Randomised clinical trial: anti-viral activity of ANA773, an oral inducer of endogenous interferons acting via TLR7, in chronic HCV.

BACKGROUND: The ANA773 is an oral prodrug of a small-molecule toll-like receptor (TLR)7 agonist. Preclinical and healthy volunteer clinical studies with ANA773 have demonstrated induction of endogenous interferon-α (IFN-α) of multiple subtypes, which supports the potential utility in the treatment of chronic hepatitis C virus (HCV) infection. AIM: To examine safety, tolerability, pharmacodynamics, pharmacokinetics and anti-viral activity of ANA773. METHODS: The ANA773 was investigated in a double-blind, placebo-controlled study in 34 patients chronically infected with HCV of any genotype. Patients were treatment-naïve or had relapsed following previous interferon-based treatment. This dose escalation study was composed of four dose groups (800, 1200, 1600 and 2000mg). In each group, six to eight patients received ANA773 and two received placebo. Patients were dosed with ANA773 every-other-day for either 28 days (800, 1200 or 1600mg) or 10days (2000mg). RESULTS: Mild to moderate adverse events were reported, with an increase in frequency and intensity with increasing dose. No serious AEs were reported and there were no early discontinuations. There were dose-related increases in various markers of IFN-α response. The mean maximum change in serum HCV RNA level from baseline was -0.34, -0.29, -0.40, -0.97 and -1.26log(10) in the placebo, 800, 1200, 1600 and 2000mg cohorts, respectively. At the 2000mg dose, ANA773 significantly (P=0.037) reduced serum HCV RNA levels (range: 0.14 to -3.10log(10) ). CONCLUSION: The ANA773 was generally well tolerated and resulted in a dose-related IFN-dependent response leading to a significant decrease in serum HCV RNA levels in the 2000mg dose group.

Pulmonary hemosiderosis in scimitar syndrome after prolonged management of pulmonary hypertension.

OBJECTIVE: To report a fatal outcome from pulmonary hemosiderosis in an infant with scimitar syndrome after prolonged pulmonary vasodilator therapy. DESIGN: Case report. SETTING: A tertiary care pediatric intensive care unit. SUBJECT: An infant with scimitar syndrome. INTERVENTIONS: Treatment included redirection of anomalous right pulmonary venous drainage and closure of atrial septal defect, assisted ventilation via tracheostomy, and protracted nitric oxide and prostacyclin therapy until his death at 1 yr of age. RESULTS: Inhaled nitric oxide (iNO) and/or prostacyclin (PGI(2)) were administered for 6.5 months. Numerous echocardiograms demonstrated good control of pulmonary pressures and no evidence of pulmonary venous obstruction. Repeated attempts to slowly wean from the pulmonary vasodilators resulted in return of pulmonary pressures to systemic levels. Although there was no clinically apparent hemoptysis, pulmonary infiltrates worsened, prompting an open-lung biopsy that revealed pulmonary hemosiderosis. During the last 4 days of the patient's life, the pulmonary hypertensive crises with suprasystemic pressures and pulmonary infiltrates worsened regardless of aggressive vasodilator therapy with iNO, PGI(2), alkalinization, and isoproterenol. Vasodilator therapy was withdrawn and the patient rapidly died. CONCLUSION: We achieved long-term control of pulmonary hypertension with iNO and/or PGI(2) without apparent tachyphylaxis or other major reported side effects. Although pulmonary hypertension was successfully controlled with prolonged iNO and intravenous PGI(2) administration in this patient with scimitar syndrome, the patient died of hypoxemic respiratory failure from pulmonary hemosiderosis. Early evaluation of roentgenographic infiltrates for hemosiderosis and potential lung transplantation in similar patients may be warranted.

Metabolic acidosis, rhabdomyolysis, and cardiovascular collapse after prolonged propofol infusion.

The authors present the hospital course of a 13-year-old girl with a closed head injury who received a prolonged infusion of propofol for sedation and, subsequently, died as a result of severe metabolic acidosis, rhabdomyolysis, and cardiovascular collapse. The patient had been treated for 4 days at a referring hospital for a severe closed head injury sustained in a fall from a bicycle. During treatment for elevations of intracranial pressure, she received a continuous propofol infusion (100 microg/kg/min). The patient began to exhibit severe high anion gap/low lactate metabolic acidosis, and was transferred to the pediatric intensive care unit at the authors' institution. On arrival there, the patient's Glasgow Coma Scale score was 3 and this remained unchanged during her brief stay. The severe metabolic acidosis was unresponsive to maximum therapy. Acute renal failure ensued as a result of rhabdomyolysis, and myocardial dysfunction with bizarre, wide QRS complexes developed without hyperkalemia. The patient died of myocardial collapse with severe metabolic acidosis and multisystem organ failure (involving renal, hepatic, and cardiac systems) approximately 15 hours after admission to the authors' institution. This patient represents another case of severe metabolic acidosis, rhabdomyolysis, and cardiovascular collapse observed after a prolonged propofol infusion in a pediatric patient. The authors suggest selection of other pharmacological agents for long-term sedation in pediatric patients.

Instillation of calf lung surfactant extract (calfactant) is beneficial in pediatric acute hypoxemic respiratory failure. Members of the Mid-Atlantic Pediatric Critical Care Network.

OBJECTIVE: Prospective study of the efficacy of calf lung surfactant extract in pediatric respiratory failure. DESIGN: Multi-institutional, prospective, randomized, controlled, unblinded trial. SETTING: Eight pediatric intensive care units (ICU) of tertiary medical centers. PATIENTS: Forty-two children with acute hypoxemic respiratory failure characterized by diffuse, bilateral pulmonary infiltrates, need for ventilatory support, and an oxygenation index of >7. INTERVENTION: Instillation of intratracheal surfactant (80 mL/m2). MEASUREMENTS AND MAIN RESULTS: Ventilator parameters, arterial blood gases, and derived oxygenation and ventilation indices were recorded before and at intervals after surfactant administration. Complications and outcome measures, including mortality, duration of mechanical ventilation, and length of pediatric ICU and hospital stay, were also examined. Patients who received surfactant demonstrated rapid improvement in oxygenation and, on average, were extubated 4.2 days (32%) sooner and spent 5 fewer days (30%) in pediatric intensive care than control patients. There was no difference in mortality or overall hospital stay. Surfactant administration was associated with no serious adverse effects. CONCLUSIONS: Administration of calf lung surfactant extract, calfactant, appears to be safe and is associated with rapid improvement in oxygenation, earlier extubation, and decreased requirement for intensive care in children with acute hypoxemic respiratory failure. Further study is needed, however, before widespread use in pediatric respiratory failure can be recommended.

Pediatric sedation with analgesia.

Sedation with analgesia is frequently required to perform painful or invasive procedures in children. The best medication combination for pediatric sedation with analgesia is yet to be identified. Sixty-four of 243 total sedation with analgesia procedures from January 1994 through August 1995 were randomly chosen for descriptive retrospective review and analysis. Four minor complications from the procedures were identified, and recovery was complete in all cases. One medication combination (fentanyl 1 microg/kg with propofol 1.5 to 2 mg/kg, followed by an infusion of 150 microg/kg/min) provided the shortest mean time to dismissal (17.8 minutes v 38 minutes) when compared with other combinations used. No episodes of respiratory depression, hypotension, or nausea and vomiting occurred in the fentanyl/propofol group. These results show that fentanyl/propofol was superior to other medications used during this study period for pediatric sedation with analgesia. Prospective comparison of this medication combination with other short-acting agents in patients undergoing both elective and emergency procedures is necessary.

Transcutaneous renal function monitor: precision during unsteady hemodynamics.

OBJECTIVE: Hospital acquired renal dysfunction, most commonly caused by renal hypoperfusion, dramatically increases mortality in intensive care patients. Glomerular filtration rate (GFR) is rapidly altered during renal hypoperfusion, and a more rapid means of GFR measurement may prompt institution of renal-specific therapy. We hypothesized that a transcutaneous renal function monitor can rapidly and accurately assess acute changes in GFR within a time frame much shorter than the 2-4 hours currently available. METHODS: The study design was a prospective determination of the capability to measure GFR transcutaneously. In three different studies, concurrent transcutaneous measurement of GFR, using the rate of disappearance of 99mTc-diethylenetriaminepentaacetic acid (DTPA), was compared by correlation and standard deviation (SD) to reference standards of DTPA plasma clearance, serum inulin clearance, or serum creatinine. RESULTS: Continuous transcutaneous clearance (TC) measurement correlated with standard DTPA plasma clearance techniques (r = 0.93). Acute pharmacologically induced changes in GFR are detectable by TC measurement within 12-20 min, a time interval significantly affected by the data acquisition interval. Excess patient movement in the ICU patients created clearance artifacts in 50% of clearance traces. Retrospective analysis of ICU patient data reveal TC measurements are 93% specific and 92% sensitive for serum creatinine levels in critically ill patients. CONCLUSIONS: TC monitoring provides prompt indication of directional changes in GFR and may provide the clinician warning of inadequate resuscitation. Prospective analysis of the specificity, sensitivity, and TC guided renal-specific resuscitation is needed.

Calf's lung surfactant extract in acute hypoxemic respiratory failure in children.

OBJECTIVE: Open-label trial of the safety and short-term efficacy of calf's lung surfactant in pediatric respiratory failure. DESIGN: Multi-institutional, uncontrolled, observational trial. SETTING: Six pediatric intensive care units of tertiary medical centers. PATIENTS: Twenty-nine children with acute hypoxemic respiratory failure, characterized by diffuse, bilateral, pulmonary infiltrates, need for ventilator support, and an oxygenation index of > or = 7. INTERVENTIONS: Up to four doses of intratracheal surfactant (80 mL/m2). MEASUREMENTS AND MAIN RESULTS: Ventilator parameters, arterial blood gases, and derived oxygenation and ventilation indices were recorded before, and at intervals after, surfactant administration. Complications and outcome measures were also noted. There was immediate improvement in oxygenation and moderation of ventilator support associated with surfactant administration in 24 of 29 patients. A modest but statistically insignificant effect was seen with subsequent doses. The only complications occurred in three patients who developed airleaks, two of which were coincident with surfactant administration. The overall mortality rate was 14%, which compares favorably with other published series. CONCLUSIONS: Administration of calf's lung surfactant appears to be safe and is associated with rapid improvement in oxygenation and moderation of ventilator support in children with acute hypoxemic respiratory failure. These results set the stage for a randomized, controlled study.

Age-dependence of effects of A1 adenosine receptor antagonism in rat hippocampal slices.

1. Population excitatory postsynaptic potentials (EPSPs) and population spikes evoked in area CA1 of hippocampal slices from aged Fischer 344 rats were significantly smaller in amplitude than responses obtained in slices from young Fischer 344 rats. 2. The A1 adenosine receptor antagonist 8-cyclopentyltheophylline (8-CPT) produced a concentration-dependent increase in synaptic potentials in slices from both young and aged rats. Low concentrations (1 nM) of 8-CPT were effective in producing increases in both population spike amplitudes and population EPSP slopes in young and aged rat slices. Response increases were maximized by 100 nM 8-CPT in slices from rats of both age groups. 3. Adenosine antagonism produced greater average increases in synaptic responses in hippocampal slices from aged rats at all concentrations tested (1.0 nM-1.0 microM). A qualitative age-related difference in the response to 8-CPT was also observed; 8-CPT produced a late component, consisting of multiple population spikes, in evoked responses in slices obtained from aged but not young rats. 4. Adenosine antagonism significantly increased the maximum evocable response (both spike amplitude and EPSP slope) in slices from aged rats, relative to increases observed in slices from young rats. This suggested that smaller synaptic potentials seen in slices from aged rats were in part due to greater levels of "tonic" adenosinergic inhibition. 5. Slices from young and aged rats were incubated in the adenosine reuptake inhibitor soluflazine (R64719; 1.0, 10, and 100 microM) and the inhibition of population EPSPs was observed for 60 min. No difference was observed in the rate of inhibition or the maximal level of inhibition produced by soluflazine, in slices from rats of either age group. 6. Application of (+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclo-hepten- 5,10-imine hydrogen maleate (MK-801) and 2-amino-5-phosphonopentanoic acid (2-AP5), antagonists of N-methyl-D-aspartate (NMDA) excitatory amino acid (EAA) receptors, reduced the late multiple population spike component in slices from aged rats incubated in 8-CPT. A smaller direct effect of the NMDA antagonists was observed in slices from aged rats in the absence of 8-CPT treatment at maximal response levels. No effect of NMDA receptor antagonism was observed in slices from young rats under either condition. 7. Hippocampal tissue, from young and old rats utilized in the electrophysiological experiments, was assayed for A1 adenosine binding site density with a saturating concentration of radiolabeled agonist and antagonist. Guanine nucleotide modulation of agonist binding was also measured.(ABSTRACT TRUNCATED AT 400 WORDS)

Endogenous adenosine contributes to hypoxic synaptic depression in hippocampus from young and aged rats.

1. Extracellular field potentials were recorded to study the role of endogenous adenosine during hypoxia in area CA1 of rat hippocampal slices. 2. Hypoxic conditions, induced by 15 min exposure to 95% N2-5% CO2 at 32 degrees C and in high-glucose incubation medium, produced a rapid and reversible depression of evoked synaptic potentials. 3. In slices from young Sprague-Dawley rats, the hypoxia-induced synaptic depression was reduced in a concentration-dependent manner by the adenosine antagonist 8-cyclopentyltheophylline (8-CPT; 100 nM-2.0 microM). 4. Recovery of synaptic potentials after hypoxia was complete under each experimental condition. 5. Extended periods of hypoxia lasting 30 min likewise produced a rapid and near total suppression of the evoked synaptic potentials. In the presence of 8-CPT, both the population excitatory postsynaptic potential (EPSP) slope and population spike amplitude were significantly preserved throughout the hypoxic episode. 6. Neither the onset rate nor the degree of the hypoxia-induced synaptic depression were significantly different in slices from young, adult, or aged Fischer 344 rats. Reduction of the hypoxia-induced response depression by 8-CPT was also similar in all age groups. 7. These findings have further characterized the important involvement of endogenous adenosine in the potentially neuroprotective synaptic depression observed in hippocampal slices from young and aged rats during hypoxia.

Low-dose droperidol versus standard-dose droperidol for prevention of postoperative vomiting after pediatric strabismus surgery.

STUDY OBJECTIVE: To determine whether a low dose of droperidol is as effective as a high dose in preventing vomiting after pediatric strabismus surgery. DESIGN: Randomized, double-blind study. SETTING: Operating room and recovery room at a university medical center. PATIENTS: One hundred children undergoing strabismus procedures. INTERVENTIONS: Patients were divided randomly into three groups and received either droperidol 75 microgram/kg, droperidol 20 microgram/kg, or saline. MEASUREMENTS AND MAIN RESULTS: Vomiting was assessed in all groups, as was time to discharge and ability to perform a satisfactory postoperative eye examination. Children who received droperidol vomited less frequently than those who did not (p = 0.0521). There was no difference in the frequency of vomiting between the two groups that received droperidol. CONCLUSION: Droperidol 20 microgram/kg is as effective as droperidol 75 microgram/kg in preventing vomiting after pediatric strabismus surgery. Because higher doses of droperidol may sedate some patients, the lowest effective dose should be used. In this study, however, there was no statistically significant difference with regard to length of recovery room stay.

Inhibitory refinement of spatial frequency selectivity in single cells of the cat striate cortex.

Single cells in the cat striate cortex are more selective for the spatial frequency of sinewave grating stimuli than are cells of the retina or lateral geniculate nucleus. We have explored the possibility that this enhancement of selectivity results from spatial-frequency-selective inhibition. Stimulation with two superimposed gratings, one to excite the cell and one to prove for inhibition, revealed spatial frequency-dependent response suppression in 74% of the total population studied. Suppression was slightly more prevalent in simple cells (80%) than in complex cells (68%). In 93% of the cases where suppression was found, its tuning was complementary to excitatory spatial frequency tuning, and the strongest suppression was usually found where the excitatory tuning function approached zero imp./sec. Characteristics of the phenomenon were independent of cortical layers. We conclude that organized inhibitory mechanisms serve to refine the spatial frequency bandpass of striate cortical cells. This provides evidence for another degree of nonlinearity in the organization of cortical receptive fields and supports the hypothesis that a fundamental function of the visual cortex is image dissection in the domain of spatial frequency.

A 1-heteroaryl-4-piperidinyl-methyl pyrrolidinone, BMY 21502, delays the decay of hippocampal synaptic potentiation in vitro.

The effects of the substituted pyrrolidinone, BMY 21502, on the properties of cell membranes, synaptic transmission and synaptic plasticity, were assessed in area CA1 of hippocampal slices from the rat. Application of the compound to the bath had no consistent direct effects on parameters of the cell membrane or evoked synaptic potentials, at concentrations of less than 30 microM. In a blind experimental design, BMY 21502 at 1.0 and 10 microM, but not 25 microM, significantly delayed the decay of long-term potentiation in slices obtained from young animals; in slices obtained from very old rats (2.5-3.2 yr), 10 microM BMY 21502 significantly delayed decay of long-term potentiation. Therefore BMY 21502 was active in a physiological model that may predict of cognitive enhancement.

The adenosine antagonist 8-cyclopentyltheophylline reduces the depression of hippocampal neuronal responses during hypoxia.

Exposure of rat hippocampal slices to hypoxic conditions for 15 min produced a rapid, profound, but completely reversible depression of evoked synaptic potentials. The specific A1 adenosine receptor antagonist 8-cyclopentyltheophylline (8-CPT) significantly reduced hypoxia-induced synaptic depression in a concentration-dependent manner. It is concluded that adenosine, which is neuroprotective when exogenously applied during severe hypoxia because of its ability to depress synaptic transmission, may have an important and exploitable endogenous role in the protection of sensitive neurons.