Phytomedicine 22 (2015) 1195–1200 Contents lists available at ScienceDirect Phytomedicine journal homepage: www.elsevier.com/locate/phymed Antitussive effect of a fixed combination of Justicia adhatoda, Echinacea purpurea and Eleutherococcus senticosus extracts in patients with acute upper respiratory tract infection: A comparative, randomized, double-blind, placebo-controlled study Anders Barth b, Areg Hovhannisyan c,∗, Kristina Jamalyan a, Mikael Narimanyan a a Yerevan State Medical University of Armenia, Koryun 2 0025, Yerevan, Armenia b Partus Kvinnohälsa, Södra v. 2, 412 54, Göteborg c Anti-doping Service of Republican Centre of Sport Medicine, Acharyan Street, 2/6, Yerevan, Armenia article info abstract Article history: Background: Kan Jang® oral solution (KJ) is a fixed combination of aqueous ethanolic extracts of Justicia Received 20 August 2015 adhatoda L. leaf,Echinaceapurpurea(L.) Moench root, and Eleutherococcus senticosus (Rupr. & Maxim.) Harms Revised 2 October 2015 root. It is approved in Scandinavia as an herbal medicinal product for respiratory tract infection treatment. Accepted 4 October 2015 Purpose: The present clinical trial aimed to compare the antitussive effect of KJ with placebo (PL) and bromhexine (BH) among patients of 18–65 years old with non-complicated upper respiratory infections (URI; Keywords: i.e., common cold). Cough Study design: We performed a parallel-group, randomized, double-blinded, placebo-controlled trial in in 177 Kan Jang patients with acute URI over a 5 day period. Randomized controlled trial Methods: We investigated the antitussive effects of a KJ (30 ml/day; 762 mg genuine extracts with stan- dardized contents of 0.2 mg/ml vasicine, 0.8 mg/ml chicoric acid, and 0.03 mg/ml eleutherosides B and E), bromhexine hydrochloride (24 mg/30 ml/day) and PL on cough and blood markers. The primary outcome was cough relief, which was assessed as the change of cough frequency from baseline (cough index). Secondary outcomes were safety with regards to reported adverse events (AEs) and hematological data. Results: Both KJ and BH relieved cough more effectively than placebo. On the third and fourth days of treat- ment, we observed faster improvement in the group receiving KJ compared to in the groups receiving BH (100%) or PL (100%), indicating a slightly shorter recovery time in the KJ group. KJ showed a good tolerability and safety profile. Conclusion: KJ exerted significant antitussive effects in URI. The present data further support the therapeutic use of KJ in upper respiratory tract infections. © 2015 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Introduction sneeze and cough reflexes (Gwaltney and Ruckert, 1997). URIs are usually self-limiting, and thus treatments focus on reducing symp- An acute upper respiratory infection (URI) can affect the nose, si- tom duration and intensity, maximizing patient comfort, and limiting nuses, pharynx, larynx, and/or bronchi. Common URI symptoms in- complications. Cough due to URI is a frequent and disruptive symp- clude cough associated with serous or mucoid sputum (tracheitis, tom. Only limited evidence supports the few therapeutic agents avail- bronchitis); runny nose, sniffling, and nasal congestion (rhinitis); able to treat acute URI-related cough (Paul, 2012). Common cough hoarseness (laryngitis); difficulty swallowing and a sore, scratchy, treatments include narcotic antitussives, such as codeine and dex- and phlegmy throat (pharyngitis and tonsillitis); sore muscles and tromethorphan. Cough suppressants act on the brain to depress the general malaise; headache; and tiredness (Gwaltney, 2000). When cough reflex center (Reisine and Pasternak, 1996), and might be use- nasal cells are infected by a cold virus, inflammatory mediators are ful in some instances, but their efficacy is not fully proven when ex- released, stimulating nociceptors (pain nerve fibers) and activating pectoration is required (Heinrich et al., 2004). Preclinical studies show that J. adhatoda extracts have antitus- Abbreviations: KJ, Kan Jang ® oral solution; PL, placebo; BH, bromhexine. sive (Sarkar et al., 2014; Nosalova et al., 2013; Dhuley, 1999), ex- ∗ Corresponding author. Tel.: +37494 28 20 18. pectorant (Gibbs, 2009; Sharafkhaneh et al., 2007; Soni et al., 2008; E-mail address: [email protected] (A. Hovhannisyan). http://dx.doi.org/10.1016/j.phymed.2015.10.001 0944-7113/© 2015 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 1196 A. Barth et al. / Phytomedicine 22 (2015) 1195–1200 Grange and Snell, 1996), mucolytic (Gibbs, 2009; Sharafkhaneh et al., KJ compared to that of bromhexine (BH; positive control) and placebo 2007; Grange and Snell, 1996), antibacterial (Bose and Chatterjee, (PL; negative control). The study enrolled patients from the Yere- 2015; Zulqarnain et al., 2015; Singh and Sharma, 2013; Jha et al., van State Medical Centre of Armenia who presented acute uncompli- 2012; Shahwar et al., 2012; Jayashankar et al., 2011; Ignacimuthu cated URIs involving cough (ICD-10 codes J00–J06) between Novem- and Shanmugam, 2010; Gupta et al., 2010), and anti-inflammatory ber 2012 and August 2014. Inclusion criteria were age of 18–65 years (Singh and Sharma, 2013; Nosalova et al., 2013; Chakraborty and and predominant complaint of the first signs and symptoms of un- Brantner, 2001; Sharafkhaneh et al., 2007) effects. Several studies complicated URI (e.g., sore throat, blocked nose, runny nose, hoarse- describe the antitussive and respiratory effects of alkaloid vasicine ness, cough, headache, and general malaise). Patients were excluded and its oxidation product vasicinone isolated from Justicia adhatoda if they had a known history of allergies to cut flowers, herbs, or bit- L. leaves (Amin and Mehta, 1959; Cambridge et al., 1962; Mehta ter substances; had acute symptoms for over 36 hours or fever of et al., 1963; Bhide et al., 1974, 1976; Liu et al., 2015). Both in vitro and ˃38.5 °C; were taking antibiotics, anti-inflammatory drugs, or anti- in vivo studies show bronchodilatatory activity of vasicine at doses of histamine; or were pregnant or breast-feeding. Of the 180 patients 2.5–10 mg/kg, which increases with the combination of vasicine and recruited, 177 were included in the study. vasicinone. Vasicine reportedly shows the greatest activity against All included patients gave their written informed consent. The histamine-induced bronchospasm (Cambridge et al., 1962), increases study protocols were approved by the Health Research Ethics Board ciliary movements, and inhibits bronchial mucus secretion by 40–50% at the Yerevan Medical State University of Armenia (Protocol no. 01- (Gupta et al., 1977). Thus, the cough relief effects of Justicia adhatoda 2011-10-13). All patients monitoring was in compliance with the re- L. extract are mainly associated with the bronchodilation and mu- vised declaration of Helsinki. colytic effects of vasicine. However, the extract’s antitussive activity (Dhuley, 1999) is due to some other active constituents (Gupta et al., Subject withdrawals 1977). In animal studies, Justicia adhatoda L. extract shows 1/20–1/40 the antitussive activity of codeine with intravenous administration in Patients were free to withdraw from the study at any time. More- mechanically and electrically induced coughing, and antitussive ac- over, subjects were asked to withdraw from the study if they de- tivity similar to codeine with oral administration in coughing induced veloped an allergy or hypersensitivity to the study medication, de- by irritant aerosols (Dhuley, 1999). veloped serious side-effects, showed abnormal clinical biochemistry In vitro and in vivo experiments also show that Echinacea pur- values, or did not comply with the study protocol. No patients with- purea (L.) Moench, and Eleutherococcus senticosus (Rupr. & Maxim.) drew from the study. extracts activate immune system-stimulating cell defense mecha- nisms against viral and microbial infections (Echinaceae Purpureae Radix, 2009; Eleutherococci Radix, 2009). Moreover, E. senticosus in- Intervention and control treatments duces nonspecific resistance through adaptogenic effects that can ac- celerate recovery processes during convalescence (Radix Eleuthero- The KJ solution contained 9 mg/ml genuine extract (in 55% cocci, 2002). ethanol) from 23–63 mg dried root of Echinacea purpurea (L.) Moench The concepts of multi-target therapy and synergy suggest these radix (purple coneflower), 14 mg/ml genuine extract (in water) from three herbal drugs could be combined to produce a more effective 49–70 mg dried leaves of Justicia adhatoda L. folium (Malabar nut), and safe treatment, as has been demonstrated with numerous medi- and 2 mg/ml genuine extract (in 70% ethanol) from 34–60 mg cal treatments (Williamson, 2001; Wagner, 2006; Wagner and Ulrich- dried root of Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. Merzenich, 2009; Efferth and Koch, 2011). However, synergistic in- radix (Siberian ginseng). The solution base comprised sorbitol, hus- teractions of multiple constituents can be accompanied by many tenkräuter aroma, ginger extract, peppermint oil, dark syrup, ben- antagonistic and undesirable interactions (Panossian et al., 2013). zoate, and water. The preparation was standardized for contents of Therefore, clinical studies are needed to confirm the efficacy and vasicine (0.2 mg/ml), chicoric acid (0.8 mg/ml), and eleutherosides