Influence of honey on adverse reactions due to anti-tuberculosis drugs in pulmonary tuberculosis patients

Abstract

The aim was to assess the influence of honey on adverse drug reactions induced by Anti-tuberculosis (Anti-TB) drugs in newly diagnosed sputum acid fast bacilli (AFB) positive pulmonary tuberculosis patients of category I receiving directly observed treatment short course (DOTS) under revised national tuberculosis control programme (RNTCP) for a period of two months (i.e. intensive phase). A high percentage of ADRs was experienced in control (69.88%) as compared to case (47.06%). Most of the ADRs were mild to moderate and transient in nature. The most common adverse reactions reported among control patients were anemia (21.16%), joint pains (15.6%), itching (18%) and nausea (14.4%). The least percentage of adverse reactions among control patients reported was diarrhoea (2.4 %), while there was no diarrhea observed in patients receiving honey along with anti-tubercular treatment (ATT). Honey with ATT minimizes the adverse drug reactions induced by Anti-TB drugs in AFB positive pulmonary positive tuberculosis patients. Thus, honey can be used as an adjuvant along with ATT in pulmonary TB patients.

Full text

Continental J. Pharmacology and Toxicology Research 2: 6 - 11, 2008.
© Wilolud Online Journals, 2008.
INFLUENCE OF HONEY ON ADVERSE REACTIONS DUE TO ANTI-TUBERCULOSIS DRUGS IN PULMONARY
TUBERCULOSIS PATIENTS
Manju Sharma
1
, Khalid U. Khayyam
2
*, Vinay Kumar
1
, Faisal Imam
1
, KK Pillai
1
, D. Behera
2
1
Department of Pharmacology, Faculty of Pharmacy Jamia Hamdard, New Delhi-110062 India.
2
Lala Ram Sarup Institute of Tuberculosis and Respiratory Diseases, New Delhi-110030, India.
ABSTRACT
The aim was to assess the influence of honey on adverse drug reactions induced by Anti-tuberculosis
(Anti-TB) drugs in newly diagnosed sputum acid fast bacilli (AFB) positive pulmonary tuberculosis
patients of category I receiving directly observed treatment short course (DOTS) under revised national
tuberculosis control programme (RNTCP) for a period of two months (i.e. intensive phase). A high
percentage of ADRs was experienced in control (69.88%) as compared to case (47.06%). Most of the
ADRs were mild to moderate and transient in nature. The most common adverse reactions reported
among control patients were anemia (21.16%), joint pains (15.6%), itching (18%) and nausea (14.4%).
The least percentage of adverse reactions among control patients reported was diarrhoea (2.4 %), while
there was no diarrhea observed in patients receiving honey along with anti-tubercular treatment (ATT).
Honey with ATT minimizes the adverse drug reactions induced by Anti-TB drugs in AFB positive
pulmonary positive tuberculosis patients. Thus, honey can be used as an adjuvant along with ATT in
pulmonary TB patients.
KEY WORDS: Tuberculosis, Adverse Drug Reactions, Honey, Direct Treatment Outcome, Revised
National Tuberculosis Control Program and Acid Fast Bacilli.
INTRODUCTION
According to World Health Organization (WHO) one third of the world’s population is infected with Mycobacterium
tuberculosis resulting in 8.4 million new tuberculosis cases in 1999 (WHO, 2001). India accounts for a fifth of the world’s
new TB cases and 2/3
rd
of the cases in South- East Asia. In India, pulmonary tuberculosis is one of the major causes of adult
deaths (Garner et al., 2004). This makes India the highest TB burden country in the world. As per WHO estimates in 2004,
370,000 persons in India died of tuberculosis (mortality rate 30 per 100,000 persons), which was estimated at over 500,000
annually prior to 2000.
The increase in incidence of infection leads to increase in number of morbidity and mortality and is
more or less because of serious adverse reactions induced by Anti-TB drugs (Kopanoff et al., 1978; Burman and Reves.,
2001).
The ADRs induced by Anti-TB drugs is the matter of concern in many communities. Hepatotoxicity is one of the serious
ADRs reported in various studies. Rate of hepatotoxicity reported differs from different studies (British Thoracic and
Tuberculosis Association., 1975; Tanaja and Kaur., 1990; Snider et al., 1984).
The type of reaction depends upon the
genotype of patients receiving Anti-TB drugs e.g. rapid-acetylator patients are more susceptible for isoniazid induced
hepatotoxicity. Studies show that the risk of hepatotoxicity in patients from India is higher than those reported in West
(11.5% versus 4.3%) (Sharma et al., 2002). Taking in to account the significant difference reported between Asian and
Western people in developing Anti-TB drugs induced hepatotoxicity, there is a need to detect the rate of Anti-TB drugs
induced ADRs with emphasize on hepatotoxic reactions in Indian patients.
Nutritional supplements are needed to help the body regain strength and fight the illness. Apitherapy or therapy with the bee
products as honey is an old tradition. Honey has potent bactericidal activity against many pathogenic organisms. A mixture of
honey and aged butter is said to be especially curative of TB transferred by cold temperatures. TB of the neck is treated with
honey, milk and herbs (Al-Jabri et al., 2003).
Avicenna, the great Iranian scientist and physician, almost 1000 years ago, had recommended honey as one of best remedies
in the treatment of tuberculosis (Avicenna., 1991).
Therapeutic effects of honey include its use in the treatment of infantile
gastroenteritis (Haffejee and Moosa., 1985), ulcers, wound healing (Oryan and Zaker., 1998), laxative action, cough and sore
throat, eye diseases, topical antisepsis (Bansal et al., 2005). The immunomodulatory and antioxidant effects of honey has also
been recently reported (Tonks et al., 2003; Gheldof et al., 2003).

Manju Sharma et al: Continental J. Pharmacology and Toxicology Research 2: 6 - 11, 2008.
Table 1: Study patients enrolled from different locality of South Delhi.
S.No. Controls (Group I) Cases (Group II)
1.
Mahipalpur Tigri
2.
Safdarjung Dakshinpuri
3.
Malviya Nagar SangamVihar I-block
4.
Ber Sarai, New Delhi SangamVihar J-block
5.
- SangamVihar G-block
Considering protective effects of honey on gastric and hepatic function, we designed present study to investigate whether
honey with Anti TB drugs has any influence on ADRs profiles in pulmonary TB patients receiving Direct Observed
Treatment Short-course (DOTS) under Revised National Tuberculosis Control Programm (RNTCP).
MATERIALS AND METHODS
Study was performed on pulmonary new sputum acid-fast bacilli positive patients of tuberculosis registered under Revised
National Tuberculosis Control Program for Direct Observed Treatment Short-course during three months (January to March
2007). These patients were diagnosed at RNTCP- Lala Ram Sarup Institute of Tuberculosis and Respiratory, Sri Aurobindo
Marg, New Delhi-110030, INDIA.
A total of 185 patients were enrolled in this study, were divided into two groups (Group-I and Group-II) on the basis of
treatment. Group-I served as controls, consist of 83 patients, received short course chemotherapy as per RNTCP guidelines
i.e. four drugs (Isoniazid, Rifampicin, Pyrazinamide and Ethambutol) thrice weekly for two months in the intensive phase.
Group II served as cases, consist of 102 patients, received short course chemotherapy as per RNTCP guidelines i.e. four
drugs (Isoniazid, Rifampicin, Pyrazinamide and Ethambutol) and one teaspoonful (5ml) honey [Wings Pharmaceuticals Pvt.
Ltd.,] 5 minutes prior to ATT, thrice weekly for two months in the intensive phase. Patients included in this study were taken
from different areas of South Delhi (Table 1).
Patients with history of allergy to honey and / or related products were excluded from the study. Patients taking over the
counter (OTC) drugs or drugs for co-morbidity (such as asthma, diabetes mellitus), serious or hospitalized patients, pregnant
women or women taking oral contraceptives and patients of paediatric age group were also excluded from the study.
All mentally retarded, drug addicts, unconscious and patients unable to respond to verbal questions were also excluded from
the study. A signed written informed consent was taken from the patients prior to enrollment in the study. The study was
initiated after the approval of the study protocol by Institutional Research Committee of Lala Ram Sarup Institute of TB and
Respiratory Disease, New Delhi.
The adverse drug reactions experienced by the patients were documented on ADR monitoring form designed on the basis of
CDSCO guidelines. The form includes data like age, sex, demographic details, past medical history, present drug treatment,
description of adverse drug reaction, its assessment and treatment for the drug reaction. The ADR definition used in this
study is that of the WHO “Any noxious and unintended response to a drug, which occurs at doses normally used in human
for the prophylaxis, diagnosis or treatment of disease or for the modification of physiological function” (WHO, 1972; WHO,
1996).
Serious: A serious adverse event (AE) or reaction is any untoward medical occurrence that at any dose:
- results in death,
- requires inpatient hospitalization or prolongation of existing hospital stay,
- results in persistent or significant disability/incapacity,
- is life threatening.
The term “severe” is not synonymous with serious. Words “severe” is used to describe the intensity of specific event (as in
mild, moderate or severe); the event itself, however, may be relatively minor medical significance (such as severe headache).
Seriousness (not severe) which is based on patient/event outcome or action criteria (Venulet and Ham., 1996).

Manju Sharma et al: Continental J. Pharmacology and Toxicology Research 2: 6 - 11, 2008.
Detection and monitoring was done by interviewing patients and consulting the physicians about the patient’s clinical
problems and ADRs were recorded routinely. Patients developed ADRs were kept under supervision until recovery.
Table 2: Distributions of adverse reactions on the basis of severity
Group Severity of ADR No. of Patients with ADR (%)
Control (group
I)
Mild ADRs 36 (62.07)
Moderate ADRs 22 (37.93)
Case (group II) Mild ADRs 29 (60.42)
Moderate ADRs 19 (39.58)
RESULTS AND DISCUSSION
The present study confirmed that intolerance of anti-tuberculosis standard therapy due to adverse effects is still a serious
problem of patients with tuberculosis and there is a need for the monitoring of patients receiving anti-tubercular treatment.
During this study, a total of 185 patients were diagnosed with positive pulmonary TB, enrolled for the study. Out of 185
patients 131 (71%) were male as compared to 54 (29%) female. A high percentage of ADRs was experienced in control
(69.88%) as compared to case (47.06%). In gender distribution of patients; the prevalence of ADR were found to be more in
male as compared to female in both, control group (60.34%) and case group (56.25%). Among the case group, about 48
(47%) patients showed at least one adverse reaction while in control group 58 (70%) patients showed at least one adverse
reaction. This relatively high percentage of adverse reactions among patients of control group indicates that there is a need
for extensive evaluation of ADRs in these patients. In case group, honey was administered to the patients along with standard
DOTS therapy under RNTCP, which shows that honey improves the adverse reaction profile of pulmonary tuberculosis
patients. These effects of honey are probably due to its protective effects on human gastrointestinal system such as its
influence on human gastric and hepatic function (Baltukeviius and Eksteryte., 1998)
and its use in oral rehydration products.
Honey is also useful in the treatment of various ophthalmic conditions (Al-Waili., 2004). Honey is reported to stimulate
inflammatory cytokines production from monocytes (Tonks et al., 2003) and also known to increase serum antioxidant
capacity in human (Gheldof et al., 2003). Most of the ADRs were mild to moderate and transient in nature. Out of 58 ADRs,
36 (62.07%) were mild and 22 (37.93%) were moderate in patients of control group, whereas 29 (60.42%) were mild and 19
(39.58%) were moderate in patients of case group (Table 2). The rate of adverse reactions was varies in different age groups.
The majority of ADRs were found be in patients of age group of 25 to 54 years and in elderly age group i.e. 65 years and
above (Table 3). The reasons of more ADRs in these age group patients are due to, high disease prevalence in these age
group patients. It is reported that, the patients with age group of 25-50 years and elderly patients are more vulnerable to
develop ADRs (Sharma et al., 2007). Among the 185 patients, about 109 (59%) were smokers while 76 (41%) were
nonsmokers. Smokers were found to have more risk of ADR in both groups, i.e. 38 (20.54 %) in case as well as 45 (24.32%)
in control group as compare to nonsmoker 10 (05.41%) in case and 13 (07.03%) in control group (Table 4). Smokers had a
73 percent increased risk of becoming infected with tuberculosis and were more than twice as likely as to develop active
tuberculosis than the nonsmokers (American Thoracic Society, 2007).
The most common adverse reactions reported among control patients were anemia (21.16%), joint pains (15.6%), itching
(18%) and nausea (14.4%), while in case the most common adverse reactions reported were anemia (10.78%), itching (7.8%)
and nausea (6.8%). The least percentage of adverse reactions reported was diarrhea (2.4 %) among control patients while
there was no diarrhea observed in patients receiving honey along with ATT (Table 5). However some studies reported
hepatotoxicity as most frequent ADRs followed by constipation (Gholami et al., 2006; Gulbay et al., 2006).
This difference
in ADRs among the patients of control group and patients of case group was due to honey which is reported to improve
appetite, gastrointestinal disorders, anemia, diarrhea, headache and tuberculosis (Haffejee et al., 1985; Bansal et al., 2005;
Oryan et al., 1998; Tonks et al., 2003).
CONCLUSION
The results of the present study provide evidence for potential corrective effect of honey on adverse drug reactions. Further
investigations with more properly conducted clinical trials are warranted to explore the full potential of

Manju Sharma et al: Continental J. Pharmacology and Toxicology Research 2: 6 - 11, 2008.
honey. Honey minimizes the adverse drug reactions induced by Anti- TB drugs in AFB +ve pulmonary tuberculosis patients.
Therefore, honey can be given as an adjuvant to pulmonary TB patients as it may improve patient’s compliance and thus may
reduce the cases of resistance.
ACKNOWLEDGMENTS: The project was supported by financial assistance from the University Grant Commission (UGC),
New Delhi (INDIA).
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Table 3: Distribution of adverse reactions among TB patients according to age group
Age group Control Group Case Group
Patients Patients with
ADR (%) Patients Patients with
ADR (%)
14-24 9 06 (10.34) 15 06 (12.50)
25-34 18 12 (20.68) 22 10 (20.83)
35-44 21 15 (25.86) 25 12 (25.00)
45-54 13 09 (15.51) 17 08 (16.67)
55-64 7 04 (6.89) 8 03 (6.25)
65 and
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Adverse reactions Case Group Control Group
Frequency Percentage of
ADRs Frequency Percentage of
ADRs
Nausea 7 6.8% 12 14.4%
Loss of appetite 4 3.9% 8 9.6%
Icterus
6
5.8%
9
10.8%
Itching 8 7.8% 15 18%
Rash 1 0.09% 3 3.6%
Eye symptoms 1 0.09% 4 4.8%
Joint pains 5 4.9% 13 15.6%
Vomiting 4 3.9% 8 9.6%
Anemia 11 10.78% 18 21.16%
Fever 3 2.9% 6 7.2%
Headache 5 4.9% 7 8.4%
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Drowsiness 15 7.8% 5 6.02%
Diarrhoea 0 0% 2 2.4%
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Received for Publication: 28/03/2008
Accepted for Publication: 24/06/2008
Corresponding Author
Dr. Khalid U Khayyam
HOD, Epidemiology and Public Health, LRS Institute of TB & Resp. Diseases, Sri Aurobindo Marg New Delhi-110030.
India
E-mail: dr.khalidukhayyam@yahoo.co.in