[The Antiseptic (2001): (98), 9, 332-335] Evaluation of Efficacy of Diakof in Chronic Cough in Diabetic Patients Rangamani, K., M.D. Professor of Medicine, Bowring and Lady Curzon Hospitals, Shivajinagar, Bangalore, India. [Corresponding author: Dr. Rangesh Paramesh, M.D. (Ay), R&D Center, The Himalaya Drug Company, Makali, Bangalore, India] ABSTRACT This study was undertaken in patients with productive and non productive types of chronic cough. The response to treatment with Diakof, a sugar free polyherbal formulation was evaluated for its effect in diabetic patients. These patients did not have symptoms suggesting variable airflow obstruction, and had normal spirometric values and peak expiratory flow variability, no airway hyper responsiveness or sputum eosinophilia (> 3%). Fifty-one patients with chronic cough were identified among 200 referrals. The patients were suffering from various upper and lower respiratory tract infections, but a majority of them had bronchitis. The patients were dispensed Diakof syrup at a dose of 2 teaspoonsful three to 4 times a day for 2-3 weeks. The diabetic patients began to respond from the first week. 43% were totally relieved, 25.49% had mild symptoms and 17.64% had moderate symptoms, while cough persisted in 13.72%. After 15 days treatment, 76.47% of the patients were completely relieved, while 3.92% of the patients had moderate symptoms and 13.72% had mild symptoms. In 3 patients who reported only marginal relief, adjuvant therapy had to be given for their ailments. In 8 of the patients who had a follow-up sputum analysis, the eosinophil count decreased significantly from 16.8% to 1.6%. Thus, Diakof can be a useful drug in treating symptoms of cough in diabetic patients. INTRODUCTION Chronic cough is a common symptom in clinical practice, which if not treated may become refractory in nature. Some researchers have identified asthma, rhinitis, and gastroesophageal reflux (GER) as the most common causes of chronic cough 1-4. Frequently, patients have more than one of these conditions. The underlying mechanisms of cough in these conditions are not defined. Hyperresponsiveness of the upper airway (UAHR) resulting from inflammatory mediator release could be a common mechanism of cough in these patients 5,6. The upper airway has abundant cough receptors, and stimulation of these receptors leads to cough, reflex laryngeal closure and intermittent upper airway obstruction. The release of inflammatory mediators 7 could cause hypersensitivity of the upper airway to histamine, which is present in patients with symptoms resembling asthma (including cough), ACE inhibitor cough 8 and in rhinitis. Inflammation is a feature of the most common conditions which are associated with chronic cough. In asthma and rhinitis, there is mucosal inflammation with eosinophils and mast cells 9-11. Proximal reflux of acid in GER results in posterior laryngitis 12 and hypersensitivity of the cough reflex 13. In addition, ACE inhibition, which is also associated with chronic cough, and UAHR could enhance the tussive effects of tachykinins, which are normally inactivated by ACE in lung tissue 14. The presence of inflammatory mediators in the upper airway could
enhance the sensitivity of afferent nerves. Thus, it is hypothesised that airway inflammation induced by these diseases would cause hyper-responsiveness of the upper airway to histamine provocation and that this would be the unifying mechanism that explains the occurrence of chronic cough in asthma, rhinitis, GER and ACE inhibitor therapy. The above symptoms can be controlled with different conventional formulations. However, in diabetic patients it has limitations because most of the available cough syrups contain sugar. Therefore a study with Diakof Linctus, a non-sugar formulation was conducted. MATERIAL AND METHODS Patients with chronic cough lasting for more than 3 weeks were identified from new patient referrals made by primary care physicians in both rural and urban areas. The patients were aged between 28 and 76 years. The patients with chronic cough had no clinical or radiologic evidence of significant lung disease at the time of referral. Thirty adult male and 20 female diabetic patients referred to the respiratory outpatient clinics with chronic cough as the predominant symptom gave informed consent to be enrolled in the study. All the patients had cough for more than 4 weeks and a normal chest X-ray prior to inclusion in the study. The subjects had a full history taken and a physical examination was performed. The history was recorded on a standardized questionnaire, and previous medical problems, medications, smoking history, amount of sputum and hemoptysis were recorded. The primary diagnosis was rhinitis in 7, asthma in 9, post-viralinfection status in 5, bronchitis in 21, gastroesophageal reflux in 3, COPD in 1, bronchiectasis in 2 and ACE inhibitorinduced cough in 3. The cause of chronic cough remained unexplained in 5 patients Table 1: Causes of Chronic Cough (n=51) Disease No. of patients Percentage (%) Rhinitis 7 13.71 Asthma 9 17.64 Post viral 5 9.80 Bronchitis 21 41.17 Gastro esophageal reflux 3 5.88 COPD 1 1.98 Bronchiectasis 2 3.92 ACE inhibitor induced cough 3 5.88 Unexplained 5 9.80 (Table 1). Subjects rated the frequency, severity, and symptoms suppression related to cough using 4-point scale, where 0 corresponded to no symptoms, 1 to mild symptoms, 2 to moderate symptoms, and 3 to maximum symptom intensity. Complications of chronic cough, including rib fracture, syncope, headache, sleep disturbance, urinary incontinence and social disruption more recoded. Symptoms of intercurrent disease such as post-nasal drip, GER, and asthma were reported on the 7-point scale. A standard self-administered psychiatric symptom questionnaire (SCL-90R) was also administered. Sputum volume and the size and number of plugs were recorded. Clinical diagnoses were made according to the following criteria: rhinitis was considered to be present when there was a history of current (past week) symptoms of post-nasal drip, nasal stuffiness, or sneezing rated 4/7 on the 7 point scale; asthma was diagnosed when there was a history of cough and current variable airflow obstruction clinically, GE reflux was diagnozed when symptoms of indigestion and regurgitation of fluids and food were present at a severity of 4 on a scale of 1 to 7, sinusitis
was diagnozed by a history of facial pain and a response to antibiotics. Subjects using ACE inhibitors, either recurrently or previously at the time of coughing were considered to have ACE inhibitor cough. The cough was present for an average of 4-6 weeks. The majority of the patients had been on unsuccessful trials of medications, with 16 having received inhaled corticosteroids, 10 antibiotics, 6 inhaled β 2 agonists, 7 histamine-type 2 receptor antagonists, 8 antacids, 6 oral corticosteroids, 4 inhaled cromoglycate, 2 nasal decongestants, 2 nasal corticosteroids, and 1 omeprazole. Most (38/51) patients had experienced several cough related complications. These included sleep disturbance (17/51), social disruption (16/51), urinary incontinence (5/51), presyscope (6/51), headache (15/51), syncope (2/51), back and chest Table 2: Psychological symptoms in the patients (n=51) Symptom No. of patients Percentage (%) Sleep disturbances 17 33.33 Social disturbances 16 31.37 Urinary incontinence 5 9.80 Presyscope 6 11.76 Headache 15 29.41 Syncope 2 3.92 Back and chest pain 28 54.90 Exhaution 10 19.60 Hoarseness 8 25.80 pains (28/51), exhaution (10/51) and hoarseness of voice (8/51) (Table 2). These patients were asked to get their fasting and postprandial blood sugar levels checked till the end of the study period. They were also requested not to stop antidiabetic treatment for any reason. RESULTS The results showed that most of the patients responded well to the cough syrup. The patients who came for follow-up after a week reported that they had felt a soothing effect over the inflamed upper respiratory tract. Out of the 51 patients who came for follow up, 22 were totally relieved of the cough symptoms. However, they were advised to continue the medication for another 8 days. Thirteen patients had mild symptoms, 9 patients reported moderate symptoms and the symptoms of cough persisted in 7 patients. These patients were advised salt water gargle in addition to consumption of the cough syrup. After 15 days, 39 patients reported complete relief from chronic cough and were psychologically free from any symptoms. Seven patients had minimal cough occurring occasionally and continued the treatment till the symptoms disappeared totally. Two had moderate symptoms and 3 patients out of the 51 felt that the symptoms were still present and requested for additional medication (Table 3). They were prescribed additional oral antihistamine tablets along with Diakof syrup. Table 3: Presence of cough symptoms before and after treatment with Diakof Linctus in diabetic patients Duration Before treatment After 7 days After 15 days Symptoms No of patients Percentage (%) Severe 36 70.58 % Moderate 11 21.56 % Mild 4 7.84 % Nil - - Severe 7 13.72 % Moderate 9 17.64 % Mild 13 25.49 % Nil 22 43.13 % Severe 3 5.88 % Moderate 2 3.92 % Mild 7 13.72 % Nil 39 76.47 % DISCUSSION The cause or causes for chronic cough in most patients, confirming the diagnostic value of the anatomic-diagnostic approach was successful identified 15. The treatment success rate of 90.19
% was very similar to those reported by Irwin and colleagues 16 and others 17 in a similar patient population, and was slightly higher than that reported by O'Connell and coworkers 13 and McGarvey and associates 18 in patients referred to a tertiary referral center. Thus, it was confirmed that rhinitis and bronchitis are common causes of chronic cough in this clinical setting. The modified protocol recognized bronchitis in 41.17% of patients. The occurrence of chronic cough due to gastroesophageal reflux as seen in this study is now well established, and mechanisms have been described by other authors 19. The data suggest that assessment of airway inflammation is an important addition to the algorithm for investigating chronic cough. The airway inflammation was assessed with induced sputum, since this method is noninvasive and has been shown to be successful in the majority of patients with asthma 20. Sputum differential cell counts have been shown to be valid and repeatable in patients with asthma 21. Sputum induction is also successful in most patients with chronic cough, and that sputum eosinophilia is the only significant finding in 13% of cases of such cough. Although induced sputum was analyzed, spontaneous sputum could be used if patients have a productive cough. Differential cell counts are similar with the two methods, but the cell viability is greater and squamous cell contamination less with induced sputum, resulting in better quality cytospin preparations 22. The association between psychological symptoms and cough is interesting in this study. The validity of the relationship is supported by an epidemiological association between chronic cough and anxiety, and multiple case reports of psychogenic cough in the pediatric and adult literature 23,24. It is unclear, however, whether psychological distress is a cause or an effect of chronic cough. Persistent cough could contribute to excessive psychological distress because of its ability to disturb sleep, normal work and social activities. Further studies are needed to clarify these issues. Diakof Linctus contains many herbs, which include Vitis vinifera, Ocimum sanctum, Tinospora cordifolia, Adhatoda vasica, Glycyrrhiza glabra, Balsamodendron mukul and others. The combined action of all these herbs provide anti-inflamatory and non sedating antihistaminic property to the linctus. Since diabetic patients with a long persistent cough have low immune status, herbs such as Tinospora cordifolia provide immune boosting properties. The patients in the study presented with cough without wheezing, dyspnea, or objective evidence of variable airflow obstruction, and thus did not meet conventional criteria for the diagnosis of asthma. There was subjective improvement in the cough and a significant decrease in their sputum eosinophil count after treatment with Diakof. The improvement began within a week after the treatment begun. CONCLUSION In this study it was evident that diabetic patients can safely use Diakof Linctus for managing symptoms of cough. The blood sugar level remained constant throughout the study period. No untoward side effects were seen in any of the patients.
REFERENCES 1. Irwin, R.S., Curley, F.J. and French, C.L. (1990). Chronic cough: The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Am. Rev. Resp. Dis., 141, 640-647. 2. Poe, R.H., Harder, R.V., Israel, R.H. and Kallay, M.C. (1989). Chronic persistent cough: experience in diagnosis and outcome using an anatomic diagnostic protocol. Chest, 95, 723-728. 3. Pratter, M.R., Bartter, T., Akers, S. and DuBois, J. (1993). An algorithmic approach to chronic cough. Ann. Intern. Med., 119, 977-983. 4. Corrao, W.M. (1996). Chronic persistent cough: diagnosis and treatment update. Pediatr. Ann., 25, 162-168. 5. Bucca, C., Rolla, G., Scappaticci, E., Baldi, S., Caria, E. and Oliva, A. (1991). Histamine hyperresponsiveness of the extrathoracic airway in patients with asthmatic symptoms. Allergy, 46, 147-153. 6. Bucca, C., Rolla, G., Brussino, L., De Rose, L. and Bugiani, M. (1995). Are asthma-like symptoms due to bronchial or extrathoracic airway dysfunction? Lancet 346, 791-795. 7. Choudry, N.B., Fuller, R.W. and Pride, N.B. (1989). Sensitivity of the human cough reflex: effect of inflammatory mediators prostaglandin E2, bradykinin, and histamine. Am. Rev. Respir. Dis., 140, 137-141. 8. Bucca, C., Rolla, G., Scappaticci, E. et al. (1990). Hyperresponsiveness of the extrathoracic airway in patients with captopril-induced cough. Chest, 98, 1133-1137. 9. Bucca, C., Rolla, G., Scappaticci, E., Chiampo, F., Bugiani, M., Magnano, M. and D'Alberto, M. (1995). Extrathoracic and intrathoracic airway responsiveness in sinusitis. J. Allergy Clin. Immunol., 95, 52-59. 10. Pin, I., Gibson, P.G., Kolendowicz, R. et al. (1992). Use of induced sputum cell counts to investigate airway inflammation in asthma. Thorax, 47, 525-529. 11. Gibson, P.G., Dolovich, J., Denburg, J.A., Ramsdale, E.H. and Hargreave, F.E. (1989). Chronic cough: eosinophilic bronchitis without asthma. Lancet, i, 1346-1348. 12. Kambic, V. and Radsel, Z. (1994). Acid posterior laryngitis: aetiology, histology, diagnosis, and treatment. J. Laryngol. Otol., 98, 1237-1240. 13. O'Connell, F., Thomas, V.E., Pride, N.B. and Fuller, R.W. (1994). Capsaicin cough sensitivity decreases with successful treatment of chronic cough. Am. J. Respir. Crit. Care Med., 150, 374-380. 14. Ryan, W.J. (1982). Processing of endogenous polypeptides by the lungs. Ann. Rev. Physiol., 44, 241-255.
15. Irwin, R.S., Corrao, W.M. and Pratter, M.R. (1981). Chronic persistent cough in the adult: the spectrum and frequency of causes and successful outcome of specific therapy. Am. Rev. Respir. Dis., 123, 413-417. 16. Irwin, R.S., Curley, F.J. and French, C.L. (1990). Chronic cough: the spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Am. Rev. Respir. Dis., 141, 640-647. 17. Poe, R.H., Harder, R.V., Israel, R.H. and Kallay, M.C. (1989). Chronic persistent cough: experience in diagnosis and outcome using an anatomic diagnostic protocol. Chest, 95, 723-728. 18. McGarvey, L.P., Heaney, L.G., Lawson, J.T., Johnston, B.T., Scally, C.M., Ennis, M., Shepherd, D.R. and MacMahon, J. (1998). Evaluation and outcome of patients with chronic non-productive cough using a comprehensive diagnostic protocol. Thorax, 53: 738-743. 19. Ing, A., Ngu, M.C. and Breslin, A.B.X. (1994). Pathogenesis of chronic cough associated with gastroesophageal reflux. Am. J. Respir. Crit. Care Med., 149, 160-167. 20. Hunter, C.J., Ward, R., Woltmann, G., Wardlaw, A.J. and Pavord, I.D. (1999). The safety and success rate of sputum induction using a low output ultrasonic nebuliser. Respir. Med., 93, 345-348. 21. Pizzichini, E., Pizzichini, M.M.M., Efthimiadis, A., Evans, S., Morris, M.M., Squillace, D., Gleich, G.J., Dolovich, J. and Hargreave, F.E. (1996). Indices of airway inflammation in induced sputum: reproducibility and validity of cell and fluid phase measurements. Am. J. Respir. Crit. Care Med., 154, 308-317. 22. Pizzichini, M.M., Popov, T.A., Efthimiadis, A., Hussack, P., Evans, S., Pizzichini, E., Dolovich, J. and Hargreave, F.E. (1996). Spontaneous and induced sputum to measure indices of airway inflammation in asthma. Am. J. Respir. Crit. Care Med., 154, 866-869. 23. Riegel, B., Warmoth, J.E., Middaugh, S.J., Kee, W.G., Nicholson, L.C., Melton, D.M., Parikh, D.K. and Rosenberg, J.C. (1995). Psychogenic cough treated with bio-feedback and psychotherapy: a review and case report. Am. J. Phys. Med. Rehabil., 74, 155-158. 24. Blager, F.B., Gay, M.L. and Wood, R.P. (1988). Voice therapy techniques adapted to treatment of habit cough: a pilot study. J. Commun. Disord., 21: 393-400.