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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.

ABSTRACT

Background: Kan Jang[R] oral solution (KJ) is a fixed combination of aqueous ethanolic extracts of Justicia adhatoda L. leaf, Echinacea purpurea (L.) Moench root, and Eleutherococcus senticosus (Rupr. & Maxim.) Harms root. It is approved in Scandinavia as an herbal medicinal product for respiratory tract infection treatment.

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; i.e., common cold).

Study design: We performed a parallel-group, randomized, double-blinded, placebo-controlled trial in in 177 patients with acute URI over a 5 day period.

Methods: We investigated the antitussive effects of a KJ (30 ml/day; 762 mg genuine extracts with standardized 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 treatment, 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 URL The present data further support the therapeutic use of KJ in upper respiratory tract infections.

Keywords:

Cough

Kan Jang

Randomized controlled trial

Introduction

An acute upper respiratory infection (URI) can affect the nose, sinuses, pharynx, larynx, and/or bronchi. Common URI symptoms include cough associated with serous or mucoid sputum (tracheitis, bronchitis); runny nose, sniffling, and nasal congestion (rhinitis); hoarseness (laryngitis); difficulty swallowing and a sore, scratchy, and phlegmy throat (pharyngitis and tonsillitis); sore muscles and general malaise; headache; and tiredness (Gwaltney, 2000). When nasal cells are infected by a cold virus, inflammatory mediators are released, stimulating nociceptors (pain nerve fibers) and activating sneeze and cough reflexes (Gwaltney and Ruckert, 1997). URIs are usually self-limiting, and thus treatments focus on reducing symptom duration and intensity, maximizing patient comfort, and limiting complications. Cough due to URI is a frequent and disruptive symptom. Only limited evidence supports the few therapeutic agents available to treat acute URI-related cough (Paul, 2012). Common cough treatments include narcotic antitussives, such as codeine and dextromethorphan. Cough suppressants act on the brain to depress the cough reflex center (Reisine and Pasternak, 1996), and might be useful in some instances, but their efficacy is not fully proven when expectoration is required (Heinrich et al., 2004).

Preclinical studies show that J. adhatoda extracts have antitussive (Sarkar et al., 2014; Nosalova et al., 2013; Dhuley, 1999), expectorant (Gibbs, 2009; Sharafkhaneh et al., 2007; Soni et al., 2008; Grange and Snell, 1996), mucolytic (Gibbs, 2009; Sharafkhaneh et al., 2007; Grange and Snell, 1996), antibacterial (Bose and Chatterjee, 2015; Zulqarnain et al., 2015; Singh and Sharma, 2013; jha et al., 2012; Shahwar et al., 2012; Jayashankar et al., 2011; Ignacimuthu and Shanmugam, 2010; Gupta et al., 2010), and anti-inflammatory (Singh and Sharma, 2013; Nosalova et al., 2013; Chakraborty and Brantner, 2001; Sharafkhaneh et al., 2007) effects. Several studies describe the antitussive and respiratory effects of alkaloid vasicine and its oxidation product vasicinone isolated from Justicia adhatoda L. leaves (Amin and Mehta, 1959; Cambridge et al., 1962; Mehta et al., 1963; Bhide et al., 1974, 1976; Liu et al., 2015). Both in vitro and in vivo studies show bronchodilatatory activity of vasicine at doses of 2.5-10 mg/kg, which increases with the combination of vasicine and vasicinone. Vasicine reportedly shows the greatest activity against histamine-induced bronchospasm (Cambridge et al., 1962), increases ciliary movements, and inhibits bronchial mucus secretion by 40-50% (Gupta et al., 1977). Thus, the cough relief effects of Justicia adhatoda L. extract are mainly associated with the bronchodilation and mucolytic effects of vasicine. However, the extract's antitussive activity (Dhuley, 1999) is due to some other active constituents (Gupta et al., 1977). In animal studiesjustida adhatoda L. extract shows 1/20-1/40 the antitussive activity of codeine with intravenous administration in mechanically and electrically induced coughing, and antitussive activity similar to codeine with oral administration in coughing induced by irritant aerosols (Dhuley, 1999).

In vitro and in vivo experiments also show that Echinacea purpurea (L) Moench, and Eleutherococcus senticosus (Rupr. & Maxim.) extracts activate immune system-stimulating cell defense mechanisms against viral and microbial infections (Echinaceae Purpureae Radix, 2009; Eleutherococci Radix, 2009). Moreover, E. senticosus induces nonspecific resistance through adaptogenic effects that can accelerate recovery processes during convalescence (Radix Eleutherococci, 2002).

The concepts of multi-target therapy and synergy suggest these three herbal drugs could be combined to produce a more effective and safe treatment, as has been demonstrated with numerous medical treatments (Williamson, 2001; Wagner, 2006; Wagner and Ulrich-Merzenich, 2009; Efferth and Koch, 2011). However, synergistic interactions of multiple constituents can be accompanied by many antagonistic and undesirable interactions (Panossian et al., 2013). Therefore, clinical studies are needed to confirm the efficacy and safety of new combinations.

Kan Jang[R] oral solution (KJ) is a fixed combination of aqueous ethanolic extracts of Justicia adhatoda L. leaf, Echinacea purpurea (L.) Moench root, and Eleutherococcus senticosus (Rupr. & Maxim.) Harms root, which is approved in Scandinavia as an herbal medicinal product for URI treatment. A clinical study demonstrated the efficacy of KJ (30 ml taken 3 times daily for 6 days) for relief of inflammatory symptoms (e.g., throat irritability, cough severity, efficacy of mucus discharge in the respiratory tract, nasal congestion, and general feelings of sickness) among patients with acute URIs (Narimanian et al., 2005). That study included three arms--KJ, the combination of Echinacea purpurea and Eleutherococcus senticosus, and the positive active control bromhexine hydrochloride--without a placebo group. Thus, there remains a need to test the antitussive potential and safety of KJ compared with placebo.

The present study aimed to evaluate the efficacy and tolerability of KJ compared to placebo and the active control bromhexine, with regard to its antitussive effect in patients with non-complicated URIs.

Materials and methods

Study design

We designed a randomized, placebo-controlled, three-arm parallel-group, double-blind phase II trial to investigate the efficacy of KJ compared to that of bromhexine (BH; positive control) and placebo (PL; negative control). The study enrolled patients from the Yerevan State Medical Centre of Armenia who presented acute uncomplicated URIs involving cough (ICD-10 codes J00-J06) between November 2012 and August 2014. Inclusion criteria were age of 18-65 years and predominant complaint of the first signs and symptoms of uncomplicated URI (e.g., sore throat, blocked nose, runny nose, hoarseness, cough, headache, and general malaise). Patients were excluded if they had a known history of allergies to cut flowers, herbs, or bitter substances; had acute symptoms for over 36 hours or fever of > 38.5 [degrees]C; were taking antibiotics, anti-inflammatory drugs, or antihistamine; or were pregnant or breast-feeding. Of the 180 patients recruited, 177 were included in the study.

All included patients gave their written informed consent. The study protocols were approved by the Health Research Ethics Board at the Yerevan Medical State University of Armenia (Protocol no. 01-2011-10-13). All patients monitoring was in compliance with the revised declaration of Helsinki.

Subject withdrawals

Patients were free to withdraw from the study at any time. Moreover, subjects were asked to withdraw from the study if they developed an allergy or hypersensitivity to the study medication, developed serious side-effects, showed abnormal clinical biochemistry values, or did not comply with the study protocol. No patients withdrew from the study.

Intervention and control treatments

The KJ solution contained 9 mg/ml genuine extract (in 55% ethanol) from 23-63 mg dried root of Echinacea purpurea (L.) Moench radix (purple coneflower), 14 mg/ml genuine extract (in water) from 49-70 mg dried leaves of Justicia adhatoda L. folium (Malabar nut), and 2 mg/ml genuine extract (in 70% ethanol) from 34-60 mg dried root of Eleutherococcus senticosus (Rupr. & Maxim.) Maxim, radix (Siberian ginseng). The solution base comprised sorbitol, hustenkrauter aroma, ginger extract, peppermint oil, dark syrup, benzoate, and water. The preparation was standardized for contents of vasicine (0.2 mg/ml), chicoric acid (0.8 mg/ml), and eleutherosides B and E (0.03 mg/ml). Validated HPLC methods were used to evaluate selectivity, accuracy, and precision (RSD < 5%) (Supplementary Fig. 1). KJ was manufactured following GMP and released by the Swedish Herbal Institute Research & Development, Vallberga, Sweden (Batch no. 2733).

The active control was the standard over-the-counter medication bromhexine hydrochloride (Batch no. 116075; Boehringer Ingelheim) at a concentration of 1.6 mg/ml. This BH was dissolved in a liquid matrix containing the same excipients as the Kan Jang oral solution: sorbitol, hustenkrauter aroma, ginger extract, peppermint oil, dark syrup, benzoate, and water. The final BH concentration was 0.8 mg/ml (Batch no. 50136). The placebo was a mixture of sorbitol, hustenkrauter aroma, ginger extract, peppermint oil, dark syrup, benzoate, and water (Batch no. 50135). Reference samples were stored at the QC laboratory of the Swedish Herbal Institute.

Allocation and blinding

Participants each received a labeled paper box containing either KJ, bromhexine, or placebo in a dark glass 300 ml bottle with a cap, sealing ring, and a measuring dosage cup (graduated at 5, 10, 15, 20, and 30 ml). KJ, BH, and PL preparations all had a similar appearance, test, smell, color, test, and viscosity and were organoleptically undistinguishable. The trial subjects were blinded to their treatment since the labeled bottles contained solutions of identical appearance.

To ensure that the study was double-blind, the study investigators were also blinded to the treatment type using the following procedures. Prior to the study, a treatment randomization code was generated at the factory, which contained information about the contents of each bottle, e.g., encoding KJ, BH, or PL This code was generated using the Excel Random Number Generator, with a table containing three columns (A, B, and C) that was filled with randomly distributed unique numbers from 1 to 198. KJ, PL, and BH were assigned to sets of bottles A, B, and C at the manufacturing site. The treatment randomization code was kept by a qualified pharmacist (QP) at the investigational product manufacturing site, and was provided to the Principal Investigator when all patients completed the treatment.

Participants were enrolled by the principal investigator in collaboration with study doctors. The study monitor assigned patients to study groups A, B, and C. The study monitor did not receive the randomization code until the end of the study. The Principal Investigator generated the Study Participants list, identifying the patients and the study supplement packages (treatment numbers). At the end of the study, statistical analyses were performed using the Study Participants list to compare the data obtained in groups A, B, and C. Following these statistical analyses, the QP broke the code providing the actual assignments of groups A, B, and C.

Patient intervention and examinations

At visit 1 (Supplementary Fig. 2), patients underwent a routine medical examination that included physical examinations (anamnesis collection, detailed chest auscultation and percussion, and thermometry) and laboratory blood hematological tests. During this initial examination, the doctor counted the cough frequency (number of coughing bouts within 30 min), recorded the results in the Case Report Form (CRF), and instructed patents in how self-assess their cough frequency at home. Each participant was provided a report form, and was instructed to count the number of coughing bouts for 30 min following the first coughing incident in the morning immediately after waking up.

Patients who passed their initial examination and gave informed consent to participate were then assigned to a randomized study medication. They were provided this medication and asked to take 30 ml of oral solution per day for the next 5 days. The medication was to be taken 30 min after eating breakfast. The patients were also instructed to regularly record the degree of their clinical symptoms and the amount of medication taken daily on a patient's-self assessment forms. At the end of the study (visit 2, day 5), the patients again met with a doctor. At this visit, the doctor checked compliance (liquid consumption) and checked and signed the patient's completed forms.

Outcomes

The primary outcome was efficacy of treatment (Cough Relief Index), which was determined based on the difference between the cough frequency on day 1 (baseline, determined by the physician at visit 1) and on each successive day of treatment (determined by the patient at home). Cough frequency (the number of coughing bouts in 30 min) was expressed using a fixed scale from 0 to 9, where 0 indicated no cough, 1-3 a mild cough, 4-6 a moderate cough, and 7-9 a severe cough. The mean cough frequency value at baseline was 5.0-5.3, indicating a moderate cough (Table 1). Patients were instructed to immediately contact the investigator should they experience any study events, defined as any relevant event experienced by the patient during the study. Given examples included adverse effects and inter-current illness. In the event of any allergic reactions, such as skin rash, the medication would be stopped.

In addition to study events, safety was monitored using hematological data. Laboratory blood analyses were performed using samples from day 1 and day 5. Analyses included hemoglobin, red blood cell count (RBC), color index, neutrophil count, basophil count, eosin plates, and white blood cells (WBC), and were performed using an Automated Hematology Analyzer pocH-100i (Sysmex Corporation, Cobe, Japan).

Sample size considerations

The sample size for the present study was calculated based on an effect size of 1.42 from a comparable study of KJ in URIs, in which cough and other inflammatory symptoms were used as efficacy outcome measures (Narimanian et al., 2005). Using a two sided, two-sample t-test, it was calculated that 30 participants in each group were required to detect an absolute mean difference of 1.42 on the cough relief score between the KJ and BH groups with 95% power at a 0.05 level of significance (Stat-Mate, version 2.00, 2004; GraphPad Software, Inc.). We prepared for a 20% drop-out rate, increasing our intended sample size to 118 participants (36 in each group). In the completed trial, we had over 99% power to detect a between-means difference of 0.28 with a two-tailed alpha of 0.05: KJ, n = 66, SD = 0.43; BH, n = 57, SD = 0.40; and PL, n = 54, SD = 0.28.

Statistical analysis

At each visit, data were recorded using a standardized assessment method, and recorded in an Excel database that was used for further data management and statistical analyses (Evererett, 1989). GraphPad Prism software version 3.03 for Windows (San Diego, CA, USA) was used for statistical analyses and graph generation. The primary analysis followed intention-to-treat principles. Statistical analyses were performed using "observed" data, and involved evaluating the patient's change in scores from the initial visit (baseline) to later days of the study and the final visit. All statistical tests were two-sided, with a 0.05 level of significance.

Before within-group or between-group comparisons, all data were checked for normality, with a cut-off value of 0.05. Based on the normality test results, comparative assessment of the baseline characteristics between groups (KJ vs. PL and BH) was performed using either the Kruskal--Wallis non-parametric one-way ANOVA rank-order test, with post-hoc Dunn's Multiple Comparison Test or the parametric one-way independent measures ANOVA with Dunnett's Multiple Comparison Test. Changes within treatment groups over the course of the study (before vs. after) were analyzed using the paired t-test for parametric data (variables with normal distribution) and the Wilcoxon signed-rank test or the Friedman test for several repeated measures for non-parametric data. To assess the efficacy of the study supplements, we compared the mean changes from baseline for each patient and each group (KJ vs. PL and BH) using the Kruskal--Wallis non-parametric one-way ANOVA rank-order test, with post-hoc Dunn's Multiple Comparison Test, and/or the parametric one-way independent measures ANOVA with Dunnett's Multiple Comparison Test (for variables with normal distribution).

Results

Study participants and baseline variables

A total of 180 subjects were recruited and 177 patients were included in this study. These patients were randomly divided into three groups. Participants flow is outlined in Supplementary Fig. 3. Table 1 presents the baseline demographic and clinical characteristics of each group and the relevant baseline data. The groups did not significantly differ in baseline demographics or other parameters (Table 1).

Treatment efficacy

Over the course of the study, each group showed significant relief of cough compared to the baseline and/or each previous day (Tables 2 and 3).

Cough relief was measured as the change of the cough index from baseline. On the third and fourth days of treatment, we found a significantly greater cough relief effect with KJ treatment compared to PL and BH (Table 4, Supplementary Fig. 4). On the third treatment day, the cough relief effect was 1.97 [+ or -] 0.021 in the KJ group, compared to 1.759 [+ or -] 0.079 in the placebo group (P < 0.05) and 1.772 [+ or -] 0.083 in the BH group (P < 0.05). The difference in effect and the statistical significance of the difference between the KJ and BH groups was maximal on day 4 (P < 0.01). At the end of treatment (day 5), all patients had recovered, and the cough relief effects were similar in the KJ and BH groups (P > 0.05). Our data also showed a greater speed of recovery (assessed as cough relief effect) for patients in the KJ and positive control groups compared to in the placebo group.

Safety

The treatment was well tolerated. No serious adverse events were observed. Over the 5 day study period, a total of 12 minor adverse events were observed in 12 patients: 4 in the PL group (7.4%), 2 in the KJ group (3.9%), and 6 in the BH group (10.5%). Minor adverse events included pruritus, diarrhea, abdominal pain, and skin rash. The proportion of patients reporting adverse events did not significantly differ between groups, and these events were not considered to be treatment-related.

Hematological and immunological parameters

The only statistically significant between-group difference at the end of the study (day 5) was that lymphocyte count differed between the BH and KJ groups (Table 5).

Discussion

Kan Jang[R] is a brand of herbal medicinal products that are used in Scandinavia to treat URls. Previous trials of drugs in various stages of development have investigated formulations containing Herba Adrographidis extract, including a monodrug (Hancke et al., 1995; Caceres et al., 1997) and fixed combinations of Herba Andrographidis extract with Radix Eleutherococci (Melchior et al., 2000; Gabrielian et al., 2002; Kulichenko et al., 2003; Poolsup et al., 2004; Kligler et al., 2006) or Radix Echinacea extracts (Spasov et al.,2004). Herbal tablets or capsules with standardized andrographolide content are mainly indicated for early prevention and relief of the symptoms of URIs.

Another group of Kan Jang formulations includes fixed combinations of Folia Adhatoda extracts with extracts of Radix Eleutherococci and E. pallida (Thom and Wollan, 1997) or E. purpurea (Narimanian et al., 2005). Oral solutions of these fixed combinations are indicated for cough relief, with the efficacy presumably due to the antitussive, bronchodilating, and expectorant effects of the alkaloid vasicine (Amin and Mehta, 1959; Cambridge et al., 1962; Mehta et al., 1963; Bhide et al., 1974, 1976; Liu et al., 2015), which is an active constituent of J. adhatoda leaf extract. Its semi-synthetic derivative bromhexine (Bisolvon) (Grange and Snell, 1996) is widely used as an over-the-counter mucolytic medication to reduce cough (Parvez et al., 1996), particularly as an adjunct to antibiotics for acute pneumonia in children and adults (Chang et al., 2014).

The present clinical trial investigated the antitussive effect of a Kan Jang[R] oral solution containing a fixed combination of aqueous and ethanolic extracts of Justicia adhatoda L. leaf, Echinacea purpurea (L.) Moench root, and Eleutherococcus senticosus (Rupr. & Maxim.) Harms root extracts (KJ). Our randomized double-blind three-arm study aimed to compare the efficacy and tolerability of KJ with a placebo and with the active control BH with respect to the antitussive effect. The efficacy was analyzed based on patient self-evaluations using a standard rating scale from 0-9 to indicate cough frequency and intensity.

The three treatment groups did not significantly differ at baseline or at the end of treatment when all patients were almost fully recovered. On the second day of treatment, we observed significant improvement and antitussive effect in all treatment groups (including placebo), which gradually increased over the following days. On the third and fourth days of treatment, the KJ group showed a greater reduction of cough intensity compared to both the PL and BH groups, indicating a quicker recovery in the KJ group. All treatments were well tolerated, with no serious adverse events, and only 12 minor adverse events, including mild pruritus in 6 patients (2 in each group). Overall, our data showed that KJ exerted significantly more rapid antitussive effects in acute upper respiratory tract infections compared to both BH and placebo. Moreover, KJ showed good tolerability and a good safety profile.

Conclusion

Kan Jang[R] oral solution exhibits significant antitussive effects in acute upper respiratory tract infections. It has good tolerability profile.

ARTICLE INFO

Article bistory:

Received 20 August 2015

Revised 2 October 2015

Accepted 4 October 2015

Conflict of interest

No conflict of interests declared.

Acknowledgments

This work was supported in part by the Swedish Herbal Institute Research & Development.

Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.phymed.2015.10.001.

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Anders Barth (b), Areg Hovhannisyan (c),*, Kristina Jamalyan (a), Mikael Narimanyan (3)

(a) Yerevan State Medical University of Armenia, Koryun 2 0025, Yerevan, Armenia

(b) Partus Kvinnohalsa, Sodra v. 2, 412 54, Goteborg

(c) Anti-doping Service of Republican Centre of Sport Medicine, Acharyan Street, 2/6, Yerevan, Armenia

Abbreviations: KJ, Kan Jang[R] oral solution; PL, placebo; BH, bromhexine.

* Corresponding author. Tel.: +37494 28 20 18.

E-mail address: areg@armnado.am (A. Hovhannisyan).

http://dx.doi.org/10.1016/j.phymed.2015.10.001
Table 1
Demographic characteristics and baseline of frequency
of cough of patients entered the study, n = 177.

                      Mean [+ or -] SD

                      KJ                    PL

Number of patients    66                    54
Males/Females         30/36                 25/29
Age                   34.8 [+ or -] 11.39   31.9 [+ or -] 11.57
Cough frequency       5.30 [+ or -] 0.07    5.04 [+ or -] 0.09

                      Mean [+ or -] SD      P value

                      BH

Number of patients    57                    KJ vs. PL   KJ vs. BH
Males/Females         21/36                 >0.05       >0.05
Age                   32.1 [+ or -] 10.38   >0.05       >0.05
Cough frequency       5.12 [+ or -] 0.08    >0.05       >0.05

Table 2
Baseline cough frequency scores at the beginning (day 1) and
the end (day 5) of the study.

Baseline score            Day 5 score

Score   KJ   PL   BH      Score   KJ   PL   BH

7       3    0    0       4       2    4    0
6       26   20   26      3       3    9    4
5       70   65   60      2       29   31   40
4       2    13   14      1       65   48   44
3       0    2    0       0       2    7    12

Table 3
Cough frequency in the course of the study and cough relief
(Cough index) at the end of the treatment: within group
comparison.

                        KJ                      PL
                        n = 66                  n = 54
                        mean [+ or -] SD        mean [+ or -] SD

Baseline, Day 1         5.303 [+ or -] 0.554    5.037 [+ or -] 0.643
Day 2                   4.333 [+ or -] 0.591    4.111 [+ or -] 0.691
Day 3                    3333 [+ or -] 0.591    3.278 [+ or -] 0.787
Day 4                   2.364 [+ or -] 0.598    2.463 [+ or -] 0.884
Day 5                   1.379 [+ or -] 0.651    1.537 [+ or -] 0.905
Cough index on the      3.924 [+ or -] 0.1052   3.500 [+ or -] 0.1511
  day 5: change from    <0.0001                 <0.0001
  baseline, P value

                        BH
                        n = 57
                        mean [+ or -] SD

Baseline, Day 1         5.140 [+ or -] 0.666
Day 2                   4.281 [+ or -] 0.726
Day 3                   3.368 [+ or -] 0.858
Day 4                   2.526 [+ or -] 0.966
Day 5                   1.351 [+ or -] 0.744
Cough index on the      3.772 [+ or -] 0.1290
  day 5: change from    <0.0001
  baseline, P value

* The intensity of cough measured as a cough index between groups
did not show any significant difference at the start.

Table 4
Efficacy of treatment of the frequency of cough: cough index
(cough relief effect form the baseline, day 1) in treatment
groups in the course of the treatment: between groups comparison.

         KJ                     PL
         n = 66                 n = 54
         mean [+ or -] SD       mean [+ or -] SD

Day 2    0.970 [+ or -] 0.173   0.926 [+ or -] 0.381
Day 3     1.97 [+ or -] 0.172   1.759 [+ or -] 0.581
Day 4    2.939 [+ or -] 0.241   2.574 [+ or -] 0.716
Day 5    3.924 [+ or -] 0.404   3.500 [+ or -] 0.795

         BH                     KJ vs. PL         KJ vs. BH
         n = 57                 P value and       P value and
         mean [+ or -] SD       summary           summary

Day 2    0.860 [+ or -] 0.398   >0.05 ns          >0.05 ns
Day 3    1.772 [+ or -] 0.627   <0.05 *           <0.05 *
Day 4    2.614 [+ or -] 0.773   <0.01 **          <0.01 **
Day 5    3.772 [+ or -] 0.567   <0.001 ***        >0.05 ns

Table 5
Inter-groups comparison of hematological/immunological parameters.

                         KJ                      PL
                         n = 66                  n = 54
                         mean [+ or -] SD        mean [+ or -] SD

Hemoglobin, (g/l) [Norm--120-160 g/l]
Baseline                 127.1 [+ or -] 13.31    128.2 [+ or -] 13.06
Day 5                    126.4 [+ or -] 13.23    127.6 [+ or -] 12.88
Change from baseline     0.677 [+ or -] 2.310    0.531 [+ or -] 2.496

RBC, (10 x 12/l) [Norm--3.5-5.0 [10.sup.12]/l]
Baseline                 3.718 [+ or -] 0.387    3.752 [+ or -] 0.367
Day 5                    3.644 [+ or -] 0.366    3.687 [+ or -] 0.338
Change from baseline     0.074 [+ or -] 0.065    0.065 [+ or -] 0.068

Color Index, [Norm--0.85-1.05]
Baseline                 0.942 [+ or -] 0.049    0.943 [+ or -] 0.05
Day5                     0.945 [+ or -] 0.050    0.946 [+ or -] 0.05
Change from baseline     -0.003 [+ or -] 0.009   -0.004 [+ or -] 0.01

Neutrophils, % [Norm--1-6%]
Baseline                 3.045 [+ or -] 1.513    3.037 [+ or -] 1.479
Day 5                    2.530 [+ or -] 1.14     2.519 [+ or -] 1.285
Change from baseline     0.561 [+ or -] 0.096    0.518 [+ or -] 0.267

Basophils, % [Norm--47-72%]
Baseline                 64.08 [+ or -] 4.368    64.09 [+ or -] 4.127
Day 5                    62.97 [+ or -] 4.325    62.70 [+ or -] 3.451
Change from baseline     1.106 [+ or -] 0.785    1.389 [+ or -] 0.732

Eosinophils, % [Norm--0.5-5.0%]
Baseline.                3.515 [+ or -] 0.662    3.426 [+ or -] 0.716
Day 5                    2.955 [+ or -] 0.409    2.870 [+ or -] 0.516
Change from baseline     0.5606 [+ or -] 0.096   0.556 [+ or -] 0.120

Lymphocytes, %, [Norm--19-37%]
Baseline                 24.24 [+ or -] 4.581    25.22 [+ or -] 4.756
Day 5                    23.38 [+ or -] 4.205    23.37 [+ or -] 5.275
Change from baseline     0.864 [+ or -] 0.765    1.852 [+ or -] 0.967

Monocytes, % [Norm--2.9-11%]
Baseline                 3.045 [+ or -] 0.325    2.963 [+ or -] 0.433
Day 5                    3.000 [+ or -] 0.248    2.907 [+ or -] 0.293
Change from baseline     0.045 [+ or -] 0.050    0.055 [+ or -] 0.071

Erythrocytes sedimentation rate (ESR). mm/h [Norm--2-20 mm/h]
Baseline                 20.74 [+ or -] 4.531    19.26 [+ or -] 4.639
Day 5                    19.21 [+ or -] 4.219    17.33 [+ or -] 4.421
Change from baseline     1.530 [+ or -] 0.762    1.926 [+ or -] 0.872

Whyte blood cells, WBC (10 x 9/L) [Norm -4-9.0 [10.sup.9]/l]
Baseline                 8.524 [+ or -] 0.581    8.287 [+ or -] 0.673
Day 5                    8.232 [+ or -] 0.612    8.023 [+ or -] 0.640
Change from baseline     0.292 [+ or -] 0.104    0.264 [+ or -] 0.127

                         BH                      KJ vs. PL   KJ vs. BH
                         n = 57                  P value     P value
                         mean [+ or -] SD

Hemoglobin, (g/l) [Norm--120-160 g/l]
Baseline                 124.3 [+ or -] 14.61    >0.05       >0.05
Day 5                    123.7 [+ or -] 14.34    >0.05       >0.05
Change from baseline     0.568 [+ or -] 2.711    >0.05       >0.05

RBC, (10 x 12/l) [Norm--3.5-5.0 [10.sup.12]/l]
Baseline                 3.626 [+ or -] 0.423    >0.05       >0.05
Day 5                    3.567 [+ or -] 0.408    >0.05       >0.05
Change from baseline     0.060 [+ or -] 0.078    >0.05       >0.05

Color Index, [Norm--0.85-1.05]
Baseline                 0.939 [+ or -] 0.049    >0.05       >0.05
Day5                     0.940 [+ or -] 0.049    >0.05       >0.05
Change from baseline     -0.002 [+ or -] 0.009   >0.05       >0.05

Neutrophils, % [Norm--1-6%]
Baseline                 3.228 [+ or -] 1.476    >0.05       >0.05
Day 5                    2.649 [+ or -] 1.275    >0.05       >0.05
Change from baseline     0.579 [+ or -] 0.258    >0.05       >0.05

Basophils, % [Norm--47-72%]
Baseline                 63.79 [+ or -] 3.261    >0.05       >0.05
Day 5                    62.74 [+ or -] 2.955    >0.05       >0.05
Change from baseline     1.053 [+ or -] 0.583    >0.05       >0.05

Eosinophils, % [Norm--0.5-5.0%]
Baseline.                3.614 [+ or -] 0.675    >0.05       >0.05
Day 5                    2.930 [+ or -] 0.495    >0.05       >0.05
Change from baseline     0.684 [+ or -] 0.110    >0.05       >0.05

Lymphocytes, %, [Norm--19-37%]
Baseline                 24.21 [+ or -] 5.460    >0.05       >0.05
Day 5                    23.21 [+ or -] 5.02     >0.05       >0.05
Change from baseline     1.000 [+ or -] 0.982    >0.05       >0.05

Monocytes, % [Norm--2.9-11%]
Baseline                 2.947 [+ or -] 0.440    >0.05       >0.05
Day 5                    2.930 [+ or -] 0.258    >0.05       >0.05
Change from baseline     0.017 [+ or -] 0.067    >0.05       >0.05

Erythrocytes sedimentation rate (ESR). mm/h [Norm--2-20 mm/h]
Baseline                 19.98 [+ or -] 4.725    >0.05       >0.05
Day 5                    16.12 [+ or -] 4.886    >0.05       >0.05
Change from baseline     2.140 [+ or -] 0.9      >0.05       >0.05

Whyte blood cells, WBC (10 x 9/L) [Norm -4-9.0 [10.sup.9]/l]
Baseline                 8.287 [+ or -] 0.759    >0.05       >0.05
Day 5                    8.023 [+ or -] 0.696    >0.05       <0.05 *
Change from baseline     0.264 [+ or -] 0.128    >0.05       >0.05
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Author:Barth, Anders; Hovhannisyan, Areg; Jamalyan, Kristina; Narimanyan, Mikael
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Report
Date:Dec 1, 2015
Words:6461
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