Clinical drug-drug interaction assessment of ivacaftor as a potential inhibitor of cytochrome P450 and P-glycoprotein.

Ivacaftor is approved in the USA for the treatment of cystic fibrosis (CF) in patients with a G551D-CFTR mutation or one of eight other CFTR mutations. A series of in vitro experiments conducted early in the development of ivacaftor indicated ivacaftor and metabolites may have the potential to inhibit cytochrome P450 (CYP) 2C8, CYP2C9, CYP3A, and CYP2D6, as well as P-glycoprotein (P-gp). Based on these results, a series of clinical drug-drug interaction (DDI) studies were conducted to evaluate the effect of ivacaftor on sensitive substrates of CYP2C8 (rosiglitazone), CYP3A (midazolam), CYP2D6 (desipramine), and P-gp (digoxin). In addition, a DDI study was conducted to evaluate the effect of ivacaftor on a combined oral contraceptive, as this is considered an important comedication in CF patients. The results indicate ivacaftor is a weak inhibitor of CYP3A and P-gp, but has no effect on CYP2C8 or CYP2D6. Ivacaftor caused non-clinically significant increases in ethinyl estradiol and norethisterone exposure. Based on these results, caution and appropriate monitoring are recommended when concomitant substrates of CYP2C9, CYP3A and/or P-gp are used during treatment with ivacaftor, particularly drugs with a narrow therapeutic index, such as warfarin.

Design and measurement of quality improvement indicators in ambulatory pulmonary care: creating a "culture of quality" in an academic pulmonary division.

BACKGROUND: Quality improvement (QI) measures often are cited as goals for individual practices and medical centers and may someday form a component of reimbursement guidelines. Relatively few QI metrics relevant to ambulatory pulmonary medicine have been published. We describe the development and implementation of a QI program in an academic pulmonary division, including progress to date and lessons learned. METHODS: Metrics for the pulmonary QI Dashboard were developed based on an extensive literature review. Patients were identified through International Classification of Diseases-based billing databases, and results data were obtained from a manual and automated review of the electronic medical record. The performance of the division was monitored and presented in regular faculty meetings. Quarterly, confidential, individual scorecards gave each clinician feedback about his or her performance and compared the feedback to that of the faculty of the entire division. RESULTS: Significant improvements were found in many QI measures during a 2-year period. The number of patients with asthma who received appropriately prescribed inhaled corticosteroids increased from a baseline of 76 to 92% to 98%. Flu shot and pneumococcal vaccine administration documentation for patients with COPD increased from baseline values of 11 to 32% and 11 to 34%, respectively, to 90% and 93%, respectively. The COPD Global Initiative for Obstructive Lung Disease pharmacotherapy guidelines adherence increased substantially for patients with all disease stages. Chest CT scan results notification documentation improved from a baseline of 67 to 76% to 98%. Comparison between baseline and QI periods yielded statistically significant increases for these indicators. CONCLUSIONS: QI measures for an ambulatory pulmonary practice can be designed, implemented, and monitored. Key components include a well-structured electronic medical record, measurable outcomes, strong QI leadership, and specific interventions, such as providing feedback through QI review meetings and individual "report cards."

Baroreflex responsiveness during ventilatory acclimatization in humans.

We tested the hypothesis that the decline in muscle sympathetic activity during and after 8 h of poikilocapnic hypoxia (Hx) was associated with a greater sympathetic baroreflex-mediated responsiveness. In 10 healthy men and women (n=2), we measured beat-to-beat blood pressure (Portapres), carotid artery distension (ultrasonography), heart period, and muscle sympathetic nerve activity (SNA; microneurography) during two baroreflex perturbations using the modified Oxford technique before, during, and after 8 h of hypoxia (84% arterial oxygen saturation). The integrated baroreflex response [change of SNA (DeltaSNA)/change of diastolic blood pressure (DeltaDBP)], mechanical (Deltadiastolic diameter/DeltaDBP), and neural (DeltaSNA/Deltadiastolic diameter) components were estimated at each time point. Sympathetic baroreflex responsiveness declined throughout the hypoxic exposure and further declined upon return to normoxia [pre-Hx, -8.3+/-1.2; 1-h Hx, -7.2+/-1.0; 7-h Hx, -4.9+/-1.0; and post-Hx: -4.1+/-0.9 arbitrary integrated units (AIU) x min(-1) x mmHg(-1); P<0.05 vs. previous time point for 1-h, 7-h, and post-Hx values]. This blunting of baroreflex-mediated efferent outflow was not due to a change in the mechanical transduction of arterial pressure into barosensory stretch. Rather, the neural component declined in a similar pattern to that of the integrated reflex response (pre-Hx, -2.70+/-0.53; 1-h Hx, -2.59+/-0.53; 7-h Hx, -1.60+/-0.34; and post-Hx, -1.34+/-0.27 AIU x min(-1) x microm(-1); P < 0.05 vs. pre-Hx for 7-h and post-Hx values). Thus it does not appear as if enhanced baroreflex function is primarily responsible for the reduced muscle SNA observed during intermediate duration hypoxia. However, the central transduction of baroreceptor afferent neural activity into efferent neural activity appears to be reduced during the initial stages of peripheral chemoreceptor acclimatization.

Ventilatory, hemodynamic, sympathetic nervous system, and vascular reactivity changes after recurrent nocturnal sustained hypoxia in humans.

Recurrent and intermittent nocturnal hypoxia is characteristic of several diseases including chronic obstructive pulmonary disease, congestive heart failure, obesity-hypoventilation syndrome, and obstructive sleep apnea. The contribution of hypoxia to cardiovascular morbidity and mortality in these disease states is unclear, however. To investigate the impact of recurrent nocturnal hypoxia on hemodynamics, sympathetic activity, and vascular tone we evaluated 10 normal volunteers before and after 14 nights of nocturnal sustained hypoxia (mean oxygen saturation 84.2%, 9 h/night). Over the exposure, subjects exhibited ventilatory acclimatization to hypoxia as evidenced by an increase in resting ventilation (arterial Pco(2) 41.8 +/- 1.5 vs. 37.5 +/- 1.3 mmHg, mean +/- SD; P < 0.05) and in the isocapnic hypoxic ventilatory response (slope 0.49 +/- 0.1 vs. 1.32 +/- 0.2 l/min per 1% fall in saturation; P < 0.05). Subjects exhibited a significant increase in mean arterial pressure (86.7 +/- 6.1 vs. 90.5 +/- 7.6 mmHg; P < 0.001), muscle sympathetic nerve activity (20.8 +/- 2.8 vs. 28.2 +/- 3.3 bursts/min; P < 0.01), and forearm vascular resistance (39.6 +/- 3.5 vs. 47.5 +/- 4.8 mmHg.ml(-1).100 g tissue.min; P < 0.05). Forearm blood flow during acute isocapnic hypoxia was increased after exposure but during selective brachial intra-arterial vascular infusion of the alpha-blocker phentolamine it was unchanged after exposure. Finally, there was a decrease in reactive hyperemia to 15 min of forearm ischemia after the hypoxic exposure. Recurrent nocturnal hypoxia thus increases sympathetic activity and alters peripheral vascular tone. These changes may contribute to the increased cardiovascular and cerebrovascular risk associated with clinical diseases that are associated with chronic recurrent hypoxia.

Hemodynamics and muscle sympathetic nerve activity after 8 h of sustained hypoxia in healthy humans.

Hemodynamics, muscle sympathetic nerve activity (MSNA), and forearm blood flow were evaluated in 12 normal subjects before, during (1 and 7 h), and after ventilatory acclimatization to hypoxia achieved with 8 h of continuous poikilocapnic hypoxia. All results are means +/- SD. Subjects experienced mean oxygen saturation of 84.3 +/- 2.3% during exposure. The exposure resulted in hypoxic acclimatization as suggested by end-tidal CO(2) [44.7 +/- 2.7 (pre) vs. 39.5 +/- 2.2 mmHg (post), P < 0.001] and by ventilatory response to hypoxia [1.2 +/- 0.8 (pre) vs. 2.3 +/- 1.3 l x min(-1).1% fall in saturation(-1) (post), P < 0.05]. Subjects exhibited a significant increase in heart rate across the exposure that remained elevated even upon return to room air breathing compared with preexposure (67.3 +/- 15.9 vs. 59.8 +/- 12.1 beats/min, P < 0.008). Although arterial pressure exhibited a trend toward an increase across the exposure, this did not reach significance. MSNA initially increased from room air to poikilocapnic hypoxia (26.2 +/- 10.3 to 32.0 +/- 10.3 bursts/100 beats, not significant at 1 h of exposure); however, MSNA then decreased below the normoxic baseline despite continued poikilocapnic hypoxia (20.9 +/- 8.0 bursts/100 beats, 7 h Hx vs. 1 h Hx; P < 0.008 at 7 h). MSNA decreased further after subjects returned to room air (16.6 +/- 6.0 bursts/100 beats; P < 0.008 compared with baseline). Forearm conductance increased after exposure from 2.9 +/- 1.5 to 4.3 +/- 1.6 conductance units (P < 0.01). These findings indicate alterations of cardiovascular and respiratory control following 8 h of sustained hypoxia producing not only acclimatization but sympathoinhibition.

Recognition and management of complex sleep-disordered breathing.

PURPOSE OF REVIEW: The recent rapid evolution of our understanding of the mechanisms involved in control of respiration during sleep has yielded new insights to guide our care of difficult-to-treat sleep apnea patients with complex sleep-disordered breathing. This review will describe these recent advances in the literature and suggest a model for their incorporation into clinical practice. RECENT FINDINGS: Control of respiration during sleep shows amplified instability relative to that seen during wake in these difficult patients. Baseline (eupneic) carbon dioxide levels as well as the responsiveness of the ventilatory system to changes in carbon dioxide are all-important in this relative instability. Furthermore, the instability seen during sleep varies widely across sleep states. A further refinement of our definition of stable and unstable sleep has been developed that directly informs our understanding of the control of respiration across a night of sleep. SUMMARY: Complex sleep-disordered breathing is a distinct form of sleep apnea. It has recognizable characteristics that are present without, and often worsened during, positive airway pressure treatment. Both sleep state stability and the behavior of the respiratory control system contribute to this complexity. It is only with a clear understanding of the factors contributing to complex sleep-disordered breathing that implementation of truly effective clinical therapy can be achieved for this disorder, which to date is poorly controlled.

Mechanisms of arousal from sleep and their consequences.

PURPOSE OF REVIEW: In recent years, understanding of the mechanisms by which sleep is maintained and the consequences of abnormal arousal from sleep has improved rapidly. This review describes the recent insights into the nature of sleep and arousal and the particular insights gained in common disease states such as sleep-disordered breathing. RECENT FINDINGS: Expansion of the definitions of the classic stages of non-REM and REM sleep to include consideration of the role of cyclic alternating pattern sleep as a gating mechanism for arousal and maintenance of stable sleep has led to a significant advancement in understanding the nature of normal and pathologic arousals from sleep. In addition, the effect of arousals from sleep on cerebral cortical electrophysiology and autonomic activation has been further defined, with a potential effect on clinical practice. SUMMARY: Arousal from sleep is dependent on wake-promoting influences overwhelming forces promoting sleep. Autonomic activation and cortical arousal can significantly affect and destabilize sleep homeostasis. The understanding of sleep-respiration interactions continues to evolve. The definition of the minimal arousal event is an important research goal. It will be important in clinical practice and research to consider sleep stability domains as a complement to sleep depth staging to allow better understanding of the relative stability and instability of the system and to consider all components of the consequences of arousal.