The general data protection regulation, the clinical trial regulation and some complex interplay in paediatric clinical trials.

Although a number of authors have commented upon the impact of the GDPR on clinical trial conduct, few have examined the specific setting of paediatric trials. Whilst the general principles are the same as those for adults, some additional considerations arise. The ages of consent relating to data privacy and clinical trial participation are different in a number of countries, but the distinction is often not recognised in non-drug trials. Accidental pregnancies in clinical trials always raise complexities, but these are amplified when the trial subject is a minor, and the processes described in clinical trial protocols rarely take account of GDPR requirements. This paper describes approaches which can be taken to ensure the rights of children are respected.Conclusion: The conduct of paediatric clinical trials within GDPR requirements is quite possible provided authors think carefully when drafting protocols. What is Known: • GDPR is applicable to clinical trials, including paediatric trials. • A number of challenges at the interface between the GDPR and CTR have been described. What is New: • The application of the GDPR to certain specific situations in paediatric trials does not appear to have been explored. • Three such situations are described and solutions offered.

An open-label trial of rituximab therapy in pulmonary alveolar proteinosis.

Rituximab, a monoclonal antibody directed against the B-lymphocyte antigen CD20, has shown promise in several autoimmune disorders. Pulmonary alveolar proteinosis (PAP) is an autoimmune disorder characterised by autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF). An open-label, proof-of-concept phase II clinical trial was conducted in 10 PAP patients. The intervention consisted of two intravenous infusions of rituximab (1,000 mg) 15 days apart. Bronchoalveolar lavage (BAL) fluid and peripheral blood samples were collected. The primary outcome was improvement in arterial blood oxygenation. Both arterial oxygen tension and alveolar-arterial oxygen tension difference in room air improved in seven out of the nine patients completing the study. Lung function and high-resolution computed tomography scans, which were secondary outcomes, also improved. Peripheral blood CD19+ B-lymphocytes decreased from mean ± sem 15 ± 2% to <0.05% (n = 10) 15 days post-therapy. This decrease persisted for 3 months in all patients; at 6 months, CD19+ B-cells were detected in four out of seven patients (5 ± 2%). Total anti-GM-CSF immunoglobulin (Ig)G levels from baseline to 6 months were decreased in BAL fluids (n = 8) but unchanged in sera (n = 9). In this PAP cohort: 1) rituximab was well-tolerated and effectively ameliorated lung disease; and 2) reduction in anti-GM-CSF IgG levels in the lung correlated with disease changes, suggesting that disease pathogenesis is related to autoantibody levels in the target organ.

A resource of mapped human bacterial artificial chromosome clones.

To date, despite the increasing number of genomic tools, there is no repository of ordered human BAC clones that covers entire chromosomes. This project presents a resource of mapped large DNA fragments that span eight human chromosomes at approximately 1-Mb resolution. These DNA fragments are bacterial artificial chromosome (BAC) clones anchored to sequence tagged site (STS) markers. This clone collection, which currently contains 759 mapped clones, is useful in a wide range of applications from microarray-based gene mapping to identification of chromosomal mutations. In addition to the clones themselves, we describe a database, GenMapDB (http://genomics.med.upenn.edu/genmapdb), that contains information about each clone in our collection.

Sequential bilateral bundle branch block during dofetilide, a new class III antiarrhythmic agent, in a patient with atrial fibrillation.

INTRODUCTION: The mechanism of wide QRS complex tachycardias during dofetilide infusion was studied in a patient with atrial fibrillation. METHODS AND RESULTS: Endocardial recordings from the intraventricular conduction system showed that dofetilide caused "classic" aberrant conduction (Ashman phenomenon, typical QRS morphology) at high prematurity ratios (preceding interval = 1.78 x coupling interval--290), thus mimicking ventricular ectopy. In addition, there was frequent sequential bilateral bundle branch block, caused by a significant difference in preceding bundle-to-bundle intervals (mean difference +/- 1 SD: 74 +/- 26 msec). CONCLUSION: The present findings may prove helpful in the clinical assessment of wide QRS complex rhythms after dofetilide and possibly other "pure" Class III antiarrhythmics.

Dofetilide, a novel class III antiarrhythmic agent.

Dofetilide is a potent and selective class III antiarrhythmic agent that is under development for the treatment of re-entrant tachyarrhythmias (ventricular tachycardia/ventricular fibrillation, atrial fibrillation/atrial flutter, and paraoxysmal supraventricular tachycardia). In animal studies, dofetilide selectively inhibits the rapid component of the time-dependent outward potassium current (IKr) and therefore increases the effective refractory period and action potential duration without affecting the fast inward sodium current. Studies in dogs have shown that dofetilide (a) prolongs the effective refractory period in a dose-dependent manner, (b) elevates ventricular fibrillation threshold, (c) facilitates conversion of electrically induced ventricular fibrillation or fibrilloflutter to sinus rhythm, (d) does not influence conduction within the His-Purkinje system or within the myocardium, (e) does not impair cardiac contractility, and (f) reduces dispersion of ventricular repolarization. Dofetilide has been administered to healthy volunteers as well as to patients with ischemic heart disease or with supraventricular arrhythmias; the compound has generally been well tolerated. Side effects have occasionally been reported, but have generally been transient and mild and occur in placebo-treated subjects as well. No clinically significant changes in laboratory safety tests have been detected. The pharmacokinetic profile of dofetilide both in healthy volunteers and patients includes a linear dose-plasma concentration relationship and also a linear plasma concentration-QTc relationship. The terminal plasma elimination half-life is approximately 9-10 h and systemic bioavailability in the region of 100%. The elimination pattern is balanced, with 50% being excreted unchanged via the kidney, the remaining 50% being metabolized in the liver to inactive metabolites, with greater than 90% of circulating drug-related material being unchanged dofetilide. After intravenous administration of the compound, a slight hysteresis in the plasma drug level-QTc relationship has been detected. Pharmacodynamic data demonstrate dose- and concentration-dependent effects on myocardial repolarization as evidenced by prolongations of the QTc interval. This is reflected in significant prolongations in the effective and functional refractory periods and monophasic action potential duration throughout the myocardium. No effects on sinus node function, conduction parameters, or cardiac contractility have been detected in any of the clinical studies, supporting the contention that dofetilide is a highly selective class III antiarrhythmic agent.

Electrophysiologic properties of UK-66,914, a novel class III antiarrhythmic agent.

A class III antiarrhythmic agent that preferentially increases the effective refractory period without altering conduction velocity holds considerable promise for the treatment of life-threatening cardiac arrhythmias dependent on a reentrant mechanism. In the present study, the cellular electrophysiologic effects of a novel class III antiarrhythmic agent, UK-66,914, were evaluated. UK-66,914 prolonged action potential duration and extended the effective refractory period in isolated canine ventricular muscle and Purkinje fibers in a concentration-dependent manner, beginning at a threshold concentration of 0.1 microM. Analogous effects were found in isolated rabbit atrium beginning at a threshold concentration of 2 microM. At concentrations of UK-66,914 up to 20 microM there was no effect on the maximum rate of phase 0 depolarization (Vmax) or the amplitude of the action potential. In guinea pig papillary muscles. UK-66,914 at concentrations from 0.1 to 20 microM increased the effective refractory period at stimulation frequencies of 1 or 5 Hz, but did not slow conduction velocity. Therefore, UK-66,914 exhibits high selectivity for a class III antiarrhythmic effect in normal tissue. To elucidate the mechanisms responsible for the increase in effective refractory period, voltage clamp procedures were used in guinea pig ventricular myocytes. UK-66,914 reduced the amplitude of outward tail currents following depolarizing clamp steps with little effect either on the background K+ current or calcium currents, indicating that UK-66,914 selectively blocked the time-dependent potassium current. In anesthetized dogs, UK-66,914 (10 micrograms/kg to 1 mg/kg i.v.) prolonged both atrial and ventricular effective refractory periods, but in contrast to the studies performed in vitro, the minimum effective doses required to increase the effective refractory period in atria and ventricle were the same. Therefore, UK-66,914 is a potent selective class III antiarrhythmic agent, which owes its electrophysiologic profile to blockade of the time-dependent potassium current.

UK-68,798: a novel, potent and highly selective class III antiarrhythmic agent which blocks potassium channels in cardiac cells.

UK-68,798 increased the duration and effective refractory period of cardiac action potentials recorded in vitro from canine ventricular muscle and Purkinje fibers in a concentration dependent manner from 5 nM to 1 microM. The resting membrane potential, amplitude and maximum upstroke velocity of action potentials were unaffected by UK-68,798, indicating the selective class III antiarrhythmic properties of this agent. UK-68,798 (5 nM-1 microM) increased the effective refractory period of isolated guinea pig papillary muscles at stimulation frequencies of 1 Hz and 5 Hz without influencing the conduction velocity, further confirming that UK-68,798 is devoid of class I antiarrhythmic activity including block of the sodium channel. Studies using single voltage clamped guinea pig ventricular myocytes indicated that UK-68,798 at concentrations of 50 nM and 2 microM blocks a time-dependent K+ current, with no appreciable effects on the time-independent K+ current or the inward calcium current. UK-68,798 is therefore a highly selective K+ channel blocking agent with class III antiarrhythmic properties, a profile that holds considerable promise for the therapy of life-threatening cardiac arrhythmias.

The effect of aging on alpha-adrenoceptors and their responses in rabbits.

The effects of age on alpha-adrenoceptor responses, sensitivity and number were studied in rabbits aged from 1 to 36 months. Three types of investigation were carried out: conscious animal studies, isolated tissue studies and radioligand binding studies. Specific [3H]-prazosin binding decreased with age in both spleen and heart suggesting that the number of alpha 1-receptors declined at least in the tissues studied. The specific binding of [3H]-clonidine to spleen membranes and [3H]-yohimbine to platelets was not affected by age. In vitro responsiveness to alpha-adrenoceptor agonists decreased with age in abdominal aorta and renal artery, while the affinity of adrenoceptors for prazosin (pA2) was not altered. The decrease may be non-specific as responses to potassium were also altered. No change in alpha 2-adrenoceptor mediated platelet aggregation was observed. No change in pressor or depressor responses to full adrenoceptor agonists or to antagonists was observed in vivo. However, responses to clonidine, which is a partial agonist at alpha 1-adrenoceptors, were decreased. While aging influenced alpha-adrenoceptor subtypes differently, there was no direct relation between functional changes and number of receptors.

The recovery of alpha-adrenoceptor function and binding sites after phenoxybenzamine. An index of receptor turnover?

The recovery of peripheral alpha-adrenoceptor function and binding sites was studied in male New Zealand white rabbits after treatment with the irreversible adrenoceptor antagonist phenoxybenzamine. Phenoxybenzamine (5 mg/kg) was administered intravenously and the animals studied 30 min to 12 days later. Pressor dose response curves to intravenous phenylephrine, noradrenaline and guanabenz were constructed in vivo in conscious animals. The contractile response of abdominal aorta and renal artery to phenylephrine and noradrenaline was examined in vitro and the recovery of specific prazosin and clonidine binding to spleen membranes investigated in radioligand binding studies. The half life (t 1/2) for recovery of maximum pressor response in vivo ranged from 0.9 +/- 0.2 days for phenylephrine to 1.4 +/- 0.1 days for guanabenz. The t 1/2 for recovery of ED50 was not significantly different to t 1/2 for recovery of maximum pressor response and ranged from 0.8 +/- 0.2 days for noradrenaline to 1.3 +/- 0.3 days for phenylephrine. Half life for recovery of maximum response and EC50 in the isolated tissues was similar to that obtained in vivo for recovery of pressor responses and ranged from 0.4 +/- 0.1 days for the EC50 of noradrenaline in the renal artery to 1.2 +/- 0.6 days for maximum response to phenylephrine in the abdominal aorta. The rate of recovery of specific clonidine binding did not differ significantly from the rate of recovery of pressor responses to the alpha 2-selective agonist guanabenz. t 1/2 for maximum number of specific clonidine binding sites, Bmax was 1.6 +/- 0.9 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Recovery in vivo and in vitro of alpha-adrenoceptor responses and radioligand binding after phenoxybenzamine.

Phenoxybenzamine is an irreversible, selective alpha 1-adrenoceptor antagonist that results in long-lasting attenuation of the effects of alpha-adrenoceptor agonists in vivo and in vitro. We have studied in rabbits the time course of recovery of in vivo pressor responses to phenylephrine and in vitro contractile responses of spiral strips of renal artery to phenylephrine and noradrenaline. The maximum number of binding sites and the dissociation constant has been determined using 3H-prazosin in spleen and heart membranes prepared at intervals up to 8 days after phenoxybenzamine 5 mg/kg intravenously. In vitro contractile responses recovered over 2-3 days and by 4 days the EC50 was lower than control. In vivo pressor responses recovered over 5-8 days to control levels. The number of binding sites was only 50% of control at 8 days. It is proposed that under the conditions studied the recovery of binding sites may provide an index of turnover of alpha-adrenoceptors. The results also suggest that postreceptor mechanisms contribute to the increased responses observed in vitro.

Fertility and nuptiality changes in Spain from the late 18th to the early 20th century.

Abstract 3.1. A regional approach often reveals features of population trends not evident in national data. We have already pointed out that the 1768 census followed the ecclesiastical sub-divisions of the country; therefore its territorial data are not comparable with those derived from later enumerations. The 1787 and 1797 censuses, on the other hand, were based on civil sub-divisions, which can be compared, when aggregated, with later censuses of the modern statistical era.