Influenza, which is commonly called "the flu," is characterized by a viral infection of the lower respiratory tract that includes acute onset of cough and fever, accompanied with systemic symptoms such as headache, sweats and/or chills, fatigue, malaise, and myalgia.1 Influenza viruses are known to replicate predominately in the airway epithelia, as well as other host tissue and organs leading to airway congestion, inflammation, and necrosis.2 Unlike the common cold, the flu can cause severe illness and may result in life-threatening complications, especially with individuals considered at high risk such as young children, the elderly, pregnant women, and those with compromised immune systems. In the United States, acute respiratory tract infections severely influence morbidity and mortality during the fall and winter seasons and influenza plays a central role in this context.
An Echinacea purpurea extract is as effective as oseltamivir in early treatment of the flu.
The Centers for Disease Control presently recommends neuraminidase inhibitors for the early treatment of influenza. The neuraminidase inhibitor oseltamivir has demonstrated efficacy in reducing the duration and intensity of flu-associated symptoms. The success of drug treatment is dependent on the sensitivity of the circulating flu viruses in any given year because the influenza virus varies from year to year. Neuraminidase inhibitors, although effective, are associated with adverse effects that include nausea, vomiting, fever, and behavior changes, among others. According to Jefferson et al3, safety issues, risk of drug resistance, availability, and the importance of early administration may compromise the broad application of neuraminidase inhibitors.
Antiviral activity is present in certain phytomedicines (herbal medicine), including Echinacea, which has demonstrated antiviral activity against influenza viruses and has an established historical reference for the treatment of colds and flu. In a randomized, double-blind, double-dummy, multicenter, controlled clinical trial, the efficacy of a proprietary Echinacea purpurea formulation (Echinaforce Hotdrink) was compared with the neuraminidase inhibitor oseltamivir for the early treatment of influenza. The study results showed that Echinaforce Hotdrink was as effective as oseltamivir in the early treatment of clinically diagnosed influenza virus infections, with a reduced risk of complications and adverse effects.
PHYTOMEDICINE OVERVIEW4
Echinacea purpurea
Echinacea purpurea L. (Fam: Asteracea) is commonly known as a purple coneflower because of its distinctive petal coloration and daisy-like floral configuration. Echinacea is indigenous to North America, and holds historical significance as a medicinal plant by Native Americans who used root preparations for treating coughs, digestive upset, and easing pain associated with sore throat and toothache. Today, Echinacea is used primarily to reduce the symptoms and duration of colds, influenza, and upper respiratory tract infections and to help stimulate the activity of the immune system.
The phytochemistry, pharmacology, and medicinal properties of Echinacea preparations vary, depending on the species and the part of the plant used. Echinacea purpurea, which is one of the most widely studied and cultivated medicinal plant species, has been used as a preventive for infectious diseases in both upper and lower respiratory systems.5,6 The complex chemical composition of Echinacea purpurea aerial and root parts includes caffeic acid derivatives (0.6%-2.1% roots), including cichoric acid (1.2%-3.1% flowers), alkamides (0.001%-0.4%), water-soluble polysaccharides (arabinoxylan and arabinogalactan), and flavonoids of quercetin and kaempferol (0.48%), which are credited for the noted immunostimulatory and anti-inflammatory activities.7 The root of Echinacea purpurea differs in its constituents from the aerial plant parts by containing polyacetylene derivatives, polysaccharides (fructosans, arabinogalactans), and glycoproteins consisting of 3% protein.
The immunostimulant activity of Echinacea purpurea is a result of its combined effect of several chemical constituents and is caused by 3 mechanisms: phagocytosis activation, fibroblast stimulation, and the enhancement of respiratory activity that results in augmentation of leukocyte mobility.8 Several in vivo studies indicate that immunomodulatory and anti-inflammatory effects of Echinacea purpurea are a result of enhanced innate immunity through the administration of the plant actives and that the immune system is strengthened against pathogenic infections through activation of macrophages, neutrophils, polymorphonuclear leukocytes, and natural killer cells. In addition, the pharmacologically active alkalamides are particularly involved in the immunomodulatory effect.
Echinacea purpurea has demonstrated potent antiviral activity against viruses with membranes including specific rhinoviruses (1A and 14), influenza virus, respiratory syncytial virus, adenovirus types 3 and 11, and herpes simplex virus type 1.9 A standardized hydroethanolic extract of freshly harvested Echinacea purpurea has shown strong antiviral activity against several influenza viruses, including H1N1, H3N2, H5N1, H7N7, and H1N1pdm2009.9,10 In addition to Echinacea's direct inhibitory action against influenza viruses, its anti-inflammatory and immunomodulatory properties contribute to its overall phytopharmacologic activity.
Sambucus nigra
Sambucus nigra var. canadensis L. (Fam: Caprifoliaceae), or elderberry has been used medicinally since the fifth century BC, and is recorded in the writings of Hippocrates, Dioscorides, and Pliny. Elderberry has been used historically as a diaphoretic, diuretic, astringent, laxative, and emetic. A sweetened syrup that was made from the extracted juice of elderberries was a traditional remedy for colds, coughs, and bronchial conditions. Native Indigenous Peoples used elderberry in treating rheumatism, colds, and fever.
In modern herbal medicine, extracts of elderberries are used primarily for the treatment of colds, influenza, feverish conditions, and for its immunomodulating effects. Although the leaves, bark, and flowers have been used in phytomedicines, most clinical studies have been conducted on the berry (fruit). Elderberry fruits contain several active constituents, including flavonoids (quercetin and rutin), anthocyanins (cyaniding-3-glucoside and cyaniding-3-sambubioside), cyanogenic glycosides (including sambunigrin), and vitamins A and C. Although the pharmacokinetics of several of the constituents is not completely understood, the flavonoids and anthocyanins seem to be the primary biologically active compounds. Clinical studies have found that elderberry extracts can inhibit influenza A and B infections, and preclinical studies have shown antiviral effects.1 Clinical studies have shown that flavonoids bind to the surface of the H1N1 influenza virus and interfere with host cell receptor recognition and/or binding.11
RESEARCH IN REVIEW12 OBJECTIVE
The primary objective of this study was to compare an herbal medicine proprietary Echinacea purpurea formulation (Echinaforce Hotdrink) with the neuraminidase inhibitor oseltamivir for the treatment of influenza.
TEST AGENTS
The phytomedicine test material used in the clinical trial was the commercially available Echinaforce Hotdrink concentrate (A. Vogel Echinaforce, http://www.Avogel.ca, United States; A. Vogel Bioforce AG, Roggwil, Switzerland), a proprietary hydroethanolic extract (65% v/v) of freshly harvested Echinacea purpurea. The tinctures from the herb (drug extraction ratio 1:12) and from the roots (drug extraction ratio 1:11) are combined at a ratio of 95% to 5%. Echinaforce Hotdrink contains 228 mg/mL of Echinacea purpurea herb extract, 12 mg/mL of Echinacea purpurea root extract, 276.5 mg/mL of Sambucus nigra berry juice, and excipients that produce 1 mL of Echinaforce Hotdrink.
The comparison test material was the neuraminidase inhibitor oseltamivir that was provided as an overencapsulation (dark green gelatin capsules) of the original oseltamivir capsules (Tamiflu 75 mg; Hoffmann-La Roche AG, Basel, Switzerland). The placebo consisted of gelatin capsules containing microcrystalline cellulose that were indistinguishable from the oseltamivir containing test material.
STUDY DESIGN
This study was a randomized, double-blind, parallel, double-dummy controlled multicenter clinical trial that was conducted at 29 general practices over a period of 10 days in the Prague area of the Czech Republic. The study participants (n = 473) consisted largely of adults, between 18 and 70 years of age (n = 464); with a mean age of 37 years, and 9 (n = 9) children and adolescents between the ages of 12 and 17 who met the inclusion criteria of early acute influenza symptoms. The inclusion criteria corresponded to the circulation period of the influenza viruses common to the community from November 2013 to April 2013. Patients with clinically diagnosed influenza were recruited as early as possible, less than 48 hours after the initial onset of symptoms. Clinical diagnosis of influenza was based on the presence of at least 1 respiratory symptom, including sore throat, cough, or nasal symptoms, 1 systemic symptom (eg, headache, sweats and/or chills, fatigue, malaise, and myalgia), and fever (>=37.8[degrees]). In addition, subjects were provided nasal swab testing of nasal secretions for viral identification, which further enhanced diagnostic specificity. Inclusion prerequisites consisted of a body weight more than 40 kg, good general health, a negative pregnancy test, and a signed informed consent. The exclusion criteria consisted of the intake of steroid or immune-suppressive medication; influenza vaccination within the past 12 months; antimicrobial agents in the past month; cardiovascular disease, kidney disease, respiratory disorders; known allergic reaction to plants of the Asteraceae (Compositae) family; alcohol or drug abuse, and other limitations.
PROCEDURE
During the initial intake visit, eligible patients were given a physical examination; blood pressure and heart rate were assessed, and blood and sample nasal secretions were taken. Participants received a journal to record daily symptoms of influenza during the treatment period. The physical baseline values, including heart rate and blood pressure, were similar in the treatment groups.
Eligible patients were randomly allocated to receive either Echinaforce Hotdrink or oseltamivir treatment. A total of 237 patients (n = 237) were administered Echinaforce Hotdrink syrup and oseltamivir placebo capsules. Patients in this test group were instructed to take 5 mL of Echinaforce Hotdrink syrup dissolved into 150 mL of hot water, 5 times per day for the first 3 days, then 5 mL of the syrup, 3 times per day for the following 7-day period. At the same time, these patients were instructed to take oseltamivir placebo capsules twice a day for each of the 10 days. In the oseltamivir test group (n = 236), the same regimen was followed but with Echinaforce Hotdrink placebo and 1 capsule of oseltamivir taken twice per day for the first 5 days, followed by oseltamivir placebo capsules for the remaining 5 days.
TREATMENT ASSESSMENT
Participants recorded their influenza symptoms in the morning and evening, throughout the study period or until recovery. Severity of cough, nasal congestion, sore throat, fatigue, headache, fever, myalgia, malaise, sweats, and/or chills were recorded on a scale of 0 to 3 (0 = not present, 1 = mild, 2 = moderate, 3 = severe). Axillary body temperature was measured; sleep disturbances and the ability to resume regular daily activities were noted, along with the occurrence of any complications (eg, sinusitis, bronchitis, or pneumonia). Patients and attending physicians rated tolerability and efficacy on a subjective basis using a Likert scale of 1 to 4 (1 = very good, 2 = good, 3 = moderate, and 4 = poor).
The cumulative proportion of patients that recovered from influenza symptoms after the first, fifth, and tenth days of treatment was selected as the primary end point of the study. Recovery was defined as the first day when symptoms were rated as mild or absent in the evening. Secondary variables included measured outcomes of body temperature, days without sleep disturbance, and the time required to resume normal activities.
SUMMARY OF RESULTS
The analysis of total patients with clinically diagnosed influenza was assessed, and results indicated that both the Echinaforce Hotdrink syrup and the oseltamivir treatment were efficacious. Recovery from influenza symptoms was observed in the 2 treatment groups at 1.5% versus 4.1% after day 1, 50.2% versus 48.8% after 5 days, and 90.1% versus 84.4% after 10 days of treatment with Echinaforce and oseltamivir, respectively. The incidence of complications was lower with Echinaforce Hotdrink in comparison with oseltamivir (2.46% vs 6.45%; P = .076) and fewer adverse side effects occurred were observed in the Echinaforce Hotdrink treatment group.
Researchers concluded that the study results suggest that Echinaforce Hotdrink is as effective as the neuraminidase inhibitor oseltamivir in the early treatment of clinically diagnosed and virologically confirmed influenza infections in patients without concomitant diseases and who are not considered part of an "at risk" population. There were no reported limitations to this study.
REFERENCES