Possible Effect of Carbamazepine A Sodium Channel Blocker on Urinary Bladder Dysfunction in Type-1 Diabetic Patients

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1 Med. J. Cairo Univ., Vol. 84, No. 1, March: 85-90, Possible Effect of Carbamazepine A Sodium Channel Blocker on Urinary Bladder Dysfunction in Type-1 Diabetic Patients MAGDA ZAKI, M.D.*; HISHAM ATTIA, M.D.*; HESHAM M. MAHMOUD, M.D.*; HOSNI KHAIRI, M.D.** and AMR MAHER M.B.B.Ch.* The Departments of Pharmacology* and Urology**, Faculty of Medicine, Cairo University Abstract Background: Diabetic cystopathy is a complication of diabetes mellitus; it usually develops in diabetic patients with long-standing and poorly controlled disease. It has been found that the urothelium epithelial sodium channels enhance release of excitatory agents on afferent neurons upon bladder stretch. Objective: In the present study the therapeutic effect of Carbamazepine in the management of Overactive Bladder (OAB) in diabetic patients. Material and Methods: Fifty males and females patients with type-1 diabetes mellitus and OAB randomly assigned in the present study to use Placebo 5mg/12hrs for one month, Tolterodine 2mg/12hrs for one month or Carbamazepine 100mg/12hrs for one month. Results: Tolterodine treatment significantly decreased voiding diary parameters (urgency/day, urgency incontinence/ week, frequency of micturition/day and nocturia episodes/day) and cystometric estimated bladder capacities (first desire capacity and maximum bladder capacity) compared to placebo group, while Carbamazepine treatment showed insignificant decrease in most of voiding diary parameters and an insignificant increase in bladder capacities compared to that of placebo group. However, Carbamazepine significantly reduced urgency compared to placebo group. Conclusion: A part from reducing the urgency of micturition compared to placebo group, the present study didn't show a significant role for carbamazepine in improving the voiding diary parameters and all bladder capacities. A further clinical study with higher doses of Carbamazepine as well as bigger sample size are required. Key Words: Carbamazepine Urinary bladder dysfunction Type-1 diabetic patients. Introduction OVERACTIVE Bladder (OAB) has a global prevalence ranging from 8% to 14% according to different studied populations [1]. Diabetes associated Correspondence to: Dr. Magda Zaki, The Department of Pharmacology, Faculty of Medicine, Cairo University with a 30%-70% increased risk of incontinence and a 50% increased risk of urge incontinence in women with bladder dysfunction [2]. The epithelial sodium channels (ENaC) are often found in the urothelium and detrusor muscles, they markedly rise in patients with obstructive bladders and OAB symptoms [3]. Furthermore, it has been found that upon bladder stretch there is increased expression of the mechanosensitive ENaC in the urothelium which enhances release of excitatory agents on afferent neurons [4]. So, the present study was conducted to investigate the possible therapeutic effect of carbamazepine as a Na + channel blocker on type- 1 diabetic OAB. Patients, Material and Methods The study was conducted on fifty patients with type- 1 diabetes mellitus and OAB. After approval of research ethical committee, Faculty of Medicine Cairo University, all patients were provided informed consent to participate in this study. All recruited patients were subjected to history taking before and after treatment through voiding diary and lower urinary symptom sheet [5] as well as cystometric investigation. Inclusion criteria: Patients age range from 20 to 50 years old including males and females, their body weight range between 60-80Kg and they suffer from type- 1 diabetes mellitus and OAB symptoms. Exclusion criteria: Patients with neurological disorder "rather than peripheral neuritis", disc prolapsed or type-2 diabetes mellitus, also patients taking other drugs affecting the central nervous system; were excluded from the study. 85

2 86 Possible Effect of Carbamazepine A Sodium Channel Blocker Drugs: Tolterodine (Tolterodine) 2mg tablets were purchased from Sabaa, Egypt while Tegretol (Carbamazepine) 1 00mg tablets were purchased from Novartis, Egypt and Placebo: Starch 5mg in the form of tablets purchased from El-Nasr Pharmaceutical Chemicals, Egypt. Methodology: Cystometric study urodynamic study" was conducted by instilling sterile saline at room temperature through urinary catheters at a filling rate of 30ml/min. Intravesical pressure was measured through the other catheter. The intra-abdominal pressure was obtained with a rectal balloon catheter. The detrusor pressure was electronically calculated [6] ; detrusor overactivity, maximum bladder capacity and first desire capacity were measured [5]. Patients were randomly divided into three groups: Placebo Group-I (Starch tabets 5mg/ 1 2hrs), Tolterodine Group-II (Tolterodine 2mg tablet/12hrs [7] ) and Carbamazepine Group-III (Carbamazepine 100mg tablet/12hrs [8]) all of the used drugs were given orally for one month. Urodynamic study was done and voiding diary and lower urinary symptom sheet was collected from each patient before and after treatment. Statistical analysis: Results were tabulated, expressed for each parameter investigated as mean ± the standard deviation of the mean (SD). Analysis of variance (ANOVA) will be used to compare the different groups. Results In Tolterodine Group-II treated patients the urgency/day, urgency incontinence/week, nocturia episodes/day and frequency of micturition/day (2.6 ±0.52, 4±0.67, 2.2±0.42 and 7.7± 1.34 respectively) were significantly decreased in comparison to placebo Group-I (4.1 ±0.74, 9.2± 1.03, 3.4±0.52 and 10.7± 1.89 respectively) while no significant decrease were found in Carbamazepine Group-III treated patients for urgency incontinence/week, nocturia episodes/day and frequency of micturition/ day (9.1 ± 1.4, 3.5±0.53 and 8.4± 1.51 respectively) compared to that of placebo Group-I [(Table 1), Fig. (1)], however a significant decrease in urgency/ day (2.7±0.48) compared to placebo Group-I. A significant increase in the maximum bladder capacity and first desire capacity in Tolterodine treated patients (473.3 ±64.29, 136.3±22.77cc respectively) compared to that of placebo Group-I (364.6±57.77, 104.5± 10.81cc respectively) while no significant increases were found in Carbamazepine treated patients (366.9 ±60.26, 112.8± cc respectively) compared to that of placebo Group- I [(Table 2), Fig. (2)]. Percent Percent Urgency /day Urgency incontinence /week Nocturia Frequency of micturition /day Placebo (Group I) Tolterodine (Group II) (2mg/12hrs) Carbamazepine (Group III) (100mg/12hrs) Fig. (1): The effect of oral tolterodine and carbamazepine for one week on the percent changes of urgency/day, urgency incontinence/week, nocturia episodes/day and frequency of micturition/day in relation to placebo Group-I in type-1 diabetic patients with over active bladder. : Significant changes ( p<0.05). : Insignificant (p>0.05). Maximum bladder capacity First desire capacity Placebo (Group I) Tolterodine (Group II) (2mg/12hrs) Carbamazepine (Group III) (100mg/12hrs) Fig. (2): The effect of oral tolterodine and carbamazepine for one week on the percent changes of maximum bladder capacity and first desire capacity in relation to placebo Group-I in type-1 diabetic patients with over active bladder. : Significant changes ( p<0.05). : Insignificant (p>0.05).

3 88 Possible Effect of Carbamazepine A Sodium Channel Blocker Discussion In the present clinical study Overactive Bladder (OAB) studied in 50 type-1 diabetic patients. In the work of Karoli et al., [9] they studied women with type-2 diabetes in comparison with agematched controls that did not have diabetes but had lower urinary tract symptoms. They found that significant increase in storage symptoms (frequency, nocturia and urgency) and incontinence episodes compared to control group. Moreover, Lee et al., [10] studied the urodynamic characteristics and bladder sensory function in diabetic women; they reported that a significant decrease in maximum bladder capacity was found in detrusor overactivity diabetic group compared to normal bladder function diabetic group. In the present study, as regard urgency/day, urgency incontinence/week and nocturia episodes/ day of diabetic patients, the tolterodine Group-II showed a significant decrease in these parameters compared to Placebo Group-I, while there was no significant change as regard frequency of micturition/day. These results are in agreement with the work of Burgio et al., [11] who studied the effects of drug on urgency and voiding frequency and they concluded that a significant decrease in severity of urgency and frequency episodes were found after tolterodine treatment. In addition, Hsiao et al., [12] compared the urodynamic effects, therapeutic efficacy and safety of solifenacin (selective blocker of type 3 muscarinic receptors) versus tolterodine for female overactive bladder syndrome. They concluded a significant decrease in frequency of micturition and nocturia episodes after tolterodine treatment. Moreover, Masumori et al., [13] studied the OAB symptoms after at least 4 weeks treatment using tolterodine. They concluded that urgency and urgency incontinence significantly decreased compared to placebo after 4 weeks of treatment. In addition, Kenton et al., [14] studied patient satisfaction with drug therapy and combined drug therapy and behavioral training for urgency urinary incontinence in women. They concluded that a significant decrease in severity of urgency and number of incontinence episodes were found after tolterodine treatment. Also, Ginsberg et al., [15] found that compared with placebo, OAB subjects receiving tolterodine had significantly greater improvements in frequency of maturations/day, urgency episodes/day and incontinence/day. In the same line, Khullar et al., [16] found that maturations frequency/day and incontinence episodes/day significantly improved in tolterodine treated group compared to placebo group. Moreover, Aziminekoo et al., [17] evaluated the efficacy of tolterodine in treatment of Overactive Bladder (OAB) after 4 weeks treatment. They concluded that a significant decrease in the urinary urgency and incontinence episodes after treatment were seen but an insignificant improvement was seen in tolterodine group as regard the frequency of micturition. Also, in the present study, as regard the urgency incontinence/week, the nocturia episodes/day and the frequency of micturition/day of diabetic patients, the carbamazepine Group-III showed an insignificant change in these parameters compared to Placebo Group-I, this may be subjected to the limited patients' number included in this study and the subjectivity of the used parameters. On the other hand carbamazepine Group-III showed a significant decrease in urgency/day compared to Placebo Group-I, this in agreement with the results of Clouse et al., [18] who found that Carbamazepine decreased the peak micturition pressure, micturition interval, and void volume in rats. In the present study, the tolterodine Group-II showed a significant increase in the first desire capacity and the maximum bladder capacity parameters compared to Placebo Group-I. These are in agreement with Tang et al., [19] who evaluated the efficacy of tolterodine in women with idiopathic overactive bladder. They concluded that there were significantly greater improvements in the conditions of the first desire to void capacity and the maximum bladder capacity after treatment with tolterodine. Also, in the present study, the carbamazepine Group-III showed an insignificant change in the first desire capacity and the maximum bladder capacity parameters compared to Placebo Group- I, in contrast, the results of Clouse et al., [18] stated that Carbamazepine in rats has a reduction in micturition pressure and functional bladder capacity, similar to previous observations with muscarinic antagonists. Conclusion: Tolterodine has a potential role in management of OAB through reducing urgency, urgency incontinence and nocturia episodes significantly and increasing the maximum bladder capacity and first desire capacity. A part from reducing the urgency of micturition compared to placebo group, the present study didn't show a significant role for carbamazepine in improving most of the voiding diary parameters and all baldder capacities. A further clinical study with higher doses of Carbamazepine as well as bigger sample size are required.

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5 90 Possible Effect of Carbamazepine A Sodium Channel Blocker