Efficacy, safety and effect on biomarkers of AZD9668 in cystic fibrosis

The aim of this study was to evaluate the safety and effect on clinical outcomes and biomarkers of inflammation and tissue damage of the neutrophil elastase inhibitor AZD9668 (60 mg twice daily orally for 4 weeks) in cystic fibrosis. This was a randomised, double-blind, placebo-controlled study. Primary outcome measures were sputum neutrophil count, lung function, 24-h sputum weight, BronkoTest® diary card data and health-related quality-of-life (revised cystic fibrosis quality-of-life questionnaire). Secondary end-points included sputum neutrophil elastase activity, inflammatory biomarkers in sputum and blood, urine and plasma desmosine (an elastin degradation marker), AZD9668 levels and safety parameters (adverse events, routine haematology, biochemistry, electrocardiogram and sputum bacteriology). 56 patients were randomised, of which 27 received AZD9668. There was no effect for AZD9668 on sputum neutrophil counts, neutrophil elastase activity, lung function or clinical outcomes, including quality of life. In the AZD9668 group, there was a trend towards reduction in sputum inflammatory biomarkers with statistically significant changes in interleukin-6, RANTES and urinary desmosine. The pattern of adverse events was similar between groups. Consistent reductions in sputum inflammatory biomarkers were seen in the AZD9668 group, and reduction in urinary desmosine suggests that AZD9668 impacts elastin cleavage by neutrophil elastase.

Cognitive, global, and functional benefits of donepezil in Alzheimer's disease and vascular dementia:results from large-scale clinical trials

Alzheimer's disease (AD) and vascular dementia (VaD) are both associated with deficits in cholinergic neurotransmission that are amenable to therapeutic intervention. The cholinesterase inhibitor, donepezil, is clinically effective in both AD and VaD. Results from a 10-study metaanalysis of donepezil (5 or 10 mg/day) in AD and a two-study combined analysis of donepezil (5 or 10 mg/day) in VaD are presented to compare patient characteristics and donepezil treatment outcomes. The analyzed studies were randomized, placebo-controlled, and of up to 24 weeks duration. In both AD and VaD, donepezil provided significant benefits compared with placebo on measures of cognition and global function. Placebo-treated AD patients showed a decline in cognition and global function, whereas placebo-treated VaD patients remained stable, suggesting treatment effects of donepezil in VaD were driven by improvement rather than stabilization or reduced decline. More VaD patients than AD patients received concomitant medications. Cardiovascular adverse events were more common in VaD than AD patients but were not increased by donepezil. In conclusion, although there are differences between AD and VaD patients in comorbid conditions and concomitant medications, donepezil is effective and well tolerated in both types of dementia.

Economic aspects of pharmacotherapy for chronic constipation

Constipation is one of the most common digestive complaints. It is a symptom, not a disease. The subjectivity that this involves means that assessments of clinical epidemiology, socioeconomic costs and pharmacotherapy are difficult, since there is no definition of 'normal' bowel habit. Although constipation can affect all ages, the problem increases with age, and is of particular concern for those who are frail and in long term care. Cultural influences may affect the prevalence in older people. Drug therapy of constipation cannot be considered in isolation, since there are issues in the prevention of constipation and the principles of good management that also apply. Furthermore, some consideration of the pathophysiology and diagnosis is important. This is because a number of remediable causes can be identified, and the diagnostic process involves patient education, which in turn may be effective in reducing costs. It is the complaint of constipation which leads either to self-medication or to consultation with the medical profession. Both of these courses of action have a significant influence on utilisation of laxatives (cathartics), obtained both over-the-counter and by prescription. Although there are a large number of laxative preparations available, therapy has changed little in half a century. Costs may vary considerably, and with such a significant problem there is a need for comparative studies. However, study methodologies are difficult, and a significant placebo response may be found. Education and preventive measures have been shown to reduce laxative use and costs in institutions. Unfortunately, there are few comparative studies of individual laxatives and even fewer cost-effectiveness studies. Those that there are have been based in institutions, and so extrapolation to other situations may be difficult. In general, little attention is given to constipation. It is, however, an area with significant resource implications in which education and preventive measures have been shown to be beneficial. Even so, there is still a need for good comparative studies, particularly where cost effectiveness is concerned.

The effects of ibuprofen and indomethacin on renal function in the presence and absence of frusemide in healthy volunteers on a restricted sodium diet

1. Since salt depletion stimulates the renal prostaglandin system to maintain renal function, the effects of indomethacin and ibuprofen upon renal haemodynamics, electrolyte excretion and renin release were examined in eight healthy male volunteers on a salt restricted diet, before and after frusemide administration. 2. Neither indomethacin (50 mg) nor ibuprofen (400 mg and 800 mg) affected renal blood flow, glomerular filtration rate or electrolyte excretion before frusemide. 3. Renal blood flow and glomerular filtration rate were significantly increased in the first 20 min after frusemide. These changes were significantly attenuated by indomethacin compared with placebo and ibuprofen 400 mg. Frusemide-induced diuresis but not natriuresis was inhibited by all treatments. 4. Both nonsteroidal agents inhibited equally the rise in renin activity seen after frusemide. 5. In this group of healthy volunteers on a salt restricted diet, ibuprofen and indomethacin had no detrimental effects on renal function in the absence of frusemide. The changes in renal haemodynamics due to frusemide were suppressed more by indomethacin than by ibuprofen, probably reflecting the more potent nature of indomethacin as an inhibitor of prostaglandin synthesis.

Comparison of the acute renal and peripheral vascular responses to frusemide and bumetanide at low and high dose

1. The effects of equipotent doses of frusemide (10 mg and 100 mg) and bumetanide (250 micrograms and 2.5 mg) upon renal and peripheral vascular responses, urinary prostaglandin excretion, plasma renin activity, angiotensin II and noradrenaline were compared in nine healthy volunteers. 2. Frusemide (10 mg and 100 mg) and bumetanide (2.5 mg) increased renal blood flow acutely compared with placebo but bumetanide (250 micrograms) had no effect. The changes in peripheral vascular responses were not significantly different from placebo. 3. Urinary prostaglandin metabolite excretion was acutely increased by all treatments, with no inter-treatment difference. Plasma renin activity was increased acutely by both doses of frusemide and by bumetanide (2.5 mg) compared with placebo and to bumetanide (250 micrograms). There were no differences between the latter two treatments. Angiotensin II was increased significantly 30 min after frusemide 100 mg and bumetanide 2.5 mg, and by all four treatments at 50 min when compared with placebo. There were no significant differences between either of the low doses or the higher doses. Plasma noradrenaline was unchanged by all treatments. 4. Frusemide 100 mg and bumetanide 2.5 mg have the same effects on the renal vasculature and the renin-angiotensin-prostaglandin system. Under the conditions of this study, frusemide 10 mg had different effects on plasma renin activity than bumetanide 250 micrograms.

The effects of cilazapril alone and in combination with frusemide in healthy subjects

1. In a fourway double-blind placebo controlled study, the effects of cilazapril, a new angiotensin converting enzyme inhibitor, on renal function and the responses to intravenous frusemide were studied in a group of twelve salt depleted male volunteers. 2. Cilazapril produced an increase in effective renal plasma flow and urinary output of prostaglandin E2 metabolite (PGE2-M) but no effect on sodium, potassium or water excretion. 3. Pretreatment with cilazapril antagonised the effects of frusemide on glomerular filtration, PGE2-M and sodium excretion.

A double-blind cross-over study of nifedipine retard in patients with Raynaud's phenomenon

The effectiveness of nifedipine retard as a treatment for Raynaud's phenomenon was assessed in 15 patients in a placebo controlled double blind study. An associated connective tissue disease was evident in 7 patients. Changes in finger and forearm blood flow (venous occlusion plethysmography), digital skin temperature and digital systolic pressure were measured acutely before and after a 2-week treatment period. Subjective assessment of efficacy was based on patient diary data. In addition alpha 2-adrenoceptor density on platelets was measured before and after chronic nifedipine therapy in both the patient group and in an age-and-sex-matched control group. No significant haemodynamic changes were observed. Nifedipine retard significantly reduced the frequency (p less than 0.05) with no change in either the duration or severity of vasospastic attacks. Side effects were common following nifedipine retard. A reduction in alpha 2-adrenoceptor density on platelets was observed in patients compared to a control group (p less than 0.05). Alpha 2-adrenoceptor density was unchanged following a 2-week treatment period with nifedipine retard. This study concludes that nifedipine retard is not effective in the treatment of Raynaud's phenomenon over a short time course. Patients with Raynaud's phenomenon have reduced alpha 2-adrenoceptor densities on their platelets.

The effect of chronic captopril therapy on adrenergic receptors, plasma noradrenaline and the vascular responses to infused noradrenaline

Adrenergic receptors (alpha 2, beta 2), plasma noradrenaline, heart rate and the pressor responsiveness to infused noradrenaline were examined in ten healthy male volunteers before and after 2 weeks of placebo or captopril therapy in a double blind cross-over study. No significant differences in these measurements were observed between the captopril and placebo treated groups. The study shows that in sodium replete normotensive subjects, long-term angiotensin converting enzyme inhibition does not lead to changes in adrenoceptor density. There is also no alteration in plasma noradrenaline levels nor in the pressor responsiveness to infused noradrenaline. These data suggest that the known interaction between the renin-angiotensin system and the sympathetic nervous system observed in animals is probably of little significance in man.

Donepezil and memantine for moderate-to-severe Alzheimer's disease

Background: Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer's disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease. Methods: We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and who had moderate or severe Alzheimer's disease (a score of 5 to 13 on the Standardized Mini-Mental State Examination [SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function]) to continue donepezil, discontinue donepezil, discontinue donepezil and start memantine, or continue donepezil and start memantine. Patients received the study treatment for 52 weeks. The coprimary outcomes were scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment). The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS.
Results: Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P<0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P = 0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone.
Conclusions: In patients with moderate or severe Alzheimer's disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months. (Funded by the U.K. Medical Research Council and the U.K. Alzheimer's Society; Current Controlled Trials number, ISRCTN49545035).

Bone-targeting radiopharmaceuticals including radium-223

ABSTRACT: Bone-seeking radionuclides including samarium-153 ethylene diamine tetramethylene phosphonate and strontium-89 have been used for decades in the palliation of pain from bone metastases especially from prostate cancer. Emerging evidence of improved survival in metastatic castration-resistant prostate cancer (CRPC) with the first-in-class a-radionuclide, radium-223 (Ra) has rekindled interest in the role of bone-seeking radionuclide therapy.We review the literature for randomized controlled trials of bone-seeking radionuclides and explore some of the issues regarding the optimal use of these agents. In particular, we discuss dose, dose rate, radiobiology, and quality of radiation and postulate on potential future directions in particular combination schedules. ß-Emitting, bone-seeking radionuclides have proven ability to control pain in prostate cancer metastatic to bone with pain response rates in the order of 60% to 70% when used as single agents. Most of the published trials were underpowered to detect differences in survival; however, there is evidence of the potential for disease modification when these agents are used in combination with chemotherapy or in multiple cycles.Data from the recent phase III ALSYMPCA trial that compared Ra to placebo in symptomatic CRPC demonstrate a significant improvement in median overall survival of 3.6 months for patients with symptomatic CRPC metastatic to bone treated with 6 cycles of the a-emitting radionuclide Ra compared with placebo. The success of Ra in improving survival in CRPC will lead this agent to become part of the treatment paradigm for this disease, and with such an excellent safety profile, Ra has huge potential in combination strategies as well as for use earlier in the natural history of metastatic prostate cancer.

α-Adrenergic agonism enhances the growth hormone (GH) response to GH-releasing hormone through an inhibition of hypothalamic somatostatin release in normal men

The purpose of this study was to investigate the precise mechanism by which central a-adrenergic pathways modulate GH secretion in humans. In 10 normal subjects we compared the pattern of clonidine-induced GH release to that elicited by GH-releasing hormone (GHRH) given at a time of presumably similar responsiveness of the somatotrope. We also evaluated the effect of stimulation by GHRH (either endogenous, by administration of clonidine, or exogenous) on the GH response to a further exogenous GHRH stimulation. In 2 experiments the administration of clonidine (0.150 mg, orally) at 0 or 60 min was followed by a GHRH [GRF-(1-29); 1 µg/kg, iv] challenge at 180 min. In other experiments subjects received on separate occasions placebo or clonidine at 0 min, followed by GHRH at 60 min and again at 180 min. In a further experiment the administration of clonidine at 0 min was followed by 2 GHRH challenges (60 and 180 min later). The administration of clonidine 60 or 120 min, but not 180 min, before the GHRH bolus significantly (P <0.01) increased the GH responses to this challenge compared to those elicited by GHRH when given after placebo in a period of a similar somatotrope responsiveness. These, in turn, were significantly (P <0.05) higher than those elicited by clonidine alone. The close relationship between pre-GHRH plasma GH values and GHRH-elicited GH peaks, not observed for clonidine, was lost after pretreatment with this drug. These data indicate that clonidine was able to disrupt the intrinsic hypothalamic-somatotroph rhythm, suggesting that a-adrenergic pathways have a major inhibitory effect on somatostatin release. Our data also indicate that GH responses to a GHRH bolus administered 120 min after a prior GHRH challenge are dependent on two parameters: the intrinsic hypothalamic-somatotroph rhythm at the time of the second GHRH bolus, and the magnitude of GH secretion elicited by the previous somatotroph stimulation. In summary, a-adrenergic agonism appears to act primarily in GH control by inhibiting the hypothalamic release of somatostatin, rather than by stimulating GHRH secretion.

Le survivant de la Shoah face au texte de fiction: un écran protecteur ou un écran projecteur? L’exemple d’Anna Langfus

La terminologie ‘écriture écran’ est souvent utilisée dans un sens proche de celui que lui donne Annie Ernaux lorsqu’elle écrit que ‘la fiction protège’ en permettant à un auteur de dire tout en gardant le lecteur à distance. Pourtant, de Blanchot à Genette, de nombreux critiques ont souligné que le texte est par essence un espace qui n’existe que dans et par cet échange, le lecteur – surtout dans le cas des textes de fiction – devant s’investir, se projeter dans le texte lu. Le texte de fiction serait-il donc un écran protecteur pour celui qui tient la plume et un écran projecteur pour celui qui tient le livre ? En nous basant principalement sur des textes de la psychanalyste Rachel Rosenblum et de l’auteure et survivante de la Shoah Anna Langfus, nous suggèrerons que, pour l’auteur comme pour le lecteur, le texte de fiction est à la fois un écran protecteur et un écran projecteur, ces deux fonctions étant étroitement liées et nullement contradictoires. Nous montrerons en effet qu’aucun genre n’est a priori protecteur puisque c’est l’acte de lecture ou d’écriture qui peut se transformer en morbide compulsion de répétition quand la mémoire d’un lecteur ou d’un auteur est devenue pathologique.

Oral prednisone in guarded filtration procedures supplemented with antimetabolites

BACKGROUND AND OBJECTIVE: To evaluate whether a three-day course of oral prednisone perioperatively improves the surgical outcome of guarded filtering procedures supplemented with antifibrosis agents. DESIGN, MATERIALS AND METHODS: A prospective, randomized, double-masked, placebo-controlled, clinical trial was designed. Adult patients with non-inflammatory glaucoma undergoing a guarded filtration procedure supplemented with antimetabolite were enrolled. Patients received a three-day course of prednisone (50 mg BID) or placebo perioperatively. The main outcome measures were intraocular pressure (IOP) and number of antiglaucoma medications. Surgical success was defined before data collection according to two different criteria: 'success- I': IOP level = 15 mmHg with no more than one anti-glaucoma medication, and 'success-II': IOP reduction of at least 20% of baseline level with no more than one antiglaucoma medication. RESULTS: Thirty-five subjects were enrolled. Seventeen patients were treated with prednisone and eighteen with placebo. Mean follow-up was 9.2 months ± 6.2 months. The probability of success-I at 9 months was 63.0% in the study group and 65.6% in the control groups (p>0.05). The probability of success-II at 9 months was 60.2% in the study group and 55.0% in the control groups, (p>0.05). The difference in frequency of postoperative complications between groups was not statistically significant. The most common complication was choroidal detachment (n=2) in the prednisone-treated group and bleb leak (n=2) in the control group. CONCLUSION: The perioperative use of oral prednisone did not alter the surgical outcome of filtering procedures associated with antifibrosis agents in this population of glaucoma patients.

Effect of sublingual application of cannabinoids on intraocular pressure:A pilot study

PURPOSE: The purpose of this study was to assess the effect on intraocular pressure (IOP) and the safety and tolerability of oromucosal administration of a low dose of delta-9-tetrahydrocannabinol (?-9-THC) and cannabidiol (CBD). PATIENTS AND METHODS: A randomized, double-masked, placebo-controlled, 4 way crossover study was conducted at a single center, using cannabis-based medicinal extract of ?-9-THC and CBD. Six patients with ocular hypertension or early primary open angle glaucoma received a single sublingual dose at 8 AM of 5 mg ?-9-THC, 20 mg CBD, 40 mg CBD, or placebo. Main outcome measure was IOP. Secondary outcomes included visual acuity, vital signs, and psychotropic effects. RESULTS: Two hours after sublingual administration of 5 mg ?-9-THC, the IOP was significantly lower than after placebo (23.5 mm Hg vs. 27.3 mm Hg, P=0.026). The IOP returned to baseline level after the 4-hour IOP measurement. CBD administration did not reduce the IOP at any time. However, the higher dose of CBD (40 mg) produced a transient elevation of IOP at 4 hours after administration, from 23.2 to 25.9 mm Hg (P=0.028). Vital signs and visual acuity were not significantly changed. One patient experienced a transient and mild paniclike reaction after ?-9-THC administration. CONCLUSIONS: A single 5 mg sublingual dose of ?-9-THC reduced the IOP temporarily and was well tolerated by most patients. Sublingual administration of 20 mg CBD did not reduce IOP, whereas 40 mg CBD produced a transient increase IOP rise. Copyright © 2006 by Lippincott Williams & Wilkins.

Haptoglobin Phenotype, Preeclampsia and Response to Supplementation with Vitamins C and E in Pregnant Women with Type 1 Diabetes.

Objective The phenotype of the antioxidant and pro-angiogenicprotein haptoglobin (Hp) predicts cardiovascular disease risk andtreatment response to antioxidant vitamins in individuals withdiabetes. Our objective was to determine whether Hp phenotypeinfluences pre-eclampsia risk, or the efficacy of vitamins C and Ein preventing pre-eclampsia, in women with type-1 diabetes.
Design This is a secondary analysis of a randomised controlledtrial in which women with diabetes received daily vitamins C andE, or placebo, from 8 to 22 weeks of gestation until delivery.
Setting Twenty-five antenatal metabolic clinics across the UK (innorth-west England, Scotland, and Northern Ireland).
Population Pregnant women with type-1 diabetes.
Methods Hp phenotype was determined in white women whocompleted the study and had plasma samples available (n = 685).
Main outcome measure Pre-eclampsia.
Results Compared with Hp 2-1, Hp 1-1 (OR 0.59, 95% CI 0.30–1.16) and Hp 2-2 (OR 0.93, 95% CI 0.60–1.45) were notassociated with significantly decreased pre-eclampsia risk afteradjusting for treatment group and HbA1c at randomisation. Ourstudy was not powered to detect an interaction between Hpphenotype and treatment response; however, our preliminaryanalysis sugge sts that vitamins C and E did not prevent pre-eclampsia in women of any Hp phenotype (Hp 1-1, OR 0.77, 95%CI 0.22–2.71; Hp 2-1, OR 0.81, 95% CI 0.46–1.43; Hp 2-2, 0.67,95% CI 0.34–1.33), after adjusting for HbA1c at randomisation.
Conclusions The Hp phenotype did not significantly affect pre-eclampsia risk in women with type-1 diabetes.