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Original Article Adjuvant Role of Vitamin B Analogue -(Sulbutiamine) with Anti-Infective Treatment in Infection Associated Asthenia Siddharth N Shah*, For the Sulbutiamine Study Group** Abstract Aims of the study : Asthenic symptoms such as weakness accompany illness. This study investigates whether the centrally acting cholinergic agent, vitamin B analogue (sulbutiamine), is effective and acceptable in relieving these symptoms in infectious disease when combined with specific anti-infective treatment. Methodology : In a prospective uncontrolled, non-randomised, commercial, observational study, 1772 patients with an infectious disease and asthenic symptoms, drawn from the practice of 350 randomly selected physicians throughout India, received vitamin B analogue (sulbutiamine) in addition to specific anti-infective treatment for 15 days. The primary outcome variable was complete resolution of asthenic symptoms with treatment. Results : The number (%, 95% confidence interval) of patients with complete resolution of all asthenic symptoms was 916 (51.7, 49.4-54). In the remaining patients, severe asthenia was reduced but persisted in 11 (0.6, 0-26); and moderate asthenia in 94 (5.3, 0-17.6). The response was greater in patients with acute infection and symptoms more related to cerebral function. Side effects occurred in 10 (0.6%), patients and well being improved significantly. Conclusions : Vitamin B analogue (sulbutiamine) may be a useful adjunct to specific anti-infective treatment. INTRODUCTION I n clinical practice, despite specific treatment, patients with acute or chronic disease frequently complain of symptoms such as weakness, inability to concentrate, or loss of appetite - collectively known as asthenia. Surveys suggests that the incidence of asthenia in the general population is as high as 65%, and that in 77% it is serious enough for patients to request specific treatment.1 Furthermore, asthenic symptoms often persist after completion of specific treatment, and prevent full recovery leading to loss of working days and productivity. There is, therefore, a clinical need for the treatment of asthenia along with the regular treatment of the associated disease. Although the pathogenesis of asthenia is unclear, it has been suggested that deactivation of the ascending reticular formation during states of stress such as disease may be *Hon. Diabetologist, SL Raheja Hospital, Sir HN Hospital and Bhatia Hospital, Bombay Mutual Terrace, Mumbai. Received : 7.9.2001; Revised : 22.4.2003; Accepted : 5.8.2003 JAPI • VOL. 51 • SEPTEMBER 2003 involved.2 Vitamin B analogue namely sulbutiamine may increase acetylcholine transmission in the reticular formation3,4 and has been shown in a study to reduce asthenic symptoms during states of stress such as infection.5 However, such efficacy has not been demonstrated by observational studies in the broad setting of daily clinical practice among Indian patients with asthenia. In India, an estimated 60% of all disease is due to infection.6 The objective of this large prospective observational multicentre study is to evaluate the efficacy and acceptability of combination therapy with specific anti-infective treatment and vitamin B analogue (sulbutiamine) in relieving asthenic symptoms associated with common infections in the Indian general practice setting. MATERIAL AND METHODS Selection of participating physicians Three hundred and fifty physicians, regularly using sulbutiamine for infection associated asthenia in their daily practice were randomly selected, all over the country and agreed to participate in the study. 891 Table 1 : Baseline characteristics of patients with infectious disease and associated asthenic symptoms Fig. 1 : Patients with infectious disease* showing resolution or improvement of asthenic symptoms** after combination therapy with specific anti-infective treatment and sulbutiamine (N=1772) *Acute respiratory infection, tuberculosis, malaria, hepatitis, or typhoid; **Weakness, loss of appetite and concentration, sleep or sexual disturbance Selection of patients Each participating physician identified consecutive patients of any age or sex from their general practice with a clinical diagnosis of acute respiratory infection, tuberculosis, malaria, typhoid, or infection hepatitis during April to June 2000. Of these, patients who complained of at least one asthenic symptom (weakness, loss of appetite, lack of concentration, disturbed sleep, or impaired sexual function) were eligible for the study. Patients not suspected to be pregnant or with a known sensitivity to sulbutiamine were selected for final inclusion. Assessments and treatment After giving their informed consent, patients were assessed at baseline for demographic, clinical, and asthenic symptom characteristics (Table 1). Each asthenic symptom, when present was self-assessed by patients on a discrete subjective scale of 0 to 3 (absent, mild, moderate, or severe). Overall state of well being was described by patients on a continuous visual analogue scale of 0 (poor) to 10 (good). Following baseline assessment, patients were prescribed 2 tablets (200 mg each) sulbutiamine daily with breakfast for 15 days, together with specific anti-infective treatment as indicated. The type of anti-infective treatment was at the discretion of the physician. After 15 days study treatment, patients were reassessed for change in severity of asthenic symptoms and well being; side effects; the physicians’ opinion about the efficacy of sulbutiamine; and daily compliance with medication. Statistical analysis The primary outcome was the number of patients who responded to treatment with complete resolution of asthenic symptoms. The secondary outcome was the number of patients with symptom improvement from moderate and severe to mild. Response to treatment in both primary and secondary outcomes was analyzed on an intention to treat basis. Categorical data was expressed as a percentage with 892 Characteristic N=1772* Age (years) Male sex Occupation Service Business Housewife Student Retired Others Type of infection Acute respiratory Tuberculosis Malaria Typhoid Infective hepatitis Asthenic symptoms Weakness Loss of appetite Sleep disturbance Sexual dysfunction Loss of concentration Severity of asthenic symptoms Mild Moderate Severe Duration of asthenic symptoms (days) Weight (kg) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) 37.8 ± 12.1 1239 (69.9) 628 (35.5) 484 (27.3) 352 (19.9) 174 (9.8) 49 (2.8) 85 (4.8) 725 235 259 319 234 (40.9) (13.3) (14.6) (18.0) (13.2) 1561 (88.1) 1473 (83.1) 1350 (76.2) 981 (55.4) 1380 (77.9) 390 (22) 1015 (57.3) 367 (20.7) 37.4 ± 59.4 60.7 ± 12.5 124.3 ± 14.3 80.2 ± 8.8 *Plus/minus values are means ± standard deviation. All other values are numbers of patients followed in parenthesis by percentages of the group its 95% confidence interval (95% CI). Continuous variables were compared by the standard error of difference in means. Significance was defined as a two tailed P < 0.05. RESULTS The 350 physicians in general practice, selected randomly, and distributed throughout India, included 1772 patients with infectious disease and at least one asthenic symptom. As shown, in Table 1, about 95% of patients were in the active age group of between 15 to 60 years. Most were male, and engaged in productive work. About 10% were students. More than half of all cases had acute respiratory infection or tuberculosis. All asthenic symptoms were present for over a month and except for impaired sexual function, the rest were very frequent - manifesting together in over 75% of patients. Overall response of asthenic symptoms After 15 days’ combination therapy with specific antiinfective treatment and sulbutiamine (Fig. 1), all asthenic symptoms completely resolved in 916 (51.7%, 95% CI, 49.454.0) patients. The number (%) of patients with severe symptoms decreased from 367 (20.7) to 11 (0.6), P < 0.01; and with moderate symptoms from 1015 (57.3) to 94 (5.3), P < 0.01. Patients with mild symptoms increased from 390 (22.0) to 751 (42.4), P < 0.01. JAPI • VOL. 51 • SEPTEMBER 2003 Fig. 3 : Patients with infectious disease* reporting resolution or improvement of asthenic symptoms after combination therapy with specific anti-infective treatment and sulbutiamine *Acute respiratory infection, tuberculosis, malaria, hepatitis, or typhoid Fig. 2 : Patients with specific infections reporting resolution or improvement of asthenic symptoms* after combination therapy with specific anti-infective treatment and sulbutiamine *Weakness, loss of appetite and concentration, sleep or sexual dysfunction Response of asthenic symptoms in specific infections The resolution and improvement of asthenic symptoms with the combination treatment in malaria, typhoid, acute respiratory infections, and hepatitis was greater than in tuberculosis (Fig. 2). Response of specific asthenic symptoms in infection As shown in Fig. 3, except for sexual dysfunction all the other symptoms showed an improvement greater than 75%. Acceptability of treatment Overall patients’ perception of well being measured by the visual analogue scale increased from a mean (SD) of 2.8 (2.1) at baseline to 5.8 (3.5), P < 0.01 after treatment. The majority (83.6%) of physicians rated the suitability of sulbutiamine for the treatment of asthenia as good to excellent, and 72.7% of patients fully complied with daily medication. Treatment did not significantly alter heart rate or blood pressure. Side effects with the combination of specific antiinfective treatment and sulbutiamine were reported by 10 (0.6%) patients (nausea, 5; and headache, insomnia, diarrhoea, tremor, and drowsiness, 1 each). DISCUSSION In the population of Indian patients with common infections seen in daily general practice selected for this study, each of the asthenic symptoms — weakness, loss of appetite, JAPI • VOL. 51 • SEPTEMBER 2003 sleep disturbance, and lack of concentration — occurred with nearly the same high frequency (about 75%), indicating that they tend to occur together at the same time (Table 1). Patients most affected were in the fourth decade of life, engaged in productive work, and experienced infection-associated asthenic symptoms for about a month’s duration. The addition of vitamin B analogue (sulbutiamine) for 15 days to specific anti-infective treatment completely resolved all asthenic symptoms in about half the patients, with a further fifth showing substantial improvement (Fig. 1). The cure rates of asthenic symptoms was more marked in acute infection such as malaria, typhoid, acute respiratory infection, and hepatitis compared to chronic infections such as tuberculosis (Fig. 2). This may indicate a greater efficacy of the combination treatment studied in asthenia of recent origin associated with acute infection. Symptoms more clearly related to central nervous system function such as lack of concentration, disturbed sleep, and loss of appetite responded more completely to the combination treatment than symptoms such as weakness which originates in the peripheral sense organs (Fig. 3). The treatment was well accepted with an improvement in patients’ subjective well being, low frequency of reported side effects, and high compliance with daily medication. The pathogenesis of asthenia may be related to the level of activation of the ascending reticular formation (ARF) in the brain stem.2 The normal state of “well-being” is a feeling perceived in the cerebral cortex. Cognitive and peripheral stimulti are received in the ARF, modulated, and continuously relayed to the cortex.2 In states of stress such as infection, peripheral stimuli are altered; the level of activation of the ARF is reduced; and perceived in the cortex as asthenic symptoms. The feeling of asthenic symptoms is therefore a self-regulatory defense mechanism, which signals the body to slow down and rest when subjected to stress. The principal 893 neurotransmitters in the ARF are acetylcholine and serotonin.2 Vitamin B analogue (sulbutiamine) has been shown to increase the density of acetylcholine receptors in the brain stem 3,4 and may act by a mechanism that increases acetylcholine transmission and level of activation of the ARF. A randomized placebo controlled study on 104 patients with asthenia of less than three months had previously demonstrated that one months’ treatment with sulbutiamine reduced the intensity of asthenic symptoms.5 Although the lack of a control in the present study is a limitation, it is well accepted7 that because of their interventional nature, results of randomized controlled studies are not always reflected in day to day clinical practice, and require to be confirmed in large observational studies. This study was designed to meet that objective. The study clearly lacks control, standard design, and randomisation. Also it reflects an uncontrolled observation but will form the base for a more well designed larger placebo-controlled trial in future. The present study was on a large number (1772) of patients with common infections, drawn from the general practice of randomly selected physicians distributed throughout India. Relief from asthenic symptoms cannot be attributed exclusively to sulbutiamine. However, the results do demonstrate that infection-associated asthenia present for about a month was resolved in over half the patients, and substantially reduced in a further fifth, by the combination therapy of specific anti-infective treatment and sulbutiamine for 15 days. Patient acceptability of treatment was good. In the absence of specific treatment with a defined mode of action, sulbutiamine may be a useful adjunct to specific antiinfective treatment for the relief of asthenic symptoms in daily clinical practice. Acknowledgements **Dr. David Park, Dr. Preeti Modi and Dr. Jayalakshmi Aiyangar of Serdia for their assistance in organising the study and to the following doctors who participated in the study (listed city wise and in alphabetical order): Study Group Chairman: Siddharth N Shah; Agra: V Ahuja, S Bansal, MK Gupta, A Kulshreshta, A Rajan; Ahmedabad: VK Agarwal, MB Anandjiwala, S Bhatt, M Brahmbhatt, S Dave, ST Kodnani, SL Mehta, H Parekh, BV Patel, HH Patel, JM Patel, AN Shah, BM Shah, NJ Shah, RR Shah, S Shah, VM Shah, AB Sheth, RD Tibriwal, CT Tindwani; Amritsar: V Arora, S Bhatia; Aurangabad: SR Bajaj, A Boralka, TS Chhabda, R Naik, SZ Naqshabandi, M Narkhede, HR Tibrewala; Bangalore: C Belal, MN Bojamma, MD Gowda, V Gowda, R Joyprakash, GR Kolar, SA Kumar, S Lingaiah, S Malesh, S Prabhu, KS Prasanna Kumar, MBS Raman, RN Ramesh Kumar, KP Shanbhogue, R Shetty, NB Shivakumar, Capt. Srinivas, Subramanyam, RG Venu; Bhopal: Chandrashekar, A Hussain, IM Jain, H Malvi, A Singh, G Vyas, MD Yousuf, Calcutta: S Acharya, SK Agarwal, A Ahmad, B Banerjee, K Banerjee, SK Banerjee, P Basak, C Batabyal, S Bhattacharya, S Bhowmick, G Chakrabarty, S Chandrasen, N Chatterjee, S Chatterjee, AK Chaudhuri, AR Chowdhury, B Chowdhury, AK Das, A Datta, T Debmallik, S Ghosh, S Guha, S Lilha, SK Mahinta, SN Maiti, 894 N Mallik, AC Mondol, A Mukhopadhyay, S Nandi, A Nath, RK Paud, D Ray, D Roy, GC Saha, AK Samanta, Samarnath, P Shah; Chandigarh: A Bhardwaj, VK Chhabra, SK Khanna; Chennai: R Bajaj, S Baskaran, VT Bhaskaran, KN Bhatt, G Chandrasekhar, P Durai, M Geetha, S Krishnan, RA Kumar, L Mahender, MJ Mehta, RMS Mohandas, J Navaseelan, SP Prabhakar, M Rameshkumar, M Ravindran, G Sairamanan, AA Selvaraj, K Srinivas, V Srivatsan, G Thooyamani, Uma, Varalakshmy, M Varma, MR Vidhya, V Vijayalakshmi; Cochin: CK Balan, A Thatchel, S Vasudevan, N Zachariah; Combatore: S Dhandapani, US Prakash, G Raja, L Raman, SP Rao, S Sridharan; Delhi : P Aneja, A Arora, VK Arora, RC Bhatia, P Bhowmick, RM Chabra, DS Chadha, OP Chadha, A Chandna, A Damir, A Dixit, AK Gandhi, ML Goglani, SK Goyal, SK Jain, P Jhuraney, SM Kazim, S Khoche, GK Khurana, H Krishna, S Makhija, V Mittal, S Nagpal, GRVR Reddy, R Sachdeva, H Sahni, K Sain, JK Sharma, PK Sharma, J Singh, SP Singh; Ghaziabad: S Chakravorty, S Chandragupta, S Gupta, VB Jindal, M Poddar, AK Rathi, KM Singh; Gurgaon: SK Bansal, A Biswas; Guwahati: AK Adhikari, S Adhikari, PK Biswas, B Goswami, D Saruna; Hyderabad: M Abu Baker, A Ekbote, MA Faroqui, B Prahlad, P Puranik, J Ramesh, A Rao, VS Rao, J Shah; Indore: SZ Jaffery, A Jain, M Jain, S Jain, FA Saifee, AK Sharma, B Trivedi; Jaipur: A Agarwal, S Agarwal, N Bagh, K Chaturvedi, VP Ganda, D Jain, R Jain, R Prakash, D Raja, GN Saxena, P Sharma; Jalandhar: R Oberoi, R Singh; Jodhpur: CS Bhargav, B Derashri, BR Mardia, TC Sangatramani, N Sen, BR Vyas, S Vyas; Kanpur: JS Kushwaha, GS Seth, I Sharma, SC Wadhwani; Kolhapur: SR Patil, Y Shetye; Lucknow: CP Bajpai, N Bhasin, DP Bhatnagar, AK Chawla, KL Dange, NK Jain, A Khanna, A Mehrotra, O Singh, A Srivastava, HN Tripathi; Ludhiana: S Bali, N Bassi, R Chhabra, BR Goel, JP Jain, MS Marwah, PS Sidhu; Madurai: N Anbuvel, KA Ramasubramani Raja, N Ravel, RH Ravindranathbabu, S Somasundaram; Mangalore: AK Bhat, RN Bhat, A Kumar, H Mascarani, S Rao; Meerut: D Agarwal, RK Aren, R Bhatia, VK Goel, PK Gupta, P Jain, KC Joshi; Mohali: SS Bhatia, DP Gopal; Mumbai: V Agera, EK Ajitkumar, KS Bhagunde, RK Dalal, N Dastur, RR Deshpande, A Divekar, SR Dube, R Harale, J Jain, RP Jain, V Jain, J Jani, K Jariwala, S Jethwani, MG Joshi, I Kazi, MG Keny, R Kewalramani, RN Kini, VC Kodkani, RP Kushwaha, J Maru, GK Moharir, S Mulgaokar, R Narsule, U Nayak, RC Panchal, D Panwalkar, RD Parmar, S Pillai, S Raje, S Rao, SD Rao, NS Shetty, A Thakur, M Tiwaskar, RH Trivedi, RS Tangare, S Vora; Nagpur: JM Deshmukh, J Hasan, AS Jain, PD Pandit, M Rathi, P Thakkar; Nashik: VP Dhondge, NJ Kasliwal, U Mauskar, M Patel, M Tembe, SR Vyavahare; Panchkula: S Malik; Panjim: N Furtado, GV Prabhu, AR Rodrigues, SP Souza; Patna: AK Bhavnani, BK Chodhry, SN Jha, M Kumar, P Kumar, U Kumar, AK Mishra, RK Modi, MP Singh, N Singh, AK Sinha, R Sinha, DK Srivastava, NN Tripathy; Pune: VB Bhagali, SG Chavan, B Dixit, V Gundecha, S Gupta, Y Kadam, KS Kavediya, M Kavediya, SV Khare, PM Patil, GV Ranade, RK Sethiya; Raipur: P Bhagwat, SM Bhawni, P Kamal, V Rahim, A Rai, A Sahai; Silchar: B Banik, SR Bhattacharji, A Chattacharya, B Roy, A Swami; Trichy: M Balamurughan, V Ravindranath; JAPI • VOL. 51 • SEPTEMBER 2003 Trivandrum: DS Mohan, KP Paulose, Rajasekaran; Udaipur: K Ali Shah, G Wadhawan; Varanasi: SA Ansari, RN Bajpai, R Khanna, J Mishra, R Mishra, S Pndey, VB Singh, VP Singh, K Srivastava, AK Tandon, R Tandon, PK Tiwari, K Tripathi, AL Yadav; Vijaywada: Y Ajith Babu, BB Nambiar, MN Prasad, G Samaram; Visakhapatnam: AS Raju, A Sreenivasulu. The study had commercial interest as vitamin B analogue (sulbutiamine) is marketed by Serdia who formed a part of the study team. of medical physiology, 8th ed. Philadelphia: WB Saunders Company 1991:648-51. 3. Du Boistesselin R. Role of certain regulatory structures in asthenia: detection of Arcalion’s binding by histofluoroscence. Gaz Med France 1998;95(Suppl 3):21-4. 4. Feuerstein C. Neurophysiological data concerning fatigue. Role of the reticular activating system. Entretiens de Bichat 1992;(Suppl):11-9. 5. Jouquan J. Sulbutiamine in asthenia: 60 to 90% success rate according to manifestations, which should be chosen? CR Ther Pharm Clin 1985;4:36. REFERENCES 1. Ollivier B, Grandchamp P. Epidemiology of fatigue (Survey). J Int Med 1987;100:4-8. 6. Government of India, Ministry of Health (1977). Centre calling, 12. No.4-5,15. 2. Guyton AC, Behavioral and motivational mechanisms of the brain - the limbic system and the hypothalamus. In: Textbook 7. Polock SJ, Elbourne DA. Randomized trials or observational tribulations? N Engl J Med 2000;342:1907-9. ANNOUNCEMENT Physicians interested in HIV / AIDS CARE Send Brief CV to JAPI Box. No. 4 DR. JK MEHTA CLINIC Commissariat Bldg., 3rd Floor, 231 DN Road, Mumbai 400 001. JAPI • VOL. 51 • SEPTEMBER 2003 895