THE EFFECT OF “LAGUNDI”( a local herb) TABLETS ON
BRONCHIAL ASTHMA IN ADULTS: A RANDOMIZED
DOUBLE BLIND STUDY WITH THEOPHYLLINE*

By: Romeo P. Chu, M.D. **

ABSTRACT

Forty otherwise asthmatics were included in a randomized double-blind comparative study between lagundi tablets and the standard drug theophylline. There were 20 subjects per treatment group; 7 of the subjects were males and 33 females. The patient profiles of both treatment groups were comparable. Likewise, the baseline parameters of both groups were also comparable. Results showed that both Lagundi and Theophylline caused significant bronchodilation over time. Statistical analysis showed significant increase in the mean peak expiratory flow rate (PEFR) of the lagundi group beginning at the 3rd hour. This shows the onset of action of lagundi to be at 3 hours post dosing. For the theophylline group, significant increase in the PEFR values was noted at 1 hour which corresponds to its onset of action. ANOVA with repeated measures showed no significant difference between lagundi and theophylline with respect to their effects on PEFR. However, since the sample size is inadequate, it cannot yet be concluded that lagundi is as effective as theophylline. Patients treated with lagundi failed to show a significant improvement of their wheezing over time but might have prevented the wheezing from getting worse. Patients treated with theophylline however, showed significant improvement of their wheezing as early as the 2nd hour. The theophylline treated patients had significantly better wheezing scores then the lagundi group at the 6th, 8th, 24th and 48th hour. There were no significant difference in the severity of the cough, dyspnea and chest pain in both treatment groups over time. However, the theophylline treated group had better “cough” than the “lagundi” group at the 24th and 48th hour. The theophylline group also had better “dyspnea” scores than the lagundi group at the 48th hour. There was no significant difference between lagundi and theophylline in terms of the effects on pulse rate (PR), respiratory rate (RR), and blood pressure (BP) readings. However, there was significant decrease in the mean sitting systolic BP and standing diastolic BP over time. This needs further investigation. Side effects reported in the lagundi group were vomiting, desquamation of the skin over the palms and increased urination. In the theophylline group, the side effects reported were nausea, vomiting, cold sweats, palpitation, tremors, headache and epigastric pain. Overall, lagundi displayed significant bronchodilating effects. Although theophylline has a slight edge in terms of therapeutic efficacy, lagundi still holds to be a promising drug in the future.

INTRODUCTION

The use of plants for medicinal purposes is as old as man himself. Primitive man probably learned their medicinal value from intuition and observation of the animals around him. Through trial and error, he discovered the efficacy of some plants for certain ailments and he passed this knowledge on to his neighbors. From such beginnings sprung our present knowledge of the use of plant constituents in the treatment of disease.

Philippine flora abounds with plants of medicinal value. Scientific proof of efficacy, established through the isolation of their active constituents and studies on their pharmacologic actions, has been accomplished on some of these plants. This work was done principally by the University of the Philippines, the National Institute of Science and Technology (NIST) and the Philippine Council for Health Research and Development (PCHRD). However, there remain a large number of plants, widely used in folk medicine, still to be investigated. One of these plants is Lagundi.

Vitex negundo (Lagundi, Tag.) is an erect, branched shrub which grows throughout the Philippines. It is more commonly found in low and medium altitudes, in waste places, thickets and in similar locations. The leaves usually have 5 leaflets (rarely 3) which are palmately arranged. These leaves are found to have an essential oil and resin, while the fruit contains an acid resin and an astringent organic acid. The leaves and seed of the plant were first reported as a medicine by Fr. Clain. Thereafter, more medicinal uses of the plant have been reported, among which are: as cleanser for ulcers, lactagogue, febrifuge, expectorant, wound disinfectant and for flatulence. The leaves in particular have been used as insecticide, anti-inflammatory, expectorant and for catarrh and headache.

Open clinical trials have shown that the decoction of leaves of the lagundi decreased the frequency of cough and increased the volume of expectoration. In a study in guinea pigs, using citric acid as cough inducer, the anti-tussive effect of the decoction was comparable to that of dextromethorphan.

Anecdotal reports seem to show a favorable response of asthmatic patients to lagundi leaves decoction. The bronchodilating activity of lagundi leaves has repeatedly been shown using the cat tracheal chain model. One child in acute asthma showed improvement of the FEVI, FVC and PEFR after a single dose of lagundi leaves decoction.

OBJECTIVES:

1. To determine the therapeutic efficacy of lagundi tablets on bronchial     asthma in adults;
2. To compare the effect of lagundi tablet to that of theophylline tablet on     bronchial asthma;
3. To determine the onset of action of the bronchodilating activity of     lagundi tablet on bronchial asthma;
4. To compare the adverse effect/s of lagundi tablets (if any) to that of     theophylline tablets on bronchial asthma.

METHODOLOGY:

A. Preparation of Test Drugs
1. Lagundi tablets made from pulverized dried lagundi leaves were     manufactured by PCHRD. The tablets utilized were from lot. No.     28108601.
2. Theophylline tablets (125 mg/tab) were street purchased.

B. Selection of Patients
1. Inclusion Criteria:

a. Males and females 14 years and above with definite history of asthma
b. Patients whose PEFR is less than 85% of predicted value and who are     able to demonstrate that their brochospasms is reversible in the     following manner:

The patient’s peak expiratory flow rate is recorded before and 15 minutes after 2 inhalations of a metered dose (100 mcg) of salbutamol aerosol. Only patients whose PEFR is increased by 20% will be admitted to the study.

c. Except for asthma, patients must be in good general health.
d. Patients who have been fully informed of the possible risks and benefits     of participation and have voluntarily agreed to participate in this study.     For minors, parents or guardians who are fully informed shall also sign     the consent.

2. Exclusion Criteria:
a. Patients with severe asthma as defined:
    i. grade 2A or worse (se Appendix A)
    ii. presence of resting tachycardia
    iii. pulsus paradoxus k 20 mmHg
    iv. PEFR 120 or less
    v. impending ventilatory failure
b. Patients who require maintenance doses of any medication other than     the test drug. Patients on beta-2 agonists agents and short or long     acting theophylline preparations are required to stop medications at     least 24 hours prior to the study.
c. Patients who have used systemic steroids chronically within 6 months     before entry into the study; or have used a single dose of     dexamethasone or betamethasone within 6 weeks before entry into the     study; or have used short-acting systemic steroids within 14 days     before entry into the study.
d. Patients who have used disodium cromoglycate or ketotifen within 7     days before entry into the study
e. Patients with any of the following:
    i. cardiac arrhythmia
    ii. moderate to severe hypertension
    iii. patients on beta-blocker therapy
    iv. insulin-dependent diabetes mellitus
    v. significant hepatic or renal disease
    f. Patients who are pregnant or lactating

C. Study Design

This is a double blind standard drug controlled study utilizing 40 patients who are randomly assigned to 2 groups: Group 1 ( 20 patients) to receive theophylline (3 mg/kg/dose) repeated every 8 hours for 9 doses. Group 2 (20 patients) to receive lagundi (15 mg/kg/dose) repeated every 8 hours for 9 doses.

After a patient has been selected as a candidate for the study and has given informed consent, the following procedures were performed:

1. complete medical history and physical examination with emphasis on    PEFR, sitting and standing BP, respiratory rate, pulse rate and    auscultation of the chest
2. routine laboratory test:
   i. hematology: hemoglobin, hematocrit, total white blood cell count,       differential count, erythrocyte sedimentation rate, reticulocyte count       and platelet count
   ii. blood chemistries: BUN, creatinine, SGPT, RES
   iii. urinalysis
3. chest x-ray (optional)

In all patients enrolled in the study, sufficient time was allowed for recovery from the salbutamol test (at least 8 hours). Once the PEFR is again less then 85%, than the study is resumed.

During the course of the study, all food substances must be caffeine-free. No coffee, tea, chocolate or soft drinks allowed.

Prior to giving of medication (baseline), and at 15minutes, 30 minutes, 1, 2, 3, 4, 6, 8, 24 ,48, and 72 hours post-dosing, the following were examined (or asked) and properly recorded:

1. sitting and standing blood pressure
2. pulse rate
3. respiratory rate
4. PEFR at standing position (the highest of at least 3 acceptable efforts     was recorded)
5. chest auscultation noting the degree of wheezing scored as follows:
    none –0; mild –1; moderate—2; severe—3
6. severity of cough scored as above
7. degree of dyspnea scored as above
8. degree of chest pain scored as above

Side effects or adverse reactions were described and properly recorded.

D. Intercurrent Events

Patients were not allowed to take concomitant medications during the study. If the patient does not respond to either lagundi or theophylline, then salbutamol tablets at a maximum dose of 2 mg every 8 hours will be added to the regimen and recorded.

DATA ANALYSIS

Analysis of variance (ANOVA) with repeated observations with respect to time was used for data on theophylline and lagundi dosed for the four variables: blood pressure, pulse rate, respiratory rate and PEFR. If a statistically significant result is obtained, Duncan Multiple Range Test was employed to determine the specific periods of observation which are significantly different from baseline.

Friedman Two Way analysis of variance was employed to determine if there was significant difference in the severity of cough, wheezing, dyspnea and chest pain over time.

Mann-Whitney U test was used to determine if there was significant difference between the two treatment groups with respect to their effect on the severity of wheezing, cough, dyspnea and chest pain.

RESULT AND DISCUSSION

From Sept 22 to Dec 31, 1987, 43 subjects participated in the clinical trial. 3 dropped out of the study after 24 hours. All of them were in the theophylline group. The first one dropped out to take care of her sick child; the second due to inclement weather (typhoon) and the third for unknown reason. Only 40 subjects were included in the following discussion.

Patient Profile

The 40 subjects were equally distributed for each treatment group—20 in the lagundi group and 20 in the theophylline group. There were 7 males and 33 females with a ratio of 1:4.7. In the lagundi group, there were 19 females and only 1male, while in the theophylline group; there were 14 females and 6 males.

The mean age for the lagundi group (31.2 yrs) was slightly lower than the theophylline group (34.7 yrs). The mean age for all subjects was 32.95 years. The age range for the lagundi group was from 20 to 48 years while that of the theophylline group was from 16 to 72 years. Mean duration of illness for the lagundi group was 13.3 years while that of the theophylline group was 18.1 years. The mean duration of illness for all subjects is 15.7 years. The frequency of attacks was similar for both groups which ranged from weekly to yearly. All the subjects included in the study had previously been taking either a theophylline preparation, beta-2 agonist agents, or both. There were 3 subjects with concomitant illness, 2 patients in the lagundi group had mild hypertension and 1 patient in the theophylline group had nodular non-toxic goiter.

Laboratory Tests Results

All blood chemistries were well within normal limits except for 2 patients. One of these is in the lagundi group and has a WBC count of 13,000/mm3. The other patient is in the theophylline group and has a WBC count of 10,000/ mm3. Both have normal differential counts and had no clinical evidence of infection.

2 patients in the lagundi group have slightly elevated eosinophil count at 0.04 x 109/l. 2 patients in the theophylline group also showed elevations at 0.03 and 0.07 x 109/l. respectively.

25 out of the 40 subjects had their chest x-ray done within the year. All showed normal findings except for 4 patients. 2 showed minimal infiltrates in the upper lung fields interpreted as minimal pulmonary tuberculosis activity undetermined. One of these belong to the lagundi group while the other to the theophylline group. One of the patients in the lagundi group had a chest x-ray which showed emphysematous changes while the other patient in the theophylline group showed streaky densities in the lower lung fields interpreted as chronic non-specific inflammatory disease.

Figure 1 illustrates graphically the mean PEFR values of both the lagundi and theophylline treated groups over time.

The ANOVA repeated measures showed a significant difference in the mean PEFR values of both the treated groups over time. This means that both drugs, lagundi and theophylline, caused significant bronchodilation over time.

Duncan multiple range test showed significant increase in the mean PEFR values (from baseline of 238.75 L/min) of the lagundi group beginning at the 3rd hour reaching 267.5 L/min. (this was sustained for 8 hours). This means that the onset of action of lagundi is at 3 hours post-dosing. For the theophylline group, significant increase in the PEFR was noted at 1 hour (from baseline of 257.75 L/min to 288.75 L/min) which corresponds to its onset of action. This effect was sustained throughout the study period.

Comparing the 2 drugs in terms of their effect on the PEFR values using the ANOVA with repeated measures, the result showed no significant difference between the 2 treatment groups at P>0.05. However, since the sample size is still inadequate, it cannot yet be concluded that lagundi is as effective as theophylline.

Figure 2 illustrates graphically the mean pulse rate of both treatment groups over time. ANOVA with repeated measures showed no significant difference in the pulse rate of both treatment groups over time. This means that both drugs are safe and that they do not significantly affect the pulse rate. They are neither myocardial stimulants nor depressants.

There was also no significant difference between the 2 groups in terms of their effect on the pulse rate.

Figure 3 illustrates graphically the mean respiratory rate (RR) of both treatment groups over time. ANOVA with repeated measures showed no significant difference in the mean RR of both treatment groups over time. This could be so because most of the patients included in this study had only mild asthma and are thus not tachypneic. In fact, the mean RR for all subjects was only 20.5/min. Even if the patients responded to the medications and had relief of their bronchospasm, no significant drop in the RR is expected because of the above stated reason. What is important to note is that the mean RR did not increase which means that the patients did not get worsen.

Figure 4 illustrates graphically the mean sitting blood pressure (BP) of both the treatment groups over time. There was significant difference in the mean sitting systolic BP over time for both treatment groups. In the lagundi group, the mean baseline systolic BP at sitting position was 109.75 mmHg. At 30 mins and at the 6th hour, this was significantly lower at 30 mins with a mean reading of 106.9 mmHg. This was also noted at the following observation periods: 2 hrs, 4 hrs, 5 hrs, 6hrs, 8 hrs and 72 hrs. These changes could be due to the fact that the patients were rested for a longer period of time. It is also important to note that although there was a significant decrease in the sitting systolic BP, this effect was not consistent throughout the study periods. No patient reached hypotensive levels nor were there complaints of dizziness attributable to the decline in BP. All these plus the fact that all patients (except for the 2 previously mentioned hypertensives) were normotensive seem to point out that these differences were not really that important. These findings were also not consistent with the 2 patients (both in the lagundi group) with mild hypertension. One patient had a slight increase in systolic BP while the other had a slight decrease.

Comparing the two, there was no significant difference between the lagundi and theophylline in terms of their effect on the sitting systolic BP.

For the sitting diastolic BP, there was no significant difference in the 2 treatment groups over time. There was no significant difference between the 2 groups in terms of their effect on the sitting diastolic BP.

Figure 5 illustrates graphically the mean standing BP readings of both treatment groups over time. ANOVA with repeated measurements showed no significant difference in standing systolic BP of both groups over time. There was also no significant difference between the two groups in terms of their effects on the standing systolic BP.

There was significant difference in the mean standing diastolic BP for both treatment groups over time. For the lagundi group, the baseline mean diastolic BP in standing position was 84 mmHg and there was a significant decrease to 77 mmHg noted at the 4th hour up to the 8th hour and at the 24th hour. For the theophylline group, the baseline mean standing diastolic BP was 79.8 mmHg which significantly decreased to 75 mmHg at 30 mins. , the first hour and the 4th hour. Again, the reason previously cited could be used to explain the significant decrease in the BP readings, i.e. – relief of bronchospasm and longer period of rest. Similarly, the significant decrease was not persistent throughout the study period and the patients did not reach hypotensive levels.

Clinical Findings

The study shows that in the severity score for wheezing in the lagundi group over time, the higher the rank sum, the more severe is the wheezing. Note that the changes in the scores are minimal. Using the Friedman 2 way ANOVA, there is no significant difference in the severity of wheezing at P>0.05. This means that patients treated with lagundi failed to show significant improvement of their wheezing over time but might also mean that lagundi prevented their wheezing from getting worse.

The severity scores for wheezing in the theophylline group over time showed results of statistical analysis indicating significant improvement in the severity of wheezing at P>0.05. This was noted as early as the second hour and was sustained throughout the study period.

Mann Whitney U test was utilized to compare the 2 treatment groups with respect to their effects on wheezing. There was a significant difference between the 2 treatment groups noted at the 6th, 8th, 24th and 48th hours. This means that the improvement in the severity of wheezing in the theophylline group was significantly better than the lagundi group at the observation period stated above.

Cough

Statistical analysis of the severity scores for cough in the lagundi group over time showed no significant difference in the severity of cough in this treatment group at P>0.05. This means that patients treated with lagundi failed to show significant improvement or deterioration of their cough over time. A larger sample size might be able to detect a significant difference. Although previous studies showed lagundi to be effective against cough of viral origin, the parameter used was more of frequency rather than severity, so the results are not quite comparable.

Statistical analysis of the severity scores in the theophylline treated group over time also showed no significant difference in the severity of cough in this treatment group over time at p>0.05. Although theophylline afforded significant relief of the bronchospasm and improvement of wheezing, there is still no significant improvement of its associated cough. A larger sample size might be able to detect a significant difference.

Comparing the two treatment groups with respect to their effects on cough, there is a statistically significant difference between the lagundi group and the theophylline group at the 24th and 48th hour. This means that the improvement of cough in the theophylline treated group was significantly better than the lagundi treated group at the above stated observation periods.

Dyspnea

Statistical analysis of the severity scores for dyspnea in the lagundi treated group showed no significant difference in the severity of dyspnea in this treatment group over time at p>0.05. This means that although patients treated with lagundi had significant relief of their bronchospasm, there was no significant improvement in the severity of their dyspnea. However, lagundi might have prevented them from getting worse.

With regards to the severity scores of dyspnea in the theophylline treated group over time, statistical analysis showed no significant difference in the severity of dyspnea in this treatment group over time at p>0.05. This means that the degree of dyspnea in patients treated with theophylline neither improved nor worsened.

Comparing the 2 treatment groups with respect to their effects on dyspnea, there was a statistically significant difference between the 2 groups at the 48th hour. This means that the improvement in the severity of cough in the theophylline treated group was significantly better than the lagundi treated group at the observation period stated above.

Chest Pains

Friedman 2 way ANOVA showed no significant difference in the severity of chest pains overtime for the lagundi group at p>0.05. This means that patients treated with lagundi failed to show a significant improvement or worsening of their chest pains over time.

For the severity scores for chest pain in the theophylline group over time, statistical analysis showed no significant difference in the severity of chest pain over time for this treatment group at p>0.05. This means that patients treated with theophylline failed to show a significant improvement or worsening of their chest pain over time.

Comparing the two treatment groups with respect to their effect on chest pain, there is no significant difference between the lagundi and theophylline group at any observation period. Not one drug is superior over the other with respect to their effect on chest pain.

Number of Salbutamol Tablets

12 patients (30% of the sample size) took salbutamol tablets after 24 hrs because they developed asthmatic attacks. Eight were in the lagundi group and four were in the theophylline group. Of the 8 patients in the lagundi group, one patient took 8 salbutamol tablets (this patient had been on prednisone for 10 days but has stopped since 3 weeks prior to the study and had fair control of her asthma. Her bronchial airway hyperactivity might have flared up again); one patient took 4 tablets; another took 2 tablets and 3 patients took 1 tablet each. The total number of salbutamol tablets taken in the lagundi group was 27. Of the 4 patients in the theophylline group, 1 patient took 3 tablets and 3 patients took 1 tablet each. Total number of salbutamol tablets taken in the theophylline group was only 6. No statistical analysis was employed to analyze the difference between the 2 treatment groups in terms of the number of additional medications taken but it seems apparent that theophylline patients fared better than the lagundi patients in that they took less salbutamol tablets.

The fact that these patients took salbutamol tablets did not invalidate the previous conclusions drawn for the above parameters, regardless of the treatment group. All patients took these additional medications after the first 8 hour observation period which leaves us to account only for the 24th, 48th and 72nd hour. Reviewing the individual charts revealed, however, that all parameters went down (reflecting worsening condition) during these three observation periods even if the patients took salbutamol tablets in contrast to the general trend which shows that the parameters were going up (reflecting improving conditions). This means that the intake of salbutamol tablets did not contribute significantly enough to alter the results of the different parameters under study.

Adverse Effects

Two (2) patients in the lagundi group complained of vomiting; another 2 noted desquamation of the skin over their palms and another complained increase frequency (but not amount) in urination.

Three (3) patients in the theophylline group complained of nausea and one of them vomited; 2 complained of cold sweats and palpitations; another 2 complained of headaches; 1 complained of epigastric pain and another one complained of dizziness.

CONCLUSION AND RECOMMENDATIONS

Results of this study showed lagundi caused significant bronchodilating activity and had fewer side effects. Although theophylline has a slight edge in terms of therapeutic efficacy, yet lagundi still holds to be a promising drug in the future. The lagundi tablets used were but made from crude dried leaves and might contain only minimal active compounds. Thus, the dosage used although at 15 mg/kg/dose might actually be inadequate. Further investigations must be undertaken and the following steps are recommended:

1. Active principal should be isolated
2. Studies should be done correlating bronchodilation with serum levels
3. Pharmacokinetics and pharmacodynamics of lagundi should be     studied.

The increasing uses of medicinal plants, the present return to Mother Earth and nature’s product, the number of people from all over the world who rely partly or completely on herbal cures and the success they achieve, are clear indications of the position these plants occupy in the practice of medicine today.

In our country, the cost of imported medicine is becoming prohibitive. This shows us clearly the urgent need for extensive research on our medicinal plants. Never before had we been so forced to rely upon our own resources as we are then when the very life of our nation (for people are the nation) depend upon the herbs that God had graciously given us.

LAGUNDI IS A SPARK AND WE HOPE
THIS SPARK SHALL START A FLAME.

APPENDIX A

Grading of Asthma

Grade 1 A Patient only able to carry out housework or job with great difficulty. Sleep infrequently disturbed.

Grade 1 B Patient only able to carry out housework or job with great difficulty. Sleep frequently disturbed.

Grade 2 A Patient confined to the chair or bed but able to get up with great difficulty. Sleep is disturbed with little or no relief from inhaler.

Grade 2 B Patient confined to chair and bed and only able to get up with great difficulty. Unable to sleep. Pulse rate over 120/min.

Grade 3 Patient totally confined to chair or bed. No sleep. No relief from inhaler. Pulse rate over 120/min.

Grade 4 patient immobilized and totally exhausted.

ACKNOWLEDGEMENT

The author is indebted to the following persons and institutions for their invaluable advise and assistance in making this research possible:

Nelia Cortes-Maramba, M.D. Dina de Leon, M.D.
Angelita Camacho, M.D. Nina Chikiamco-Dizon, M.D.
Winston Tan, M.D. Rodrigo Alenton, M.D.
Cynthia Cordero, M.B.S. Alice Caragay, M.D.
Maria Teresa Angeles, M.D. Jimmy Chua, M.D.
Industrial Pharmacology, U.P., Manila NSTA—Project 7711
PCHRD

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Fishman, A. Pulmonary Diseases and Disorders. MacGraw Hill Book Co. c. 1980. pp. 560-576; 582-592

Goodman, L., Gilman, A. The Pharmacologic Basis of Therapeutics Sixth Edition. MacMillan Co. c. 1985. pp 358-369

Ladion, H. Healing Wonders of Herbs. Philippine Publishing House. C.1985. pp. 14, 18, 25, 32-33, 104
Maramba, N. et.al. Guidebook on the Proper Use of Medicinal Plants, NSTA, Bulacan, Taguig, Metro Manila. c. 1982. pp.3-6; 105

Padua, L. et.al. Handbook on Philippine Medicinal Plants Vol. 1. U.P. Los Baños. c. 1978. pp.18-19.

Quisumbing, E. Medicinal Plants of the Philippines. Bureau of Printing. c. 1951. pp. 21-48; 806.

Reins Atschul, S. Drugs and Foods from Little-Known Plants. Harvard University Press. c. 1973. pp. 246-247.

Figure 1. MEAN PEFR VALUES OF LAGUNDI AND THEOPHYLLINE
TREATED GROUPS OVER TIME

Figure 2 MEAN PULSE RATE OF LAGUNDI AND THEOPHYLLINE
TREATED GROUPS OVER TIME




Figure 3 MEAN RESPIRATORY RATE OF LAGUNDI AND
THEOPHYLLINE TREATED GROUPS OVER TIME