University of Groningen. Transdermal delivery of anticholinergic bronchodilators Bosman, Ingrid Jolanda

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1 University of Groningen Transdermal delivery of anticholinergic bronchodilators Bosman, Ingrid Jolanda IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 996 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Bosman, I. J. (996). Transdermal delivery of anticholinergic bronchodilators: methodological and clinical aspects Groningen: s.n. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 0 maximum. Download date:

2 Chapter 9 Effects of transdermal scopolamine on bronchial hyperresponsiveness to methacholine 9.0. Summary In a double-blind, placebo-controlled, cross-over study, the therapeutic effects of two simultaneously applied Scopoderm TTS patches were evaluated in ten patients with bronchial hyperresponsiveness to methacholine. We found no significant effects on pulmonary function, symptoms, use of extra β 2 -agonists and bronchial hyperresponsiveness to methacholine. However, several adverse events were reported, especially headache, blurred vision/mydriasis, dry mouth, and dizziness. One patient reported depressive feelings, starting six days after removal of the patches. In 24-hours urine, we measured 4.5 (± 4.) µg free and 34.0 (± 43.7) µg total scopolamine. In plasma the concentrations of free and total scopolamine were 0.0 (± 44.8) pg/ml and (± 25.3) pg/ml, respectively. Although the concentrations of free scopolamine in plasma were doubled compared to the previous study with one scopolamine patch, they apparently were still too low to reach therapeutically relevant levels at the muscarinic receptors in the lungs.

3 20 Chapter Introduction Anticholinergic agents are bronchodilators that act via inhibition of cholinergic activity, thereby diminishing airways obstruction in patients with obstructive airways disease. They can also be used to reduce bronchial responsiveness to stimuli such as methacholine, because they are competitive inhibitors of acetylcholine at muscarinic receptors. Inhaled anticholinergics are available in a short acting form (Atrovent, ipratropium bromide), however they have to be used several times daily which may reduce patient compliance. Because of their relatively short duration of action, they cannot prevent airways obstruction at night. Long acting inhaled anticholinergics are not yet available. In a previous study, we evaluated the effects of transdermally administered scopolamine (Scopoderm TTS) on pulmonary function and symptoms, during day and night, in patients with (partially) reversible airways obstruction []. Administration of anticholinergics via the transdermal route enables a constant influx of drugs over a prolonged period of time resulting in a sustained, constant and controlled drug plasma concentration. This, theoretically, may improve both symptoms and pulmonary function, especially during the night. In a study which was not placebo-controlled, Demeter and Cordasco [2] indicated that transdermal delivery of scopolamine was effective in a small group of patients who had diverse types of lung diseases. In contrast, we did not find a significant improvement by transdermal scopolamine neither on pulmonary function nor on symptoms []. Lack of improvement may have been due to a too low dosage of scopolamine, resulting in subtherapeutic plasma concentrations with respect to pulmonary effects. Therefore, we set up this study to evaluate the effects of twice the dose of transdermal scopolamine on pulmonary function (FEV, PEF) and symptoms. We also evaluated the effects of transdermal scopolamine on the hyperresponsiveness to methacholine Patients and Methods Patients We selected ten patients of either sex, aged between 25 and 60 years with bronchial hyperresponsiveness to methacholine (PC 20 < 8 mg/ml) and with an improvement in PC 20 methacholine of more than 2 doubling doses, 45 min after inhalation of 80 µg ipratropium bromide, as measured on a separate day. The PC 20 is defined as the concentration of methacholine causing a 20% fall in the forced expiratory volume in one second (FEV ). The absolute lower limit of the FEV was.00 l. Exclusion criteria were pregnancy, hypersensitivity to scopolamine, use of anticholinergics or agents having effects on the central nervous system, open angle glaucoma, pyloric obstruction, obstruction of the neck of the urinary bladder, obstruction of the intestines, severe renal, hepatic or cardiovascular disease, epilepsy, or (a history of) psychiatric diseases.

4 Effects of transdermal scopolamine on bronchial hyperresponsiveness 2 Other exclusion criteria were the use of oral corticosteroids, beta-blocking agents, anticoagulants, or nitrates, continuous use of antibiotics, a history of angina pectoris, previous myocardial infarct, previous stroke, diastolic blood pressure persistently > 00 mm Hg, occupational asthma, other serious lung diseases requiring continuous medical care (e.g. tuberculosis, sarcoidosis, lung cancer), or ongoing hyposensitization program. The study was approved by the Hospital Medical Ethics Committee, and all subjects gave their written informed consent to participate Study medication We used Scopoderm TTS patches (size 2.5 cm 2 ), a transdermal therapeutic system containing a drug reservoir of.5 mg of scopolamine. Each patch is programmed to deliver 0.5 mg of scopolamine over a three day period. A priming dose (40 µg) is incorporated in the adhesive layer (to saturate certain binding sites within the skin and to accelerate achievement of steady state blood levels) and the remainder is released at a constant rate of approximately 5 µg/hour [3]. Placebo patches did not contain the drug scopolamine but otherwise they were identical. During the patch days, two patches were applied on the hairless skin behind the ears for 72 hours, one patch behind each ear Study design At two separate days (visit one and visit two) volunteers came to the outpatient clinic for history taking, physical examination, blood analysis and methacholine provocation tests. At visit one, a methacholine provocation test was performed at least 8 hours after the use of short-acting β 2 -agonists or ipratropium bromide. At visit two, the test was performed at approximately the same time of the day, 45 min after inhaling 80 µg ipratropium bromide. Participants who met the inclusion criteria entered the double-blind, placebo-controlled, cross-over study, which was divided into three phases. The first phase consisted of six days, at which symptoms and peak expiratory flows were recorded. Then two similar phases of ten days followed, each phase consisting of three patch days and a seven days wash-out period (Figure 9.). During the study, patients discontinued the use of ipratropium bromide. The use of a short acting β 2 -agonist by inhalation was allowed if necessary. Patients kept a diary card, recording cough, expectoration, daytime and nighttime symptoms (dyspnea and/or wheeze) and adverse events, on a four-point severity scale (0 = no symptoms and 3 = severe symptoms). The number of inhalations of β 2 -agonist during the day and night, and the highest of three measurements of morning and evening peak expiratory flow (PEF), using a Wright mini peak flow meter (Clement Clarke International, Ltd., London, UK), were noted as well. Patients were asked not to use β 2 -agonists 4 hours before the PEF measurements. Urine was collected every third patch day (days 9 and 9) during 24 hours. Every Figure 9.. Study design of the double-blind, placebo-controlled, cross-over study.

5 22 Chapter 9 fourth patch day (days 0 and 20), blood was collected, and a methacholine provocation challenge was performed, after which the patches were removed Pulmonary function and methacholine provocation challenges Prechallenge FEV was performed using a calibrated water-sealed spirometer according to standardized guidelines [4]. The highest of three reproducible FEV values was used for analysis and was expressed as a percentage of the predicted FEV (FEV %pred). Inhalation provocation tests were performed according to a 2 min tidal breathing method adapted from Cockcroft and coworkers [5]. Solutions of methacholine were administered at room temperature as aerosols generated from a starting volume of 3 ml in a DeVilbiss 646 nebulizer (DeVilbiss Health Care Inc, Somerset, PA), connected to the central chamber of an inspiratory and expiratory valve box with an expiratory aerosol filter. Solution output was 0.3 ml/min. After inhalation of 0.9% sodium chloride solution, doubling concentrations of to 9.6 mg/ml methacholine bromide were inhaled. FEV was measured 30 and 90 s after each inhalation. The challenge was discontinued when FEV had fallen with 20% of the prechallenge level or when the highest concentration had been administered. The concentration of methacholine, causing a 20% fall in FEV was calculated (PC 20 ).

6 Effects of transdermal scopolamine on bronchial hyperresponsiveness Scopolamine analysis Urine and plasma samples were analysed to determine the levels of free (unconjugated) and total (free plus conjugated) scopolamine. The procedure included a semi-automated solid-phase extraction, followed by the analysis of scopolamine using radioreceptor assays. For urine samples of ml, the limit of detection (LOD) of the assay was 550 pg/ml and the limit of quantitation (LOQ) was 60 pg/ml. For plasma samples of.5 ml, the LOD was 6 pg/ml and the LOQ was 38 pg/ml [6] Data analysis All variables were checked for normal distribution with Kolmogorov-Smirnov tests (p < 0.05). Because of the cross-over design the possibility of a period effect and a treatment-period interaction was tested. To test a period effect a two sample Student t-test was used comparing the differences between the periods in the two groups of patients. To test a treatment-period interaction, a two sample Student t-test was used comparing patient s average response to the two treatments. No statistically significant period effect and /or treatment-period interaction was found (level of significance p < 0.05). Therefore, the effects of the two treatments were simply compared using paired Student t-tests [7]. Data of day 2 and 3 of the patch days were used to calculate mean morning PEF and mean evening PEF, as well as mean diurnal PEF variation: ( morning PEF - evening PEF / mean PEF) * 00%. The sum of scores of the specific symptoms and the total number of inhalations of β 2 -agonists on day 2 and 3 of the patch days were used to analyse the treatment effects (Wilcoxon signed rank sum tests). Calculations of PC 20 were performed with the base-2 logarithm (log 2 ) as this reflects doubling concentrations. All data were analysed using the statistical package SPSS/PC+ (Norusis MJ, SPSS Inc., 990, Chicago) Results Patients Ten patients participated in the study. Their mean age was 37 years and four of them were male. The FEV (%pred) at visit one was 88%, and after inhaling 80 µg ipratropium bromide there was an improvement in FEV of 8.7%. Log 2 PC 20 methacholine was mg/ml, and increased by 4.07 doubling concentrations after 80 µg ipratropium bromide (Table 9.).

7 24 Chapter 9 Table 9.. Patient characteristics. No. Male, no. Age (years), mean (sd) Use of inhaled steroids, no. Smoking habits Current/ex/never, no. Pulmonary function (%pred), mean (sd) FEV, pre ipr.br. * FEV, post ipr.br. FEV Peak expiratory flow (l/min), mean (sd) *2 PEF morning evening variation Log 2 PC 20 methacholine (mg/ml), mean (sd) Log 2 PC 20 metacholine, pre ipr.br. Geometric mean PC 20 Log 2 PC 20 methacholine, post ipr.br. Geometric mean PC 20 Log 2 PC 20 methacholine /4/ (3) (20.) (6.8) (7.4) (7) (30) (7) (.50) (.52) (.2) * ipr.br. = ipratropium bromide. *2 Data of days 5 and Scopolamine analysis Urine collected over 24 hours during day 3 of the patch days contained 4.5 µg (range µg) of free scopolamine and 34.0 µg (range µg) of total scopolamine (Table 9.2). In plasma, collected at day 4 of the patch days before the methacholine challenge test, the concentrations of free and total scopolamine were 0.0 pg/ml (range pg/ml) and pg/ml (range pg/ml), respectively (Table 9.3). In the placebo phase no scopolamine was detected in either urine or plasma Effects of transdermal scopolamine treatment There were no significant differences between the scopolamine phase and the placebo phase for all parameters (Table 9.4). The FEV %pred improved with 2.9% (p = 0.73), PC 20 methacholine improved with 0.56 doubling concentrations (p = 0.09) and PEF variation declined with 3.5% (p = 0.074). There were also no significant changes in symptoms and number of inhalations of β 2 -agonists, and

8 Effects of transdermal scopolamine on bronchial hyperresponsiveness 25 Table 9.2. Free and total scopolamine (µg) in 24 hours-urine of 0 patients. Patient Free Phase Free Phase 2 Total Phase Total Phase mean sd cv n=0: mean sd cv Phase : Patients first received scopolamine, then placebo. Phase 2: Patients first received placebo, then scopolamine. All urines from patients that received placebo showed no detectable scopolamine concentrations. there were no significant correlations between the levels of free scopolamine in plasma and the changes in pulmonary function and/or PC 20 methacholine. Several adverse events were reported, varying from mild to moderate (Table 9.5). The following symptoms were classified as severe only one time: Headache, blurred vision/mydriasis, dry mouth and depressive feelings. All adverse events in the scopolamine phase started during the patch days, except for the depressive feelings. This event started six days after removal of the scopolamine patches and lasted for one week. This patient discontinued the study Discussion and Conclusions In this placebo controlled, cross-over study we evaluated the effects of two simultaneously applied Scopoderm TTS patches, on pulmonary function, symptoms, use of extra β 2 -agonists and bronchial hyperresponsiveness to methacholine. There were no significant differences in these parameters between scopolamine and placebo.

9 26 Chapter 9 Table 9.3. Free and total scopolamine (pg/ml) in plasma of 0 patients. Patient Free Phase Free Phase 2 Total Phase Total Phase mean sd cv n=0: mean sd cv Phase : Patients first received scopolamine, then placebo. Phase 2: Patients first received placebo, then scopolamine. All plasma samples from patients that received placebo showed no detectable scopolamine concentrations. Table 9.4. Effects of scopolamine and placebo on FEV, PEF and PC 20 methacholine. Scopolamine Placebo Difference p-value FEV (%pred) 87.0 (22.2) 84.0 (20.3) 2.9 (5.9) 0.73 Mean PEF (l/min) morning evening variation (26) (42) (5) (2) (47) (5) (25) (4) (5) Log 2 PC 20 methacholine (mg/ml) Geometric mean PC (.75) (.32) 0.56 (0.92) 0.09

10 Effects of transdermal scopolamine on bronchial hyperresponsiveness 27 Table 9.5. Adverse events during scopolamine phase and placebo phase. Headache Blurred vision/mydriasis Dry mouth Depressive feelings * Dizziness Skin irritation Sleep disturbance Lack off coordination Scopolamine Placebo 2 * Event started after the patch days. In a previous study, using only one Scopoderm TTS patch, we did not find a significant improvement on pulmonary function and symptoms []. Lack of clinical effects might have been due to the fact that with a single patch only subtherapeutic scopolamine levels in plasma were obtained. In this study, we doubled the dose of scopolamine and we evaluated the effects on FEV, PEF, symptoms and the use of extra β 2 -agonists. We furthermore assessed effects on bronchial hyperresponsiveness to methacholine, a cholinergic agonist. Since scopolamine is a competitive inhibitor of acetylcholine at muscarinic receptors, a reduction of bronchial hyperresponsiveness to methacholine is expected. Therefore, we included patients with bronchial hyperresponsiveness to methacholine and with an improvement of PC 20 methacholine with 2 doubling concentrations after inhalation of the anticholinergic ipratropium bromide. The mean improvement in PC 20 methacholine was 4 doubling concentrations. During steady state, which is reached within 24 hours, about 20 µg of scopolamine per patch is delivered to the patient in one day [3]. Using two patches simultaneously, we found that 6% of the dose was excreted unchanged, whereas 56% of the dose was excreted as glucuronide and sulphate conjugates, in 24 hours urine. In comparison with one patch, less of the administered dose is excreted as conjugates in urine, and more is excreted unchanged. The measured plasma concentrations of free and total scopolamine were 0.0 pg/ml and pg/ml, respectively. These concentrations were 2.5 and.9 times higher than the concentrations in our previous study, with only one Scopoderm TTS patch. Although the levels of free scopolamine were more than doubled, we found no significant correlations between these levels and FEV, PEF and PC 20 methacholine. In our previous study with one Scopoderm TTS patch, no severe side effects were reported. Only three patients reported a dry mouth and one patient reported skin irritation. In this study, in which we used two Scopoderm TTS patches simultaneously, more adverse events were reported, especially blurred

11 28 Chapter 9 vision/mydriasis (scopolamine phase: placebo phase, 7:), headache (5:2), dry mouth (5:0), and dizziness (4:). All but one of the adverse events started during the patch days. One patient reported depressive feelings, starting six days after removal of the Scopoderm TTS patch and lasting for one week. Because of this event, the patient decided not to complete the study. The present study shows that the concept of giving scopolamine transdermally to obtain sustained pharmacologically active plasma concentrations is a viable one. Yet, unfortunately, with the present dose of two Scopoderm TTS patches, the well known side effects of anticholinergic drugs already became apparent, whereas no significant improvement on pulmonary function or bronchial hyperresponsiveness was seen. In other words, the plasma levels of free scopolamine obtained with the two patches are sufficient to trigger a number of unwanted side effects, but are still too low to reach therapeutical levels at the cholinergic receptor sites in the lungs. We used scopolamine because it was the only anticholinergic drug available in a transdermal patch. In view of the above results, it will be of interest to investigate other anticholinergics for dermal application. These drugs should have a higher binding affinity to the muscarinic receptor sites in the lungs than those in the central nervous system, responsible for the side effects Acknowledgement Ciba Geigy is thanked for providing Scopoderm TTS and placebo patches, and for financial support References [] Bosman IJ, Douma WR, Ensing K, de Zeeuw RA, Postma DS. Effects of transdermal scopolamine on pulmonary function and symptoms in patients with (partially) reversible airways obstruction. Submitted for publication in Eur. J. Pharm. Sci. (Chapter 8, this thesis). [2] Demeter SL, Cordasco EM. Transdermal scopolamine in the treatment of asthma: a preliminary report. J. Asthma 23 (4); , 986. [3] Clissold SP, Heel RC. Transdermal hyoscine (scopolamine). A preliminary review of its pharmacodynamic properties and therapeutic efficacy. Drugs 29; , 985. [4] Quanjer PhH. Standardized lung function testing. Bull. Eur. Physiopathol. Respir. 9 (Suppl 5); -95, 983. [5] Cockcroft DW, Killian DN, Mellon JJA, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin. Allergy 7; , 977. [6] Bosman IJ, Douma WR, Ensing K, de Zeeuw RA. A semi-automated solid-phase extraction and radioreceptor assay for the analysis of scopolamine in urine and plasma. Submitted for publication in Eur. J. Pharm. Sci. (Chapter 7, this thesis). [7] Altman DG. Crossover trials. In: Practical statistics for medical research, Chapman & Hall, 992,