Fitness to drive and cannabis: Validation of two blood THCCOOH thresholds to distinguish occasional users from heavy smokers.

Many studies based on either an experimental or an epidemiological approach, have shown that the ability to drive is impaired when the driver is under the influence of cannabis. Baseline performances of heavy users remain impaired even after several weeks of abstinence. Symptoms of cannabis abuse and dependence are generally considered incompatible with safe driving. Recently, it has been shown that traffic safety can be increased by reporting the long-term unfit drivers to the driver licensing authorities and referring the cases for further medical assessment. Evaluation of the frequency of cannabis use is a prerequisite for a reliable medical assessment of the fitness to drive. In a previous paper we advocated the use of two thresholds based on 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THCCOOH) concentration in whole blood to help to distinguish occasional cannabis users (≤3μg/L) from heavy regular smokers (≥40μg/L). These criteria were established on the basis of results obtained in a controlled cannabis smoking study with placebo, carried out with two groups of young male volunteers; the first group was characterized by a heavy use (≥10 joints/month) while the second group was made up of occasional users smoking at most 1 joint/week. However, to date, these cutoffs have not been adequately assessed under real conditions. Their validity can now be evaluated and confirmed with 146 traffic offenders' real cases in which the whole blood cannabinoid concentrations and the frequency of cannabis use are known. The two thresholds were not challenged by the presence of ethanol (40% of cases) and of other therapeutic and illegal drugs (24%). Thus, we propose the following procedure that can be very useful in the Swiss context but also in other countries with similar traffic policies: if the whole blood THCCOOH concentration is higher than 40μg/L, traffic offenders must be directed first and foremost toward medical assessment of their fitness to drive. This evaluation is not recommended if the THCCOOH concentration is lower than 3μg/L and if the self-rated frequency of cannabis use is less than 1 time/week. A THCCOOH level between these two thresholds cannot be reliably interpreted. In such a case, further medical assessment and follow-up of the fitness to drive are also suggested, but with lower priority.

Acetylcholinesterase inhibitor treatment for myasthenia gravis.

BACKGROUND: In myasthenia gravis, antibody-mediated blockade of acetylcholine receptors at the neuromuscular junction abolishes the naturally occurring 'safety factor' of synaptic transmission. Acetylcholinesterase inhibitors provide temporary symptomatic treatment of muscle weakness but there is controversy about their long-term efficacy, dosage and side effects. This is the second update of a review published in The Cochrane Library Issue 2, 2011. OBJECTIVES: To evaluate the efficacy of acetylcholinesterase inhibitors in all forms of myasthenia gravis. SEARCH METHODS: On 8 July 2014 we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE and EMBASE for randomised controlled trials and quasi-randomised controlled trials regarding usage of acetylcholinesterase inhibitors in myasthenia gravis. Two authors scanned the articles for any study eligible for inclusion. We also contacted the authors and known experts in the field to identify additional published or unpublished data and searched clinical trials registries for ongoing trials. SELECTION CRITERIA: The types of studies were randomised or quasi-randomised trials. Participants were myasthenia gravis patients diagnosed by an internationally accepted definition. The intervention was treatment with any form of acetylcholinesterase inhibitor. Types of outcome measures Primary outcome measureImprovement in the presenting symptoms within one to 14 days of the start of treatment. Secondary outcome measures(1) Improvement in the presenting symptoms more than 14 days after the start of treatment.(2) Change in impairment measured by a recognised and preferably validated scale, such as the quantitative myasthenia gravis score, within one to 14 days and more than 14 days after the start of treatment.(3) Myasthenia Gravis Association of America post-intervention status more than 14 days after start of treatment.(4) Adverse events including muscarinic side effects. DATA COLLECTION AND ANALYSIS: One author (MMM) extracted the data, which were checked by a second author. We contacted study authors for extra information and collected data on adverse effects from the trials. MAIN RESULTS: We did not find any large randomised or quasi-randomised trials of acetylcholinesterase inhibitors in generalised myasthenia gravis either for the first version of this review or this update. One cross-over randomised trial using intranasal neostigmine in a total of 10 participants was only available as an abstract. It included three participants with ocular myasthenia gravis and seven with generalised myasthenia gravis. Symptoms of myasthenia gravis (measured as improvement in at least one muscle function) improved in nine of the 10 participants after the two-week neostigmine treatment phase. No participant improved after the placebo phase. Lack of detail in the report meant that the risk of bias was unclear. Adverse events were minor. AUTHORS' CONCLUSIONS: Except for one small and inconclusive trial of intranasal neostigmine, no other randomised controlled trials have been conducted on the use of acetylcholinesterase inhibitors in myasthenia gravis. The response to acetylcholinesterase inhibitors in observational studies is so clear that a randomised controlled trial depriving participants in a placebo arm of treatment would be difficult to justify.

The effect of the N-methyl-D-aspartate receptor antagonist dextromethorphan on perioperative brain injury in children undergoing cardiac surgery with cardiopulmonary bypass: results of a pilot study.

Experimental evidence indicates a role of the N-methyl-D-aspartate receptor in the pathogenesis of brain injury occurring during cardiac surgery with cardiopulmonary bypass (CPB). Dextromethorphan is a noncompetitive antagonist of this receptor with a favorable safety profile. Thirteen children age 3-36 months undergoing cardiac surgery with expected CPB of 60 minutes or more were randomly assigned to treatment with dextromethorphan (36-38 mg/kg/day) or placebo administered by naso-gastric tube. Dextromethorphan was absorbed well and reached putative therapeutic levels in blood and cerebrospinal fluid. Adverse effects were not observed. Mild hemiparesis developed after operation in one child of each group, and severe encephalopathy in one of the placebo group. Sharp waves were recorded in postoperative continuous electroencephalography in all placebo (n = 7) but only in 2/6 dextromethorphan treated children (p = 0.02). Pre- and postoperative cranial magnetic resonance imaging (MRI) revealed less pronounced ventricular enlargement in the dextromethorphan group (not significant). An increase of periventricular white matter lesions was visible in two placebo-treated children only. No elevations of cerebrospinal fluid enzymes were observed in either group. Although children with dextromethorphan showed less abnormalities in electroencephalography and MRI, dissimilarities of the treatment groups by chance diminished conclusions to possible protective effects of dextromethorphan at this time.

Felodipine-metoprolol combination tablet: a valuable option to initiate antihypertensive therapy?

The aim of the present study was to assess the efficacy and tolerability of a calcium antagonist/beta-blocker fixed combination tablet used as first-line antihypertesnive therapy in comparison with an angiotensin converting enzyme inhibitor and placebo. Patients with uncomplicated essential hypertension (diastolic blood pressure between 95 and 110 mm Hg at the end of a 4-week run-in period) were randomly allocated to a double-blind, 12-week treatment with either a combination tablet of felodipine and metoprolol (Logimax), 5/50 mg daily (n = 321), enalapril, 10 mg daily (n = 321), or placebo (n = 304), with the possibility of doubling the dose after 4 or 8 weeks of treatment if needed (diastolic blood pressure remaining >90 mm Hg). The combined felodipine-metoprolol treatment controlled blood pressure (diastolic < or =90 mm Hg 24 h after dose) in 72% of patients after 12 weeks, as compared with 49% for enalapril and 30% for placebo. A dose adjustment was required in 38% of patients receiving the combination, in 63% of patients allocated to placebo, and 61% of enalapril-treated patients. The overall incidence of adverse events was 54.5% during felodipine-metoprolol treatment; the corresponding values for enalapril and placebo were 51.7% and 47.4%, respectively. Withdrawal of treatment due to adverse events occurred in 18 patients treated with the combination, in 10 patients on enalapril, and 12 patients on placebo. No significant change in patients' well-being was observed in either of the three study groups. These results show that a fixed combination tablet of felodipine and metoprolol allows to normalize blood pressure in a substantially larger fraction of patients than enalapril given alone. This improved efficacy is obtained without impairing the tolerability. The fixed-dose combination of felodipine and metoprolol, therefore, may become a valuable option to initiate antihypertensive treatment.

Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis.

BACKGROUND: A single infusion of intravenous zoledronic acid decreases bone turnover and improves bone density at 12 months in postmenopausal women with osteoporosis. We assessed the effects of annual infusions of zoledronic acid on fracture risk during a 3-year period. METHODS: In this double-blind, placebo-controlled trial, 3889 patients (mean age, 73 years) were randomly assigned to receive a single 15-minute infusion of zoledronic acid (5 mg) and 3876 were assigned to receive placebo at baseline, at 12 months, and at 24 months; the patients were followed until 36 months. Primary end points were new vertebral fracture (in patients not taking concomitant osteoporosis medications) and hip fracture (in all patients). Secondary end points included bone mineral density, bone turnover markers, and safety outcomes. RESULTS: Treatment with zoledronic acid reduced the risk of morphometric vertebral fracture by 70% during a 3-year period, as compared with placebo (3.3% in the zoledronic-acid group vs. 10.9% in the placebo group; relative risk, 0.30; 95% confidence interval [CI], 0.24 to 0.38) and reduced the risk of hip fracture by 41% (1.4% in the zoledronic-acid group vs. 2.5% in the placebo group; hazard ratio, 0.59; 95% CI, 0.42 to 0.83). Nonvertebral fractures, clinical fractures, and clinical vertebral fractures were reduced by 25%, 33%, and 77%, respectively (P<0.001 for all comparisons). Zoledronic acid was also associated with a significant improvement in bone mineral density and bone metabolism markers. Adverse events, including change in renal function, were similar in the two study groups. However, serious atrial fibrillation occurred more frequently in the zoledronic acid group (in 50 vs. 20 patients, P<0.001). CONCLUSIONS: A once-yearly infusion of zoledronic acid during a 3-year period significantly reduced the risk of vertebral, hip, and other fractures. (ClinicalTrials.gov number, NCT00049829.)

Referrals of cancer versus non-cancer patients to palliative care consult team : do they differ ?

Depuis la fin du XXème siècle, les soins palliatifs se sont développés essentiellement autour de patients souffrant de cancer en phase terminale. Or depuis une dizaine d'années, un nombre croissant d'études rapporte que les patients souffrant de maladies non cancéreuses avancées expérimentent également une variété de problèmes, de dimension physique, psychosociale ou spirituelle. Ces problèmes peuvent avoir un fort impact sur leur qualité de vie. Malheureusement, seule une minorité de patients non cancéreux en phase terminale a accès à des soins palliatifs. Le but de cette étude est de mieux comprendre les similitudes et les différences entre les patients cancéreux et non cancéreux lorsqu'ils sont encore hospitalisés dans un hôpital universitaire de soins aigus et réferrés à une équipe mobile de soins palliatifs intrahospitalière. Méthodologie : Dans cette étude rétrospective, les dossiers des 100 premiers patients non cancéreux adressés à l'équipe mobile de soins palliatifs (EMSP) ont été comparés avec ceux de 506 patients cancéreux, durant la même période (2000-2001). Nous avons répertorié leurs profils démographiques, les types de demandes des professionnels de 1ère ligne s'adressant à l'EMSP, les symptômes ainsi que la médication des patients. Conclusions : Dans les deux groupes de patients, nous avons retrouvé de manière égale un haut taux de symptômes : 79% de patients non cancéreux et 71% de patients cancéreux expérimentent au moins 3 symptômes ou plus. Cependant, malgré cette similitude en termes d'inconfort, l'équipe de soins palliatifs est appelée plus tardivement pour les patients non cancéreux. Au vu des problèmes de communication verbale chez les patients non cancéreux, les demandes d'évaluation formulées auprès de l'EMSP sont plus orientées vers « une évaluation globale » au lieu d'une aide sur un problème spécifique. Nous retrouvons également une différence en termes d'analgésie entre les deux populations de patients, les patients non cancéreux sont plus fréquemment en surdosage. Selon nos données, un plus grand taux de décès survient à l'hôpital auprès des patients non cancéreux. Dans les limites de cette étude, les résultats permettent de confirmer que les patients non cancéreux hospitalisés dans un hôpital de soins aigus sont encore peu référés à une EMSP et très tardivement. Pour y rémédier, il serait nécessaire de contourner ces obstacles au vu des problèmes d'évaluation et d'identification exposés dans cette étude, d'améliorer la collaboration avec les professionnels de 1ère ligne et peut-être de mettre en place des guidelines institutionnels afin que tous les patients palliatifs puissent avoir la meilleure qualité de vie possible, et ce, jusqu'au bout de leur trajectoire hospitalière.

Evaluation of acute administration of natural products with potential diuretic effects, in humans

In order to evaluate the potential diuretic effect of two natural products, Elephantopus scaber and Alpinia speciosa, a trial administration was carried out in ten healthy volunteers and the effects compared to the those of a placebo. The substances were given on different days, with a seven day interval between doses. The amount of substance administered to the subjects was five times the usual dose i.e. 7.5 g/100 ml and 0.8 g/100 ml respectively. The following parameters parameteres were measured: urinary and plasma sodium, potassium, uric acid, calcium, phosphate, urea, creatinine. The subjects were also examined clinically and total urinary volume was assessed. The only significant finding (p < 0.05) was a slight diuresis with Alpinia speciosa, which also lowered the diastolic (p < 0.05) and systolic (p < 0.01) blood pressures. No effect on electrolytes or renal function parameters was observed, and this probably excludes any renal tubular or glomerular effect from these substances.

The effectiveness of tipi in the treatment of hip and knee osteoarthritis: a preliminary report

Osteoarthritis (OA) is a common painful inflammatory condition occurring mainly in the later half of life. Hipe and knee are the joints mostly affected. Petiveria alliacea (tipi) popularly known as an anti-rheumatic medicine, has been used by OA patients to relief pain. This one-week cross-over double-blind trial has preliminary evaluated the analgesic effect of tipi tea in 14 patients with hip and knee OA. Imperata exaltata (sape) was used as the Placebo tea. The pain assessments that were made at baseline and before the start of the second treatment period by treatment groups were comparable. While taking tipi or placebo tea patients experienced a statistically significant improvement in pain on motion and pain at night. The comparison between the improvements reported while on tipi and placebo tea, however, did not disclose any statistically significant difference. At the conclusion of the study 7 patients preferred tipi tea and 6 preferred placebo tea (NS). Two patients reported insomnia, one durign placebo treatment and the other during tipi treatment. In this preliminary report both teas succeeded in the aim of relieving pain.

Angiotensin II receptor blockade prevents acute renal sodium retention induced by low levels of orthostatic stress.

BACKGROUND: Depending on its magnitude, lower body negative pressure (LBNP) has been shown to induce a progressive activation of neurohormonal, renal tubular, and renal hemodynamic responses, thereby mimicking the renal responses observed in clinical conditions characterized by a low effective arterial volume such as congestive heart failure. Our objective was to evaluate the impact of angiotensin II receptor blockade with candesartan on the renal hemodynamic and urinary excretory responses to a progressive orthostatic stress in normal subjects. METHODS: Twenty healthy men were submitted to three levels of LBNP (0, -10, and -20 mbar or 0, -7.5, and -15 mm Hg) for 1 hour according to a crossover design with a minimum of 2 days between each level of LBNP. Ten subjects were randomly allocated to receive a placebo and ten others were treated with candesartan 16 mg orally for 10 days before and during the three levels of LBNP. Systemic and renal hemodynamics, renal sodium excretions, and the hormonal response were measured hourly before, during, and for 2 hours after LBNP. RESULTS: During placebo, LBNP induced no change in systemic and renal hemodynamics, but sodium excretion decreased dose dependently with higher levels of LBNP. At -20 mbar, cumulative 3-hour sodium balance was negative at -2.3 +/- 2.3 mmol (mean +/- SEM). With candesartan, mean blood pressure decreased (76 +/- 1 mm Hg vs. 83 +/- 3 mm Hg, candesartan vs. placebo, P < 0.05) and renal plasma flow increased (858 +/- 52 mL/min vs. 639 +/- 36 mL/min, candesartan vs. placebo, P < 0.05). Glomerular filtration rate (GFR) was not significantly higher with candesartan (127 +/- 7 mL/min in placebo vs. 144 +/- 12 mL/min in candesartan). No significant decrease in sodium and water excretion was found during LBNP in candesartan-treated subjects. At -20 mbar, the 3-hour cumulative sodium excretion was + 4.6 +/- 1.4 mmol in the candesartan group (P= 0.02 vs. placebo). CONCLUSION: Selective blockade of angiotensin II type 1 (AT1) receptors with candesartan increases renal blood flow and prevents the antinatriuresis during sustained lower body negative pressure despite a modest decrease in blood pressure. These results thus provide interesting insights into potential benefits of AT1 receptor blockade in sodium-retaining states such as congestive heart failure.

Activation of a dendritic cell-T cell axis by Ad5 immune complexes creates an improved environment for replication of HIV in T cells.

The STEP HIV vaccine trial, which evaluated a replication-defective adenovirus type 5 (Ad5) vector vaccine, was recently stopped. The reasons for this included lack of efficacy of the vaccine and a twofold increase in the incidence of HIV acquisition among vaccinated recipients with increased Ad5-neutralizing antibody titers compared with placebo recipients. To model the events that might be occurring in vivo, the effect on dendritic cells (DCs) of Ad5 vector alone or treated with neutralizing antiserum (Ad5 immune complexes [IC]) was compared. Ad5 IC induced more notable DC maturation, as indicated by increased CD86 expression, decreased endocytosis, and production of tumor necrosis factor and type I interferons. We found that DC stimulation by Ad5 IC was mediated by the Fcgamma receptor IIa and Toll-like receptor 9 interactions. DCs treated with Ad5 IC also induced significantly higher stimulation of Ad5-specific CD8 T cells equipped with cytolytic machinery. In contrast to Ad5 vectors alone, Ad5 IC caused significantly enhanced HIV infection in DC-T cell cocultures. The present results indicate that Ad5 IC activates a DC-T cell axis that, together with the possible persistence of the Ad5 vaccine in seropositive individuals, may set up a permissive environment for HIV-1 infection, which could account for the increased acquisition of HIV-1 infection among Ad5 seropositive vaccine recipients.

The impact of iron supplementation efficiency in female blood donors with a decreased ferritin level and no anaemia. Rationale and design of a randomised controlled trial: a study protocol.

ABSTRACT: BACKGROUND: There is no recommendation to screen ferritin level in blood donors, even though several studies have noted the high prevalence of iron deficiency after blood donation, particularly among menstruating females. Furthermore, some clinical trials have shown that non-anaemic women with unexplained fatigue may benefit from iron supplementation. Our objective is to determine the clinical effect of iron supplementation on fatigue in female blood donors without anaemia, but with a mean serum ferritin </= 30 ng/ml. METHODS/DESIGN: In a double blind randomised controlled trial, we will measure blood count and ferritin level of women under age 50 yr, who donate blood to the University Hospital of Lausanne Blood Transfusion Department, at the time of the donation and after 1 week. One hundred and forty donors with a ferritin level </= 30 ng/ml and haemoglobin level >/= 120 g/l (non-anaemic) a week after the donation will be included in the study and randomised. A one-month course of oral ferrous sulphate (80 mg/day of elemental iron) will be introduced vs. placebo. Self-reported fatigue will be measured using a visual analogue scale. Secondary outcomes are: score of fatigue (Fatigue Severity Scale), maximal aerobic power (Chester Step Test), quality of life (SF-12), and mood disorders (Prime-MD). Haemoglobin and ferritin concentration will be monitored before and after the intervention. DISCUSSION: Iron deficiency is a potential problem for all blood donors, especially menstruating women. To our knowledge, no other intervention study has yet evaluated the impact of iron supplementation on subjective symptoms after a blood donation. TRIAL REGISTRATION: NCT00689793.

Interaction between calcium intake and menarcheal age on bone mass gain: an eight-year follow-up study from prepuberty to postmenarche.

Both late menarcheal age and low calcium intake (Ca intake) during growth are risk factors for osteoporosis, probably by impairing peak bone mass. We investigated whether lasting gain in areal bone mineral density (aBMD) in response to increased Ca intake varies according to menarcheal age and, conversely, whether Ca intake could influence menarcheal age. In an initial study, 144 prepubertal girls were randomized in a double-blind controlled trial to receive either a Ca supplement (Ca-suppl.) of 850 mg/d or placebo from age 7.9-8.9 yr. Mean aBMD gain determined by dual energy x-ray absorptiometry at six sites (radius metaphysis, radius diaphysis, femoral neck, trochanter, femoral diaphysis, and L2-L4) was significantly (P = 0.004) greater in the Ca-suppl. than in the placebo group (27 vs. 21 mg/cm(2)). In 122 girls followed up, menarcheal age was recorded, and aBMD was determined at 16.4 yr of age. Menarcheal age was lower in the Ca-suppl. than in the placebo group (P = 0.048). Menarcheal age and Ca intake were negatively correlated (r = -0.35; P < 0.001), as were aBMD gains from age 7.9-16.4 yr and menarcheal age at all skeletal sites (range: r = -0.41 to r = -0.22; P < 0.001 to P = 0.016). The positive effect of Ca-suppl. on the mean aBMD gain from baseline remained significantly greater in girls below, but not in those above, the median of menarcheal age (13.0 yr). Early menarcheal age (12.1 +/- 0.5 yr): placebo, 286 +/- 36 mg/cm(2); Ca-suppl., 317 +/- 46 (P = 0.009); late menarcheal age (13.9 +/- 0.5 yr): placebo, 284 +/- 58; Ca-suppl., 276 +/- 50 (P > 0.05). The level of Ca intake during prepuberty may influence the timing of menarche, which, in turn, could influence long-term bone mass gain in response to Ca supplementation. Thus, both determinants of early menarcheal age and high Ca intake may positively interact on bone mineral mass accrual.

The efficacy of melatonin for sleep problems in children with autism, fragile X syndrome, or autism and fragile X syndrome.

STUDY OBJECTIVE: To determine the efficacy of melatonin on sleep problems in children with autistic spectrum disorder (ASD) and fragile X syndrome (FXS). METHODS: A 4-week, randomized, double blind, placebo-controlled, crossover design was conducted following a 1-week baseline period. Either melatonin, 3 mg, or placebo was given to participants for 2 weeks and then alternated for another 2 weeks. Sleep variables, including sleep duration, sleep-onset time, sleep-onset latency time, and the number of night awakenings, were recorded using an Actiwatch and from sleep diaries completed by parents. All participants had been thoroughly assessed for ASD and also had DNA testing for the diagnosis of FXS. RESULTS: Data were successfully obtained from the 12 of 18 subjects who completed the study (11 males, age range 2 to 15.25 years, mean 5.47, SD 3.6). Five participants met diagnostic criteria for ASD, 3 for FXS alone, 3 for FXS and ASD, and 1 for fragile X premutation. Eight out of 12 had melatonin first. The conclusions from a nonparametric repeated-measures technique indicate that mean night sleep duration was longer on melatonin than placebo by 21 minutes (p = .02), mean sleep-onset latency was shorter by 28 minutes (p = .0001), and mean sleep-onset time was earlier by 42 minutes (p = .02). CONCLUSION: The results of this study support the efficacy and tolerability of melatonin treatment for sleep problems in children with ASD and FXS.

Efficacy of niclosamide as a potential antipenetrant (TAP) against cercariae of Schistosoma mansoni monkeys

A 1% (W/V) formulation of Niclosamide (2', 5-Dichloro-4-nitrosalicylanilide) (TAP) was tested on Cebus apella monkeys as a topical prophylatic against schistosomiasis mansoni. Two experiments were conducted using the same formulation. In the first experiment, the TAP provided complete protection against schistosomiasis for 3 days. Of the 4 monkeys treated with TAP 7 days before exposure to Schistosoma mansoni cercariae, 2 were completely protected. The remaining 2 monkeys of the 7 day treatment group had a 78% or greater reduction in adult worm buderns when compared to the placebo treated monkeys. The second experiment was designed determine the time between day 3 and 7 when the TAP no longer provided complete protection. However, all of the TAP treated monkeys in this experiment were completely protected, even the monkeys treated 7 days earlier. In both experiments, all monkeys used as infection controls and those receiving only the placebo became infected and showed typical experimental schistosomiasis. These results demonstrate that the TAP could provide fast acting, short-term protection to people who must enter cercariae infested water.

Dose-dependent acute and sustained renal effects of the endothelin receptor antagonist avosentan in healthy subjects.

The endothelin receptor antagonist avosentan may cause fluid overload at doses of 25 and 50 mg, but the actual mechanisms of this effect are unclear. We conducted a placebo-controlled study in 23 healthy subjects to assess the renal effects of avosentan and the dose dependency of these effects. Oral avosentan was administered once daily for 8 days at doses of 0.5, 1.5, 5, and 50 mg. The drug induced a dose-dependent median increase in body weight, most pronounced at 50 mg (0.8 kg on day 8). Avosentan did not affect renal hemodynamics or plasma electrolytes. A dose-dependent median reduction in the fractional renal excretion of sodium was found (up to 8.7% at avosentan 50 mg); this reduction was paralleled by a dose-related increase in proximal sodium reabsorption. It is suggested that avosentan dose-dependently induces sodium retention by the kidney, mainly through proximal tubular effects. The potential clinical benefits of avosentan should therefore be investigated at doses of <or= 5 mg.