Download Adjuvant Role of Vitamin B Analogue

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.
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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
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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
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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,
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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.
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