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WH-1 A Breakthrough in the Treatment of Vaginitis
(White discharge in women)
WH-1 is an Ayurvedic Herbal Formula Developed by
Dr. V.R. Bapat, Bangalore, India. For his profile click here
He has experience of treating with this formulation over
a period of 35 years in his clinical practice.

 
 Clinical Trials
 

 

A prospective, Open labelled, randomized, comparative efficacy and safety trial between polyherbal formulation WH-1-1 vs. FAS-3 kit & Fluconazole in female patients with vaginosis / vaginitis

Mishra Devesh + , Deb Jarita + , Dias Mary*, Mhaskar Rita**, Mohammed A. S. ***, Kulkarni Chanda +

+ Division of Clinical Pharmacology
* Department of Microbiology
** Department of OBG
** Department of Community Medicine

St. John's Medical College & Hospital, Bangalore: 560034

Running title: Efficacy and safety of polyherbal formulation for vaginosis / vaginitis

Principal Investigator
    
Dr. Mrs. Chanda Kulkarni , MD, PhD, FSASMS,
     Prof. and Head Clinical Pharmacology

Co- investigators
 
•  Dr. Rita Mhaskar , MD., - Prof. and Head of Obstetrics & Gynecology
  •  Dr. Jarita Deb - Tutor
  •  Mr. Devesh Mishra - Lecturer
  •  Mary Dias - Assistant Professor
  •  Mohammed A. S - Assistant Professor

Study site

St. John's Medical College & Hospital Bangalore 560 034

Author for Correspondence :
Dr. Mrs. Chanda Kulkarni, MD; PhD; FSASMS;
Professor and Head, Division of Clinical Pharmacology
St. John's Medical College
Bangalore : 560034
Ph: +91-80-2206 5045, +91-98866 63286
Email: drchandakulkarni@gmail.com

Temporary Clinical Trial Registration No: 020911479-0607200997748

This article has been sent for publication to an Indian Medical Journal

Abstract:

Problem: Vaginosis/Vaginitis is one of the commonest symptoms in gynecological outpatient setting and involves multiple causative organisms - bacteria, fungi and protozoa. The available treatment options produce a variety of adverse effects and do not influence the recurrence of this condition.

Purpose: To compare efficacy and safety of a polyherbal formulation with that of presently available treatment for vaginosis/vaginitis.

Method: Non-pregnant, adult women, with diagnosis of vaginosis/vaginitis, were randomized to receive either polyherbal formulation - Wh-1 vs. standard treatment (FAS-3 kit or Fluconazole), based on microbiological assessment. Efficacy parameters were evaluated subjectively, clinically and microbiologically, while safety was assessed by subjective assessment and biochemical investigations.

Result: There was no significant difference in demographic profile and chronicity of infection, between the groups. The clinical and microbiological improvement was comparable in both the groups. The subjective symptoms of vaginosis / vaginitis showed significant improvement [P < 0.05] in patients treated with FAS-3 kit compared to Wh-1, while the adverse effects were significantly higher in patients receiving FAS-3 kit [P < 0.05].

Conclusion: The polyherbal preparation Wh-1 was found to be equi-effective with lesser adverse effects compared to conventional treatment, in subjects with vaginosis/vaginitis. Wh-1 may therefore, be considered as a safer option for vaginosis/vaginitis, however, studies involving long term treatment and follow up are necessary to confirm the findings.

Key words: Wh-1, FAS-3 kit, Fluconazole, vaginosis, vaginitis, clinical evaluation.

Introduction:

Vaginosis /vaginitis, is the commonest reason for a female patient to consult a physician in a primary care setting. The infection often becomes chronic with difficulty in its eradication. The three most common types of acute vaginitis are Bacterial Vaginosis, (BV) Vaginal Candidiasis (VC), and Trichomoniasis (TM). It is reported that nearly 75% of all adult women have had at least one genital Candida infection in their lifetime. BV is the most common cause of vaginitis accounting for 50% of cases . While, current standard treatment includes systemic/topical antifungal, antiprotozoal and antibacterial agents; these medications decrease infection temporarily and often disrupt the normal vaginal flora which may lead to recurrent infection.

WH-1 in the form of soft gelatin capsule containing - Woodfordia floribunda (Dhataki flower), Cyperus scariosus (Musta root), Bombax malabaricum (Mocharas gum), Symplocos racemosus (Lodhra root) and Caesalpinia bonduc (Lata Karanja seed) is reported to have antifungal, antimicrobial, antiseptic, astringent and demulcent properties . A preliminary trial with polyherbal formulation - Wh-1, has reported its usefulness in BV, VC as well as TM. . Therefore, based on results of preliminary study the present study was designed to compare efficacy, spectrum of activity and safety of Wh-1 with that of FAS-3 Kit / Fluconazole, in patients with vaginosis/vaginitis.

Material and Method

The study was carried out by the Division of Clinical Pharmacology, in collaboration with the departments of Gynecology and Microbiology after obtaining approval from IERB, St. John's Medical College & Hospital. This was a randomized, open-labelled , comparative efficacy and safety study in subjects with vaginosis / vaginitis. Subjects were enrolled at the Obstetrics and Gynecology out-patient, based on the inclusion and exclusion criteria.

Objectives

Primary objective: - To compare the efficacy and safety of Wh-1 with FAS-3 kit/ Fluconazole.

Secondary objective: To evaluate the spectrum of activity of Wh-1 against various organisms causing vaginitis/vaginosis.

Inclusion Criteria

•  Married women between 18 to 60 years

•  Female subjects diagnosed to have vaginitis on the basis of symptoms, clinical and microbiological examination.

•  Subjects otherwise healthy.

•  Subjects as well as their spouses who have given written and informed consent.

Exclusion criteria

•  Pregnant and lactating women.

•  Clinical and biochemical evidence of diabetes, hepatic and renal impairment.

•  History of any other major systemic disorder.

•  Women with multiple partners.

•  History of smoking, alcohol and drug dependence.

•  Participation in any other study within six weeks preceding day one of the study.

Method

The study subjects with characteristic clinical symptoms of both acute (< 2 months duration) and chronic (> 2 months duration) of vaginosis/vaginitis were examined by a gynecologist to confirm diagnosis. Biochemical parameters (RBS, KFT, and LFT) were estimated. Subjects were then enrolled based on the inclusion and exclusion criteria. Thereafter microbiological assessment was used to determine the type of infection. They were then randomized using a manual randomization sheet to receive the test (Group A) or standard treatment (Group B) for the condition

Group A: Treated with test drug - Wh-1, a polyherbal preparation.

Group B: Treated with standard drugs - FAS-3 kit /Fluconazole

Attempt was made to treat both partners. Written informed consent was taken from the subjects as well as their respective partners before enrolment. A specially designed case record form (CRF) was used to enter the various assessment parameters before and after the treatment.

Assessment of efficacy

Following parameters were used to assess efficacy

•  Subjective assessment

The study subjects were assessed for symptoms of itching, discharge, dysuria and dyspareunia. Each parameter was given a score of: - mild = 1 moderate = 2 or severe = 3 . Pre and post treatment scores were compared.

•  Clinical assessment

Gynecological examination was done for presence or absence of infection prior to and after the treatment period and graded as: - cured, improved, not improved or aggravated.

•  Microbiological assessment

Two vaginal swabs were collected from each patient at the first and last visits and were processed as follows:

  • pH of vaginal smear was tested using pH paper. .
  • Whiff test using 10% KOH and for amine odor production. A strong fishy odor was considered suggestive of Bacterial Vaginosis [BV] .
  • Smears from vaginal swab, were subjected to Gram staining and graded on the basis of Nugent score for the diagnosis BV.
  • Wet mount preparation was examined for presence of yeast cells, clue cells and actively mobile trophozoites of Trichomonas vaginalis [TV] .
  • Diagnosis of candidiasis was made, when smear showed presence of numerous yeast cells and pus cells .

Presence of more than one infection with bacteria, candida, trichomonals and numerous pus cells in a smear was grouped under mixed infection . Samples which did not fit into either of the three conditions (Bacterial vaginosis, Candidiasis, Trichomoniasis) but had numerous pus cells with normal vaginal flora; or have altered vaginal flora showing abnormal Gram positive bacilli not resembling lactobacilli, or Gram negative bacilli not resembling Gardnella/Prevotella morphotype were categorized as nonspecific vaginitis . Smears with presence of Polymorphonuclears (PMNs) was graded in a semi quantitative manner as - none and +, ++, +++ representing - mild, moderate, and severe infection respectively .

Follow up swabs collected from each of these subjects were processed similarly and assessment of microbiological improvement was graded as follows:

•  Bacterial vaginosis: Reduction of Nugent score from > 6 before the treatment to < 3 after treatment.

•  Vaginal candidiasis: Reduction in yeast cells and PMNs on Gram staining.

•  Trichomoniasis: Absence of motile trophozoites in wet mount.

•  Nonspecific vaginitis: Reduction in PMNs from +++ to ++ or +; from ++ to + or none, with return of lactobacilli as normal vaginal flora.

Assessment of Safety

Safety of treatment medications was assessed through subjective parameters and biochemical investigations, carried out for all the female subjects entering the study and only for respective partners who received Wh-1.

•  Subjective Assessment

The study subjects (and partners who received Wh-1) were evaluated for adverse effects after treatment and were graded as: mild = 1, moderate = 2, severe = 3.

•  Biochemical Assessment

This was done before (on day zero) and after the treatment period (day fourteen) for all women enrolled in the study irrespective of arms and included - Random blood sugar (RBS), various parameters of Kidney Function Tests (KFT) and Liver Function Tests (LFT). The values were considered normal when they matched with standard laboratory values. Only those partners receiving Wh-1 were subjected to biochemical investigations to assess safety, since the safety of other study medications/ standard therapy is well established.

Drug Treatment schedule

Subjects with confirmed diagnosis of mixed infection/nonspecific vaginitis were randomized to receive test or standard treatment. Partners of the study subjects who gave informed written consent were also given the same treatment as per randomization. Study subjects with their respective partners who received treatment were asked to come for follow up on day fourteen .

Subjects under Group - A, received test drug Wh-1, one capsule, three times a day. The various components of Wh-1 with quantity of each ingredient are given in Table-1. They were advised to take medications with water after food for a period of 10 days. Subjects under Group - B, received contents of FAS-3 Kit (1 tablet Fluconazole 150 mg, given after breakfast, one tablet of Azithromycin 1 gm, one hour before lunch and 2 tablets of Secnidazole 1 gm, after dinner as a single dose.

Similarly, a small number of subjects who were positive for Candida infection were randomized to receive Fluconazole 150 mg, stat or Wh-1 as mentioned above.

Instructions to subjects

The study subjects and their partners were instructed not to take any other medication during the trial period and were monitored for any adverse reactions throughout the trial period. Compliance to study medications was monitored through a calendar provided to them and by recording number of unused medications at the time of final follow up visit.

Statistical analysis

The values for age and chronicity of infection was calculated using unpaired‘t' test. The statistical analysis to compare microbiological parameters and clinical improvement was carried out using ? 2 test and the subjective symptoms between the groups by using unpaired students'' test. The safety parameters were compared using' test test for comparing occurrence of adverse reactions.

Result

A Total 57 subjects were enrolled in the study, out of these, 48 female subjects were positive for mixed infection/nonspecific vaginitis and 9 were positive for candida. All 48 subjects met the inclusion/exclusion criteria, were randomized to group A or B. 41 subjects completed the study; seven were lost for follow up and hence were considered as dropouts. Subjects positive for candida were not included in the statistical analysis. Group-A, had twenty one subjects who received study drug and Group - B, had twenty subjects who received standard treatment (Table 1).

The test and standard treatment groups were homogenous with respect to age and chronicity of infection (P > 0.05) [Table - 2].The difference in improvement between group A and B with respect to microbiological and clinical parameters was calculated using test but the difference was not significant (P > 0.05).

The difference in the mean post - treatment values for subjective improvement when compared between group A (1.65 ± 0.988) and group B (2.50 ± 1.539) using unpaired students 't' test, showed marginally significant improvement in the group receiving standard therapy (P = 0.044) Table 2.

The comparison of biochemical parameters as a part of evaluation of safety profile between the two groups A and B, using t test, did not show statistically significant difference (P > 0.05). In the test drug group 1/21 had adverse reaction viz. drowsiness, as against 6/20 in the standard treatment group (2-mild gastritis, 1- mild diarrhea, 1- moderate diarrhea, 1- nausea and vomiting, 1- mild body ache and fatigue). The comparison for occurrence of adverse drug reactions was significantly higher among the patients who received standard treatment compared to the group which received test drug ( test, p = 0.0396).

There were nine subjects who were microbiologically positive for Candida. Among these eight completed the study with one dropout. Five subjects from this group received Wh-1 and three Fluconazole. They were analyzed descriptively after the treatment period. According to Clinical / Microbiological assessment in Wh-1 group, three patients improved while two did not, whereas in the Fluconazole group all three patients showed improvement.

Discussion

Several studies have been carried out to examine the factors influencing, as well as the treatment outcome of bacterial vaginosis. National Health Examination Analytic and Reporting Guidelines, have been formulated to study the condition (2005) . It is well established that vaginosis when left untreated increases the risk of PID in turn leading to infertility, premature delivery, low birth weight, in addition to endometritis and cervical neoplasia as some of its long term complications. Data suggests that bacterial vaginosis is an important predictor of adverse reproductive outcome and more complete dynamics connecting the socio-demographic characteristics is anticipated to create targeted interventions.

Though, modern treatment options for systemic administration are available for bacterial vaginosis these are reported to have adverse effects. Furthermore, they are known to disturb the normal vaginal flora causing recurrent infection. While, only limited number of studies have evaluated the efficacy of alternative therapies, a systematic review on CAM therapies for vaginitis has revealed that women particularly those with chronic vaginal symptoms are increasingly rejecting antimicrobial therapies in favor of alternative remedies(96%) and these are usually educated health conscious women . Few of the specific therapies are: lactobacilli recolonization by oral and vaginal administration, douching, boric acid, tea tree oil and garlic. While, review supports the benefits of these ingredients, it has also highlighted the adverse effects associated with each of them. Comparative studies with various douching formulations have revealed increased prevalence of PID, risk of ectopic pregnancy, endometritis and salpingitis associated with this procedure. Routine douching has been shown to double the risk of acquiring vaginitis. Further, boric acid treatment is reported to produce vaginal excoriation and use of topical tea tree oil or garlic is known to cause allergic reaction while oral garlic is said to produce heartburn and bloating . In addition the recommendations of previous review include - improvement in the study design, acceptable diagnostic criteria and validated outcome measures. The test preparation, Wh-1 in the present study did not have any significant adverse effects. In this context the present study meets few of these recommendations such as study design, well defined assessment criteria, outcome measures and reliable results, hence may be considered superior to earlier studies .

A preliminary study carried out elsewhere, with Wh-1, revealed both symptomatic and clinical improvement in subjects with vaginitis of varied etiology but this was not a comparative study. Also, objective assessment using microbiological parameters and statistical analysis was lacking in the previous study .

The present study was designed to evaluate systematically the efficacy and safety of test drug Wh-1, in comparison with standard treatment regimen FAS-3 kit, in women suffering from mixed / non-specific vaginitis using subjective as well as objective criteria. The study also included assessment of lactobacilli count which was not a part of the earlier studies. The important efficacy parameters such as microbiological as well as clinical examination showed that Wh-1 is equipotent to standard therapy. It is reported that the combination of antibacterial, antifungal and antiprotozoal agents in the modern therapy alter the normal vaginal flora leading to super infection and /or increasing chances of recurrence of infection. Interestingly, the present test preparation Wh-1 showed absence of such associated complications. This finding appears to be unique to Wh-1 and may be attributed to multiple mechanisms of actions of the various components of this formulation which are known to reduce irritation, inflammation and secretion with added anti-septic activity ( Table 2).

Either maintenance or improvement in the lactobacilli count was seen with Wh-1, in the present study. In contrast 2/20 patients on standard treatment had aggravation of symptoms and super infection with Candida respectively while only 1/20, had aggravation with super infection. Although, a long term follow up was not a part of the present study protocol, some patients were contacted at one to two months after Wh-1, who showed improvement compared to those who received the standard treatment, as far as relapse/recurrence was concerned. It is interesting to note that although the duration of treatment was ten days with Wh-1 as against single dose treatment with FAS-3 Kit; all patients except one were compliant. Vaginitis/Vaginosis produces disturbing symptoms which may be one of the reasons why the patients were not averse to taking medication for long duration.

Patients with candida infection also showed clinical and microbiological improvement with Wh-1, but the number of patients was too small and so, no statistical comparison to standard Fluconazole therapy was performed.

To conclude, our study confirms the observations of the previous preliminary study reports . Wh-1 was found to be equally efficacious as standard drugs of FAS-3 Kit and Fluconazole in mixed infection, nonspecific vaginitis as well as vaginal candidiasis. Adverse effects were higher in standard treatment group. Certain positive findings of the present study with Wh-1 were its global utility in the treatment of Vaginitis/Vaginosis caused by multiple pathogens, minor incidence of adverse drug reactions, increment in lactobacilli count, and 100% compliance despite longer duration of treatment. There was no biochemical evidence of side effects with Wh-1 regimen. Wh-1 can therefore be considered to be an effective and safe option for treatment of vaginitis/Vaginosis.

It may be suggested that studies in larger number of patients with longer duration of treatment as well as follow up will be necessary to understand benefits and usefulness of Wh-1, in preventing recurrence of bacterial vaginosis/vaginitis and in treating candidiasis in patients with diabetes.

Acknowledgement: The authors wish to thank gratefully Dr. V. R. Bapat, for funding this project and for free supply of Wh-1 capsules and Dr. S.C. Savitri, District Ayush Officer, Govt. of Karnataka for her help.

Table 1

The Mean ± SD values for age and chronicity of vaginitis in trial Subjects treated under various groups.

Subjective Improvement

Group A

Group B

P Value

Pre-Treatment

2.75 ± 1.517

3.27 ± 1.383

> 0.315 Not Significant

Post Treatment

1.10 ± 1.210

0.7 ± .0733

> 0.214 Not significant

Post Treatment Between Groups

1.65 ± 0.988

2.50 ± 1.539

< 0.044 Significant

Table 2

Comparison of subjective improvement of symptoms of vaginitis / vaginosis in patients receiving Wh-1 (Group- A) and. FAS-3 Kit (Group- B)

Treatment Groups

Number of Patients

Age: Mean ± SD P > 0.05

Chronicity

Group A- Wh-1

21

30.90 ± 8.03

Acute+15; Chronic=06

Group B-FAS-3Kit

20

30.25 ± 9.52

Acute=12, Chronic =08

 

 

 

 

Table 3

Ingredients and pharmacological properties of Wh-1 soft gelatin capsules

Source: FRLHT Plants of Ayurveda

Sr. No.

Botanical name

Active IngredientIn mg

Actions and Uses

1

Woodfordia floribunda

20

Stimulant, Astringent, Tonic used in leucorrhoea, Menorrhagia

2

Cyperus scariosus

40

Carminative, Anti-bacterial, Antifungal

3

Bombax malabaricum

22.5

Used in Dysentery, Leucorrhoea, Menorrhagia

4

Symplocus racemosus

100

Astringent. Used in wound healing

5

Caesalpinia bonduc

50

Antiseptic, Anti-parasitic. Used in skin diseases

6

Ghee - Clarified cow's butter

q.s.

Medium for formulation

References:

1. http://www.webmd.com/a-to-z-guides/vaginal-infections page 1 & 2 .

2. www.holisticonline.com/Herbal-Med/_Herbs/h143.htm accessed -November 9,2009 .

3.  Ayurvedic Pharmacopoeia of India (API), Reference Vol- I, page 32 & 82,serial 22 , Vol- II, page 93,serial 43 & 53, Vol- III, page129      & 183,serial 59 & 81.

4  Bapat VR, Alfred L, Shobha Rani RH, Ksheerasagar PT, Hegde G, Lund SK .Preliminary clinical study of polyherbal formulation     (Wh1) in the treatment of vaginitis. Indian journal of Pharmacy Practice 2009; 2(1):60-65.

5.  biomedgt . nci . nih . gov / wiki /index.php/CTCAE4 accessed -November, 2009

6  Speilgel CA, AmselR, Holmes KK. Diagnosis of Bacterial vaginosis by direct Gram stain of vaginal fluid. Journal of Clinical      Microbiology July1983; 18(1): 170-177.

7.  Nugent RP, Krohn MA, Hiller SL. Reliability of diagnosing Bacterial vaginosis is improved by a standardized method of Gram       stain interpretation. Journal of Clinical Microbiology. feb 1991; 29(2): 297-301.

8.  Vertaelen H, Verhelst Ret al. Modified classification of Gram stained vaginal smear to predict spontaneous preterm birth; a       prospective cohort study. American Journal of Obstetrics and Gynecology June 2007;196: 528-29.

9.  Pirotta MV, Garland SM. Genital candida species detected in samples from women in Melbourne Australia before and after      treatment with antibiotics. J Clin Microbial2006; 44(9): 3213-7.

10. Centre for disease control and prevention,(CDC), national centre for health statistics(NCHS),national health and nutrition        examination analytic and reporting guidelines Hyattsville(MD):U.S. department of health and human services, centers for        disease control and prevention; (2005)

11. Allsworth JE, Peipert JF. Prevalence of bacterial vaginosis: 2001-2004 National Health and Nutrition Examination Survey data.       Obstet gynaecol. 2007; 109(1): 114-20.

12. Kessel KV, Assefi N, Marrazzo J, Eckert L Common complementary & alternative therapies for Yeast vaginitis & Bacterial        vaginosis; a systematic review. Obstetrical & Gynecological Survey.2003;58(5):351-358.

13. Trutnovysky G, Law C, Simpson JM, Mindel A. Use of complementery therapies in a sexual health clinic setting. International        journal of STD and AIDS 2001;12: 307-309.

 
 
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