Robert D. Murdoch

Does a single dose of the phosphodiesterase 4 inhibitor, cilomilast (15 mg), induce bronchodilation in patients with chronic obstructive pulmonary disease?

Maintenance treatment with PDE(4) inhibitor cilomilast improves FEV(1) in chronic obstructive pulmonary disease (COPD) patients. We investigated the acute bronchodilating effects of a single dose of cilomilast with or without concomitant administration of inhaled salbutamol and/or ipratropium bromide in 21 patients with COPD (mean (SD) age 64 (8.1) y, post-salbutamol FEV(1) 47.7 (13.2) %predicted). FEV(1) was measured before and up to 8 hourly intervals after intake of placebo, cilomilast, or cilomilast in combination with inhaled salbutamol 400 microg and/or ipratropium bromide 80 microg. Maximum increase in FEV(1) from pre-dose baseline was calculated after each treatment and differences between treatment arms were analyzed by ANOVA. The mean (SEM) maximum increase in FEV(1) was 139.6 (18.5) ml following cilomilast and 151.5 (18.5) ml following placebo (95% C.I. for mean difference between cilomilast and placebo: -67.3, 43.6 ml). Furthermore, combined treatment of cilomilast with salbutamol or ipratropium resulted in a maximum increase in FEV(1) of 280.7 (25.6) and 297.0 (25.9) ml, respectively, while this was 379.0 (24.6) ml following cilomilast with both salbutamol and ipratropium (p < 0.01). We conclude that a single dose of cilomilast does not produce acute bronchodilation in patients with COPD who otherwise respond to inhaled bronchodilators. Our results implicate that the change in lung function seen after long-term treatment with cilomilast is not the result of acute bronchodilation in patients with COPD.

Efficacy and safety of granisetron in the prevention of chemotherapy-induced emesis in paediatric patients

In an open ascending-dose study, granisetron, a specific 5-HT3 receptor antagonist, was administered to 24 paediatric patients (17 male, 7 female, mean age 6.2, range 3-15 years) who were receiving moderately or highly emetogenic chemotherapy for malignant disease. Single doses of 10, 20 and 40 micrograms/kg were administered by intravenous infusion 1 h before chemotherapy. Each dose level was studied in a group of 8 patients. With the 40 micrograms/kg dose, 5 of 8 patients experienced no nausea or vomiting in the 24 h after granisetron treatment. With 20 micrograms/kg, a similar response was seen, but with 10 micrograms/kg only 2 of 8 patients experienced complete antiemetic protection despite additional prophylactic chlorpromazine in this group. Granisetron was very well tolerated, and there were no clinically important changes in pulse rate, blood pressure or Holter electrocardiogram. It is concluded that granisetron was very well tolerated by paediatric patients. In addition, there was clear evidence of a major antiemetic effect for at least 24 h after a single intravenous dose of 20 or 40 micrograms/kg.

A combination of cetirizine and pseudoephedrine has therapeutic benefits when compared to single drug treatment in allergic rhinitis.

UNLABELLED Antihistamines and nasal decongestants are well-established therapeutics in allergic rhinitis. However, no data are available which directly compare the effect size of the single substances with their combination in a single study including placebo (PLA) treatment. OBJECTIVE The aim of this study was to evaluate the effect of a combination of cetirizine (CET) and pseudoephedrine (PSE) and to compare it to treatment with CET or PSE alone and to PLA during grass pollen allergen challenge in an environmental challenge chamber (ECC). MATERIAL AND METHODS In a randomized, double-blind, placebo-controlled, four-way crossover study the effect of a combination of 10 mg CET with 120 mg PSE (CET + PSE) versus CET or PSE alone or PLA on symptoms, nasal flow, and nasal secretions was investigated in 49 patients with intermittent allergic rhinitis. Subjects underwent four 6-h pollen exposures in an ECC with administration of the drugs after 2 h. RESULTS The induction of nasal symptoms, nasal secretion and nasal obstruction (measured as nasal flow) during the first 2 h of pollen exposure was highly reproducible at the 4 consecutive exposures. The symptom of nasal obstruction was significantly reduced after treatment with CET + PSE compared to the treatment with CET or PSE alone or PLA (p < 0.0001). Furthermore, the combination treatment significantly reduced the total nasal symptom score (TNSS) and visual analogue scale score (VAS) compared to the single treatments or PLA. Nasal flow was significantly increased after treatment with CET + PSE and PSE and nasal secretions were significantly reduced by CET + PSE and CET without significant additional improvement of the combination therapy. CONCLUSION The combination treatment with CET and PSE is more effective than treatment with single substances in subjects with allergic rhinitis.

An Overview of the Pharmacokinetics of Cilomilast (Ariflo®), a New, Orally Active Phosphodiesterase 4 Inhibitor, in Healthy Young and Elderly Volunteers

The oral pharmacokinetics of cilomilast (Ariflo®) were investtigated in five separate studies in healthy volunteers. Cilomilast was rapidly absorbed, and pharmacokinetics were dose proportional after single and repeat dosing. The elimination half‐life was 7 to 8 hours; accordingly steady state was reached on the 3rd day of dosing. The degree of accumulation following repeat twice‐daily dosing was predictable from the data following a single dose. Although systemic exposure (AUC) was, on average, 21% higher in elderly (65–84 years) compared with young subjects, values for Cmax and t1/2 were similar, and no difference in tolerability was noted. Single and repeat doses of cilomilast up to and including 15 mg (dosed before or taken between meals) were well tolerated. Dosing with food reduced the rate of absorption without affecting total bioavailability. Hence, tolerability was optimal in the fed state; repeat doses up to and including 30 mg twice daily after meals were well tolerated following dose titration.

The effects of a TRPV1 antagonist, SB-705498, in the treatment of seasonal allergic rhinitis.

BACKGROUND Current pharmacotherapy for allergic rhinitis (AR) does not totally ameliorate all symptoms for all patients. Residual symptoms could be due to nasal neuronal hyperresponsiveness caused by stimulation of the ion channel transient receptor potential vanilloid 1 (TRPV1). SB-705498 is a TRPV1 antagonist that has been developed in an intranasal formulation for treatment of AR. METHODS This randomized, double-blind, 3-way incomplete block crossover study evaluated the effects of 8 days treatment with SB-705498 12 mg alone, SB-705498 12 mg plus fluticasone propionate 200 μg (FP), FP 200 μg alone or placebo on allergen-induced symptoms in 70 patients with AR. The primary endpoint was total nasal symptom score (TNSS), expressed as mean over 4 hours or maximum TNSS during allergen challenge in the Vienna Challenge Chamber on 8th day of treatment. RESULTS At the end of treatment, there were no differences in allergen-induced mean TNSS between SB-705498 alone and placebo or between SB-705498 plus FP and FP alone. Treatment with FP and SB-705498 plus FP resulted in a significant decrease in TNSS vs. placebo. Mean (90% CI) treatment differences in TNSS over 0 - 4 hours were: SB-705498 - placebo: -0.2 (-0.9, 0.4); SB-705498 plus FP - FP: 0.7 (0.2, 1.2); FP - placebo: -2.9 (-3.4, -2.5); SB-705498 plus FP - placebo: -2.3 (-2.8, -1.8). SB-705498 had no impact on diary card symptoms, nasal airflow or Rhinoconjunctivitis Quality of Life Questionnaire scores. SB-705498 was well tolerated and pharmacokinetics exposure results supported the dosing regimen. CONCLUSION SB-705498 12 mg for 8 days did not alleviate the allergen-induced symptoms of AR, or provide additional relief of symptoms when in combination with FP. Despite engagement of the TRPV1 receptor there was no translation to clinical efficacy, suggesting redundancy in symptom pathways.

Bioavailability of the oral selective phosphodiesterase 4 inhibitor cilomilast

Study Objective. To determine the absolute bioavailability of cilomilast, and assess the effects of food, dosing time, and coadministration of antacid agents on its bioavailability and pharmacokinetics in healthy volunteers.

Anti-allergic drug testing in an environmental challenge chamber is suitable both in and out of the relevant pollen season

BACKGROUND An environmental challenge chamber (ECC) is a useful tool to expose allergic patients to relevant allergens in a controlled indoor setting and to test anti-allergic treatment. Hitherto, ECC studies with grass pollen are conducted primarily outside of the pollen season to avoid the influence of natural pollen exposure. OBJECTIVE To investigate whether an established anti-allergic treatment, a combination of cetirizine (CET) and pseudoephedrine (PSE), shows an equivalent treatment effect within and outside of the grass pollen season when tested in an ECC. METHODS In a randomized, placebo-controlled, double-blind, four-way crossover study, the effect of a combination of 10 mg CET and 120 mg PSE compared with placebo on nasal symptoms, nasal flow, and nasal secretion was investigated in 70 patients with seasonal allergic rhinitis. Subjects underwent four 6-hour pollen challenges in an ECC with administration of the drugs after 2 hours. Two challenges were conducted within the grass pollen season and two out of the grass pollen season. RESULTS The active treatment significantly improved nasal symptoms and nasal flow and significantly reduced the amount of nasal secretion compared with placebo both within and outside of the pollen season (P < .0001 each). The treatment effect was not different between the seasons (P > .05). CONCLUSION Controlled allergen provocation in an ECC can be used to test anti-allergic treatment both within and outside of the grass pollen season.

Cilomilast: pharmacokinetic and pharmacodynamic interactions with digoxin

BACKGROUND Cilomilast is an orally active, selective phosphodiesterase 4 inhibitor currently in clinical development for the treatment of chronic obstructive pulmonary disease. OBJECTIVE The purpose of this study was to examine the tolerability and steady-state pharmacokinetics of cilomilast and digoxin when coadministered at standard therapeutic doses in healthy adults. METHODS In an initial, open-label phase, healthy young adults received cilomilast 15 mg BID for 5 days. After a 7-day washout period, subjects entered a double-blind, crossover phase during which they received oral digoxin (375 microg once daily) for 2 consecutive 14-day periods with no intervening washout period. Cilomilast 15 mg BID or placebo was coadministered during the first 14-day period. Subjects then crossed over to the alternative treatment for the second 14-day period. Blood and urine samples were collected at appropriate times for evaluation of digoxin and cilomilast steady-state pharmacokinetic parameters. The size of the study was sufficient to achieve 90% power to correctly exclude an effect of cilomilast. RESULTS Twelve of the 16 subjects enrolled completed the study. There were 4 withdrawals--1 due to noncompliance, 1 due to a positive drug screening, and 2 due to adverse events. At steady state, cilomilast 15 mg BID had no significant effect on the steady-state pharmacokinetic parameters of digoxin, with 90% CIs for both primary end points--area under the plasma concentration-time curve (AUC) over a 24-hour dosing interval and minimum plasma concentration--completely contained within the specified interval for equivalence (0.80-1.25). A mean reduction in maximum observed plasma concentration of digoxin of 11% was observed during coadministration with cilomilast, and time to maximum concentration was delayed by a median of 1 hour, suggesting a small reduction in the rate of digoxin absorption. Digoxin did not appear to markedly affect cilomilast steady-state pharmacokinetics. The most frequently reported adverse event was headache. CONCLUSIONS Cilomilast 15 mg BID had no clinically significant effect on steady-state AUC or on predose trough plasma concentrations of digoxin (375 microg once daily). The steady-state pharmacokinetics of cilomilast 15 mg BID were similar whether administered alone or with digoxin at steady state (375 microg once daily).

Pollen starch granules in bronchial inflammation

BACKGROUND Pollen grains with a diameter of more than 10 μm preferentially deposit in the upper airways. Their contribution to lower airway inflammation is unclear. One hypothesis is that lower airway inflammation is mainly caused by allergen containing pollen starch granules, which are released from the pollen grains and can easily enter the peripheral airways because of their smaller size. OBJECTIVE To investigate the differential effect of pollen grains and pollen starch granules on nasal symptoms and lower airway inflammation. METHODS In a 2-period crossover design, 30 patients with allergic rhinitis and mild intermittent asthma underwent 2 allergen challenges on consecutive days in an environmental challenge chamber with either a mixture of pollen grains plus starch granules or starch granules only. End points were the total nasal symptom score (TNSS), nasal secretion weight, nasal flow, spirometry, and exhaled nitric oxide (eNO). RESULTS The presence of pollen grains had a significant and considerable effect on increase in TNSS and secretion weight and on decrease in nasal flow. Starch granules alone only had minimal effects on nasal symptoms. Challenges with starch granules significantly increased eNO. Pollen had no effect on eNO. CONCLUSION Pollen grains cause nasal symptoms but do not augment lower airway inflammation, whereas starch granules trigger lower airway inflammation but hardly induce nasal symptoms.

Lack of Pharmacokinetic Interactions Between Cilomilast and Theophylline or Smoking in Healthy Volunteers

The pharmacokinetic profile of cilomilast (Ariflo®), a selective phosphodiesterase 4 (PDE4) inhibitor, was investigated in three separate studies. Two of these studies explored the drug interaction potential of cilomilast with the nonselective PDE inhibitor, theophylline, and a third study compared the pharmacokinetic profile of cilomilast in smokers and nonsmokers. Repeated administration of cilomilast had no effect on the steady‐state pharmacokinetics of theophylline in either a pilot dose‐ranging or definitive therapeutic study. At therapeutic doses, the point estimate and 90% confidence interval for theophylline AUC0–12 and Cmax were completely contained within the range (0.8, 1.25). Similarly, repeated administration of theophylline had little clinically relevant effect on the steady‐state pharmacokinetics of cilomilast when compared to placebo, as only slight average increases in cilomilast AUC0–12 and Cmax (6% and 3%, respectively) were observed. In addition, mean cilomilast exposure (AUC0–∞) was found to be similar in both smokers and nonsmokers (8.47±2.20 μg•h/mL and 7.70 ± 2.25 μg•h/mL, respectively). Throughout all three studies, cilomilast was well tolerated, and concomitant use of these selective and nonselective inhibitors, although unlikely in the clinic, is hypothetically feasible. Taken together, these studies clearly differentiate cilomilast from theophylline for drug‐drugliability issues in a smoker and nonsmoker population, as well as highlight the potential to switch from one drug to another without undue clinical concern.