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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 37  |  Issue : 2  |  Page : 43-48

Effectiveness and safety of fexofenadine in chronic idiopathic urticaria − open-label noncomparative study in daily practice


Dermatology and Venerology Department, Alex University, Alex, Egypt

Date of Submission20-Jul-2016
Date of Acceptance26-Mar-2017
Date of Web Publication4-Aug-2017

Correspondence Address:
Magdy Ragab
Dermatology and Venerology Department, Alex University, 28 alt Basha Zolfakar Roshdy Alex
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ejdv.ejdv_38_16

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  Abstract 


Objective
This study aimed to evaluate effectiveness and safety of fexofenadine in the treatment of chronic idiopathic urticaria (CIU) in routine practice in Egypt.
Patients and methods
This study is a local, multicenter, noninterventional, prospective, open-label, noncomparative, observational product registry conducted across Egypt. Three mandatory visits were made by the investigator for each eligible patient, and patients were assessed by urticaria symptoms score.
Result
The results of this study showed a statistically significant reduction (P<0.001) in signs and symptoms of CIU evaluated by the urticaria-related signs and symptoms score according to patients’ completed diary cards. Pruritis was decreased in 74.9% of patients and was improved in 22.3% of patients. Hives were relieved in 81.1% of patients and were improved in 17.5% of patients, whereas other related signs and symptoms of CIU were decreased in 75.5% of patients and improved in 22.2% of patients. Mild dizziness was reported in 0.2% of total enrolled patients that recovered after 3 days without corrective treatment.
Conclusion
Fexofenadine demonstrated statistically significant reduction in symptoms and signs of CIU. Pruritis status was decreased in 74.95% of patients. Hives status were relieved in 81.1% of patients, after a mean treatment duration of 14.93±5.49 days at visit 2 and 27.94±4.56 days at visit 3 (end of study). In addition, treatment with fexofenadine was well tolerated.

Keywords: chroinc, idiopthric, urticaria


How to cite this article:
Fouad M, Ragab M. Effectiveness and safety of fexofenadine in chronic idiopathic urticaria − open-label noncomparative study in daily practice. Egypt J Dermatol Venerol 2017;37:43-8

How to cite this URL:
Fouad M, Ragab M. Effectiveness and safety of fexofenadine in chronic idiopathic urticaria − open-label noncomparative study in daily practice. Egypt J Dermatol Venerol [serial online] 2017 [cited 2017 Dec 18];37:43-8. Available from: http://www.ejdv.eg.net/text.asp?2017/37/2/43/212226




  Introduction Top


Urticaria is a common condition that affects 20% of the general population, clinically characterized by the sudden appearance of raised erythematous skin lesions at different sites, which are usually pruritic and then tend to disappear [1],[2]. Urticaria is classified as chronic idiopathic urticaria (CIU) when the cutaneous wheals occur daily or almost daily and persist for more than 6 weeks, followed by spontaneous remission. The etiology of CIU is unknown [3].

CIU, defined as the occurrence of daily, or almost daily, wheals and itching for at least 6 weeks, with no obvious cause, has not been the subject of detailed epidemiological studies. Published figures for frequency are confounded by uncertainty of the diagnosis, as the term ‘chronic idiopathic urticaria’ is often taken to encompass physical urticarias and CIU. However, a figure of 0.5% for the life-long prevalence is probably not wide of the mark and this figure does not seem to vary greatly across different regions of the world. In any case, it is widely acknowledged that CIU is a major affliction causing serious disability to a degree equal to that experienced by those suffering from triple coronary arterial disease [4].

The major advance in our understanding of CIU in recent years has been the discovery that in 30–50 percent of patients with CIU the disease is due to an autoimmune process, and therefore it is not strictly ‘idiopathic’. In autoimmune urticaria, circulating immunoglobulin G autoantibodies react specifically with the α-chain of the high-affinity immunoglobulin E receptor on dermal mast cells and basophiles, evoking release of histamine and other mediators, which cause urticaria and angioedema. The remainder of this review deals with the differential diagnosis of CIU, the pathophysiology of autoimmune chronic urticaria and its diagnosis, significance, clinical and laboratory features, and treatment. The problem of patients with CIU that is not autoimmune is also discussed, and approaches to its investigation and management are proposed [5],[6],[7],[8].

Fexofenadine is a selective and peripherally acting H1-receptor antagonist [9]. It is a selective histamine H1-receptor antagonist that does not cross the blood–brain barrier; therefore, it is not associated with sedation or adverse cognitive effects. Unlike older antihistamines, fexofenadine does not have anticholinergic activity [10].

Fexofenadine is clinically effective in the treatment of seasonal allergic rhinitis and CIU for which it is a suitable option for first-line therapy. In clinical trials, fexofenadine did not prolong the QT interval or decrease the heart rate, unlike terfenadine [9].

Fexofenadine is rapidly absorbed, has an onset of action ranging from 1 to 2 h, and a long elimination half-life (11–14 h). It relieves the symptoms of allergic rhinitis, such as itching, sneezing, rhinorrhoea, and itchy watery red eyes. Importantly, 2 weeks’ treatment with fexofenadine administered once (120 or 180 mg) daily showed greater improvement in symptom scores than placebo, indicating 24 h effectiveness. Fexofenadine dosages of up to 20 mg twice daily and 180 mg once daily demonstrated significant improvements in mean pruritus severity scores compared with placebo in two double-blind trials in patients with CIU [9].

The drug effect is seen within 1 h [9]. The drug can be used for long periods with no evidence of tolerance [11],[12].

In 2.4 weeks, trials of fexofenadine, doses ranging from 20 to 240 mg twice daily, were statistically superior to placebo with respect to the score for pruritus (the primary end point) and the score for the number of wheals (the secondary end point) [13].

A study of 439 patients revealed that fexofenadine, at a dose of 60, 120, or 240 mg/day, was significantly more efficacious than placebo, as assessed by the mean pruritus score, the mean number of wheals per day, the mean daily symptom score (the sum of the wheal and pruritus scores), and the degree of interference with sleep, activities of daily living, or both. Increasing the dose from 120 to 240 mg/day increased the efficacy only slightly [12].

The study aimed at inspecting and evaluating effectiveness of fexofenadine as a second generation nonsedating antihistaminic of choice in routine medical practice, in terms of improvement and decrease rates of all signs and symptoms of CIU; in addition, this study evaluated the drug safety profile.


  Patients and methods Top


Study design

This study was a local, multicenter, noninterventional, prospective, open-label, noncomparative, observational product registry conducted across Egypt. This registry was conducted in accordance with the principles established by the 18th World Medical Assembly (Helsinki, 1964) and all applicable amendments laid down by it, as well as the ICH guidelines for good clinical practice. This study was conducted in compliance with all national and international laws and regulations. Written informed consent was obtained from all participants in this study. The study was conducted in 45 sites all over Egypt to study the effect of fexofenadine on type CIU patients. It was planned to enroll 500, but only 498 satisfied the eligibility criteria and were enrolled in the study. The estimated enrollment duration was 28 days; three mandatory visits were performed by the investigator for each eligible patient. Data were collected at each visit. Patients were treated with fexofenadine according to the investigators’ discretion. In baseline visit and treatment initiation (visit 1), patients demographics, symptoms, physical examination, previous medical history and codiseases/conditions, concomitant treatment, were determined all after having the informed consent. Visit 2 comprised a follow-up visit (2 weeks; day 14±2) in which data were collected about the clinical response according to the physician’s assessment/urticaria symptoms score, fexofenadine treatment status, adverse events, serious adverse events, and premature withdrawal. Visit 3 was a follow-up visit at the end of treatment (day 28±2) in which data were collected as in visit 2. At each follow-up visit, patients were assessed for clinical response to treatment by assessment of signs and symptoms of CIU according to urticaria symptoms score; adverse events were also assessed.

Patients

Only male and female patients aged up to 21 years presenting with CIU and for whom the investigator decided to prescribe fexofenadine for treatment were considered eligible and were allowed to participate in the study. Pregnant and breastfeeding women were ineligible to participate, as well as those patients with contraindication to fexofenadine according to the prescribing information/summary of product characteristics.

Outcomes

Primary efficacy outcomes were to assess the percentage of patients with clinical success evaluated by urticaria symptom score completed by the physicians during the visits and by the patients daily. Pruritus severity was assessed on a 0–3 scale (0=none; 1=mild, clearly present but minimal awareness; 2=moderate, definite awareness that is bothersome but tolerable; 3=severe, hard to tolerate), number of hives on a 0–3 scale (0, none; 1, 1–6; 2, 7–12; 3, >12), and size of the largest hive on a 0–3 scale (0, none; 1, <1.5 cm; 2, >1.5 cm; 3, >2.5 cm). Secondary efficacy outcomes were to assess reason for the choice of fexofenadine. All adverse events will be recorded during the study duration, both those observed by the investigator and reported by the patient. All patients will be analyzed for safety. Overall tolerability will be assessed depending on physician’s assessment at the end of the study using frequency tables (excellent, good, fair and poor). All efficacy and safety assessments were standard − i.e. widely used and generally recognized as reliable, accurate, and relevant (able to discriminate between effective and ineffective agents).

Statistical analysis

Descriptive statistics were done for quantitative variables: mean, SD, model minimum, median, and maximum were calculated with a confidence interval of 95%. For qualitative variables, frequency and proportions were calculated. For normal distribution of the quantitative data, χ2-test was applied for qualitative data. McNemar’s test was applied to assess the significant change in ordinal scale data. Patients not meeting all inclusion/exclusion criteria were excluded from all analysis. For the baseline analysis, all patients included according to the inclusion/exclusion criteria were described. Demographic data were expressed in frequency and percentages. For quantitative data, descriptive analyses were performed and data were expressed as mean, SD, median, and range.


  Results Top


Recruitment

The total planned number of patients to be enrolled was 500, but 498 patients with CIU were eligible and were enrolled. All of enrolled patients completed all study visits.

Patient baseline characteristics and demographics

The study population consisted of 50% male and 47.6% female patients with missing data for 2.4% of study participants (mean: 36.8±9.9 years). Out of 498 patients, 15.46% patients had concomitant diseases. The most frequent disease was hypertension in 4.41% patients, followed by diabetes mellitus in 4.22% patients, bronchial asthma in 1.41% patients, and heart diseases in 1.00% patients. Onset of the first symptom ranged from 1 day (as minimum) to 36.5 months (as maximum) with a mean duration of 33.5±84.3 days. Out of 498 patients, 36.5% patients had concomitant medications used for CIU. The most frequently taken medication was Cetirizine (Pharaonia Pharmaceuticals, Cairo, Egypt) by 4.8% patients, followed by Zyrtec (GSK, Cairo, Egypt) by 4.4% patients, whereas Atrax (Pfizer, Cairo, Egypt) and Avil (Sanofi, Cairo, Egypt) were taken by 3.8% patients for each. In total, among the enrolled patients, 42% of patients had concomitant medication: gliclazide 1.4%, bisoprolol 1%, glimepiride, nitroglycerin 0.8%, and insulin 0.6% ([Table 1]).
Table 1 Patient baseline demographics and clinical characteristics

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Outcomes

Efficacy outcome

At the end of this study, results showed statistically significant (P<0.001) improvement in all signs and symptoms of CIU. At the start of the study, all patients were assessed according to the urticaria-related symptoms and signs scores. As regards pruritis status, out of 498 patients, 49.6% had severe pruritis, 40.6% had moderate pruritis, and 9.2% had mild pruritis. However, at visit 2, the pruritis status was cured for 26.3%, 68.7% were improved, 4.8% had no change, and 0.2% worsened. At the end of the study the percentage of patients without symptoms was increased to 77.3% of patients, whereas 21.3% were improved and 1.4% had no change. At the end of the study according to patients completed diary cards, pruritis had significantly improved (P<0.001), with 0.4% of patients having severe pruritis, 2.4% of patients with moderate pruritis, and 22.3% of patients with mild pruritis, whereas for 74.9% of patients pruritis had completely disappeared (see [Figure 1]).
Figure 1 Pruritis score at the end of the study.

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Regarding the number of hives at baseline visit, 40.2% of patients had greater than 12 hives, 42.4% had seven to 12 hives, and 17.5% had one to six hives. Regarding the hives size at baseline visit, 36.5% had hives’ size greater than 2.5 cm, 40.2% had greater than 1.5 cm, and 22.5% had less than 1.5 cm. In visit 2, the hives status showed that 32.1% of patients were cured, 62.3% were improved, 3.8% had no change, and 0.2% worsened. At the end of the study according to the patient completed diary cards, the percentage of patients without symptoms increased to 81.1%, whereas 17.5% improved, 1.4% had no change, and 0.2% worsened. The number of hives had significantly declined (P<0.001), with 2.6% of patients having seven to 12 hives, 17.5% having one to six hives, and for 79.9% of patients hives were totally relieved and hives size was significantly decreased (P<0.001), with 1% of patients having hives greater than 2.5 cm, 2.2% of patients with hives greater than 1.5 cm, 15.7% with hives less than 1.5 cm, and for 81.1% of patients hives were totally relieved (see [Figure 2] and [Figure 3]).
Figure 2 Status of hives number at the end of the study.

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Figure 3 Status of hives size at the end of the study.

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The status of other related signs and symptoms at baseline presented 9% of total enrolled patients, which were angioedema in 4.8%, headache in 1.4%, bronchial asthma in 1.0%, fever in 1.0%, allergic rhinitis in 0.6%, and insomnia in 0.2%. At the end of the study, 75.5% did not have more symptoms, 22.2% improved, and 2.2% had no change [percentage was calculated based on total number of patients having other related signs and symptoms. Total study population was 45 (9%).] ([Table 2]).
Table 2 Status of other related signs and symptoms of chronic idiopathic urticaria

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Results showed that the most frequent driver for prescribing fexofenadine was efficacy in 466 (93.6%) patients, followed by safety for 463 (93%) patients, cost for 205 (41.2%) patients, and finally other drivers for 44 (8.8%) patients, mainly constituting good compliance for 15 (3%) patients, good tolerability for 11 (2.2%) patients, and nonsedating for nine (1.8%) patients.

According to the overall physicians’ assessment in visit 2, 30.1% of the patients were cured, 66.7% were improved, 3% had no change, and 0.2% worsened, whereas at the end of the study 78.7% were cured, 19.9% were improved, 1.2% had no change, and 0.2% worsened.

Safety outcome

The single reported adverse event by one (0.2%) patient was mild dizziness that recovered after 3 days without corrective treatment and with no causal relationship to the medication. The study population (498 patients) completed their total study visits. However, at end of the study, 494 (99.2%) patients completed fexofenadine treatment as prescribed, whereas four (0.8%) patients were not following the prescription as instructed by the physician. According to physicians’ assessment, fexofenadine overall tolerability at the end of the study was excellent for 497 (99.8%) patients and fair for one (0.2%) patients of the studied population. Concerning patients’ assessments, fexofenadine overall tolerability at the end of the study was excellent for 497 (99.8%) patients and poor for one (0.2%) patient of the studied population.


  Discussion Top


The etiology and diagnosis of CIU mainly remains an enigma to physicians and researchers; the majority of cases are treated simply by combinations of oral antihistamines. Nonetheless, a smaller portion of these patients may require alternative therapeutic regimens to control outbreaks. The physician’s goal is to provide an effective therapy that is safe for the duration of symptomatic CIU. The average length is 6 months, but it may persist for several years [14]. In addition, current treatment is directed at the alleviation of symptoms: reducing the intensity of itching and decreasing the number and extent of wheals. Because histamine is a major contributor, antihistamines are the first drugs considered when treating patients with CIU [15],[16].

In this study, results showed a linear trend of increase in cure rate and improvement of both pruritis hives status with fexofenadine treatment. At visit 2, the pruritis status was cured and improved for 26.3% and 68.7%, respectively. At the end of the study the percentage of cured patients increased to 77.3% of patients, whereas 21.3% of patients were improved. In addition, at visit 2 the hives status showed that 32.1% of patients were cured and 62.3% were improved, whereas at the end of the study the percentage of cured patients increased to 76.9% and 17.5% were improved (linear increase in response).

In a double-blind, placebo-controlled trial of fexofenadine HCl in the treatment of CIU, results of the primary efficacy analysis showed each of the four doses of fexofenadine to be statistically superior to placebo (P≤0.0001) in reducing mean pruritis status, with a significant linear trend for improvement with an increasing dose of fexofenadine (P=0.0001). All doses of fexofenadine HCl were statistically superior to placebo (P≤0.0010). Similarly, all fexofenadine HCl dose groups were significantly superior to placebo (P≤0.0001) for mean interference with sleep and daily activities due to urticaria, with a significant linear trend with dose (P=0.0001) [13].

In another study comparing relative potency of fexofenadine HCl 180 mg, loratadine 10 mg, and placebo using a skin test model of wheal-and-flare suppression, results showed that fexofenadine was significantly more effective than loratadine in suppressing the histamine-induced flare response at hours 2–7 and 10–12 and produced greater flare suppression than did placebo (PBO) at hours 2–25. Onset of flare suppression occurred 2 h after dosing with fexofenadine and 4 h after dosing with loratadine. Likewise, fexofenadine was superior to loratadine in suppressing the wheal response from hours 1 through 12 and was more effective than PBO at hours 1–12, 24, and 25. Throughout the 25 h measurement interval, the magnitude of difference in both wheal-and-flare suppression consistently favored fexofenadine over loratadine [17],[18].

Clinical trials (≤2 weeks’ duration) have shown fexofenadine 60 mg twice daily and 120 mg once daily to be as effective as loratadine 10 mg once daily, and fexofenadine 120 mg once daily to be as effective as cetrizine 10 mg once daily in the overall reduction of symptoms of seasonal allergic rhinitis. Although no comparative data with other H-antagonists exist, fexofenadine 180 mg once daily was effective in reducing the symptoms of CIU for up to 6 weeks [9].

In this study, fexofenadine showed significant improvement (P<0.001) in all other related signs and symptoms of CIU including angioedema.

Only seven modern second generation antihistamines (cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, rupatadine, and bilastine) have been tested in detail in urticaria. Second generation antihistamines should be considered as the first-line symptomatic treatment for urticaria because of their good safety profile [19].In this study, fexofenadine demonstrated statistically significant (P<0.001) reduction in symptoms and signs of CIU. According to patients’ assessment, it showed 74.9% cure rate and 22.3% improvement of pruritis status and 81.1% cure rate and 17.5% improvement of hives status after mean treatment duration of 14.93±5.49 days at visit 2 and 27.94±4.56 days at visit 3 (end of study) (see [Figure 4]).
Figure 4 Pruritis and hives status at the end of the study according to physician assessment.

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It was observed that treatment with fexofenadine was generally well tolerated. One adverse event was reported in the study, which was mild dizziness that recovered after 3 days without corrective treatment, which is consistent with previous studies [11],[12].

In this study, physicians’ assessment for tolerability to the treatment at end of study was excellent for 497 (99.8%) and fair for 0.2% patients of studied population. Patients’ assessment for overall tolerability to the treatment at the end of the study was excellent for 99.8% and poor for 0.2% patients of studied population. Results showed that the drive for prescribing this drug was its efficacy followed by its safety.


  Conclusion Top


In the study, fexofenadine demonstrated statistically significant (P<0.001) reduction in symptoms and signs of CIU. It showed 74.9% cure rate of pruritis status and 81.1% cure rate of hives status after mean treatment duration of 14.93±5.49 days at visit 2 and 27.94±4.56 days at visit 3 (end of study). Meanwhile, treatment with fexofenadine was well tolerated.

Acknowledgements

Sanofi was the sponsor of the study, and coordinated the study, monitored clinical sites, collected and managed the data, and performed statistical analyses.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Metzger WJ. Urticaria, angioedema and hereditary angioedema. In: Pattersen R, Grammer LC, Greenberger PA, editors. Allergic diseases, diagnosis and management. Philadelphia, PA, USA: Lippincott-Raven Publishers 1997. pp. 265–283.  Back to cited text no. 1
    
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O’Donnell BF, Lawlor F, Simpson J, Morgan M, Greaves MW. The impact of chronic urticaria on quality of life. Br J Dermatol 1997; 136:553–556.  Back to cited text no. 2
    
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Greaves MW. Chronic urticaria. N Engl J Med 1995; 332:1767–1772.  Back to cited text no. 3
    
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Nimii N, Francis DM, Kermani F, O’Donnell BF, Hide M, Kobza-Black A et al. Dermal mast cell activation by autoantibodies against the high affinity IgE receptor in chronic urticaria. J Invest Dermatol 1996; 106:1001–1010.  Back to cited text no. 5
    
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Fiebiger E, Maurer D, Holub H, Reininger B, Hartmann G, Woisetschläger M et al. Serum IgG autoantibodies directed against the α chain of Fc epsilon RI: a selective marker and pathogenetic factor for a distinct subset of chronic urticaria patients. J Clin Invest 1995; 96:2606–2612.  Back to cited text no. 6
    
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Tong LJ, Balakrishnan G, Kochan JP, Kinét JP, Kaplan AP. Assessment of autoimmunity in patients with chronic urticaria. J Allergy Clin Immunol 1997; 99:461–465.  Back to cited text no. 7
    
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Golightly LK, Greos LS. Second generation antihistamine: actions and efficacy in the treatment of allergic disorders. Drugs 2005; 65:2056–2064.  Back to cited text no. 8
    
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Hindmarch I. Comparing the safety consequences of newer antihistamines. Adv Stud Med 2004; 4(7a):s501–s507.  Back to cited text no. 10
    
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Kaplan AP. Chronic urticaria and angioedema. N Engl J Med 2002; 346:175–179.  Back to cited text no. 11
    
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Nelson HS, Reynolds R, Mason J. Fexofenadine HCl is safe and effective for treatment of chronic idiopathic urticaria. Ann Allergy Asthma Immunol 2000; 84:517–522.  Back to cited text no. 12
    
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Finn AF Jr, Kaplan AP, Fretwell R, Qu R, Long J. A double-blind, placebo-controlled trial of fexofenadine HCl in the treatment of chronic idiopathic urticaria. J Allergy Clin Immunol 1999; 103:1071–1078.  Back to cited text no. 13
    
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Fox RW. Update on urticaria and angioedema (hives). Allergy Proc 1995; 16:289–292.  Back to cited text no. 14
    
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Charlesworth EN. The spectrum of urticaria. Immunol Allergy Clin North Am 1995; 15:641–656.  Back to cited text no. 15
    
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Greaves MW, Sabroe RA. Histamine: the quintessential mediator. J Dermatol 1996; 23:735–740.  Back to cited text no. 16
    
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Finn AF Jr, Kaplan AP, Fretwell R, Qu R. Double-blind, placebo-controlled trial of fexofenadine HCl in the treatment of chronic idiopathic urticaria. Ann Allergy Asthma Immunol 2003; 90:629–634.  Back to cited text no. 17
    
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Abdelaziz MM, Devalia JL, Khair OA, Bayraum H, Prior AJ, Davies RJ. Effect of fexofenadine on eosinophil-induced changes in epithelial permeability and cytokine release from nasal epithelial cells of patients with seasonal allergic rhinitis. J Allergy Clin Immunol 1998; 101:410–420.  Back to cited text no. 18
    
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Zuberbier T, Aberer W, Asero R, Bindslev-Jensen C, Brzoza Z, Canonica GW et al. The EAACI/GA(2) LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update. Allergy 2014; 69:868–887.  Back to cited text no. 19
    


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