Introduction
In the UK, an acute respiratory infection is the commonest reason for a patient to
consult a general practitioner. Thirty million courses of antibiotics are prescribed
per year for the treatment of acute respiratory infections [1], despite evidence that they neither shorten the course of acute viral infections
nor prevent secondary bacterial infections [2]. The overuse of antimicrobial drugs for the management of respiratory infections
has important implications for healthcare costs and the potential for emergence of
antimicrobial resistance [3].
In light of the continued popularity of herbal medicine [4], an effective and well-tolerated herbal medication for the prevention and treatment
of acute respiratory infections would be a welcome addition to the therapeutic repertoire.
The leaves of Andrographis paniculatam, popular in Scandinavia as a cold and influenza remedy, are used traditionally in
Ayurvedic, Thai and Chinese medicine to treat fever associated with infectious diseases.
Pharmacological studies suggest anti-inflammatory [5], [6], antipyretic [7], [8], antiviral [9] and immunostimulatory [10] properties. The aim of this review was to systematically assess the efficacy and
safety of A. paniculata in the treatment and prevention of upper respiratory tract infections.
Methods
Identification of clinical trials
In order to identify all reports of administration of Andrographis paniculata to human subjects, systematic literature searches were conducted in the following
electronic databases: Medline (Via Pubmed), Embase, CINAHL, Amed (Alternative and
Allied Medicine Database, British Library Medical Information Centre), The Cochrane
Library (Issue 2, 2003), and the British Library Index of Conference Proceedings (all
from their inception to June 2003). The search terms used were: Andrographis paniculata, kalmegh, kiryat, chuanxinlian, chiretta, fa-tha-lai-jone and Kan Jang. Further relevant
papers were located by hand-searching the reference lists of all papers and departmental
files. Hand searching of standard reference texts [11], [12] and internet searches revealed four manufacturers/distributors of A. paniculata products who were contacted and asked to supply any published or unpublished material.
Adverse event reports
Data were requested from the following spontaneous reporting schemes: the World Health
Organisation (Uppsala Monitoring Centre), and the drug safety bodies of the United
Kingdom (Medicines Control Agency), Australia (Adverse Drug Reactions Advisory Committee)
and Germany (Bundesinstitut für Arzneimittel und Medizinprodukte).
Inclusion and exclusion criteria
For the evaluation of efficacy, only double-blind, controlled clinical trials of the
oral administration of single or combination preparations of A. paniculata for the treatment of uncomplicated upper respiratory tract infection (URTI) were
included. All retrieved data including uncontrolled trials, case reports, pre-clinical
and observational studies and clinical trials for other indications were included
in the review of safety. No language restrictions were imposed.
Data extraction and quality assessment
All articles were read in full. Data relating to sample size, study design, intervention
and control, treatment duration, primary outcome measures, number and type of adverse
events and results were extracted according to predefined criteria. The methodological
quality of each clinical trial was assessed using the Jadad scoring system [13]; a scale ranging from 0 (poorest) to 5 (highest) which assesses methods of randomisation
and blinding and the description of withdrawals and dropouts.
Study selection, data extraction and assessment of methodological quality were performed
by the first reviewer and validated by the second, with any disagreements being settled
by discussion.
Results
A total of 143 references were retrieved from the systematic literature searches;
eleven papers described the administration of A. paniculata to human subjects. These included four double-blind, controlled clinical trials of
the treatment of uncomplicated URTI (three further eligible trials were identified
from reference lists and our own departmental files) (Table [1]) [14], [15], [16], [17], [18], a phase I trial in HIV positive and negative patients [20], two studies in healthy volunteers [21], [22], and three case series [23], [24], [25]. Adverse events reported within these twelve papers are shown in Table [2].
Table 1 Double-blind, controlled trials of Andrographis paniculata for the treatment of uncomplicated URTI
First author (reference) |
Quality score |
N (rando- mised/ analysed) |
Study design |
Type of preparation |
Daily dose of androgra pholide (mg) |
Duration (days) |
Delay between onset of symptoms and start of therapy (hours) |
Main results |
Melchior
[18]
|
5 |
47/46 |
R, PC, treatment |
standardised extract; AP/ES combination |
60 |
3 - 8 |
36 |
greater improvement in patient’s overall symptom score compared with placebo (p = 0.08) |
Melchior
[18]
|
5 |
180/179 |
R, PC, treatment |
standardised extract; AP/ES combination |
60 |
3 |
36 |
greater improvement in patient’s (p = 0.0006) and physician’s (p = 0.003) overall symptom score compared with placebo |
Gabrielian
[15]
|
3 |
200/185 |
PC, treatment |
standardised extract; AP/ES combination |
60 |
5 |
N/A |
greater improvement in mean symptom score compared with placebo at day 5 (p < 0.001) |
Caceres
[14]
|
5 |
208/208 |
R, PC, treatment |
standardised extract |
60 |
5 |
48 |
improvements in all symptoms compared with placebo (p < 0.03) |
Melchior
[17]
|
3 |
50/50 |
R, PC, treatment |
standardised extract |
60 |
5 |
72 |
fewer days sick leave compared with placebo after five days (p < 0.03) |
Hancke
[16]
|
3 |
59/59 |
PC, treatment |
standardised extract |
48 |
5 |
72 |
decrease in summary scores for signs (p < 0.05) and symptoms (p < 0.01) compared with placebo after four days |
Thamlikitkul
[19]
|
3 |
152/142 |
R, C, treatment |
crude drug (high or low dose) or paracetamol |
180 or 360 |
7 |
not known |
greater eradication of sore throat and fever in high dose and paracetamol groups compared with the low dose group after three days (p < 0.001). No differences between groups after seven days |
R = randomised; PC = placebo controlled; C = comparative. |
Table 2 Adverse events reported during administration of Andrographis paniculata to human subjects
First author (reference) |
N |
Patient population |
Study design |
Daily dose of andrographolide (mg) |
Adverse events experienced (cases) |
|
|
|
|
|
Active treatment |
Placebo |
Melchior [18]
|
47 |
URTI |
R, DB, PC |
60 |
no adverse events reported |
no adverse events reported |
Melchior [18]
|
180 |
URTI |
R, DB, PC |
60 |
unpleasant sensations in the chest (1), intensified headache (1) |
no adverse events reported |
Gabrielian [15]
|
200 |
URTI |
DB, PC |
60 |
increased nasal discharge and epigastric pain (1), blocked nose (1), severe headache (1) |
no adverse events reported |
Calabrese [20]
|
18 |
HIV positive (13) and healthy volunteers (5) |
O |
5 mg/kg and 10 mg/kg increasing every 3 weeks |
allergic reaction (2), fatigue (6), headache (5), pruritis/rash (12), diarrhoea (5), nausea (1), metallic taste (6), bitter taste (2), decreased/no taste (6), dry tongue (1), decreased sex drive (1), eyes sensitive to light (1), decreased short term memory (1), dizziness (1),
heartburn (1), tender lymph nodes (3), lymphadenopathy (2) |
no placebo group |
Panossian [21]
|
16 |
healthy volunteers |
O, SD, R |
20 |
no adverse events reported |
no adverse events reported |
Caceres [14]
|
208 |
URTI |
R, DB, PC |
60 |
no adverse event information provided |
no adverse event information provided |
Caceres [35]
|
107 |
healthy students |
R, DB, PC |
11 |
no adverse event information provided; no withdrawals |
no adverse event information provided; no withdrawals |
Melchior [17]
|
50 |
URTI |
R, DB, PC |
60 |
urticaria (2) |
no adverse events reported |
Muangman [24]
|
100 |
patients with renal stones |
case series |
40 |
no adverse events reported |
no placebo group |
Hancke [16]
|
59 |
URTI |
PC, DB |
48 |
no adverse events reported |
no adverse events reported |
Zhang [23]
|
63 |
patients with cardiac and cerebral vascular disease |
case series |
various |
no adverse events reported |
no placebo group |
Thamlikitul [19]
|
152 |
sore throat and fever |
R, DB, C |
180 or 360 mg or paracetamol |
adverse events were experienced by approx. 20 % of patients in each group and included nausea, vomiting, abdominal discomfort, dizziness, drowsiness and malaise |
no placebo group |
Leelarasamee [22]
|
10 |
healthy volunteers |
SD, R, CO |
not known |
no adverse event information provided |
no adverse event information provided |
Vedavathy [25]
|
25 |
children with infective hepatitis |
case report |
not known |
no adverse event information provided |
no adverse event information provided |
R = randomised; O = open; DB = double-blind; PC = placebo-controlled; SD - single
dose. |
Evaluation of efficacy
Seven double-blind, controlled trials (n = 896) met the inclusion criteria [14], [15], [16], [17], [18], [19]. Of these, five were randomised and six were placebo-controlled; one compared the
effects of Andrographis paniculata with paracetamol. All trials scored at least three out of five points for methodological
quality.
Melchior et al. in 2000 conducted two randomised, double-blind, placebo-controlled
parallel group clinical trials of a fixed combination of standardised extracts of
the leaves of A. paniculata (60 mg andrographolide/day) and the roots of Eleutherococcus senticosus (Rupr. & Maxim) Maxim (120 mg/day) in 47 and 180 adult patients with uncomplicated
acute URTI treated within 36 hours of the onset of symptoms [18]. Primary outcome measures were patient and physician evaluation of the severity
of pre-defined signs and symptoms (e. g., muscle pain, cough, throat, nasal and eye
signs and symptoms and temperature). In the larger study, there was a significantly
greater improvement in both patient (p = 0.0006) and physician (p = 0.003) evaluated
total symptom scores in the treatment group compared with placebo, after three days.
Analysis of individual symptoms showed significant differences in muscle soreness,
cough frequency, presence of a productive cough, body temperature and dry throat.
The smaller, pilot study showed a non-significant reduction in patient evaluated total
symptom score in the treated group, compared with placebo (p = 0.08). Physician symptom
evaluation was not reported.
Two hundred men and women with a diagnosis of upper respiratory tract infection (not
requiring treatment with antibiotics) were treated with either a fixed combination
of A. paniculata (60 mg andrographolide/day) and E. senticosus (120 mg/day) or placebo for five days in a non-randomised, double-blind, parallel
group study performed in two centres in the Republic of Armenia [15]. Clinical observations included evaluation of the following signs and symptoms,
rhinitis, sinusitis, pharyngitis, fever, abnormal pulmonary findings, lymphadenopathy,
nasal discharge and stuffiness, sore throat, earache, cough and headache. Although
there was a significant difference in mean symptom scores between groups at baseline
(treatment 0.65 vs. placebo 0.82; p = 0.006) there was also a highly significant difference
at the end of treatment (treatment 0.09 vs. placebo 0.63; p < 0.001). Subsequent statistical
analyses suggest that although the baseline mean score affected the mean score post-treatment,
it did not interfere with the observed difference in improvement between the two groups.
The baseline difference was thought to be due to differences in the type of patients
recruited at the two centres; one of which was an emergency department and the other
an outpatient clinic. Headache, nasal and throat symptoms and general malaise showed
the most improvement, whilst cough and eye symptoms did not differ between the groups.
In a randomised, placebo-controlled double-blind study of 208 adult patients diagnosed
with uncomplicated URTI (ICPC classification), Caceres et al. collected patient self-evaluations
of headache, fatigue, earache, sleep disturbance, soreness of throat, nasal secretion,
expectoration and frequency and intensity of cough on a visual analogue scale, within
48 hours of the onset of symptoms and after two and four days of treatment with either
A. paniculata (60 mg andrographolide/day) or placebo [14]. Compared with placebo, fatigue, sleep disturbance, nasal secretion and soreness
of throat (p < 0.03) were all improved after two days of treatment; on day four there
were significantly greater improvements in all symptoms (all p < 0.01).
Fifty adult patients with uncomplicated URTI received a standardised extract of A. paniculata (andrographolide 60 mg/day) or placebo within 72 hours of the onset of symptoms in
a randomised, double-blind, placebo-controlled trial [17]. Although the primary outcome measures were patient- and physician-evaluated symptom
scores, these are not reported, instead the results are presented as several summary
measures. After five days of treatment, there was a significant difference between
groups in the number of sick leave days reported and the number of patients who declared
themselves ‘totally recovered’ (0.96 vs. 0.21; p < 0.03 and 67.5 vs. 36 %; p < 0.046).
Hancke et al. conducted a non-randomised, placebo-controlled double-blind study of
59 adult patients diagnosed with common cold [16]. Within 72 hours of the onset of symptoms, patients received treatment with either
a standardised extract of A. paniculata (andrographolide 48 mg/day) or placebo for five days. After four days of treatment
there was a decrease in summary scores for signs (p < 0.05) and symptoms (p < 0.01)
compared with placebo. Both groups showed significant reductions in shivering, sore
throat and muscular ache; in addition, treatment with A. paniculata was associated with reductions in the strength of the disease, tiredness, rhinitis,
sinus pains and headaches.
In a comparative study, 152 patients with sore throat and either a history of fever
or a temperature of at least 37.8 °C were randomised to receive encapsulated dried
leaves of A. paniculata (andrographolide 180 or 360 mg/day) or paracetamol (3.9 g/day) for seven days [19]. The study medications were prepared in identical capsules. There was a significant
difference in efficacy in favour of paracetamol and high dose A. paniculata for eradication of sore throat and fever at day three (p < 0.001). By day seven there
were no significant differences between the groups with almost all patients being
symptom-free.
Evaluation of safety
Spontaneous reporting schemes: As of June 2003, no reports of suspected adverse events associated with A. paniculata had been received by the national drug safety bodies of the United Kingdom, Germany
or Australia. The World Health Organisation Collaborating Centre for International
Drug Monitoring provided three reports of anaphylactic shock [1 report] and anaphylactic
reaction [2 reports]. All occurred in Sweden in 1996, no further reports had been
received. The World Health Organisation states that the information provided is not
homogeneous at least with respect to origin or likelihood that the pharmaceutical
product caused the adverse reaction and that the information does not represent the
opinion of the World Health Organisation.
Data from manufacturers: Information was received from one of the four manufacturers/distributors of Andrographis paniculata products contacted; the Swedish Herbal Institute. As of 1981, they had received five
reports of adverse events (allergic reactions). No further information was available.
Clinical trials and case series: Adverse events were reported in five of the thirteen
clinical trials identified. A phase I trial of HIV-positive patients and healthy volunteers,
was terminated early due to the large number of adverse events [20]. A contributing factor may have been the dose of andrographolide used (5 - 10 mg/kg/day)
which was in the region of six to twelve times higher than that used in all the other
studies (e. g., 60 mg/day). Adverse events reported in the remaining trials were mild,
infrequent and reversible. In three trials no adverse events were experienced by any
of the patients in either the treated or placebo groups and the remaining three reports
contained no information regarding adverse events. No adverse events were reported
in any of the case series
Experimental studies: Several animal studies were identified which suggest that A. paniculata may have contraceptive or antifertility effects following long-term treatment at
high doses [26], [27], [28]. However, there is a large degree of discrepancy in the results, with some studies
[29], [30] demonstrating no untoward effects even at doses 1000 times those used therapeutically,
possibly due to the type of extracts used and the techniques employed to detect change.
More work is needed in this area, but the evidence to date suggests that A. paniculata should not be taken during pregnancy or by men or women attempting to achieve conception.
Discussion
A paniculata alone or in combination with E. senticosus appears promising in the treatment of subjective symptoms of uncomplicated upper
respiratory tract infection. Short-term therapy at recommended doses is associated
with an encouraging safety profile, although adverse events have been demonstrated
at higher doses.
This review represents the first attempt to systematically collate the available data
on A. paniculata, in many countries a relatively unknown and little studied herb, in an area of medicine
in which most current conventional treatment options are largely ineffective. The
trials included within the review were large, well designed and of good to excellent
methodological quality, and the safety data represent all available information surrounding
the incidence of adverse events following administration of A. paniculata. We were unable to formally combine the data from individual trials in a meta-analysis
as the most appropriate primary outcome measure, sum score for patient-reported symptoms,
was available for only four of the trials, and attempts to retrieve this data for
the remaining trials from the manufacturer/authors were unsuccessful.
Several shortcomings of the review need to be addressed. Firstly, with the exception
of Thamlikitkul et al. [19], all the trials involved a standardised extract of A. paniculata manufactured by the same herbal company, a representative of whom is a co-author
on each of the papers. Pooling a relatively small number of trials of this nature
may be prone to error and potential bias. Secondly, although attempts were made to
obtain data from unpublished trials by contacting authors/manufacturers and searching
the Index of Conference Proceedings, none were located. There is evidence to suggest
that studies with significant positive results are more likely to be published [31] and this may be more pronounced with an unfamiliar therapy such as A. paniculata. Finally, the safety data should be interpreted with some degree of caution. Generally,
adverse events experienced during clinical trials were mild and infrequent, however,
trials designed to assess efficacy rarely collect rigorous information on adverse
events. Typically each trial includes a relatively small number of patients exposed
for a short period of time thus reducing the possibility of observing rare or delayed
adverse events. There have also been very few adverse events reported to the various
surveillance bodies and manufacturers. There is evidence that patients do not report
all adverse events experienced after taking over-the-counter medications whether herbal
or conventional [32] and that hospital doctors under-report adverse events [33]. We do not have any figures for the number of patients exposed to A. paniculata and the lack of reports could indicate a lack of awareness or availability of the
herb. On the other hand, the Australian surveillance body reported that Andrographis paniculata was present in 22 of the products listed on the Australian Register of Therapeutic
Goods; none of which was associated with reports of adverse events.
Studies in vitro suggest that A. paniculata may have several potential mechanisms of action relevant in the treatment of acute
upper respiratory tract infections including anti-inflammatory [5], [6], [34], immunostimulant [10] and anti-pyretic effects [7], [8]. Although, A. paniculata has been reported to inhibit viral replication in HIV infected cells [20], there are no published data of similar effects with respiratory viruses. As viral
replication in the upper respiratory tract is believed to peak on the first day of
symptoms, it is unlikely in these trials, where treatment was initiated 36 to 72 hours
after the onset of symptoms, that an antiviral mechanism of action was involved.
In conclusion, these data suggest that A. paniculata may be a promising treatment for the alleviation of subjective symptoms of acute
upper respiratory tract infection. In addition, short-term treatment, at recommended
doses, is associated with few reports of adverse events. In light of the lack of effective
therapeutic options for acute upper respiratory tract infection, A paniculata is a herbal treatment option that is worthy of consideration for further research.
Acknowledgements
JTC was supported by a research fellowship provided by Pharmaton SA, Lugano, Switzerland.