l-Lysine Acts as a Serotonin Type 4 Receptor Antagonist to Counteract In Vitro and In Vivo the Stimulatory Effect of Serotonergic Agents on Aldosterone Secretion in Man.

In the normal human adrenal gland, serotonin (5-HT) stimulates aldosterone secretion through the 5-HT4 receptor (5-HT4R). However, the physiological role of the serotonergic control of adrenocortical function is not known. In the present study, we have investigated the ability of l-Lysine, which has been shown to act as a 5-HT4 receptor antagonist, to counteract in vitro and in vivo the stimulatory effect of 5-HT4R agonists on aldosterone production. l-Lysine was found to inhibit aldosterone production induced by 5-HT and the 5-HT4R agonists BIMU8 from cultured human adrenocortical cells. The action of l-Lysine (4.95 g/day orally) on the adrenal cortex was also evaluated in 20 healthy volunteers in a double blind, cross-over, placebo controlled study. l-Lysine had no significant influence on basal plasma aldosterone levels and the aldosterone responses to upright posture, tetracosactide, and low sodium diet (10 mmol/day for 3 days). Conversely, l-Lysine significantly reduced the surge of plasma aldosterone induced by metoclopramide indicating that l-Lysine is able to efficiently antagonize the adrenal 5-HT4 receptors in vivo. These results suggest that l-Lysine supplementation may represent a new treatment of primary adrenal diseases in which corticosteroid hypersecretion is driven by overexpressed 5-HT4 receptors.

Transcutaneous electrical tibial nerve stimulation in the treatment of fecal incontinence: a randomized trial (CONSORT 1a).

OBJECTIVES: The objective of this study was to show that although transcutaneous electrical tibial nerve stimulation (TENS) is being increasingly used to treat fecal incontinence (FI), its efficacy has never been proved using controlled trials. METHODS: In this randomized, double-blind, sham-controlled trial, 144 patients aged 30-82 years from nine centers were randomly assigned to receive either active or sham stimulations for 3 months. The primary end point was the response to treatment based on the number of incontinence and urgency episodes. Secondary end points were severity scores, quality of life scores, delay to postpone defecation, patient self-assessment of treatment efficacy, physician assessment of TENS efficacy, anorectal manometry, and adverse events. RESULTS: No statistically significant difference was seen between active and sham TENS in terms of an improvement in the median number of FI/urgency episodes per week. Thirty-four patients (47%) who received the active TENS treatment exhibited a >30% decrease in the FI severity score compared with 19 patients (27%) who received the sham treatment (odds ratio 2.4, 95% confidence interval 1.1-5.1, P=0.02). No differences in delay to postpone defecation, patient self-assessment of treatment efficacy, or anorectal manometry were seen between the two groups. The evaluating physicians rated the active stimulations as more effective than the sham stimulations (P=0.01). One minor therapy-related adverse event was observed (1.5%) (see Supplementary Consort 1b). CONCLUSIONS: We failed to demonstrate any benefit of TENS on our primary end-point.

Predictive factors for successful sacral nerve stimulation in the treatment of faecal incontinence: results of trial stimulation in 200 patients.

AIM: Sacral nerve stimulation (SNS) has a place in the treatment algorithm for faecal incontinence (FI). However, after implantation, 15-30% of patients with FI fail to respond for unknown reasons. We investigated the effect of SNS on continence and quality of life (QOL) and tried to identify specific predictive factors of the success of permanent SNS in the treatment of FI. METHOD: Two hundred consecutive patients (six men; median age = 60; range 16-81) underwent permanent implantation for FI. The severity of FI was evaluated by the Cleveland Clinic Score. Quality of life was evaluated by the French version of the American Society of Colon and Rectal Surgeons (ASCRS) quality of life questionnaire (FIQL). All patients underwent a preoperative evaluation. After permanent implantation, severity and QOL scores were reevaluated after six and 12 months and then once a year. RESULTS: The severity scores were significantly reduced during SNS (P = 0.001). QOL improved in all domains. At the 6-month follow-up, the clinical outcome of the permanent implant was not affected by age, gender, duration of symptoms, QOL, main causes of FI, anorectal manometry or endoanal ultrasound results. Only loose stool consistency (P = 0.01), persistent FI even though diarrhoea was controlled by medical treatment (P = 0.004), and low stimulation intensity (P = 0.02) were associated with improved short-term outcomes. Multivariate analysis confirmed that loose stool consistency and low stimulation intensity were related to a favourable outcome. CONCLUSION: Stool consistency and low stimulation intensity have been identified as predictive factors for the short-term outcome of SNS.

Transrectal high-intensity focused ultrasound (HIFU) treatment of localized prostate cancer: review of technical incidents and morbidity after 5 years of use.

The objective of this study was to report on technical incidents and early and late complications occurring in high-intensity focused ultrasound (HIFU) treatment of patients with localized prostate cancer. We performed a retrospective review of patients who were treated by Ablatherm at our centre. We recorded all technical incidents, treatment discontinuations and early (<1 month) and late complications. A total of 74 HIFU procedures were performed in 65 patients (55 first-line HIFU treatments and 10 cases of salvage therapy after radiotherapy) over a 5-year period. Median follow-up was 41 months (10-64 months). All the procedures were well tolerated and no intra- or peri-operative deaths occurred. Six technical incidents in the overall population (8.1%) led to discontinuation of the procedure. The early complication rate in patients undergoing first-line HIFU was 36.4%: urinary retention (20%), dysuria (5.4%), urinary infection (3.6%), haematuria (3.6%) and urethral stenosis (3.6%). The late complication rate was 12.7%: urethral stenosis (9%) and dysuria (3.6%). There were no cases of rectourethral fistula. The long-term urinary incontinence rate was 20% and the de novo erectile dysfunction rate was 77.1%. Nine complications (16.4%) required surgical management. The overall complication rate was 49%. Ablatherm is a reliable technique with a relatively high complication rate. However, most complications were minor and required surgical management in a few cases only. Our results confirm that all patients who are offered HIFU treatment should be properly informed of the risks, in particular with regard to continence and sexual function.

Does magnetic stimulation of sacral nerve roots modify colonic motility? Results of a randomized double-blind sham-controlled study.

Although sacral nerve root stimulation (SNS) can result in a symptomatic improvement of faecal incontinence, the mechanism of action remains unknown. The aim of this study was to assess whether short-term magnetic SNS can inhibit pharmacologically induced propulsive colonic contractions. Twelve healthy volunteers (median age: 43.5 years old) were studied on two separate occasions and randomized into either active (15 Hz, 100% output intensity for 5 s min(-1) for 30 min) or sham rapid rate lumbosacral magnetic stimulation (rLSMS). Colorectal motility was recorded with a manometric catheter located at the most proximal transducer in the left colon and the most distal, in the rectum. Colonic contractions were provoked by instilling Bisacodyl. The effects of rLSMS on colonic, sigmoid and rectal contractions were monitored and recorded after Bisacodyl instillation. The appearance of high-amplitude contractions propagated or not (HAC/HAPC) provoked by Bisacodyl instillation was significantly delayed during active compared to sham stimulation (P = 0.03). There was no difference in the characteristics of HAC/HAPC (i.e. frequency, amplitude, duration, velocity of propagation) or the motility index with active or sham stimulation. The perception of urgency tended to be decreased with rLSMS following Bisacodyl instillation. The catheter was expulsed within a median of 16.5 min (range 8-39) after Bisacodyl administration during active stimulation compared to 14 min (range 5-40) during sham stimulation (P = 0.03). This study suggests that rLSMS could delay the appearance of the first Bisacodyl-induced colonic contractions.

Functions of GI-GPx: lessons from selenium-dependent expression and intracellular localization.

Gastro intestinal glutathione peroxidase (GI-GPx) is one of the four distinct mammalian selenoperoxidases. It had been reported to be restricted to the gastrointestinal tract but has more recently been identified also in human liver and some tumor cell lines. GI-GPx ranks high in the hierarchy of selenoproteins. The GI-GPx mRNA rather increases than decreases in selenium deficiency. GI-GPx protein responds poorly to selenium deprivation and increases fast upon resupplementation. Putative biological roles of GI-GPx, e.g. protection against food-born hydroperoxides, redox-regulation of proliferation or apoptosis, and modulation of mucosal immunity, are discussed in the light of cellular and subcellular distribution, transcriptional regulation and observations with k.o. mice.

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

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

Oil and water? Economic advantage and biomedical progress do not mix well in a government guidelines committee.

This article examines the results of the Joint National Committee's Fifth Report on the treatment of hypertension (JNC-V), especially regarding the economic arguments put forth therein. Economics are a poor basis for treatment decisions, as the cheapest therapies may not be the best for any given patient. Broad treatment guidelines based on economic motives will result in poorer patient care and less valuable medical research.

Critical assessment of combination therapy development.

Although antihypertensive treatment has been found to reduce cardiovascular morbidity and mortality, hypertensive patients are still at a significantly increased risk compared with normotensive controls. One of the reasons is that blood pressure control is often suboptimal. In fact, less than 40% of patients reach the target set by the treating physician. The development of wisely chosen fixed combinations could be one means, among others, to improve blood pressure control without compromising tolerability. The prescription, in a single pill, of two antihypertensive agents has the potential advantage of improving compliance by reducing the number of pills that need to be taken per day. There should be a pharmacological rationale, with the two agents having different and complementary modes of actions to reduce blood pressure: for example, a vascular selective calcium antagonist lowers total peripheral resistance and a beta-blocker lowers heart rate and, thus, cardiac output. These drugs can also mutually neutralise some of each others' side-effects, such as the initial heart rate increases which may occur with dihydropyridine calcium antagonists, and the rise in peripheral resistance elicited by some beta-blockers. The creation of a fixed-dose combination for effective and safe treatment of hypertension requires a complex programme of development. An example is the formulation of a combination tablet of felodipine and metoprolol in which extended-release techniques were applied to ensure that blood pressure control was maintained throughout the 24-h dosing interval. Evaluation included pharmacokinetic studies of the formulation, interaction studies and clinical trials of crossover and parallel-group designs to establish the 24-h efficacy and safety of the product.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of crossover trials to obtain antihypertensive dose-response curves and to study combination therapy during the development of benazepril.

When a new drug is developed, one of the first requirements is to establish the correct dose. Unfortunately, in dose-determination studies, not enough lessons have been learned from the past. Pilot studies are often planned without sufficient statistical power, due to an insufficient number of patients and highly variable blood pressure measurements. In the development of the new angiotensin converting enzyme (ACE) inhibitor benazepril, crossover trials were used to obtain useful information. At the end of phase II of the benazepril development, a double-blind crossover study was carried out with 25 patients, and the results made it possible to redefine the 12- and 24-h effects of benazepril in comparison with placebo. Moreover, the crossover trial allowed an investigation of the biological effects of the treatment. In further work, the efficacy of 10 mg benazepril, administered once a day, was confirmed in comparison with captopril and enalapril, with a beta-risk of less than 20%. Since this crossover study yielded reliable data, and there was no carryover effect, a similar crossover design was used to study the interaction between benazepril and nifedipine. In the past, mistakes were made and many antihypertensive drugs were administered in high doses, with no further beneficial effect on blood pressure and an increased risk of side effects. Work described in this paper shows that fewer but better designed and implemented studies can improve the efficiency and value of dose-finding studies for antihypertensive drugs.

Binding of glycyrrhetinic acid to kidney mineralocorticoid and glucocorticoid receptors.

Whether the mineralocorticoid effect of glycyrrhetinic acid is mediated by the adrenal glands or is due to a direct action on the renal tubule remains controversial. The affinity of glycyrrhetinic acid for mineralocorticoid receptors has been studied by several types of competition experiments. When rat kidney slices were incubated with 2 times 10- minus 9 M [3H]aldosterone, glycyrrhetinic acid (2 times 10- minus 5 M) was able to compete with aldosterone for the cytosolic receptor and to decrease the formation of a chromatin-[3Hi1 aldosterone-receptor complex. In cytosol, in vitro, 6 times 10- minus 4 M glycyrrhetinic acid was able to inhibit aldosterone binding by 70 percent, whereas the same dose produced only a 20 percent inhibition of dexamethasone binding. The apparent KDiss of glycyrrhetinic acid for the mineralocorticoid receptor was 2 times 10- minus 6 M. That glycyrrhetinic acid appeared to compete mainly with mineralocorticoid receptors was confirmed by sedimentation in the sucrose gradients: [3H]Aldosterone specifically bound to an 8 S peak was displaced by 5 times 10- minus 5 M glycyrrhetinic acid, whereas the [3H]dexamethasone peak was not affected by this compound. Glycyrrhizic acid showed no significant affinity for mineralocorticoid or glucocorticoid kidney receptor sites. Glycyrrhetinic acid and glycyrrhizic acid had no affinity for rat cortisol binding globulin. Glycyrrhetinic acid has a low but definite affinity for mineralocorticoid receptors and thus appears to have a direct mineralocorticoid action. The low affinity of this compound for mineralocorticoid receptors is in good agreement with the very high doses required to exhibit its biological activity.