Catherine E. O'Brien

Lubiprostone for Constipation in Adults with Cystic Fibrosis: A Pilot Study

Background Constipation is prevalent in the cystic fibrosis (CF) population and yet there are few data demonstrating the effectiveness of currently used treatments. Lubiprostone is a laxative that works by activating the type 2 chloride channel in the gastrointestinal tract and thus has the potential to be especially effective for constipation associated with CR Objective: To evaluate the effectiveness of lubiprostone for the treatment of constipation in adults with CF. Methods: In this pilot study, participants acted as their own controls and comparisons were made between run-in and treatment periods. During the 2-week run-in period, participants continued their usual treatment for constipation; during the 4-week treatment period, participants received lubiprostone 24 μg twice daily. Efficacy outcomes Included spontaneous bowel movement frequency, Bristol Stool Scale scores, and Patient Assessment of Constipation Symptoms (PAC-SYM) survey scores. Outcomes were assessed during both the run-in and treatment periods (0, 2, and 4 weeks of treatment). Safety outcomes included spirometry, body weight, and serum chemistry. Results: Seven participants completed the study. Mean (SD) baseline forced expiratory volume in 1 second was 83.0% (9.4) of predicted and body mass index was 24.0 (2.8) kg/m2, indicating an overall healthy, well-nourished group of adults with CR Lubiprostone improved overall symptoms of constipation as measured by PAC-SYM survey scores (1.18 [0.56], 0,54 (0.27], and 0.44 [0.36] at 0, 2, and 4 weeks, respectively; p < 0.001). Spontaneous bowel movement frequency and Bristol Stool Scale scores were not statistically significantly different between periods. There were no differences in safety measures. Transient chest tightness and shortness of breath were reported by 2 separate participants, although neither participant withdrew due to these adverse effects. Conclusions: Lubiprostone may be an effective option for the treatment of constipation in adults with CF

Use of the Chloride Channel Activator Lubiprostone for Constipation in Adults with Cystic Fibrosis: A Case Series

Objective: To describe the use of lubiprostone for constipation in 3 adults with cystic fibrosis (CF). Case Summary: This case series describes the use of lubiprostone for the treatment of constipation in 3 adutts with CF (mean ± SD length of therapy 17.3 ± 1.5 mo). All 3 patients were prescribed lubiprostone 24 μg twice daily after hospitalization for treatment of intestinal obstruction. Patient 1 continues on chronic polyethylene glycol (PEG) 3350 and lubiprostone and has not had a recurrence of obstruction. Patient 2 requires aggressive chronic therapy with PEG 3350, lubiprostone, and methylnaltrexone. She has had 1 recurrence of obstruction. Patient 3 continues with lubiprostone taken several times per week with good control of constipation and no recurrence of obstruction to date. The adverse effect profile has been tolerable in all 3 patients. Discussion: CF is caused by a genetic mutation resulting in a dysfunctional or absent CF transmembrane conductance regulator that normally functions as a chloride channel. This results in viscous secretions in multiple organ systems including the lungs and intestinal tract. Accumulation of viscous intestinal contents contributes to constipation, which is common among adults with CF and can sometimes lead to intestinal obstruction. Lubiprostone is indicated for chronic constipation and works by activating type 2 chloride channels (CIC-2) in the intestinal tract. Because it utilizes an alternate chloride channel, lubiprostone may be especially effective for constipation in patients with CF. Conclusions: Lubiprostone provides an additional option for the treatment of constipation in adults with CF. Its use in the CF population deserves further study.

Candesartan Cilexetil Effectively Reduces Blood Pressure in Hypertensive Children

Background: The angiotensin-receptor blocker candesartan cilexetil is a well-toleraled antihypertensive agent with demonstrated benefits in adults with hypertension. However, there are few data supporting its use in children with hypertension. Objective: To determine the efficacy and tolerability of candesartan cilexetil in the treatment of pediatric hypertension. Methods: In an open-label, uncontrolled pilot study, hypertensive pediatric patients were eligible tor participation if untreated systolic and/or diastolic blood pressure (BP) exceeded the 95th percentile for sex, age, and height. Patients underwent a 7-day washout period prior to initiation of weight-based dosing of candesartan cilexetil (2-8 mg daily). The dose was doubled after 7 days of therapy if inadequate antihypertensive response was determined by clinic-measured casual BP monitoring (CBPM) and home BP monitoring (HBPM). Three methods of BP measurement were compared before and after 2 weeks of treatment with the final dose of candesartan cilexetil: CBPM, HBPM, and 24-hour continuous ambulatory BP monitoring (ABPM). Self-reported adverse effects and clinical laboratory analyses were used to determine tolerability. Results: Eleven patients (mean age 14.2 y) received a final candesartan cilexetil median daily dose of 8 mg (0.13 mg/kg, range 2-16 mg). Study treatment resulted in significant reductions in systolic and diastolic BP as measured by CBPM (-7.4%, p = 0,03 and -5.9%, p = 0.01, respectively) and by ABPM (-6.0%, p = 0.03 and -10.8%, p = 0.006, respectively), but no significant reductions as measured by HBPM. No clinically significant changes in laboratory measures were observed, and patients reported nonspecific mild adverse effects. Conclusions: Candesartan cilexetil effectively reduced BP as demonstrated by CBPM and ABPM measurements and was well tolerated in this group of hypertensive children.

Cesium-induced QT-interval prolongation in an adolescent.

Alternative medicine is becoming increasingly popular, especially with terminally ill patients. Most alternative remedies have not been adequately studied or proven effective for the diseases for which they are promoted. In the worst cases, these therapies are harmful. We describe a 16‐year‐old girl with metastatic hepatocellular carcinoma who experienced cesium‐induced QT‐interval prolongation after the start of a cesium chloride‐based alternative treatment regimen. She had received seven courses of chemotherapy, with a cumulative doxorubicin dose of 500 mg/m2 over 5 months, resulting in minimal tumor regression. Against the advice of her oncologist, she abandoned traditional therapy and started an alternative regimen that included cesium chloride supplements. Two weeks later, the patient went to a local emergency department after experiencing two brief syncopal episodes. An electrocardiogram revealed occasional premature ventricular contractions, a QTc interval of 683 msec (normal range for females 450–460 msec), and R on T phenomenon. She was admitted to the hospital and later experienced monomorphic ventricular tachycardia, which resolved spontaneously. Lidocaine therapy was started, and the patient was transferred to a cardiac intensive care unit at our hospital. Her plasma cesium level was 2400 μg/dl (normal <1 μg/dl), and her family was told to stop her alternative treatment regimen. On hospital day 5, as no additional arrhythmias had occurred, lidocaine was discontinued. Two days later, the patients QTc interval had decreased to 546 msec, and she was discharged home. Two months later, at a follow‐up visit, her serum cesium level was 1800 μg/dl, and her QTc interval was 494 msec. According to the Naranjo adverse drug reaction probability scale, cesium was the probable cause of the patients arrhythmia. In animal models, cesium chloride has induced cardiac arrhythmias, including torsade de pointes. It inhibits delayed rectifier potassium channels in the myocardium, causing delayed repolarization and QT‐interval prolongation. Patients with cancer should be aware that alternative remedies may be harmful and ineffective. Because patients may be unlikely to self‐report alternative remedies, health care providers should specifically ask their patients about any alternative treatments they may be taking and should be knowledgeable about their toxicities.

Exploring the possible association between montelukast and neuropsychiatric events among children with asthma: a matched nested case-control study

There is conflicting evidence regarding the association between montelukast and neuropsychiatric events (NE). We sought to examine this association among children with asthma.

Fenofibrate Attenuates Neutrophilic Inflammation in Airway Epithelia: Potential Drug Repurposing for Cystic Fibrosis

A hallmark of cystic fibrosis (CF) lung disease is neutrophilic airway inflammation. Elevated neutrophil counts have been associated with decreased forced expiratory volume in 1 second and poor clinical measures in patients with CF. Interleukin 8 (IL‐8), epithelial neutrophil activating protein 78 (ENA‐78), tumor necrosis factor alpha (TNF‐α), granulocyte macrophage colony‐stimulating factor (GM‐CSF), and granulocyte colony‐stimulating factor (G‐CSF) contribute to neutrophil activation and disease pathogenesis in the airways of patients with CF. Drugs that modify the production of these chemokines in the airways could potentially benefit CF patients. Thus, we determined the effects of fenofibrate on their production in cell populations obtained from the airways. Human small airway epithelial cells and CF bronchial epithelial cells were treated with IL‐1β to induce inflammation. We cotreated the cells with fenofibrate at concentrations ranging from 10 to 50 μM to determine if this drug could attenuate the inflammation. IL‐8, ENA‐78, TNF‐α, GM‐CSF, and G‐CSF production were measured from the cell culture supernates by ELISA. ANOVA statistical testing was conducted using SPSS 17.0. IL‐1β increased the production of each of the chemokines by several fold. Fenofibrate reduced IL‐1β induced production of each of these neutrophilic chemokines at the concentrations used. IL‐1β increases the production of neutrophilic chemokines in airway epithelial cells. Cotreatment with fenofibrate blunts these processes. Fenofibrate should be explored as a therapeutic option to modulate the abundant neutrophilic inflammation observed in CF.