily aliskiren/hydrochlorothiazide (HCT) 150/12.5mg or aliskiren 150mg for 1 week and then double the doses for 11 weeks. Baseline BP was 167.1/95.0mm Hg. At week 12, both aliskiren/HCT and aliskiren provided substantial BP reductions from baseline (30.0/12.6 mm Hg and 20.3/8.2 mm Hg, respectively). Aliskiren/HCT lowered BP significantly more than aliskiren (least-squares mean between-treatment differences [95% confidence interval] were -9.7 [-12.0 to -7.4] for SBP and -4.5 [-5.8 to -3.2] for DBP; both P<.0001). Similar BP reductions were seen in the subgroups of patients with isolated systolic hypertension and obesity. Aliskiren, with or without HCT, provides clinically significant BP reductions and may therefore be an effective treatment option in patients with stage 2 hypertension.

CCK2 receptors mediate inhibitory effects of cholecystokinin on the motor activity of guinea-pig distal colon.

Cholecystokinin and related peptides are involved in the control of intestinal motility and cholecystokinin receptor ligands might represent new pharmacological tools for the treatment of symptoms associated with functional bowel disorders. However, the respective roles played by cholecystokinin receptor subtypes and the mechanisms underlying these regulatory actions remain undetermined. This study was designed to examine the influence of cholecystokinin receptor subtypes on the motor activity of guinea-pig distal colon. The effects of drugs acting on CCK1 and CCK2 receptors were assessed in vitro on the contractile activity of longitudinal smooth muscle, both under basal conditions and in the presence of transmural electrical stimulation or KCl-induced contractions. The application of cholecystokinin octapeptide sulphate (cholecystokinin-8S) to colonic preparations induced concentration-dependent contractions which were prevented by devazepide (CCK1 receptor antagonist), enhanced by GV150013 (CCK2 receptor antagonist) or N(omega)-nitro-L-arginine methylester (L-NAME, nitric oxide synthase inhibitor), and unaffected by tetrodotoxin. The application of gastrin-17 to colonic preparations resulted in relaxant responses which were insensitive to devazepide, and prevented by GV150013, L-NAME or tetrodotoxin. L-NAME, N(omega)-propyl-L-arginine (NPA, neuronal nitric oxide synthase inhibitor) or GV150013 enhanced electrically evoked contractile responses, whereas devazepide did not. When tested in the presence of L-NAME or NPA the enhancing effect of GV150013 on electrically induced contractions no longer occurred. In the presence of KCl-induced pre-contractions, cholecystokinin-8S or gastrin-17 evoked concentration-dependent relaxations, which were unaffected by devazepide and were counteracted by GV150013, L-NAME, NPA or tetrodotoxin. In conclusion, the present results indicate that, at level of distal colon, CCK1 receptors mediate direct contractile effects on smooth muscle, whereas CCK2 receptors on enteric neurons mediate relaxant responses via nitric oxide release.

Altered prejunctional modulation of intestinal cholinergic and noradrenergic pathways by alpha2-adrenoceptors in the presence of experimental colitis.

1 This study investigates the influence of intestinal inflammation on: (1) the control of intestinal neurotransmission and motility by prejunctional alpha(2)-adrenoceptors and (2) the expression of intestinal alpha(2)-adrenoceptors. Experimental colitis was induced by intrarectal administration of 2,4-dinitrobenzenesulphonic acid (DNBS) to rats. 2 UK-14,304 inhibited atropine-sensitive electrically evoked contractions of ileal and colonic longitudinal muscle preparations. UK-14,304 acted with similar potency, but higher efficacy, on tissues from DNBS-treated animals; its effects were antagonized with greater potency by phentolamine than rauwolscine. 3 Electrically induced [(3)H]noradrenaline release from ileal preparations was reduced in the presence of colitis. Tritium outflow was decreased by UK-14,304 and stimulated by rauwolscine or phentolamine: these effects were enhanced in preparations from animals with colitis. 4 Reverse transcription-polymerase chain reaction and Western blot assay demonstrated the protein expression of alpha(2A)-adrenoceptors in mucosal and muscular tissues isolated from ileum and colon. The induction of colitis increased alpha(2A)-adrenoceptor expression in both ileal and colonic muscular layers, without concomitant changes in mucosal tissues. 5 Induction of colitis reduced gastrointestinal propulsion of a charcoal suspension in vivo. In this setting, the gastrointestinal transit was inhibited by intraperitoneal (i.p.) UK-14,304 and stimulated by i.p. rauwolscine. After pretreatment with guanethidine, the stimulant action of rauwolscine no longer occurred, and UK-14,304 exerted a more prominent inhibitory effect that was antagonized by rauwolscine. 6 The present results indicate that, in the presence of intestinal inflammation, prejunctional alpha(2)-adrenoceptors contribute to an enhanced inhibitory control of cholinergic and noradrenergic transmission both at inflamed and noninflamed distant sites. Evidence was obtained that such modulatory actions depend on an increased expression of alpha(2A)-adrenoceptors within the enteric nervous system.

Improved tonsillar disposition of azithromycin following a 3-day oral treatment with 20 mg kg(-1) in paediatric patients.

The present study was performed in order to compare azithromycin concentrations in tonsils of paediatric patients treated with different dose regimens of this antibiotic. Sixty-four children, scheduled to undergo surgical removal of tonsils, were treated with azithromycin 10 or 20 mgkg(-1) daily as oral suspension for 3 days. Samples of blood and tonsil were collected during surgery at days 0.5, 2.5, 4.5, 6.5 or 8.5 after the last dose. Azithromycin concentrations were measured by reversed phase high-performance liquid chromatography. In patients treated with 10 mgkg(-1), the highest concentrations of azithromycin were detected in plasma and tonsils at day 0.5 and 2.5, respectively. Consistent drug levels could be measured in tonsils up to 8.5 days. After administration of 20 mgkg(-1), azithromycin tonsillar concentrations were higher than those obtained with 10 mgkg(-1) up to day 6.5, whereas plasma levels did not differ significantly. The present results indicate that an improved tonsillar distribution of azithromycin can be achieved when this antibiotic is administered for 3 days at doses higher than 10 mgkg(-1) daily. These findings give pharmacokinetic support to the suggestion that increments of azithromycin dosing might ensure enhanced therapeutic levels at infective sites of the upper respiratory tract.

Distribution of azithromycin in plasma and tonsil tissue after repeated oral administration of 10 or 20 milligrams per kilogram in pediatric patients.

Azithromycin concentrations in the tonsils of 56 pediatric patients, treated with 10 or 20 mg of the drug per kg of body weight for 3 days, were compared. Azithromycin levels in plasma and tonsil samples were determined up to 8.5 days after the last dose. The 20-mg/kg regimen resulted in an improved tonsillar distribution of azithromycin, suggesting the achievement of enhanced therapeutic concentrations at infective sites of the upper respiratory tract.