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We prove existence of small-amplitude modulated solitary waves for the full-dispersion Kadomtsev--Petviashvilii (FDKP) equation with weak surface tension. The resulting waves are small-order perturbations of scaled, translated and frequency-shifted solutions of a Davey--Stewartson (DS) type equation. The construction is variational and relies upon a series of reductive steps which transform the FDKP functional to a perturbed scaling of the DS functional, for which least-energy ground states are found. We also establish a convergence result showing that scalings of FDKP solitary waves converge to ground states of the DS functional as the scaling parameter tends to zero. Our method is robust and applies to nonlinear dispersive equations with the properties that (i) their dispersion relation has a global minimum (or maximum) at a non-zero wave number, and (ii) the associated formal weakly nonlinear analysis leads to a DS equation of elliptic-elliptic focussing type. We present full details for the FDKP equation., Comment: 35 pages

The paper considers the existence of one- or two-hump solutions of a singularly perturbed nonlinear Schrodinger (NLS) equation, which is the standard NLS equation with a third order perturbation. In particular, this equation appears in the field of nonlinear optics, where it is used to describe pulses in optical fibers near a zero dispersion wavelength. It has been shown formally and numerically that the perturbed NLS equation has one- or multi-hump solutions with small oscillations at infinity, called generalized one- or multi-hump solutions. The main purpose of the paper is to provide the first rigorous proof of the existence of generalized one- or two-hump solutions of the singularly perturbed NLS equation. The several invariant properties of the equation, i.e., the translational invariance, the gauge invariance and the reversibility property, are essential to obtain enough free constants to prove the existence. The ideas and methods presented here may be applicable to show existence of generalized 2 k -hump solutions of the equation.

Background & Aims: Golexanolone is a novel small molecule GABA-A receptor-modulating steroid antagonist under development for the treatment of cognitive and vigilance disorders caused by allosteric over-activation of GABA-A receptors by neurosteroids. It restored spatial learning and motor coordination in animal models of hepatic encephalopathy (HE) and mitigated the effects of intravenous allopregnanolone in healthy adults in a dose-dependent fashion. Herein, we report data on the safety, pharmacokinetics (PK) and efficacy of golexanolone in adult patients with cirrhosis. Methods: Following single/multiple ascending dose studies, adults with Child-Pugh A/B cirrhosis and abnormal continuous reaction time (CRT) on screening were randomized to 3 weeks dosing with golexanolone (10, 40 or 80 mg BID) or placebo. CRT, psychometric hepatic encephalopathy score (PHES), animal naming test (ANT), Epworth sleepiness scale (ESS) and electroencephalogram (mean dominant frequency [MDF]; delta+theta/alpha+beta ratio [DT/AB]) were obtained at baseline, 10, and 21 days. Results: Golexanolone exhibited satisfactory safety and PK. Baseline characteristics were similar between the 12 and 33 patients randomized to placebo or golexanolone, respectively. By prespecified analyses, golexanolone was associated with directionally favourable changes vs. placebo in ESS (p = 0.047), MDF (p = 0.142) and DT/AB (p = 0.021). All patients also showed directionally favourable changes in CRT, PHES and ANT, but with no statistical difference between golexanolone and placebo. Post hoc analyses taking into account the variability and improvement in CRT, PHES and ANT observed between screening and baseline suggested an efficacy signal by cognitive measures as well. Conclusion: Golexanolone was well tolerated and associated with improvement in cognitive performance. These results implicate GABA-A receptor-modulating neurosteroids in the pathogenesis of HE and support the therapeutic potential of golexanolone. Lay summary: Many patients with cirrhosis experience subtle but disabling cognitive problems, including sleepiness and poor attention span, that impair their ability to be gainfully employed or carry out activities of daily living. This pilot study tested the hypothesis that these problems with cognition, for which there is no approved treatment, might be improved by an experimental drug, golexanolone, designed to normalize the function of receptors which inhibit brain function. The results of this study suggest that golexanolone is well tolerated and may improve cognition, as reflected by measures of sleepiness, attention span and brain wave activity, paving the way for future larger studies of this promising experimental drug. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. Funding Agencies|Umecrine Cognition AB

The travelling wave problem for a particular bidirectional Whitham system modelling surface water waves is under consideration. This system firstly appeared in Dinvay et al. (2019), where it was numerically shown to be stable and a good approximation to the incompressible Euler equations. In subsequent papers (Dinvay, 2019; Dinvay et al., 2019) the initial-value problem was studied and well-posedness in classical Sobolev spaces was proved. Here we prove existence of solitary wave solutions and provide their asymptotic description. Our proof relies on a variational approach and a concentration-compactness argument. The main difficulties stem from the fact that in the considered Euler–Lagrange equation we have a non-local operator of positive order appearing both in the linear and non-linear parts. Our approach allows us to obtain solitary waves for a particular Boussinesq system as well.

OBJECTIVES The prevalence of idiopathic normal pressure hydrocephalus (iNPH) and vascular comorbidity increases with age. It has not been clarified if high age and vascular disease are negative predictors of shunt surgery outcome in patients with iNPH. The aim of this study was to investigate the impact of high age and vascular comorbidity on outcome after shunt surgery in patients with iNPH. METHODS All 332 patients with iNPH who were treated with shunts between 2011 and 2015 at a single centre were consecutively included. Hellstrom iNPH scale, without the neuropsychological tests, was calculated preoperatively and at follow-up 12 months after shunt surgery. Outcome was defined as the difference between the post-operative and preoperative iNPH scale scores. A multivariable model was used to investigate the predictive effects of age and vascular comorbidity on shunt surgery outcome. RESULTS In a multivariable analysis of covariance (ANCOVA) with post-operative outcome as the dependent variable, increasing age (years, B = -0.63, P

In this note, we study solitary wave solutions of a class of Whitham–Boussinesq systems which include the bidirectional Whitham system as a special example. The travelling wave version of the evolution system can be reduced to a single evolution equation, similar to a class of equations studied by Ehrnstrom et al. (Nonlinearity 25:2903–2936, 2012). In that paper, the authors prove the existence of solitary wave solutions using a constrained minimization argument adapted to noncoercive functionals, developed by Buffoni (Arch Ration Mech Anal 173:25–68, 2004), Groves and Wahlen (J Math Fluid Mech 13:593–627, 2011), together with the concentration–compactness principle.

We consider a two-dimensional inviscid irrotational flow in a two layer fluid under the effects of gravity and interfacial tension. The upper fluid is bounded above by a rigid lid, and the lower fluid is bounded below by a rigid bottom. We use a spatial dynamics approach and formulate the steady Euler equations as a Hamiltonian system, where we consider the unbounded horizontal coordinate x as a time-like coordinate. The linearization of the Hamiltonian system is studied, and bifurcation curves in the (β,α)-plane are obtained, where α and β are two parameters. The curves depend on two additional parameters ρ and h, where ρ is the ratio of the densities and h is the ratio of the fluid depths. However, the bifurcation diagram is found to be qualitatively the same as for surface waves. In particular, we find that a Hamiltonian-Hopf bifurcation, Hamiltonian real 1:1 resonance, and a Hamiltonian 02-resonance occur for certain values of (β,α). Of particular interest are solitary wave solutions of the Euler equations. Such solutions correspond to homoclinic solutions of the Hamiltonian system. We investigate the parameter regimes where the Hamiltonian-Hopf bifurcation and the Hamiltonian real 1:1 resonance occur. In both these cases, we perform a center manifold reduction of the Hamiltonian system and show that homoclinic solutions of the reduced system exist. In contrast to the case of surface waves, we find parameter values ρ and h for which the leading order nonlinear term in the reduced system vanishes. We make a detailed analysis of this phenomenon in the case of the real 1:1 resonance. We also briefly consider the Hamiltonian 02-resonance and recover the results found by Kirrmann. (Less)

We consider three-dimensional inviscid irrotational flow in a two layer fluid under the effects of gravity and surface tension, where the upper fluid is bounded above by a rigid lid and the lower fluid is bounded below by a flat bottom. We use a spatial dynamics approach and formulate the steady Euler equations as an infinite-dimensional Hamiltonian system, where an unbounded spatial direction $x$ is considered as a time-like coordinate. In addition we consider wave motions that are periodic in another direction $z$. By analyzing the dispersion relation we detect several bifurcation scenarios, two of which we study further: a type of $00(\mathrm{i}s)(\mathrm{i}\kappa_0)$ resonance and a Hamiltonian-Hopf bifurcation. The bifurcations are investigated by performing a center-manifold reduction, which yields a finite-dimensional Hamiltonian system. For this finite-dimensional system we establish the existence of periodic and homoclinic orbits, which correspond to, respectively, doubly periodic travelling waves and oblique travelling waves with a dark or bright solitary wave profile in the $x$-direction. The former are obtained using a variational Lyapunov-Schmidt reduction and the latter by first applying a normal form transformation and then studying the resulting canonical system of equations., Comment: 34 pages

This paper presents existence theories for several families of axisymmetric solitary waves on the surface of an otherwise cylindrical ferrofluid jet surrounding a stationary metal rod. The ferrofluid, which is governed by a general (nonlinear) magnetisation law, is subject to an azimuthal magnetic field generated by an electric current flowing along the rod. The ferrohydrodynamic problem for axisymmetric travelling waves is formulated as an infinite-dimensional Hamiltonian system in which the axial direction is the time-like variable. A centre-manifold reduction technique is employed to reduce the system to a locally equivalent Hamiltonian system with a finite number of degrees of freedom, and homoclinic solutions to the reduced system, which correspond to solitary waves, are detected by dynamical-systems methods.

Zolmitriptan is a serotonin5-HT1B/1Dreceptor agonist that is an effective and well-tolerated drug for migraine treatment. In a human positron emission tomography study, [11C]zolmitriptan crossed the blood-brain barrier but no clear pattern of regional uptake was discernable. The objective of this study was to map the binding of [11C]zolmitriptan in Rhesus monkey brain using whole hemispherein vitroautoradiography with [11C]zolmitriptan as a radioligand. In saturation studies, [11C]zolmitriptan showed specific (90%) binding to a population of high-affinity binding sites (Kd 0.95–5.06 nM). There was regional distribution of binding sites with the highest density in the ventral pallidum, followed by the external globus pallidus, substantia nigra, visual cortex, and nucleus accumbens. In competitive binding studies with 5-HT1receptor antagonists, [11C]zolmitriptan binding was blocked by selective 5-HT1Band 5-HT1Dligands in all target areas. There was no appreciable change in binding with the addition of a 5-HT1Areceptor antagonist.

Objective - To evaluate the effects of continuous duodenal infusion of levodopa over time on the disabling fluctuations in motor performance in advanced parkinsonian patients. It has earlier been demonstrated that these fluctuations can be reduced by keeping the plasma concentration of levodopa constant. Material and methods - In view of the low water solubility of levodopa a stable dispersion of the drug was developed and used for continuous intraduodenal infusion in patients with advanced Parkinson's disease. Nine patients were evaluated with respect to an optimal oral treatment, during nasoduodenal infusion by a portable pump and then followed for 6 months to 2 1/2 years when treated via transabdominal infusion. Upon each test occasion, over 2 non-consecutive days, objective movement analysis by means of an opto-electronic system was applied every 15-20 min and video recordings performed twice every h. On several test occasions plasma levodopa concentrations were analysed every 15 min. Results - The patients showed improvement and decreased variance of their motor function. In the 2 patients followed over a period of 2 1/2 years levodopa plasma concentration showed reduced fluctuations on infusion and the levodopa consumption as well as mean levodopa plasma concentration decreased. Conclusion - Continuous duodenal infusion of levodopa is an alternative treatment strategy for patients with advanced Parkinson's disease when conventional therapy has failed.

NXY-059 has a proposed mechanism of action of free-radical trapping and has been studied in clinical trials based on positive effects seen in experimental models of acute ischaemic stroke. This study evaluated the safety, tolerability and pharmacokinetics of NXY-059 in healthy Japanese male subjects compared with previous data from healthy Caucasian subjects.The primary objective of this phase 1, double-blind, randomised, placebo-controlled, dose-escalating study was to evaluate the safety and tolerability of an 8- or 24-h intravenous infusion of NXY-059 targeting an unbound plasma concentration of 25-300 micromol/L in healthy Japanese male subjects (20-45 years). NXY-059 pharmacokinetics were also assessed, and any differences in pharmacokinetics between Japanese and previously studied Caucasian subjects (20-45 years) were explored.NXY-059 was generally well tolerated and no safety concerns were identified. There was a similar incidence of adverse events between subjects receiving NXY-059 or placebo, and no obvious trend towards an increased incidence of adverse events with increasing doses of NXY-059 was observed. In addition, there was no evidence of any vasoirritative effects or changes in renal function. The tolerability profile was similar in Caucasian subjects. The pharmacokinetic results indicate proportional exposure of 8-h and 24-h infusions of NXY-059 resulting in mean unbound steady state plasma concentrations up to 417 micromol/L and 379 micromol/L, respectively. Plasma clearance values for NXY-059 were similar in both Japanese and Caucasian subjects.This study suggests that the tolerability and pharmacokinetics of NXY-059 in healthy Japanese male subjects and Caucasians are similar.

NXY-059 is a novel free-radical trapping neuroprotectant. Digoxin treatment is common in acute ischaemic stroke, the intended patient population for NXY-059. Since both digoxin and NXY-059 are eliminated primarily renally, with a substantial contribution by active renal secretion, and because digoxin has a narrow therapeutic window, this open, randomised, crossover, two-period study investigated whether NXY-059 affects the pharmacokinetics (PK) of digoxin.Twenty-two healthy subjects received 0.5 mg oral digoxin 2 h after the start of 60-h intravenous infusions of NXY-059 and placebo separated by a 14-day washout. Blood and urine were collected for 60 h. Digoxin concentrations were measured by a novel liquid chromatography-mass spectrometry assay.The ratio of the geometric mean (90% confidence interval) between NXY-059 and placebo for the digoxin area under the concentration-versus-time curve was 0.91 (0.83-0.99) and was within the predefined range for no interaction (0.80-1.25). No safety concerns were raised in the study. No serious adverse events were recorded. The most common adverse event was headache with similar frequencies in the two treatments.NXY-059 had no clinically significant effect on the PK of digoxin.

NXY-059 is a free radical-trapping neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischemic stroke. Acute ischemic stroke patients receiving NXY-059 may also be exposed to diuretics for treatment of heart failure or hypertension. NXY-059 and furosemide are partly eliminated by active tubular secretion via an organic anion transporter. This double-blind, randomized, crossover, placebo-controlled study investigated whether an infusion of NXY-059 (15 mg/mL) during 12 hours affects the diuretic and saluretic effects of a 30-mg intravenous bolus dose of furosemide (10 mg/mL) administered after 6 hours' infusion, in 13 male and 11 female healthy subjects. The net increase in urine volume and sodium excretion in the interval of 6 to 12 hours was 4.15 L and 178 mmol/L, respectively, during NXY-059 treatment (P = .93) and 4.34 L and 190 mmol/L, respectively, during placebo treatment (P = .54). NXY-059 reduced the renal clearance of furosemide by 19% (P = .019), and furosemide reduced the renal clearance of NXY-059 by 8% (P = .005). NXY-059 was well tolerated.

Objective: Triptans are highly effective in the treatment of migraine. Both central and peripheral mechanisms of action have been suggested. Until now, firm data about the passage of triptans into the CNS in humans have been lacking. The aim of the current study was to evaluate, using positron emission tomography (PET), the uptake and distribution of zolmitriptan into the CNS after intranasal administration. Subjects and methods: Eight healthy volunteers, five males and three females (mean ages 23 and 26 years, respectively), were included. Radioactive [carbonyl-11C]zolmitriptan was infused intravenously for 5 minutes on two occasions: once alone, and once 30–40 minutes after intranasal administration of unlabelled zolmitriptan 5mg. PET was used to measure the concentration of labelled zolmitriptan in the brain, from the start of the tracer infusion for 90 minutes. Regional cerebral blood volume was determined with [15O]carbon monoxide. In addition, an MRI scan was performed to obtain anatomical information. The PET images were analysed quantitatively for different areas of the brain, generating [11C]zolmitriptan time-activity data corrected for circulating tracer activity. The rate of uptake of intranasal zolmitriptan into the CNS was estimated by kinetic modelling using the PET data. Results: PET data from this study demonstrate a rapid dose-proportional uptake of [11C]zolmitriptan into the brain. Significant concentrations of [11C]zolmitriptan were found in all brain regions studied. Calculated CNS concentrations after intranasal zolmitriptan administration showed a gradual increase, reaching about 2nM (0.5 μg/L) 30 minutes after administration and 3.5nM (1.0 μg/L), or one-fifth of the plasma concentration, 1 hour after administration. Five minutes after zolmitriptan administration, the mean CNS concentration had already reached 0.5nM, which is higher than in vitro values for initiation of the agonistic action on 5-HT1B/1D receptors. Conclusion: This study demonstrates by direct measurements that zolmitriptan enters the brain parenchyma in humans, achieving an uptake rate and concentration compatible with a central mode of action.

Pharmacotherapy for Parkinson’s disease (PD) is based on levodopa, the most effective dopaminergic drug. The development of motor complications constitutes the major challenge for new or refined therapies.To evaluate the impact of levodopa pharmacokinetics on motor function, an observational study in the patients’ home environment was carried out. A high variability in plasma levodopa levels was found in all patients, irrespective of treatment regimen. The impact of levodopa pharmacokinetics was further studied in a crossover trial comparing sustained-release tablets and continuous daytime intestinal infusion. Infusion produced significantly decreased variability in plasma levels of levodopa, resulting in significantly normalised motor function. A permanent system for long-term levodopa infusion has been developed and 28 patients have been followed for 87 patient-years. Motor response was generally preserved during the long-term observation period, implying that there is no development of tolerance to infusion therapy. Levodopa tablets are normally used in multiples of 50 or 100 mg, thus a rough estimate of individual dosage. A new concept for individualising levodopa/carbidopa doses with microtablets of 5/1.25 mg is under development. An electronic drug-dispensing device for administering the microtablets was tested on patients with PD. All were able to handle the dispenser and most were interested in future use of the concept. Self-assessment of symptoms is accurate in PD, but traditional paper diaries are associated with low compliance. A wireless electronic diary was compared with a corresponding paper diary. The time-stamped and thus completely reliable patient compliance was 88% with the electronic diary.To conclude, pharmacokinetics of levodopa is the major determinant for motor fluctuations in PD. Every effort to individualise dosage and to smooth out the fluctuations in levodopa concentrations should be made, e.g. by means of microtablets or enteral infusion. Electronic patient diaries for real-time data capture are suitable for PD studies.

The mechanisms controlling rates and routes for intestinal absorption of nutrients and small compounds are still not fully clarified. In the present study we aimed to investigate the effect of solvent drag on intestinal permeability of compounds with different molecular sizes in humans and rats. The effective intestinal permeabilities (P eff ) of hydrophilic compounds (MW 60-4000) were determined in the single-pass perfused jejunum in humans in vivo and rats in situ under iso- and hypotonic conditions. The transport mechanism(s) of water and the importance of the solvent drag effect were investigated by the use of D 2 O. This is the first report in humans establishing the relation between in vivo measured jejunal P eff and molecular size for hydrophilic compounds. In addition, in rats we also found a molecular-size selectivity for hydrophilic compounds similar to man. The jejunal P eff of water and urea (MW 60) in both species were several times higher than predicted from their physicochemical properties. In humans, the jejunal absorption of urea and creatinine (MW 113) was increased by solvent drag, while no effect was found for the other investigated compounds. In rats, P eff for urea and creatinine were unaffected. In conclusion, it is still unclear if solvent drag occurs mainly through the para- or transcellular route, although, results from this study further add to our earlier reports suggesting that the transcellular route is most important from a quantitative point of view regardless of physicochemical properties of the transported compounds.

Food ingestion can influence the absorption of levodopa in the intestine and thereby contribute to fluctuations of motor functions in Parkinson patients. Obstruction of the active transport of levodopa by amino acids can be one factor. Paracellular drug absorption, a route proposed to be influenced by net transport of water across the intestinal epithelium, might occur for a small and hydrophilic drug such as levodopa. In the present study we studied how luminal L-leucine (60 mmol/L), alone or combined with hypotonicity, might stimulate net water absorption, and levodopa uptake in the human small intestine, since this possibly can contribute to the variable intestinal absorption of levodopa. The Loc-I-Gut perfusion technique was used in 10 healthy volunteers to study the effects of induced net fluid absorption on the small intestinal absorption of levodopa (2.5 mmol/L). An induced net fluid absorption was observed only when L-leucine was combined with a hypoosmolar perfusion solution. However, this did not enhance the intestinal permeability of levodopa. In conclusion, we suggest that the variability in the absorption of levodopa in Parkinson’s disease cannot be explained by differences in transmucosal water flux in the human small intestine.

Background: NXY-059 is a free radical-trapping neuroprotectant that has been reported to reduce infarct size and preserve brain function in experimental models of acute ischemic stroke. NXY-059 administered as an 8- or 72-hour IV infusion has been reported to be well tolerated in healthy young (age, 20–45 years) and older (55–75 years) white volunteers. NXY-059 is no longer in development following a lack of efficacy found in a Phase III trial in patients with acute ischemic stroke. Objectives: The primary objectives of this study were to determine the pharmacokinetic (PK) properties of an 8-hour IV infusion of NXY-059 in healthy Chinese volunteers and to compare those data with those previously reported in the white population, therefore exploring any differences in PK properties between the 2 ethnic groups. Secondary objectives were to evaluate PK linearity and tolerability. Methods: This Phase I, randomized, double-blind (within dose panels), placebo-controlled study was conducted at Peking Union Medical College Hospital, Beijing, China. Healthy male and female Chinese volunteers aged 20 to 45 years were recruited. NXY-059 was administered as a continuous 8-hour IV infusion, starting with a 1-hour loading dose (dosing rate, 3 x maintenance infusion rate) followed by a 7-hour maintenance dose infusion. Subjects were randomly assigned, in a 3:1 ratio, to receive doses calculated (based on creatinine clearance in individual subjects) to achieve 1 of 3 concentration targets, or inactive vehicle (sodium chloride; placebo). The target unbound plasma NXY-059 concentrations during constant rate infusion (steady state) (Cu ss ) in the 3 dose panels were 100,200, and 300 μmol/L. An explorative bridging analysis was used to compare PK data from this study with those previously reported in the white population. Linearity of NXY-059 PK properties was assessed. Tolerability was assessed using adverse events (spontaneous reporting, study staff observation, and open questioning), physical examination, including vital sign measurement; and electrocardiography and laboratory analysis. Results: Thirty-six subjects were randomized (mean age, 32 years [range, 20–41 years]; mean body mass index, 22.6 kg/m 2 [range, 20–26 kg/m 2 ]). The target exposures of NXY-059 were achieved (mean [SD] Cu ss values, 98.3 [8.9], 202.1 [18.3], and 287.9 [25.4] μmol/L, respectively). Steady-state concentrations appeared to have been reached after 4 hours. From the bridging analysis, comparison of PK properties in the 27 Chinese volunteers versus those in 28 white volunteers found similar total plasma clearance of NXY-059 (estimated Chinese:white clearance ratio, 1.077 [95% CI, 1.009–1.150]). There were no apparent differences in other PK parameters between the 2 ethnic groups. The PK properties of NXY-059 in Chinese volunteers were suggestive of linearity. A total of 7 adverse events were reported, all of mild intensity, in the NXY-059 and placebo groups (thirst and polyuria [each in 2 subjects who received NXY-059 and 1 subject who received placebo]; urinary tract infection [1 subject who received NXY-059]). Conclusions: The results from the present study suggest that the PK properties of NXY-059 were similar in the Chinese and historical white healthy volunteer populations.

NXY-059 is a novel free radical-trapping neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischemic stroke. It is the first neuroprotectant to demonstrate a reduction in global disability in a phase III clinical trial, as measured by the modified Rankin Scale. Any effect of NXY-059 on hemostasis may be important when treating stroke patients. This phase I randomized, double-blind, placebo-controlled, 3-period crossover study compared the effect of NXY-059, desmopressin, and placebo on bleeding time, platelet aggregation, and adhesion in 30 healthy volunteers. NXY-059 did not prolong bleeding time compared with placebo: mean (SD) time for NXY-059, 369.5 seconds (125.0 seconds) versus placebo, 369.1 seconds (136.0 seconds). There were no significant effects on platelet aggregation or adhesion. At a mean unbound plasma concentration (Cu(ss)) of 335 micromol/L, NXY-059 was well tolerated, with no major safety concerns identified. In conclusion, NXY-059 does not appear to affect primary hemostasis.

The serotonin 5-HT(1A) receptor has been ascribed a putative role in the pathophysiology and drug treatment of depression. NAD-299 (generic name robalzotan) is a new potential antidepressant with high affinity and selectivity for the 5-HT(1A) receptor.The aim of this positron emission tomography (PET) study was to examine the extent and time-course of 5-HT(1A) occupancy by NAD-299 in the human brain, in relation to plasma concentration after escalating single oral doses.Five healthy male subjects received one or more single oral doses of NAD-299 (0.5, 2.5 and 10 mg) in aqueous solution under fasting conditions. Total and unbound (after ultrafiltration) plasma concentrations of NAD-299 were determined by liquid chromatography-mass spectrometry (LC-MC), over a tentative dosage interval of 8 h. Regional 5-HT(1A) receptor occupancy in brain was calculated by the simplified reference tissue model using the radioligand [ carbonyl-(11)C]WAY-100635.After the 10 mg dose, occupancy was high in the raphe (62-85%) and neocortical regions (68-75%) at time for C(max), but had declined considerably (17-44%) at 7 h after dose intake.This study confirmed that the new selective 5-HT(1A) antagonist NAD-299 occupies 5-HT(1A) receptors in the living human brain in a dose-dependent manner following oral dosage. The curvilinear relationship between NAD-299 drug concentration and 5-HT(1A) receptor occupancy was established and can be used for dose selection in subsequent clinical patient studies.

Positron emission tomography (PET) seems to be a valuable method for the understanding of intestinal absorption mechanisms, for simultaneous quantitation of absorption rate and distribution kinetics to the tissues of interest after oral drug delivery. PET was evaluated in three Rhesus monkeys for quantitation of the absorption rate from the gastrointestinal tract and the distribution kinetics into different organs. To obtain optimal standardized conditions for the measurement of absorption the drug was administered via a naso-duodenal catheter directly to the absorption site in the proximal small intestine. l-DOPA was used as study drug given in a suspension together with carbidopa and the radiomarker l-[beta-11C]DOPA. The l-DOPA suspension was given into the duodenum without and after administration of a suspension of six l-amino acids (120 mM) in order to investigate any interaction on the intestinal absorption and distribution of l-DOPA into the liver and brain tissue. Intestinal absorption was in general minor during the first study period and higher together with administered l-amino acids. The somewhat contradictory result with increased absorption when amino acids were present in the intestinal lumen, may be a consequence of increased intestinal motility initiated by the nutrient load.

To describe health service consumption and to find out whether a series of possible explanatory variables can help us to predict the number of contacts among children.A prospective study following a cohort of children during the first four years of life.A municipality in southern Norway.183 children born in the community from October 1979 to and including December 1980.Direct and indirect encounters with general practitioners (GPs) from the bills to the national insurance office, outpatient encounters and hospital admissions from the hospital files, and episodes of illness as reported in postal questionnaires to the parents.Each child had on average 10.6 GP contacts (2.6 per year), and the frequency of contacts decreased as they grew. Telephone contacts were almost as frequent as consultations at the doctor's surgery, and the doctors made more home visits to the youngest children. Of the contacts, 4/5 took place in the day time, but most of the home visits took place during the evening/night/weekend. Each child had 1.9 hospital contacts in 4 years, i.e. 0.3 admissions and 1.6 outpatient department contacts. The parents reported an average of 11.5 episodes of illness during the period, more than twice as many in the first year as in the last year. Information about sex, duration of breast feeding, smoking in the family, family history of allergy, parents' education, whether in kindergarten, and presence of psychosocial problems cannot help in predicting health care consumption.The low number of contacts with GPs can partly be explained by the fact that the children also have contact with a well-baby clinic. In our study, a series of possible explanatory factors did not help us to predict the amount of health care consumption during the first four years of life.

1. A new method for perfusing a 10 cm segment of jejunum in humans has been used in seven subjects to study the effect of the amino acid L-leucine (40 mM) on the intestinal absorption of levodopa (2.5 mM). The tube contains six channels and has two inflatable balloons, which enable a perfusion of a closed and defined segment of the proximal small intestine. 2. L-leucine decreased the intestinal absorption of levodopa from 40 +/- 19 to 21 +/- 15% but was without effect on the absorption of antipyrine, benserazide and D-glucose. 3. We confirm that levodopa is absorbed by the active transport system normally responsible for the absorption of large neutral amino acids (LNAA) in humans. Oral absorption by passive diffusion, probably by the paracellular route, might also occur for levodopa in the proximal part of the small intestine.

Assuming the presence of clinically significant cholinergic hypofunction in amyotrophic lateral scleroses (ALS), seven patients with ALS were treated with 100-200 mg tetrahydroaminoacridine (THA) together with 11 g lecithin daily for up to 7 weeks. In a separate experiment pharmacokinetics and effects on muscle strength and neurophysiological parameters were studied following the injection of 30 mg THA intravenously. Following the injection of THA an increase in muscle strength was observed in two patients. There were no consistent pharmacokinetic differences that could explain the effect on intravenous THA on muscle strength in these two patients. The plasma clearance of THA was high and the oral bioavailability low with large interindividual differences (6-36%). No beneficial effect was seen during oral medication and side-effects were common. There were no conclusive changes observed regarding neurophysiological parameters after drug administration. THA has probably no place in the treatment of ALS.

Two brothers presented from birth with features characteristic of Sotos syndrome (cerebral gigantism): overgrowth, craniofacial abnormalities, and mental retardation with hyperactive and aggressive behavior. X-ray examination of the hands revealed imbalanced and advanced skeletal age in one, whereas anterior fontanel bones were present in both brothers. Various hormone concentrations in plasma were all within normal limits, as were the results of a search for abnormal metabolites in plasma and urine. The occurrence of this usually sporadic syndrome in two sons of possible remotely consanguineous, healthy parents, suggests that in some cases Sotos syndrome may be inherited as an autosomal recessive trait. Thus our observation may support the suggestion of heterogeneity of Sotos syndrome. Until specific tests for the identification of various types are available, genetic counseling for this syndrome is difficult.