Pharmacokinetics, safety and tolerability of single- and multiple-ascending doses of JNJ-64530440, a novel hepatitis B virus capsid assembly modulator, in healthy volunteers.

BACKGROUND: Pharmacokinetics and safety of JNJ-64530440, a hepatitis B virus capsid assembly modulator producing normal empty capsids (CAM-N), in healthy volunteers were evaluated. METHODS: This Phase I study (NCT03439488) was a double-blind, randomised, placebo-controlled study. Adults (n = 10/cohort, five Asian/five non-Asian), randomised 4:1, received single-ascending doses of oral JNJ-64530440 (first- and second-generation formulations) or placebo under fasted (50, 150, 300 and 900 mg) or fed (300, 750, 1,000, 2000 and 4000 mg) conditions. Multiple-ascending doses of 750 or 2000 mg once daily and 750 mg twice daily JNJ-64530440 (second-generation formulation) for 7 days were evaluated. Pharmacokinetic parameters were estimated from plasma concentrations. Safety was assessed throughout. RESULTS: Less than dose-proportional increases in maximum plasma concentrations (Cmax) and area under the plasma concentration-time curves (AUCs) were observed across the doses. Mean plasma half-lives ranged from 9.3 to 14.5 h. Cmax and AUC were ∼two fold higher under fed versus fasting conditions and slightly higher in Asians versus Caucasians. JNJ-64530440 doses ≥750 mg achieved plasma levels higher than protein-binding adjusted concentrations demonstrating in vitro antiviral activity. No serious adverse events (AEs), treatment discontinuations or dose-limiting toxicities were seen. AE frequency/severity did not increase with dose. CONCLUSIONS: Single (up to 4000 mg) and multiple doses (up to 2000 mg for 7 days) of JNJ-64530440 were well tolerated in healthy volunteers. Multiple doses ≥750 mg/day achieved plasma concentrations expected to have antiviral activity that may lower hepatitis B surface antigen. No clinically relevant differences in tolerability or pharmacokinetic parameters were seen between Asians versus Caucasians.

Safety, tolerability, and pharmacokinetics of AL-335 in healthy volunteers and hepatitis C virus-infected subjects.

BACKGROUND: The nucleotide analog AL-335 is a pangenotypic hepatitis C virus (HCV) nonstructural protein (NS)5B inhibitor being evaluated as treatment for chronic HCV infection. METHODS: This three-part randomized, double-blind study evaluated the safety and pharmacokinetics of single and multiple ascending oral doses of AL-335. Healthy volunteers (HVs) received single doses of AL-335 (100-1,200 mg) or placebo in a fasted or fed (400 mg) state. Non-cirrhotic subjects (HCV genotype [GT]1-4) and GT1-infected subjects with Child Pugh A cirrhosis received multiple doses of AL-335 (400, 800, 1,200 mg) or placebo once daily (QD) for 7 days. RESULTS: Forty-eight HVs and 64 subjects with HCV GT1-4 were randomized and received treatment. AL-335 was well tolerated in HVs and HCV-infected subjects with/without cirrhosis. AL-335 was rapidly absorbed and converted to the metabolites ALS-022399 and ALS-022227. ALS-022227 exposure increased less than dose-proportionally and was unaffected by food, while AL-335 and ALS-022399 exposure increased with food by 85% and 50%, respectively, in HVs. Rapid and dose-dependent reductions in HCV-RNA were observed in GT1-infected subjects. In non-cirrhotic, GT1-4-infected subjects receiving AL-335 800 mg QD, potent antiviral activity was observed, regardless of genotype (mean maximum reductions in HCV-RNA of 4.0-4.8 log10 IU/mL). The same dose in GT1-infected cirrhotic subjects resulted in a 3.5 log10 IU/mL mean maximum reduction in HCV-RNA. CONCLUSIONS: AL-335 was well tolerated when administered as single and multiple doses, with an acceptable pharmacokinetic profile. The drug also demonstrated potent antiviral activity in HCV GT1-4-infected subjects, including GT1-infected subjects with cirrhosis.

Pharmacokinetics, safety, and tolerability of the 2- and 3-direct-acting antiviral combination of AL-335, odalasvir, and simeprevir in healthy subjects.

This Phase I, open-label, two-group, fixed-sequence study evaluated the pharmacokinetics and safety of AL-335, odalasvir, and simeprevir in healthy subjects. Group 1 (n = 16) received AL-335 800 mg once daily (QD) (days 1-3, 11-13, and 21-23), simeprevir 150 mg QD (days 4-23), and odalasvir 150 mg (day 14) followed by 50 mg QD (days 15-23). Group 2 (n = 16) received the same AL-335 regimen as in Group 1 plus odalasvir 150 mg (day 4) followed by 50 mg QD (days 5-23) and simeprevir 150 mg QD (days 14-23). Blood samples were collected to determine plasma concentrations of AL-335 (prodrug) and its metabolites, ALS-022399 (monophosphate precursor) and ALS-022227 (parent nucleoside), odalasvir, and simeprevir. Thirty-two subjects were enrolled. Odalasvir and simeprevir given alone, or in combination, increased AL-335 area under plasma concentration-time curve over 24 hours (AUC 0-24 h) 3-, 4-, and 7- to 8-fold, respectively; ALS-022399 AUC 0-24 h increased 2-, 2-, and 3-fold, respectively. Simeprevir had no effect on ALS-022227 AUC 0-24 h, whereas odalasvir with/without simeprevir increased ALS-022227 AUC 0-24 h 1.5-fold. AL-335 had no effect on odalasvir or simeprevir pharmacokinetics. Odalasvir and simeprevir AUC 0-24 h increased 1.5- to 2-fold for both drugs when coadministered irrespective of AL-335 coadministration. Study medications were well tolerated with no serious adverse events. One subject prematurely discontinued study drugs (unrelated event). This study defined the preliminary pharmacokinetic and safety profiles of the combination of AL-335, odalasvir, and simeprevir in healthy subjects. These data support the further evaluation of this combination for the treatment of chronic hepatitis C virus infection.

Reference intervals of complete blood count constituents are highly correlated to waist circumference: should obese patients have their own "normal values?".

Body mass index (BMI), the prevalent indicator of obesity, is not easily grasped by patients nor physicians. Waist circumference (WC) is correlated to obesity, is better understood and has a stronger relationship to the metabolic syndrome. We compiled WC, complete blood count (CBC) parameters as well as other pertinent data of 6766 25-55-year-old US volunteers sampled in the US National Health and Nutrition Examination Survey, in the years 2005-2010. To determine reference intervals of typical US patients visiting their clinician, we used minimal exclusion criteria. We compiled hemoglobin, red blood cell count, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration, mean cell hemoglobin (MCH), red cell distribution width (RDW), platelet count, mean platelet volume, and counts of white blood cells (WBC), neutrophils, lymphocytes, monocytes, eosinophils, and basophils. In addition, we also compiled serum C reactive protein and serum iron. The three major US races were studied and reference interval diagrams were constructed for each CBC parameter plotted against WC. WBC count, RDW, lymphocyte, neutrophil, and red blood cell count increase with WC. Conversely, serum iron and MCH and MCV decrease. These relationships may be related to insulin resistance and chronic activation of the immune system and the resulting low-grade inflammatory state. WC is a strong predictor for many CBC parameters, suggesting that WC should be taken into account when evaluating blood count results. Clinicians who take care of obese patients should be aware of altered hematology and investigate and treat accordingly.

Efficacy of a Creon delayed-release pancreatic enzyme protocol for clearing occluded enteral feeding tubes.

BACKGROUND: Alkalinized Viokase pancreatic enzyme tablets restored patency to 71.9% of occluded Dobhoff tubes in a prospective study. After removal of Viokase tablets from the US market, the hospital protocol for unclogging enteral feeding tubes was adapted to use Creon pancreatic enzyme delayed-release capsules, despite the lack of published data. OBJECTIVE: To evaluate the effectiveness of a Creon-based protocol to clear occluded enteral feeding tubes. METHODS: This retrospective study included all adult and pediatric patients seen in the emergency department or in an inpatient setting who received Creon 12 000 units lipase delayed-release capsule dissolved in a solution of sodium bicarbonate 650 mg and sterile water for clearing occluded enteral feeding tubes between May 1 and November 30, 2010. The Creon protocol was deemed effective if tube clearance was documented in the medical record or if enteral feedings were resumed with no note regarding tube replacement. RESULTS: Alkalinized Creon delayed-release capsules were administered to 83 patients with a total of 118 clogged tubes. Three poorly documented cases and 5 tubes with mechanical clogs were excluded from data analysis. Patency was restored to 53 of 110 (48.2%) occluded tubes. More than 1 treatment course was attempted in 5 cases, with success in 3. CONCLUSION: An alkalinized Creon pancreatic enzyme protocol was effective in clearing approximately half of the occluded enteral feeding tubes in this retrospective study, an efficacy rate much less than that previously reported in the literature with a Viokase-based protocol.

Development of motor maps in rats and their modulation by experience.

While a substantial literature demonstrates the effect of differential experience on development of mammalian sensory cortices and plasticity of adult motor cortex, characterization of differential experience on the functional development of motor cortex is meager. We first determined when forelimb movement representations (motor maps) could be detected in rats during postnatal development and then whether their motor map expression could be altered with rearing in an enriched environment consisting of group housing and novel toys or skilled learning by training on the single pellet reaching task. All offspring had high-resolution intracortical microstimulation (ICMS)-derived motor maps using methodologies previously optimized for the adult rat. First, cortical GABA-mediated inhibition was depressed by bicuculline infusion directly into layer V of motor cortex and ICMS-responsive points were first reliably detected on postnatal day (PND) 13. Without relying on bicuculline disinhibition of cortex, motor maps emerged on PND 35 and then increased in size until PND 60 and had progressively lower movement thresholds. Second, environmental enrichment did not affect initial detection of responsive points and motor maps in non-bicuculline-treated pups on PND 35. However, motor maps were larger on PND 45 in enriched rat pups relative to pups in the standard housing condition. Rats in both conditions had similar map sizes on PNDs 60, 75, and 90. Third, reach training in rat pups resulted in an internal reorganization of the map in the hemisphere contralateral, but not ipsilateral, to the trained forelimb. The map reorganization was expressed as proportionately more distal (digit and wrist) representations on PND 45. Our data indicate that both environmental enrichment and skilled reach training experience can differentially modify expression of motor maps during development.

Persistent enhancement of functional MRI responsiveness to sensory stimulation following repeated seizures.

PURPOSE: Neural reorganization and interictal behavioral anomalies have been documented in people with epilepsy and in animal seizure models. Alterations in behavior could be due to somatosensory dysfunction. This study was designed to determine whether seizures can lead to changes in somatosensory representations and whether those changes are persistent. METHODS: Twice-daily seizures were elicited by delivering 1 s of electrical stimulation through carbon fiber electrodes implanted in both the corpus callosum and sensorimotor neocortex of young adult male Long-Evans rats until a total of 20 seizures were elicited. Either 1-3 days or 3-5 weeks following the last seizure, functional magnetic resonance imaging (MRI) was used to image the brain during electrical stimulation of each forepaw independently. KEY FINDINGS: Forepaw stimulation in control rats resulted in a focused and contralateral fMRI signal in the somatosensory neocortex. Rats that had repeated seizures had a 151% increase in the number of voxels activated in the contralateral hemisphere 1-3 days after the last seizure and a 166% increase at 3-5 weeks after the last seizure. The number of voxels activated in response to forepaw stimulation was positively correlated with the duration of the longest seizure experienced by each rat. The intensity of the activated voxels was not significantly increased at either time interval from the last seizure. SIGNIFICANCE: The increased area of activation in somatosensory cortex, which is persistent at 3-5 weeks, is consistent with previous observations of larger motor maps following seizures. Seizure-induced changes in the functioning of sensory cortex may also contribute to interictal behavioral anomalies.

Optimal parameters for microstimulation derived forelimb movement thresholds and motor maps in rats and mice.

Intracortical microstimulation (ICMS) is a technique that was developed to derive movement representations (motor maps) of the motor cortex, and was originally used in cats and the capuchin monkey. In more modern experiments, ICMS has been used in rats and mice to assess and interpret plasticity of motor maps in response to experimental manipulation; however, a systematic determination of the optimal ICMS parameters necessary to derive baseline motor maps in rats and mice has not been published. In the present manuscript, we describe two experiments. We first determined the optimal stimulation frequency, pulse number, neocortical depth, and current polarity to achieve the minimum current intensity (movement threshold) to elicit forelimb movements in rats and mice. We show that experimentally naïve rats and mice differ on several of these ICMS parameters. In the second experiment, we measured movement thresholds and map size in states of enhanced neocortical inhibition by the administration of diazepam, as well as neocortical sensitization as the result of repeated seizures. We conclude that movement thresholds are inversely related to motor map size, and that treatments result in a widespread shift the balance between excitation and inhibition in motor neocortical layer 5 influences both movement thresholds and map size.

Motor map expansion in the pilocarpine model of temporal lobe epilepsy is dependent on seizure severity and rat strain.

Functional alterations in movement representations (motor maps) have been observed in some people with epilepsy and, under experimental control, electrically-kindled seizures in rats also result in persistently larger motor maps. To determine if a single event of status epilepticus and its latent consequences can affect motor map expression, we assessed forelimb motor maps in rats using the pilocarpine model of temporal lobe epilepsy. We examined both pilocarpine-induced seizures, and status epilepticus (SE) in two strains that differ in their propensity for epileptogenesis; Wistar and Long-Evans. Pilocarpine was administered intraperitoneally at dosages that resulted in equivalent proportions of seizures, SE, and survival in both strains. Rats from both strains were given saline injections as a control. Diazepam was administered to all rats to attenuate seizure activity and promote survival. All rats had high-resolution movement representations derived using standard intracortical microstimulation methodologies at 48 h, 1 week, or 3 weeks following treatment. Pilocarpine-induced seizures only gave rise to motor map enlargement in Wistar rats, which also showed interictal spiking, and only at 3 weeks post-treatment indicating altered motor map expression in this strain following a latent or maturational period. Pilocarpine-induced SE yielded larger motor maps at all time points in Wistar rats but only a transient (48 h) map expansion in Long-Evans rats. Our results demonstrate that seizures and SE induced by a convulsant agent alter the functional expression of motor maps that is dependent on seizure severity and a genetic (strain) predisposition to develop epileptiform events.