Pharmacokinetics of Zilurgisertib With and Without Food from Single and Multiple Ascending Dose Phase 1 Studies in Healthy Adults.

Background And Objectives: The oral, potent, and highly selective activin receptor-like kinase 2 (ALK2) inhibitor zilurgisertib (INCB000928) is in development as a treatment for fibrodysplasia ossificans progressiva (FOP), and for anemia due to myelofibrosis, myelodysplastic syndromes, and multiple myeloma. Saliva is an attractive alternative to blood for drug monitoring and pharmacokinetic analysis, as it is non-invasive to retrieve. This is beneficial for patients, such as those with FOP, for whom blood draws can be challenging due to soft tissue damage susceptibility that can cause progressive heterotopic ossification, and for whom tourniquet time and blood draws must be minimized.

A real-world comparison of apnea-hypopnea indices of positive airway pressure device and polysomnography.

The apnea hypopnea index (AHI) reported by positive airway pressure (PAP) device is widely used in clinical practice, yet its correlation with standardized AHI obtained during the sleep study is not established. The current study was conducted to investigate the correlation between AHI estimated by the PAP device and reported on the smart card with the AHI found during the PAP polysomnography (PSG) in the "real world" setting at an academic sleep center. We retrospectively reviewed the medical records of 280 patients who underwent a PAP titration PSG at Drexel sleep center, and were later prescribed a PAP device.

Pharmacokinetics, absorption, and excretion of radiolabeled revexepride: a Phase I clinical trial using a microtracer and accelerator mass spectrometry-based approach.

Purpose: Gastroesophageal reflux disease involves the reflux of gastric and/or duodenal content into the esophagus. Prokinetic therapies, such as the selective 5-hydroxytryptamine receptor 4 agonist revexepride, may aid gastric emptying. This Phase I study evaluated the pharmacokinetics and excretion pathways of [C]revexepride in healthy individuals using a microtracer approach with accelerator mass spectrometry.

A Phase I Study to Investigate the Absorption, Pharmacokinetics, and Excretion of [(14)C]Prucalopride After a Single Oral Dose in Healthy Volunteers.

Purpose: Chronic constipation is a prevalent gastrointestinal disorder globally. It is often treated with medications such as laxatives. Newer therapies to improve gastric motility include the selective 5-hydroxytryptamine receptor-4 agonist prucalopride, which is licensed for the treatment of chronic constipation in adults.

Recombinant human serum amyloid P in healthy volunteers and patients with pulmonary fibrosis.

PRM-151, recombinant human Pentraxin-2 (PTX-2) also referred to as serum amyloid P (SAP), is under development for treatment of fibrosis. A First-in-Human (FIH) trial was performed to assess the safety, tolerability, and pharmacokinetics of single ascending intravenous doses of PRM-151 administered to healthy subjects, using a randomized, blinded, placebo controlled study design. Each cohort included three healthy subjects (PRM-151:placebo; 2:1).

Obstructive sleep apnea syndrome and asthma: what are the links?

Recent data suggest that obstructive sleep apnea syndrome (OSAS) is an independent risk factor for asthma exacerbations. Neuromechanical reflex bronchoconstriction, gastroesophageal reflux, inflammation (local and systemic), and the indirect effect on dyspnea of OSAS-induced cardiac dysfunction have been suggested as mechanisms that lead to worsening asthma control in patients with concomitant OSAS. Vascular endothelial growth factor-induced airway angiogenesis, leptin-related airway changes, and OSAS-induced weight gain also may play a common mechanistic role linking both disorders.

Obstructive sleep apnea syndrome and asthma: the role of continuous positive airway pressure treatment.

Objective: To review the concept of a possible link between asthma and obstructive sleep apnea syndrome (OSAS) and the impact on asthma symptoms of treatment of OSAS with continuous positive airway pressure (CPAP) in patients with both conditions.

Data Sources: The Ovid, MEDLINE, and PubMed databases from 1950 to the present were searched for relevant articles regarding a possible relationship between asthma and OSAS and the effectiveness of CPAP in treating OSAS.

Study Selection: Articles describing pathophysiologic conditions occurring in OSAS that may be linked to asthma pathogenesis were used for this review.

A phase I, single and fractionated, ascending-dose study evaluating the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of an erythropoietin mimetic antibody fusion protein (CNTO 528) in healthy male subjects.

The erythropoietin mimetic antibody fusion protein CNTO 528 was developed as a novel antibody fusion protein by constructing an active hematopoietic peptide onto an IgG1-based scaffold. This resulted in a molecule with a long circulating half-life and a prolonged effect of stimulating reticulocyte production and hemoglobin (Hgb) synthesis. To assess the safety, pharmacokinetics, and pharmacodynamics of CNTO 528, the authors gave 44 adult healthy male subjects single or fractionated doses of intravenous CNTO 528 or placebo.

Molecular, biologic, and pharmacokinetic properties of monoclonal antibodies: impact of these parameters on early clinical development.

Currently, 14 intact, unconjugated, monoclonal antibodies (Mabs) are approved for therapeutic use in the United States, and more than 100 Mabs are presently undergoing clinical development or regulatory review. Mabs are large molecular weight glycoproteins that embody structural, biochemical, and pharmacologic properties distinct from other biologics or chemically synthesized compounds. Early therapeutic Mabs were murine proteins, and clinical testing of these agents revealed serious immune-mediated toxicities.

Pharmacokinetic interactions between sirolimus and microemulsion cyclosporine when orally administered jointly and 4 hours apart in healthy volunteers.

Sirolimus (RAPA) and cyclosporine (CsA) are immunosuppressive compounds that are being used concomitantly in renal transplant patients. Both drugs are dosed orally, have common intestinal and hepatic metabolism and intestinal transport mechanisms, and thus offer potential for pharmacokinetic drug interactions. A single-dose, open-label, four-period, four-treatment, randomized crossover study was completed in 15 male and 6 female volunteers.

Oral bioavailability of pantoprazole suspended in sodium bicarbonate solution.

The bioavailability of pantoprazole when administered as a suspension in sodium bicarbonate solution and as the oral tablet was studied. In an open-label, randomized, two-period crossover study, healthy fasting subjects received either one enteric-coated 40-mg pantoprazole tablet by mouth with 240 mL of water or 20 mL of a suspension prepared from one crushed pantoprazole tablet and 840 mg of sodium bicarbonate solution and administered via a nasogastric tube. Treatments were separated by a 48-hour washout period.

Multiple-dose, linear, dose-proportional pharmacokinetics of retigabine in healthy volunteers.

Retigabine, a first-in-class selective M-current potassium channel opener, is a novel antiepileptic compound currently in clinical development. The purpose of this randomized placebo-controlled study was to assess retigabine oral safety and pharmacokinetics in healthy male volunteers (N = 45). Subjects received one dose on day 1 and doses every 12 hours for the next 14 days.

Underappreciation of sleep disorders as a cause of motor vehicle crashes.

Despite an increased risk of motor vehicle crashes (MVC) in patients with obstructive sleep apnea (OSA), we hypothesized that OSA was not considered in drivers admitted to trauma centers after an injury-producing MVC. A retrospective study on drivers involved in MVCs admitted to a level 1 trauma center was performed, with crash cause determined and the frequency of sleep studies recorded. A questionnaire was also mailed to 240 trauma centers seeking information on evaluation of patients with unexplained causes for MVCs, including screening for OSA.

Pharmacokinetics of pantoprazole in patients with moderate and severe hepatic dysfunction.

Background: Patients with impaired hepatic function usually require gastric acid-suppressant therapy but are at increased risk for drug interactions and may require dosage adjustments. The proton pump inhibitor pantoprazole is rapidly absorbed and eliminated, primarily by cytochrome P450 (CYP) 2C19 isozymes.

Objective: This study sought to determine whether dosage adjustment of pantoprazole is required in patients with moderate or severe hepatic impairment by comparing the pharmacokinetic profile of pantoprazole in such patients with that in healthy slow metabolizers of pantoprazole, in whom no dosage adjustment is required.

Nasal airway changes assessed by acoustic rhinometry and mediator release during immediate and late reactions to allergen challenge.

Background: We have found that acoustic rhinometry is a reliable means of assessing nasal airway caliber changes during the immediate reaction to nasal allergen challenge of sensitive subjects. Comparison of such changes with symptoms and patterns of mediator release could help in the understanding of mechanisms of immediate and late-phase reactions after allergen challenge and their clinical relevance.

Methods: Nasal minimal cross-sectional area (MCA) was assessed sequentially for 6 hours after two blinded challenges in random order with pollen antigens and buffer diluent in five sensitive human subjects.

Upper airway and soft tissue structural changes induced by CPAP in normal subjects.

Nasal continuous positive airway pressure (CPAP) is the treatment of choice for adults with obstructive sleep apnea. CPAP is known to increase upper airway size; however, the direct effects of CPAP on soft tissue structures surrounding the upper airway are less well understood. Magnetic resonance imaging was used to study the effect of incremental levels (0, 5, 10, and 15 cm H2O) of CPAP on the upper airway and surrounding soft tissue structures in 10 normal subjects.

Characteristics of histamine-releasing activity in the sera of patients with chronic idiopathic urticaria.

Background: The serum histamine-releasing activity (HRA) found in a sizable percentage of patients with chronic idiopathic urticaria (CIU) has been partially characterized. However, the variable effect of individual HRA+ sera in basophils of different donors and the relationship of HRA to the clinical course require further investigation.

Objective: The study was performed to characterize the HRA found in sera of some members of a sizable group of carefully evaluated patients with CIU.

Effects of one night without nasal CPAP treatment on sleep and sleepiness in patients with obstructive sleep apnea.

Nasal continuous positive airway pressure (CPAP) has become the nonsurgical treatment of choice for obstructive sleep apnea syndrome (OSAS). Recent evidence suggests that intermittent use of CPAP by patients is more common than nightly compliance. To determine the consequences of intermittent CPAP use, in terms of a return of sleep-disordered breathing and daytime hypersomnolence, 15 OSAS subjects were evaluated at three times: (1) before CPAP treatment (pretreatment), (2) after 30 to 237 days posttreatment during a night of CPAP use (on CPAP), and (3) during a night without CPAP (off CPAP).

Objective measurement of patterns of nasal CPAP use by patients with obstructive sleep apnea.

Obstruction of the upper airway during sleep (OSAS) is widely treated by having patients self-administer nasal continuous positive airway pressure (CPAP). To obtain objective evidence of the patterns of CPAP use, information was gathered from two urban sites on 35 OSAS patients who were prescribed CPAP for a total of 3,743 days. Patients were given CPAP machines that contained a microprocessor and monitor that measured actual pressure at the mask for every minute of each 24-h day for an average of 106 days per patient.