S4679 358 zakay dma04

The Journal of International Medical Research
2004; 32: 132 – 140
Z ZAKAY-RONES1, E THOM2, T WOLLAN3 AND J WADSTEIN4 1Department of Virology, Hebrew University-Hadassah Medical School, Jerusalem, Israel; 2PAREXEL Norway AS, PO Box 210, N-2001 Lillestrøm, Norway; 3Jernbanealléen 30, N-3210 Sandefjord, Norway; 4Østra Rønneholmsv 6B, 21147 Malmö, Sweden Elderberry has been used in folk medicine
in Norway. Patients received 15 ml of
for centuries to treat influenza, colds and
elderberry or placebo syrup four times a
sinusitis, and has been reported to have
day for 5 days, and recorded their
antiviral activity against influenza and
symptoms using a visual analogue scale.
herpes simplex. We investigated the
Symptoms were relieved on average 4 days
efficacy and safety of oral elderberry syrup
earlier and use of rescue medication was
for treating influenza A and B infections.
significantly less in those receiving
Sixty patients (aged 18 – 54 years) suffering
elderberry extract compared with placebo.
from influenza-like symptoms for 48 h or
Elderberry extract seems to offer an
less were enrolled in this randomized,
efficient, safe and cost-effective treatment
double-blind, placebo-controlled study
for influenza. These findings need to be
during the influenza season of 1999 – 2000
confirmed in a larger study.
KEY WORDS: BLACK ELDERBERRY; SAMBUCOL®; INFLUENZA A AND B; CLINICAL EFFICACY;
TOLERABILITY; CONTROLLED STUDY
Introduction
and the possibility of severe complications.
Influenza can be fatal, particularly in the and causes an acute respiratory tract disease.
abrupt onset of fever, headache, myalgia, sore throat and non-productive cough. The illness is usually self-limiting, with relief of symptoms occurring within 5 – 7 days.
mately 25 to > 150 per 10 000 in those aged Nevertheless, it is an important disease due ≥ 65 years; > 90% of the deaths attributed to to its ease of communicability, short incub- ation time, rapid rate of viral mutation, related morbidity, resultant loss of productivity, Z Zakay-Rones, E Thom, T Wollan et al.
Oral elderberry extract in the treatment of influenza
are detectable in plasma after oral intake of influenza-specific antiviral drugs such as complications before the influenza season countries. Standardized elderberry extract commonly used ways of reducing the impact influenza A and B viruses in vitro,13 and be effective in treating influenza B/Panama.13 with the replication cycle of type A (but not treatment of influenza-like symptoms using istered prophylactically to healthy adults or demonstrated in a colony of chimpanzees in preventing the illness in approximately the Jerusalem Zoo, Israel.1470 – 90% of influenza type A infections.
tolerability of a standardized elderberry reduce the severity and shorten the duration of an influenza A infection. Zanamivir and Patients and methods
oseltamivir belong to a new class of antiviralagents known as neuraminidase inhibitors, THE STUDY
This multicentre (four sites) randomized, effective in decreasing symptoms, none of regional ethical committee. The study was The black elder (Sambucus nigra L.) has been used in folk medicine for centuries to was known to be present in the community.
treat influenza, colds and sinusitis.3 Antiviral activity of three plants, including the elder, study was based on surveillance data received from the clinical and viral spotting system of herpes.4 The berries of black elder contain the National Laboratory of Health, Norway.
naturally occurring plant substances. Several purified flavonoids have been shown to have code was only broken once all the data had antiviral activity against herpes simplex virus type 1, respiratory syncytial virus, andthe parainfluenza and influenza viruses.6 – 9 PATIENTS
The main flavonoids found in elderberries are the anthocyanins cyanidin 3-glucoside 80 candidates presenting at an investigator’s office with respiratory influenza symptoms recently been shown that these substances Z Zakay-Rones, E Thom, T Wollan et al.
Oral elderberry extract in the treatment of influenza
Classification of Primary Care) were screened for inclusion. Those with verified influenza were enrolled in the study. All subjects had a the same type of bottles. The placebo syrup fever ≥ 38.0 °C and at least one respiratory did not contain the elderberry extract, but was otherwise identical. Both syrups were breastfeeding, those with suspected bacterial infections, recent antiviral therapy, recent participation in another clinical trial, anti- elderberry or placebo syrup four times a day, during meals, for 5 days. The first dose of healthy individuals, with the exception of the current episode of influenza, and did not onset of the influenza-like symptoms.
belong to high-risk groups. Written informedconsent was obtained from each patient CONCOMITANT MEDICATION
Patients were allowed to take concomitantmedications during the study in the form of INFLUENZA VIRUS ISOLATION
the antipyretic/analgesic agent paracetamol (Paracet®, Weifa, Oslo, Norway; 500 mg
tablets) and/or a dose-metered nasal spray (Otrivin®, Novartis, Basel, Switzerland; 1 mg/ml) to relieve the influenza symptoms Sambucol® or placebo did not help. These
convalescent haemagglutination-inhibition antibody titre and/or a positive influenza and were marketed drugs. In cases of known allergy to the rescue medications, alternatives were provided (acetylsalicylic pain killersinstead of paracetamol and salt water spray TREATMENT
instead of Otrivin®). Patients recorded the
(Sambucol®, Razei Bar, Jerusalem, Israel) was medication taken, as well as the name of the used. The syrup formulation contained 38% amounts of raspberry extract, glucose, citric medications were returned at the end of the study so that they could be checked against ensuring the absorbance at 516 nm wasabove 0.60. The extract is produced according EFFICACY EVALUATION
to good manufacturing practice, and both its production and the production facilities are certified by the Israeli Health Authorities.
assessed were: aches and pains, degree of containing 120 ml. To make the study blind, coughing, frequency of coughing, quality of Z Zakay-Rones, E Thom, T Wollan et al.
Oral elderberry extract in the treatment of influenza
sleep, mucus discharge in the respiratory tract and nasal congestion. These symptoms 54 years) were enrolled in the study. Their were assessed at baseline to investigate if the demographic characteristics, infecting virus two groups were clinically comparable at the start of the study. The visual analogue scales Table 1. At the beginning of the study, no (VAS) used at baseline had the endpoints 0 ‘no problems’ and 10 ‘pronounced problems’.
between the active treatment group (those receiving elderberry syrup; n = 30) and the cards at baseline, four times a day during placebo group (n = 30) with regard to treatment and twice daily for 5 days after the demographic characteristics, smoking status, treatment had finished. The VAS endpoints sleeping and normal activity or absenteeism improvement’ (at 0 cm) and ‘pronounced from work. The mean duration of the illness before receiving the first dose was 27.2 h.
different parameters examined are listed in their assessment of the symptom on a line Table 2. There were no significant differences separating the points 0 and 10. The distance from the zero point to the mark was used for Visual analogue scale (efficacy) scores on the follow-up days (days 2 – 10) for the varioussymptoms studied are listed in Table 3. There STATISTICAL ANALYSIS
was a significant difference (P < 0.001) in the elderberry group, most of the scores were near to ‘pronounced improvement’ (0 = no improve- Student’s t-distribution method. The standard ment and 10 = pronounced improvement)
deviation and total range were used as indices after 3 – 4 days, while the placebo group of distribution. Both inter- and intra-group reached this level after 7 – 8 days. Patients from analyses were carried out using two-tailed both groups were fully recovered after day 8.
tests with a significance level of 5%.
improvement (VAS score nearer to 10) after a mean (± SD) of 3.1 ± 1.3 days, while a similar score was obtained after 7.1 ± 2.5 days in the groups. SAS®
(Statistical Analysis System, SAS Institute, difference was significant (P < 0.001).
Cary, NC, USA) was used for all the statistical None of the patients reported any adverse participant receiving elderberry syrupdisliked the taste. As sedation is a main Recruitment of patients took place from side-effect of most anti-influenza medications,week 50 of 1999 until week 6 of 2000. This the participants were specifically asked if period was the time of main activity of an they had any problem with sedation during Z Zakay-Rones, E Thom, T Wollan et al.
Oral elderberry extract in the treatment of influenza
of influenza B/Panama.13 A complete cure was Use of rescue medication is shown in Table 4.
achieved within 2 – 3 days in nearly 90% of the Usage was significantly less (P < 0.001) in the elderberry-treated group compared with at elderberry group compared with the placebo least 6 days in the placebo group (P < 0.001).
The results of our study show that elderberry A positive correlation (P < 0.01) was found syrup is also effective against influenza A virus infections. Both studies show that the duration of the illness can be reduced by 3 – 4 days with elderberry syrup compared with placebo. The preparation was used. This indicated that all prophylactic and curative effects of this syrup patients fulfilled the compliance criteria by have been demonstrated in a study performed taking > 80% of the recommended dose in a chimpanzee colony,14 in which the(15 ml four times a day).
appearance of symptoms was reduced by two- Discussion
thirds. To our knowledge, no placebo-controlled, double-blind studies have been The efficacy of elderberry syrup has previously done with other natural remedies against the been investigated in a placebo-controlled, double-blind clinical study during an outbreak The main flavonoids present in elderberries TABLE 1:
Baseline characteristics of the 60 patients with influenza symptoms who were randomized
to the receive elderberry or placebo syrup in this study
Placebo group
Elderberry group
Cough so severe that it is associated with a feeling of vomiting Z Zakay-Rones, E Thom, T Wollan et al.
Oral elderberry extract in the treatment of influenza
TABLE 2:
Baseline (day 1) visual analogue scores for influenza symptoms and global evaluation as
assessed by the 60 patients with influenza in this study
Placebo group
Elderberry group
Mucus discharge in the respiratory tract Values given are the mean ± SD score (cm). A score of 0 cm indicates no problems and a score of 10 cmindicates pronounced problems (i.e., the higher the score, the more severe the symptoms).
are the anthocyanins cyanidin 3-glucoside and detectable in plasma after oral intake of haemagglutination of the influenza virus and elderberry extract.12 A possible mechanism of thus prevent the adhesion of the virus to the cell action of elderberry extract in the treatment of receptors.13 Anthocyanins also have an anti- influenza is that the flavonoids stimulate the inflammatory effect comparable to that of acetylsalicylic acid;19 this could explain the Sambucol® elderberry syrup (n = 30) FIGURE 1: The development of self-evaluation scores in global well-being in the
60 patients with influenza who received either elderberry syrup or placebo (15 ml,
four times daily with meals, for 5 days)
Z Zakay-Rones, E Thom, T Wollan
et al.
Oral elderberry extract in the treatment of influenza
isual analogue scores for symptoms and global evaluation on days 2 – 10 as assessed by the 60 patients with influenza in this
alues given are the mean score (cm). A score of 0 cm indicates pronounced problems and a score of 10 cm indicates no problems score the greater improvement in symptoms).
Z Zakay-Rones, E Thom, T Wollan et al.
Oral elderberry extract in the treatment of influenza
TABLE 4:
Number of patients with influenza using rescue medication in the placebo and elderberry
syrup-treated groups
Type of medication
Placebo group
Elderberry group
pronounced effect on aches, pain and fever population, including infants and children. It seen in the group treated with elderberry syrup.
Vaccination is effective for prophylaxis and in reducing the impact of influenza, but only available on the market, in the form of both about 60% of people aged 65 years and above, syrups and capsules. The extract tested in this and less than 30% of people aged less than study was standardized with respect to the 65 years, are vaccinated annually (worldwide content of flavonoids and was produced in accordance with good manufacturing practice.
A number of the other preparations available optimally to the vaccine, and the vaccine may lack or have a very low flavonoid content. We believe that adequate amounts, as well as the composition, of flavonoids present in the extract are essential for the therapeutic effect of rimantadine prevent the complications of type elderberry syrup as reported in our study.
A influenza infections among people at high In view of its in vitro and in vivo efficacy on risk. Use of these drugs is limited due to their influenza A and B viruses, elderberry extract offers an efficient, safe and cost-effective (approximately 30%) of drug resistance. No supplement to the present armamentarium of data are available to determine the efficacy of medications for the prophylaxis and treatment rimantadine among children, so it is currently of influenza. It should be stressed that our study approved for prophylaxis but not treatment of involved only adult influenza patients who were otherwise healthy, and did not include any high-risk patients. Further studies are duration of influenza A and B infections required to confirm these results in larger by 1 – 2.5 days. The route of administration is by numbers of patients and to investigate the inhalation via a Diskhaler® (GlaxoSmithKline, effect of elderberry syrup in other patient Middlesex, UK) and the drug is designed for patients aged 12 years and above.20,21Oseltamivir may reduce the duration of illness Acknowledgement
elderberries can be administered to the whole • Received for publication 12 September 2003 • Accepted subject to revision 23 September 2003 Copyright 2004 Cambridge Medical Publications Z Zakay-Rones, E Thom, T Wollan et al.
Oral elderberry extract in the treatment of influenza
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