Use of Propentofylline in Feline Bronchial Disease: Prospective, Randomized, Positive-Controlled Study
Propentofylline is a methylxanthine derivative with bronchodilating actions similar to those of theophylline. Nineteen cats with bronchial disease were enrolled in this study. All cats received a low dose of prednisolone; 10 of the cats additionally received propentofylline. Propentofylline-treated cats significantly improved in their auscultation scores, respiratory pattern scores, and radiological bronchial markings score over the observation period, and they coughed less and slept less at the end of the study. No significant changes were noted in the control group. This study provides evidence that a combination therapy with prednisolone and propentofylline in cats with bronchial disease might be superior over monotherapy with prednisolone.
Introduction
The term feline bronchial disease describes a group of respiratory diseases in cats that have a spectrum of clinical signs ranging from intermittent cough to life-threatening respiratory distress. Reported causes of feline bronchial disease are altered immunosensitivity of the respiratory tract to inhaled allergens leading to chronic inflammation of the airways, adrenergic-cholinergic imbalance, dysfunction of the mucociliary apparatus, and profound nonspecific hyperresponsiveness of the airways.1 Physiological responses to inhaled particles are exaggerated; these include bronchoconstriction, cough reflex, and mucus production. Because of the chronic inflammation, regeneration of injured tissue is impaired, often resulting in progressive remodeling of airways. Fibrosis and increases in smooth muscle and mucous gland mass can change structure and function of airways, leading to further exacerbation of the disease.2 Pathological changes in cats with bronchial disease frequently include bronchial smooth muscle hypertrophy and hyperplasia combined with inflammation, mucosal and submucosal edema, epithelial cell desquamation, intraluminal inflammatory exudates, and the presence of airway mucous plugs.3
Bronchospasm and enhanced mucus production lead to expiratory dysfunction and, therefore, play an important role in the development and severity of clinical signs in feline bronchial disease. As a result, therapy aims at reducing inflammation with glucocorticoids (as soon as bacterial infection is ruled out) and decreasing bronchoconstriction with bronchodilators.4 In addition to β2-sympathomimetic agents like terbutaline and albuterol, methylxanthine derivatives have been used as bronchodilating agents in cats. Theophylline and its ethylenediamine salt, aminophylline, are widely used compounds in veterinary practice; however, they are not available as veterinary products. While theophylline and aminophylline have been used for many years, the mechanism of action is still not completely understood. Theophylline is classified as a 1phosphodiesterase inhibitor, which should increase cyclic adenosine monophosphate (cAMP) and lead to smooth muscle dilatation, but clinically effective levels do not result in accumulation of cAMP. Theophylline has been proposed to act through adenosine antagonism and by altering calcium metabolism in cells, which may result in mild bronchodilatation. Other effects of methylxanthines include acceleration of mucociliary transport, improvement of diaphragmatic function, and antiinflammatory effects.5 Both theophylline and aminophylline have a narrow therapeutic index and commonly induce adverse effects, including central nervous system stimulation and gastrointestinal irritation.6
Another methylxanthine derivative, propentofylline, is licensed for veterinary use as Karsivana or Vivitoninb in many European countries and is available in tablets containing doses adequate for a cat’s body weight. Propentofylline has been used in dogs for a long time, although for different indications.7 Bronchodilating effects of propentofylline are comparable to those of theophylline, but propentofylline has a better therapeutic index, as a dose fivefold higher than the recommended dose (3 mg/kg) in dogs did not lead to any adverse effects in this species.8 Anecdotal reports have described veterinarians successfully administering propentofylline in cats with bronchial disease, but no studies on the use of propentofylline in cats have yet been published.8 Therefore, the aim of this study was to investigate if propentofylline is helpful in the treatment of bronchial disease in cats.
Material and Methods
Cases Included
Nineteen client-owned cats with naturally occurring bronchial disease were included in this prospective, randomized, positive-controlled study. All cats were presented to the Clinic of Small Animal Medicine at the Ludwig Maximilian University of Munich, Germany, between August 2004 and September 2006. The study fulfilled German clinical study guidelines, and all owners signed an informed consent form.
Inclusion criteria were a history of cough, wheezing, or recurring episodes of dyspnea for a minimal duration of 4 weeks before entering the study. Cats that had received long-acting glucocorticoids 8 weeks before or short-acting glucocorticoids 7 days before entry in the study were excluded.
Initial Examinations
The observation period for each cat was 9 weeks. Each cat was presented to the examiner on days 0, 13 (±2 days), and 62 (±5 days). To rule out upper respiratory tract disease, neoplasia, and cardiovascular, pleural, and mediastinal disease as potential causes for the clinical signs, all cats underwent a thorough diagnostic workup on day 0. Clinical and complete cardiological examinations, including echocardiography and electrocardiography, were performed. Thoracic radiographs were obtained in right lateral and dorsoventral views. Laboratory investigations included fecal flotation and Baermann flotation techniques to rule out airway parasites. Additionally, a complete blood count, serum biochemical analysis, and testing for feline immunodeficiency virus (FIV) antibodies and feline leukemia virus (FeLV) antigen (SNAP FIV/FeLV Combo Plus Test)c were performed in all cats. As heartworm disease is not endemic in Germany and none of the cats had been in endemic regions before entering the study, heartworm tests were not performed.
In all participating cats, bronchoalveolar lavage (BAL) was performed with a sterile nasoesophageal feeding tube, which was passed into the lower airways through an endotracheal tube under general anesthesia (described later). The BAL fluid was submitted for bacterial culture to rule out infection. Both fresh and cytocentrifuge-concentrated smears were prepared immediately after collection and stained with Wright’s stain after air drying for cytological evaluation. For each cat, the slide with the (subjectively) best quality was chosen for differential cell counts. This was performed by counting 500 inflammatory cells per slide (i.e., 100 cells in five different areas on the slide).
Owners of the participating cats were asked to assess the severity of the clinical signs at home and to assign their cat to one of four categories: 1 = cat is unimpaired by its disease and behaves normally; 2 = cat is almost unimpaired by its disease and shows normal behavior between sporadic symptomatic phases; 3 = cat is moderately impaired by its disease (e.g., tires easily when playing but normally has no clinical signs at rest); 4 = cat is considerably impaired by its disease, shows clinical signs most of the day, and therefore is clearly restricted in its activity.
Follow-up
On days 13 (±2 days) and 62 (±5 days), clinical examinations and radiological examinations were repeated. All clinical examinations were performed by the same veterinarian (Stursberg). Potential improvements in the clinical examinations were assessed on the basis of changes in respiratory rates, lung sounds on auscultation, and respiratory patterns [Table 1]. Thoracic radiographs were evaluated by a board-certified radiologist (Hecht), who was blinded to the data concerning the cats. As similarly noted in previous publications, radiographs were scored based on pulmonary pattern (i.e., bronchial, interstitial, alveolar), and a score was assigned for each pattern on a scale from 0 to 9 (0 = no grade; 1 to 3 = low grade; 4 to 6 = medium grade; 7 to 9 = high grade bronchial/interstitial/alveolar pattern).9,10 Additionally, the size of the pulmonary field was graded as normal or enlarged, and other alterations (if present) were recorded separately. As noted in previous publications, radiographic diagnosis of pulmonary hyperinflation was made based on a combination of findings: flattening and caudal displacement of the diaphragm; ventral bowing of the caudal vena cava and sternum; increased distance between the cardiac silhouette and diaphragm; barrel-shaped thorax; increased radiolucency of the lungs; extension of the lungs to the first lumbar vertebrae; and unusually clear visibility of bronchovascular markings.9–12 Diaphragmatic position was judged based on expected intersection point with the spine at the 11th to 13th thoracic vertebrae (or ninth thoracic to first lumbar vertebrae).13
During the 62±5 day observation period, the owners kept a diary in which clinical signs (e.g., cough, dyspnea, and wheezing) as well as behavior (e.g., eating, sleeping, and playing habits) were scored on a visual analogue scale. The respiratory rate was counted once daily while the cat was at rest. Additionally, owners were encouraged to write down potential adverse effects to the administered medications.
To obtain representative values for statistical investigation, all values for each clinical sign or changes in behavior during the 62±5 day observation period were summated for each cat. A mean respiratory rate over the observation period was calculated for each cat and used for comparison of the two treatment groups.
To evaluate effects on respiratory rate, clinical signs, and behavior over the observation period, the means of the first 2 weeks were compared to those of the last 2 weeks for each treatment group.
Medication
On day 0, all cats received a single dose of 0.01 mg/kg terbutalined subcutaneously prior to anesthesia, which was induced in a standard protocol using 0.2 mg/kg diazepame and 5 mg/kg propofolf intravenously (IV) titrated to effect. After BAL was performed, a single dose of 2 mg/kg prednisoloneg was administered IV to avoid deterioration of the clinical signs after the BAL procedure. From day 1 until the end of the observation period, all cats received prednisolone (0.5 mg/kg q 24 hours per os [PO]). The first week of the observation period served as a stabilization phase, during which a higher dosage of prednisolone was allowed, if needed. Additionally, all cats were treated with ibafloxacinh (15 mg/kg q 24 hours) on days 0 to 6. On day 7, 10 cats began treatment with propentofyllinei (5 mg/kg q 12 hours PO), while the remaining nine cats received a placebo containing magnesium stearate, lactose, and cellulose powder (q 12 hours PO) until the end of the observation period (in addition to the prednisolone). The owners were blinded to their cat’s treatment group.
Data Analysis
Statistical analysis was performed using SPSS Version 15.0.1.j Changes of the respiratory parameters in the clinical examinations, the scores of the pulmonary patterns in the radiographs, and the scores in the diaries kept by the owners were investigated using a Mann Whitney U test, as all data were nonparametric. Differences between paired parameters at different time points were evaluated with Wilcoxon’s test. Changes in the size of the lung in the radiographs were investigated using Fisher’s exact test; P values of <0.05 were considered significant.
Results
Fifteen (79%) domestic shorthair cats, one Siamese, one Korat, one exotic shorthair, and one domestic longhair mixed-breed cat were enrolled in the study. The cats were between 10 months and 10 years of age (mean 6 years, median 6.2 years). Seven (37%) of the cats were female, and 13 cats lived indoors only, while the remaining six cats were permitted outside.
Clinical Examinations
On day 0, no significant differences were found in the observed parameters of the clinical examination (respiratory rate P=0.806; breath sounds on auscultation P=0.476; respiratory pattern P=0.433) between the two treatment groups. As summarized in Table 2, no significant differences in respiratory rates were seen on days 0 and 62 in either treatment groups (propentofylline: P=1.000; control: P=0.233). From day 0 to day 62, the lung sounds on auscultation significantly improved in the cats treated with propentofylline (median score was 3 on day 0, and median score on day 62 was 1; P=0.034), as did the respiratory pattern (median score was 1 on day 0, and median score on day 62 was 0.5; P=0.025). The cats receiving placebo showed no significant difference in these two parameters between days 0 and 62 (P=0.140 and P=0.180, respectively). Neither on day 13 nor on day 62 was a statistically significant difference noted in any investigated parameters between the two treatment groups (data not shown).
Bronchoalveolar Lavage
Results of the differential cell counts of BAL inflammatory cells have been summarized in Table 3. Twelve (63.2%) of the 19 cats had percentages of inflammatory cells deviating from the values reported for healthy cats.14 Eosinophils were found in the bronchial lavage specimens of 14 cats, but they were the predominant cell type (>50%) in only three cats. Neutrophilic inflammation was found in six cats, whereas a mixed neutrophilic-eosinophilic inflammation was noted in three cats. No significant differences were found between the two treatment groups when comparing the percentages of eosinophils, neutrophils, and macrophages in BAL cytology performed at the beginning of the study.
Radiological Examinations
On the initial examinations, cats showed all grades of bronchial pulmonary patterns in combination with mild interstitial pulmonary alterations on thoracic radiographs. Only one cat showed an alveolar pattern in the right middle lung lobe, suspicious for atelectasis, that did not resolve during the observation period [Table 2]. No significant differences were found between the treatment groups in pulmonary pattern scores on any of the examination days. A significant difference between the scores of the bronchial pattern on day 0 (median score 5.5) and day 62 (median score 3.5) was seen in the group of cats treated with propentofylline (P=0.017); however, the difference in the control group was not significant (P=0.068).
Further, on day 0, 13 cats had normal lung sizes, and the lung fields of six cats (three in each group) were considered enlarged. No significant differences in the sizes of the lung field were seen between the two treatment groups on days 0, 13, and 62 (data not shown). No difference in size of pulmonary field within either treatment group was seen between days 0 and 62 [Table 2].
Assessment by Owners
According to the owners, most (63%) cats were almost unimpaired by their disease and showed clinical signs only occasionally before entering the study. No significant difference was seen in this owner-assessed score between cats later treated with propentofylline and those in the control group (P=0.154; data not shown). Over the whole study period, no adverse effects were noted by the owners of any of the cats.
When comparing clinical sign and behavior scores of the two treatment groups that were summed up over the whole observation period, as well as the mean respiratory rate of each cat, no significant differences were found between the cats in the two treatment groups (data not shown). Comparison of the parameters of days 0 to 3 to those of days 48 to 62 resulted in significant differences in the propentofylline-treated group regarding the parameters of coughing and sleeping. Cats treated with propentofylline coughed significantly less at the end of the study (P=0.013) and seemed to be more active than at the beginning of the study (P=0.047), whereas cats in the control group showed no significant difference in these two parameters. No significant differences were in any other parameter for either group of cats [Table 4].
Discussion
Cats with so-called “bronchial disease” comprise a heterogeneous group of cases because of the different and, as-yet poorly understood, underlying etiologies. Some authors have attempted to categorize bronchial disease in the cat further as “chronic bronchitis” and “feline asthma,” but a standardization of nomenclature is still lacking. Differentiation of the exact etiologies and diseases is hardly possible without pulmonary function tests, which are far from being routine diagnostic tools in veterinary medicine. Furthermore, not only do differences exist between the individual cases, but often clinical signs vary tremendously at different time points for one cat.15 Severity of disease and success of therapeutic interventions often are difficult to judge for a veterinarian, because affected cats might not show any clinical signs when examined.16 Therefore, the cats in this study were observed over approximately 60 days, and a combination of clinical and radiographic examinations performed by the veterinarians and assessment by the owners of the cats were used to investigate possible benefits of propentofylline therapy in feline bronchial disease.
The signalment of the participating cats was similar to that noted in previously published studies. One cat was young (only 10 months of age) and at that point had shown clinical signs for 3 months already. This seems to be a remarkably young age for a cat to have bronchial disease. The condition is commonly described in adult cats; however, in an earlier study, affected cats as young as 4 months have been reported.12
In the clinical examinations, scores for auscultation and respiratory pattern improved in both treatment groups, but this difference was only significant in the propentofylline-treated cats. This improvement could be caused by the bronchodilating actions of propentofylline leading to softened (i.e., less harsh and/or loud) breathing sounds and facilitated respiration. Interestingly, the change in respiratory rates over time was little or not at all, suggesting that high respiratory rates potentially resulted, at least in part, from stress connected with the hospital appointments.
As noted in previously published studies, BAL cytology findings were highly variable. The predominant cell types described in feline bronchial disease include eosinophils, neutrophils, or macrophages in nearly equal numbers of cats, and even normal BAL cytology can be obtained in some cats. Thus, the presence of inflammatory cells is not required for diagnosis.10,11 Obtaining a reasonable differential count is difficult in BAL cytology because of the high variability in quality, density, and distribution of cells not only between different smears but also between different local areas on the same slide. This was taken into account by counting a relatively high number of cells on different areas of the slide. To have an absolute cell count of eosinophils, as in blood samples, would be interesting. Unfortunately, the variability of lavage specimens and the presence of different amounts of mucus impede calculation of a cell count.
Radiological alterations in the participating cats were predominantly bronchial pulmonary patterns combined with mild interstitial markings. Radiological scores for both bronchial and interstitial patterns improved slightly over the treatment period. The improvement in the bronchial pattern score was only significant in the propentofylline-treated cats.
Adenosine-potentiating drugs such as propentofylline do not only possess bronchodilating effects, but they also have antiinflammatory and immunomodulatory actions.17 Propentofylline shows antagonistic actions on three (A1, A2A, A2B) of the four identified subtypes of adenosine receptors (the fourth being A3) that are expressed in a wide variety of tissues.18 A growing interest has developed in elucidating the functions of these receptors, as adenosine receptor-modulating drugs have therapeutic potential as inflammatory modulators.19 Evidence shows that adenosine A2B receptors contribute to inflammation of airways in human asthma, and the assumption is that A2B-receptor-antagonists may have beneficial effects. This is the proposed mechanism of action of theophylline.20,21 In addition, antioxidant effects have been reported for propentofylline.22 All these mechanisms together may influence underlying inflammation, causing infiltration of the airway walls with inflammatory cells, epithelial edema, and mucous gland hypertrophy and hyperplasia. In turn, these factors could all contribute to thickening of the airway walls and enhanced mucus production, which lead to the radiological changes described.23 Additionally, it should be noted that the majority of cats enrolled in this study showed only mild clinical signs. As it is hypothesized, in early stages of feline chronic bronchial disease, changes might be reversed in response to appropriate therapy and management.24
The size of the lung field was only enlarged in six cats (three in each treatment group) at the beginning of the study; the size resolved to normal at the end of the study in four of these cats (two in each treatment group). Overinflated lungs generally are a sign for severe bronchoconstriction and consecutive impairment of exhalation. The reason for the lack of significant difference between the two groups concerning the resolution of the hyperinflation might be related to glucocorticoid administration. The glucocorticoids could have resulted in amelioration of lung field size, thus masking a potential effect of propentofylline. In all cats, every attempt was made to obtain radiographs at the point of maximal inspiration. Since a similar degree of pulmonary expansion between inspiratory and expiratory radiographs attributable to increased lung volume has been described,25 acquisition of two radiographs (one at maximum inspiration and one at maximum expiration) may have allowed the detection of more cats with hyperinflation. Therefore, inspiratory and expiratory radiographs might be considered useful in future studies as additional diagnostic tools, but they were not performed in this project.
In the assessment by the owners, propentofylline-treated cats showed a better outcome than the cats in the control group. This improvement was most obvious in coughing scores, but the dyspnea and wheezing scores also improved over the treatment period in the propentofylline group (although the P values were just over the level of significance). Cats in the propentofylline group also slept less than at the beginning of the study, which could be due to either a better general condition or the result of other effects of propentofylline (such as increased blood flow to the brain, heart, and skeletal muscles and improvement of flow properties of erythrocytes) or direct actions on the brain. Propentofylline is used to treat cognitive dysfunction in dogs.26 In all cats, the increased scores in eating over the observation period most likely were induced by the prednisolone.
One limitation of this study is the small sample size. The differences between the treatment and control groups may have become more marked if a larger group of cats had been included. According to the owners, approximately two-thirds of the participating cats were only mildly affected by the disease; this segment probably represented a true cross-section of cases with feline bronchial disease seen in general veterinary practice. Results of this study do not allow for assessment of how severely affected cats might benefit from therapy with propentofylline.
No pharmacokinetic studies of propentofylline in cats have been published to date. Therefore, an exact dose and regimen of administration are unknown. Nevertheless, the applied dose of approximately 5 mg/kg body weight seemed to show some effect, and no adverse effects were noted in this study (as reported by the owners).
Most clinical scores in this study are based on assessment by the owners, which can be an unreliable factor. In the study described herein, the examiners spent considerable time explaining to the owners the nature of the disease, possible signs, and how to distinguish signs from other behavior(s). Owners in this study were also shown how to count the respiratory rate and how to use the study diary, which was checked by the authors on every follow-up examination. Still, the fact remains that the cats were not observed 100% of the time, and the assessment was subjective. In the opinion of the authors, therapy for naturally occurring feline bronchial disease cannot be assessed without integration of the owners, because owners would not agree to their cats being observed in a clinical setting for several weeks.
Another limitation of the study concerns radiological evaluation, which would have been more objective if more than one blinded radiologist had been involved. Since the major focus of this study was to compare two different treatment modalities for feline bronchial disease, and because radiographic assessment was only one part of case assessment, evaluations were performed by only one radiologist. Determination of interobserver variability in diagnosis and grading based on radiographs would be an interesting project, but it was beyond the scope of this study.
Conclusion
This prospective study revealed several results that suggest combination therapy using propentofylline and prednisolone may be superior over a monotherapy with prednisolone alone for feline bronchial disease. Studies investigating the pharmacokinetics and pharmacodynamics of propentofylline in the cat are needed to determine the optimal dosing scheme in this species. A higher dose may be well tolerated and could produce even greater beneficial effects. Further studies should be conducted to evaluate if the combination therapy with propentofylline allows reduction in glucocorticoid dosages.
Intervet Deutschland GmbH, 85716 Unterschleissheim, Germany
Intervet UK Ltd, Milton Keynes, Buckinghamshire, MK7 7AJ United Kingdom
Idexx Laboratories Inc., Westbrook, MA 04092
Bricany; AstraZeneca GmbH, 22880 Wedel, Germany
Diazepam-ratiopharm; Ratiopharm GmbH, 89079 Ulm, Germany
Narcofol; CP-Pharma GmbH, 31303 Burgdorf, Germany
Solu-Decortin H 10/25 mg; Merck Pharma GmbH, 64293 Darmstadt, Germany
Ibaflin 3% Gel; Intervet Deutschland GmbH, 85716 Unterschleissheim, Germany
Karsivan 50-mg tablets; Intervet Deutschland GmbH, 85716 Unterschleissheim, Germany
SPSS Inc., Chicago, IL 60606
