Preclinical to clinical translation of CNS transporter occupancy of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

BACKGROUND: Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters. METHODS: We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor. RESULTS: TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC50 of 11.7 ng/mL and 50.8 ng/mL, respectively, consistent with modest selectivity for NET in vivo. Accounting for species differences in protein binding, the projected human NET and SERT plasma EC50 values were 5.5 ng/mL and 23.9 ng/mL, respectively. A single-dose, open-label PET study (4-20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [(11)C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [(11)C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30-40 h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC50 for NET was estimated to be 1.21 ng/mL, and at doses of greater than 4 mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35 ng/mL. CONCLUSIONS: These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.

Clinical trial: the efficacy and tolerability of velusetrag, a selective 5-HT4 agonist with high intrinsic activity, in chronic idiopathic constipation - a 4-week, randomized, double-blind, placebo-controlled, dose-response study.

BACKGROUND: Velusetrag is an orally active 5-HT(4) receptor agonist of potential benefit in treating chronic idiopathic constipation. AIM: To evaluate the efficacy, safety and tolerability of velusetrag in chronic idiopathic constipation. METHODS: After a 2-week baseline period, patients [<3 spontaneous bowel movements (SBM)/week] received placebo or velusetrag (15, 30 or 50 mg) daily for 4 weeks in a randomized, double-blind design, followed by a 1-week follow-up period. The primary endpoint was the change from baseline in weekly SBM frequency averaged over the 4-week treatment period. RESULTS: Patients receiving velusetrag (15, 30 and 50 mg) achieved statistically and clinically significant increases in weekly SBM frequency relative to those receiving placebo. Mean increases were 3.6, 3.3 and 3.5 SBM/week respectively, compared with 1.4 SBM/week for placebo (P < 0.0001). Statistically significant increases in the weekly frequency of complete SBM (CSBM) were also reported (mean increases of 2.3, 1.8 and 2.3 for 15, 30 and 50 mg velusetrag respectively, compared with 0.6 for placebo). Common adverse events associated with velusetrag were diarrhoea, headache, nausea and vomiting, generally occurring during the initial days of dosing. CONCLUSION: Velusetrag was efficacious and well tolerated in patients with chronic idiopathic constipation (ClinicalTrials.gov identifier NCT00391820).

New reference values for echocardiographic dimensions of healthy Dutch children.

AIM: To renew the echocardiographic reference values of heart dimensions in healthy children. METHODS AND RESULTS: Group 1 consisted of 587 children, of which 361 boys and 226 girls, age from birth to 18 years, body weight over 2500 g, who visited the Pediatric Cardiology outclinic during the period January 2000 till March 2004. All included children were diagnosed as normal, or as having innocent heart murmur. The second group was taken from an earlier study and comprised 160 children (77 boys and 83 girls). The echocardiographic measures were taken from conventional M-mode recording of the left ventricle (LV) parasternal long axis view. End diastolic septal (IVS) and LV posterior wall thickness (LVPW) and end diastolic as well as end systolic LV intracavity dimensions were retrospectively analyzed. The regression lines from all measured sizes are significantly different from those collected in the early eighties. Especially the thickness of the IVS is smaller. The regression lines are independent of gender. CONCLUSIONS: New reference values have been found which should replace the presently used ones. There is no difference between boys and girls. Why the muscular wall thicknesses are thinner than found 20 years ago needs to be further explored.

Regional cardiac wall motion abnormalities during and shortly after anthracyclines therapy.

BACKGROUND: Tissue Doppler imaging (TDI) is a new non-invasive ultrasound technique that enables quantitative assessment of regional myocardial wall motion. A previous study of survivors of childhood malignancies demonstrated abnormalities of regional diastolic wall motion abnormalities many years after treatment with anthracyclines. The purpose of the present study was to investigate this phenomenon during and shortly after treatment. PROCEDURE: A total of 60 patients, age range 4.4-16.0 years, were included in this study: 43 early survivors, with a mean follow-up duration of 2.1 (range 0.3-5.2) years from end of anthracycline treatment, were evaluated retrospectively. Seventeen other patients were evaluated before, during, and 6 months after the end of anthracycline therapy. All patients received moderate cumulative doses of anthracyclines (range 120-450 mg/m2). Echocardiographic examination was performed using standardized conventional and TDI techniques. RESULTS: Of the early survivors, 26 (60%) demonstrated regional LV free wall motion abnormalities. In the prospective group, serial echocardiographic studies revealed three patients (18%) with regional abnormalities of LV free wall motion before starting chemotherapy, but 14 (82%) at the end of treatment. Six months later, however, the incidence decreased to 61% of the survivors. Subject and treatment characteristics, as well as LV wall diameters and fractional shortening were not significantly different for children with or without free wall motion abnormalities. Regional wall motion abnormalities were also seen in the interventricular septum, although this was less frequent. CONCLUSIONS: Regional diastolic wall motion abnormalities are common during and shortly after anthracyclines therapy but may be transient. The authors recommend simultaneous use of both conventional echocardiography & TDI for the monitoring of anthracycline-induced cardiotoxicity.

Female urinary genuine stress incontinence: anatomic considerations at MR imaging of the paravaginal fascia and urethra initial observations.

PURPOSE: To compare, on high-spatial-resolution magnetic resonance (MR) images, the presence and distribution of the paravaginal fascia in continent women and in those with genuine stress incontinence (GSI) to establish its role in the pathophysiology of GSI. MATERIALS AND METHODS: Eleven continent reference subjects and 10 GSI patients underwent MR imaging with a specifically designed endovaginal receiver coil. A urinary continence questionnaire and urogynecologic clinical examination had been completed. GSI was diagnosed with urodynamic tests. Paravaginal fascial tissue distribution was determined, and the paravaginal fascial volume (PFV) anteriorly associated with the urethra was measured. Retropubic urethral length (UL) in the supine position at rest was compared with its total length and expressed as a percentage ratio. Comparisons of urethral PFV and retropubic UL between reference subjects and the GSI patients were performed by means of two-sample t tests with unequal variances because data were parametric by means of the Shapiro-Francia W' test for normal data. RESULTS: The paravaginal fascia (connective tissue that contained venous plexus) was a consistent MR imaging feature in all women. Mean urethral PFV was 5.3 cm(3) +/- 0.6 (SD) in reference subjects compared with 3.5 cm(3) +/- 2.0 in GSI patients (P =.017). The ratio of the retropubic UL to its total length was 82.6% +/- 7.4 in reference subjects compared with 57.4% +/- 9.8 in GSI patients (P <.001). There was a weak correlation between urethral PFV and retropubic UL (r = 0.46). CONCLUSION: There is a significant association between urethral PFV and continence status. GSI patients have a reduced urethral PFV, and greater than 40% of their urethral length lies below the pubis in the supine position at rest. However, the effects of age and hormonal status on urethral PFV remain to be evaluated.

The influence of ductal left-to-right shunting during extracorporeal membrane oxygenation.

BACKGROUND/PURPOSE: The aim of this study was to analyze whether a ductal left-to-right (L-R) shunt will prolong extracorporeal membrane oxygenation (ECMO) in neonates with severe pulmonary hypertension. This report discusses the onset and termination of a ductal L-R shunt and its potential influences on ECMO when pulmonary hypertension decreases during venoarterial bypass. METHODS: Twenty-nine neonates were monitored during veno-arterial ECMO, using bedside echocardiography with 12-hour interval observations. RESULTS: Up to 43% of the patients showed this type of shunt already after 12 hours on bypass. In total, this type of ductal shunt was found between 12 and 72 hours on ECMO in 62% of the patients. After 72 hours, the ductal L-R shunt no longer was detected. In 38% of the patients, no ductal L-R shunt was found during ECMO. Comparisons between these 2 patient groups showed a significantly longer ECMO duration in patients with ductal L-R shunt (P <.007). The mean prolongation time was 46 hours. Also, a significant decrease of left atrium to aorta ratio (P <.01) was observed during ECMO in the ductus group after closure of the duct, illustrating the decrease in volume load for the left heart and lungs. CONCLUSIONS: Ductal L-R shunting is related with a substantial prolongation of the ECMO course (mean prolongation of almost 2 days). The authors suggest that on one side, the ductal L-R shunt will lead to pulmonary hypercirculation and on the other side, postductal stealing from the descending aortic circulation will lead to prerenal failure. Possibly because of interactions with pulmonary and renal function, a ductal L-R shunt will, among other factors, interfere with weaning from ECMO, resulting in a prolonged bypass time.

Spongy cardiomyopathy in a neonate.

Isolated noncompaction of ventricular myocardium is a rare cardiomyopathy, presumed to originate from a developmental abnormality in the evolution of the heart, and resulting in sponge-like myocardium. Isolated ventricular noncompaction can present with a variety of symptoms, but usually includes heart failure. The diagnosis is often made by echocardiography, which reveals a very distinct image of the myocardium, with many deep, confluent recesses and dense trabeculations. We encountered such findings in a moribund neonate presenting with cardiogenic shock with extremely low shortening fractions. After treatment with intravenous and oral cardiotonics, coupled with afterload reduction, we were able to optimize the balance between ventricular filling and myocardial contractility, resulting in markedly improved cardiac function as judged clinically, and as measured by echocardiography. As far as we know, this is one of the youngest patients yet reported to have a good recovery.

Discriminative ability of conventional echocardiography and tissue Doppler imaging techniques for the detection of subclinical cardiotoxic effects of treatment with anthracyclines.

This study investigated improvement of diagnosing myocardial damage caused by anthracyclines using tissue Doppler imaging (TDI). The optimal set of conventional echocardiographic and/or TDI parameters, needed for the discrimination of survivors from healthy controls, was retrospectively assessed. A total of 60 patients and 99 controls, age range 8.5 to 17.6 years, were studied. The survivors received 50 to 400 mg/m(2) cumulative dose of anthracyclines, with a mean follow-up of 7.3 (+/-2.3) years. The parameters used in the discriminant score (S-score) were selected from a large set of 51 echocardiographic parameters, using logistic regression analysis (stepwise selection). The correct classification probability (C-index) and the generalized distance (d) between the distributions of S-scores were used to measure the overall discriminative performance of each echocardiographic technique separately and in combination. The overall discriminative performance of the conventional echo-Doppler parameters (C = 77.3%, d = 1.04) was lower than that of the TDI (C = 84.2%, d = 1.37); the highest C-index was obtained using both techniques (C = 89.2%, d = 1.66). The set of parameters includes: LV fractional shortening and MV early diastolic flow velocity, two long-axis and five apical 4-CV TDI wall velocities (systolic and diastolic). In the patient group, the S-score was positively associated with cumulative dose of anthracyclines (p = 0.05) and duration of treatment (p = 0.01). The diagnostic index S-score, based on a limited number of variables from both techniques simultaneously, could retrospectively discriminate asymptomatic children with anthracycline-induced cardiomyopathy from healthy controls. The potentials of the S-score for serial and prospective studies are further investigated.

Effects of growth hormone treatment on left ventricular dimensions in children with Noonan's syndrome.

OBJECTIVE: To study the effects of long-term growth hormone (GH) treatment on left ventricular (LV) dimensions in children with Noonan's syndrome (NS). METHODS: Echocardiographic measurements of LV dimensions were performed before and during GH treatment in 27 participants (21 boys, 6 girls) in a partly controlled 3-year trial of high-dose GH treatment (0.15 IU/kg/day). Nineteen children had a congenital heart defect, 1 of them had hypertrophic obstructive cardiomyopathy. In the first 3 years, the children were assigned to 1 of 2 groups: group A with discontinuation of GH treatment in the 3rd year, or group B without GH treatment in the 1st year. After the 3rd year, 12 of the 27 children were followed up for 2 additional years to evaluate the long-term effects of GH treatment on the heart. RESULTS: At baseline, LV internal diameters were smaller, while posterior wall thickness were thicker than normal. Over the 1st year, changes in LV dimensions were comparable between the 2 groups. No significant differences were found in LV dimensions between the situation at baseline and after 4 years of GH treatment. CONCLUSION: Long-term high-dose GH treatment does not have clinically significant adverse effects on LV dimensions in children with NS.

Tissue Doppler imaging in detection of myocardial dysfunction in survivors of childhood cancer treated with anthracyclines.

The applicability of tissue Doppler imaging (TDI) was investigated for estimating cardiac function in long-term survivors of childhood cancer treated with anthracyclines. A total of 63 children (age range 7.8-17.3 y) underwent standard echo Doppler cardiographic studies of blood flow velocities, left ventricular dimensions and fractional shortening, followed by measurements of peak myocardial velocities and direction using the noninvasive tissue Doppler imaging (TDI) technique. All 63 were late survivors (median 7.1 y, range 3.5-13.5 y after end of therapy) who had received mean (+/- SD) cumulative dose of 242 (+/- 141) mg/m(2) of anthracyclines. The control group consisted of 160 healthy subjects (age range 4 to 17.9 y). Standard echo-Doppler anatomical parameters that were found significantly (p < 0.01) different for the study group are: RV wall thickness (decreased); LV diameter (increased); and LV fractional shortening (decreased). Studied hemodynamic parameters were not found to be different between the two groups. Quantitative TDI parameters: peak late diastolic myocardial velocities, as well as transmyocardial systolic and diastolic velocity differences, were significantly lower in late survivors than in the healthy pediatric population (p < 0.01). Qualitative local functional impairment of the movement of the left ventricular walls was detected in 20% of the patients. TDI might become a useful noninvasive method for detecting subclinical myocardial damage in apparently healthy children who received moderate doses of anthracyclines for treatment of childhood malignancy. Prospective studies with TDI for the detection of regional myocardial abnormalities are recommended.

Neonatal pulmonary hypertension during extracorporeal membrane oxygenation.

OBJECTIVES: This prospective study was designed to monitor severe pulmonary hypertension during extra corporeal membrane oxygenation using echo Doppler variables. BACKGROUND: All neonates treated with extracorporeal membrane oxygenation also have severe pulmonary hypertension. A study which monitors the reaction of the pre-existing pulmonary hypertension during extracorporeal oxygenation by frequent sampling of those variables related to pulmonary pressure is still lacking. Such a study is necessary to analyze the complex haemodynamic changes in patients undergoing extracorporeal membrane oxygenation. METHOD: In 29 neonates, we estimated pulmonary arterial pressure using peakflow velocity of regurgitation across the tricuspid- and pulmonary valve, peakflow velocity of shunting across persistent arterial ductus, and systolic time intervals of the right ventricle. Correlation between the several estimations of pulmonary arterial pressure were analysed with the Spearman correlation coefficient. RESULTS: Systolic pulmonary arterial pressure measured by the velocity of tricuspid regurgitation illustrated severe pulmonary hypertension prior to extra corporeal membrane oxygenation (mean 63 mmHg, sd 20). Similar levels for the systolic pulmonary arterial pressure could be derived (mean 73 mmHg, sd 17) from ductal shunting. A fair correlation of 0.76 (p< 0.002) could be demonstrated. Pulmonary hypertension responded well and quickly to treatment by extra corporeal membrane oxygenation, with reductions within 24 hours to mean systolic levels of 35 mmHg, sd 23. This very early reaction has not previously been demonstrated and could be of importance in defining parameters for weaning from cardiopulmonary bypass. Diastolic pulmonary arterial pressure was investigated because of its relation to vascular resistance. It proved more difficult to measure because of the low incidence of pulmonary regurgitation. Derived diastolic pressures did not show any good correlations. CONCLUSION: Pulmonary hypertension is well documented prior to extra corporeal membrane oxygenation and response very quickly to the institution of treatment. Ultra sound techniques are indicated at the bedside, and prove useful in monitoring pulmonary blood pressure during the procedure.

Assessment of myocardial velocities in healthy children using tissue Doppler imaging.

The objective was to determine the normal range of tissue velocities in paediatric hearts as measured by tissue Doppler imaging. A prospective study was carried out involving 160 healthy children (mean age 10.8 y, range 4.0-17.9 y). Using tissue Doppler imaging (TDI) from parasternal long axis and apical views, peak velocities and peak myocardial velocity differences across the right ventricular anterior wall, interventricular septum and left ventricular posterior wall were assessed during systole, early and late diastole. The existence of transmyocardial velocity differences between the left and right side of the interventricular septum, as well as between the endocardium and epicardium of the left ventricular posterior wall was observed throughout the heart cycle. With range-gated TDI from apical four-chamber view, peak velocities were measured within the basal, mid and apical parts of the interventricular septum, and the left and right free ventricular walls. The highest peak systolic, early and late diastolic velocities were measured within the basal parts of all myocardial walls. The ranges of the calculated velocity ratios (early-to-late diastolic velocity and early diastolic-to-systolic velocity) for the various wall parts appeared to be overlapping. The correlations of peak myocardial tissue velocities and their ratios with age and weight were weak and practically irrelevant. These normal values of peak myocardial velocities, transmyocardial velocity differences and the ratios of peak wall velocities can be used as reference values in future investigations of ventricular dysfunction in this age group.