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). SAP levels were assessed using a validated ELISA method, non-discriminating between endogenous and exogenous SAP. At a dose level of 10 mg/kg, at which a physiologic plasma level of SAP was reached, two additional healthy volunteers and three pulmonary fibrosis (PF) patients were enrolled enabling comparison of the pharmacokinetic SAP profile between healthy volunteers and PF patients. In addition, the percentage of fibrocytes (CD45+/Procollagen-1+ cells) in whole blood samples was assessed to demonstrate biological activity of PRM-151 in the target population. PRM-151 administration was generally well tolerated. In two pulmonary fibrosis patients non-specific, transient skin reactions (urticaria and erythema) were observed. PRM-151 administration resulted in a 6-to 13-fold increase in mean baseline plasma SAP levels at dose levels of 5, 10, and 20 mg/kg. The estimated t1/2 of PRM-151 in healthy volunteers was 30 h. Pharmacokinetic profiles were comparable between healthy volunteers and PF patients. PRM-151 administration resulted in a 30-50% decrease in fibrocyte numbers 24 h post-dose. This suggests that administration of PRM-151 may be associated with a reduction of fibrocytes in PF patients, a population for which current pharmacotherapeutic options are limited. The pharmacological action of PRM-151 should be confirmed in future research.

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. METHODS: Patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment received oral pantoprazole 40 mg once daily on days 1 through 4 and then on alternate days (days 6 and 8). Serial blood samples were collected on days 4 and 8 for analyses of plasma pantoprazole concentrations. Pharmacokinetic data were compared between the 2 groups with hepatic impairment and against historical data from 17 healthy subjects who were genetically slow CYP2C19 metabolizers of pantoprazole. RESULTS: Twenty-two patients participated in the study, 13 in the Child-Pugh class B group and 9 in the Child-Pugh class C group. No clinically significant differences in pantoprazole pharmacokinetics were noted between the patients with hepatic impairment and the healthy slow metabolizers of pantoprazole on days 4 and 8. Pantoprazole was well tolerated. Four Child-Pugh class B patients and 3 Child-Pugh class C patients reported > or = 1 adverse event. Adverse events were generally mild or moderate, and were similar to those reported in healthy subjects. Two patients discontinued the study because of severe events related to their underlying disease. CONCLUSIONS: The pharmacokinetics and tolerability of pantoprazole were similar in patients with moderate hepatic impairment, patients with severe hepatic impairment, and healthy slow metabolizers of pantoprazole, in whom no dosage adjustment is required. Thus, no dosage adjustment of pantoprazole is required in patients with hepatic impairment, regardless of its severity. However, caution should be exercised when giving pantoprazole to patients with severe hepatic impairment.

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. METHODS: Sera of 70 patients with CIU, evaluated with a standard protocol, were screened for increased HRA. HRA+ sera were fractionated, heated, and tested on unaltered and altered basophils obtained from a panel of normal donors. HRA levels were compared with concomitant clinical manifestations. RESULTS: HRA+ sera were found in 30% of our patients with CIU, HRA was predominantly in the IgG fraction, sensitive to 56 degrees C heating for 4 hours, and generally reacted more with IgE-stripped basophils. Considerable variation in the degree of response to HRA+ sera in the basophils of different normal subjects did not correlate with the degree of response of these cells to heterologous anti-IgE antiserum. Serum HRA levels were generally much lower when symptoms decreased in these patients with CIU. CONCLUSION: Serum HRA from patients with CIU appears to bind most commonly to the IgE receptor and may be a marker of clinical disease activity. HRA appears in an IgG-containing fraction of the serum and may contain IgE in some cases.

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. There were 122 drivers of MVCs admitted to our hospital, 60/122 (49%) had unexplained crashes and no sleep studies were performed. There were 70 survey respondents (30% return rate), 35/70 (50%) centers routinely screened for syncope after unexplained MVC, however, no center screened for OSA. US trauma centers do not screen for sleep disorders despite the associated increased crash risk and the high prevalence of crashes that can not be explained by other causes. We believe this reflects a lack of awareness of sleep disorders by health care professionals caring for trauma victims and education is of utmost importance.

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. Comparisons were made with: (1) symptom scores; (2) olfaction changes; and (3) nasal secretion levels of histamine, tryptase, leukotriene C4, serum albumin (a marker of vascular permeability), lactoferrin (a marker of local glandular secretion), and inflammatory cells in nasal scrapings. RESULTS: In four of five subjects there was a significantly greater decrease in MCA after antigen challenge than after diluent challenge, correlating with the degree of subjective nasal congestion. In two of these four subjects there was a prominent second late-phase decrease in MCA at 3 to 5 hours, whereas the MCA was persistently decreased in an additional subject with accompanying subjective congestion. No significant decrease in olfactory acuity occurred. Levels were significantly higher in nasal secretions obtained after antigen challenge than in those obtained after buffer challenge with histamine (9 +/- 2.7 ng/ml vs 1.2 +/- 0.5 ng/ml; p = 0.04); tryptase (95 +/- 83 ng/ml vs 3 +/- 0.9 ng/ml; p = 0.02), leukotriene C4 (5293 +/- 1385 ng/ml vs 578 +/- 183 ng/ml; p = 0.02), and albumin (123 +/- 9 ng/ml vs 19 +/- 1.6 ng/ml; p = 0.005) but not with lactoferrin (4.6 +/- 1.2 ng/ml vs 4.1 +/- 28 ng/ml; p = not significant). Granulocyte exudation was seen after antigen challenge but not after buffer diluent challenge. However, there was not a precise correlation between decreases in MCA with changes in levels of these mediators in individual subjects. CONCLUSIONS: Acoustic rhinometry can quantitatively assess congestion during immediate and late-phase reactions after nasal challenge without significant correlation to the degree of individual inflammatory events assessed.

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. Progressive increases in CPAP resulted in the following major findings: (1) airway volume and airway area (measured at several different locations [midregion, minimal, maximal]) within the retropalatal and retroglossal regions increased; (2) lateral airway dimensional changes were greater than anterior-posterior changes; (3) lateral upper airway soft tissue structural changes were significantly greater than anterior-posterior changes; (4) lateral pharyngeal wall thickness decreased and the distance between the lateral parapharyngeal fat pads increased. An inverse relationship was demonstrated between CPAP level and pharyngeal wall thickness; (5) minimal changes were noted in the soft palate and tongue. These data suggest that the lateral pharyngeal walls are more "compliant" than the soft palate and tongue. This investigation provides further evidence that the lateral pharyngeal walls play an important role in mediating upper airway caliber.

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). Evaluations of sleep-disordered breathing and three domains of hypersomnolence, physiologic sleep tendency, subjective sleepiness, and performance, were accomplished with the respiratory disturbance index (RDI), multiple sleep latency test (MSLT), Stanford sleepiness scale (SSS), and psychomotor vigilance task (PVT), respectively. CPAP use was encouraged and monitored from pretreatment to post-treatment by daily diaries for most subjects and an electronic device for a subset of subjects. As expected, CPAP eliminated apneas and hypopneas, and following the on CPAP night, there were statistically significant improvements in objective measures of sleepiness (MSLT and PVT). Subjective measures of sleepiness and fatigue also showed improvement. Sleeping without CPAP for one night reversed virtually all of the sleep and daytime alertness gains derived from sleeping with CPAP. This occurred despite a statistically significant reduction in the RDI on the night off CPAP (M = 36.8, SD = 28.0 events/h) relative to the pretreatment night (M = 56.6, SD = 24.8 events/h), which may be due to a lessening of the edema of the upper airway following CPAP use.(ABSTRACT TRUNCATED AT 250 WORDS)

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. They were not aware of the monitor inside the CPAP machines. Monitor output was compared with patients' diagnostic status, pretreatment clinical and demographic characteristics, and follow-up self-reports of CPAP use, problems, side effects, and aspects of daytime fatigue and sleepiness. Patients attempted to use CPAP an average of 66 +/- 37% of the days monitored. When CPAP was used, the mean duration of use was 4.88 +/- 1.97 h. However, patients' reports of the duration of CPAP use overestimated actual use by 69 +/- 110 min (p < 0.002). Both frequency and duration of CPAP use in the first month reliably predicted use in the third month (p < 0.0001). Although the majority (60%) of patients claimed to use CPAP nightly, only 16 of 35 (46%) met criteria for regular use, defined by at least 4 h of CPAP administered on 70% of the days monitored. Relative to less regular users, these 16 patients had more years of education (p = 0.05), and were more likely to work in professional occupations.(ABSTRACT TRUNCATED AT 250 WORDS)