Comparison between the efficacy of metronidazole vaginal gel and Berberis vulgaris (Berberis vulgaris) combined with metronidazole gel alone in the treatment of bacterial vaginosis
Keywords:
Berberis vulgaris, Metronidazole, VaginosisAbstract
Background: Bacterial vaginosis is one of the most prevalent complications among reproductive-aged women. Antibacterial and antifungal effects of Berberis vulgaris have been demonstrated in vitro and in vivo.
Objectives: This study aimed to compare the therapeutic effects of the vaginal gel of Berberis vulgaris 5% (in metronidazole base) with metronidazole vaginal gel 0.75% on bacterial vaginosis on 80 patients referred to the Hajar Hospital from January 2012 to April 2013.
Methods: This study was a randomized clinical trial research on 80 women affected by bacterial vaginosis, who were randomly divided into two groups of 40 participants. Diagnostic criteria were Amsel’s criteria and Gram stain. Berberis vulgaris 5% (in metronidazole gel base) or metronidazole vaginal gel for five-night usage was prescribed to each group, and after two to seven days therapeutic effects and Amsel criteria were assessed. Data analysis was performed by SPSS 16 using Student t-test, chi-square, and ANOVA tests.
Results: Findings of the study showed a statistically significant difference with regard to treatment response between the study groups (p<0.001), and the Berberis vulgaris group had a better response than the metronidazole gel group. The patients in groups of Berberis vulgaris in a metronidazole gel base did not experience any relapse, but, in the metronidazole group, 30% of patients experienced relapse during three weeks’ follow-up.
Conclusions: Findings of the study showed that adding Berberis vulgaris fruit extract on metronidazole improve the efficacy of bacterial vaginosis therapy.
Clinical trial registration: The trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the IRCT ID: IRCT201411102085N13.
Funding: Shahrekord University of Medical Sciences supported this research.
References
Seyyedi F, Rafiean-Kopaei M, Miraj S. Comparison of the Effects of Vaginal Royal Jelly and Vaginal
Estrogen on Quality of Life, Sexual and Urinary Function in Postmenopausal Women. J Clin Diag Res.
; 10(5): 1-5. doi: 10.7860/jcdr/2016/17844.7715. PMID: 27437306, PMCID: PMC4948482.
Miraj S, Kiani S. Menstrual diseases as stated in canon fil-Tibb. Der Pharmacia Lettre. 2016; 8(6): 261-8.
Farage MA, Miller KW, Ledger WJ. Determining the cause of Vulvovaginal symptoms. Obstet Gynecol
Surv. 2008; 63(7): 445-64. doi: 10.1097/OGX.0b013e318172ee25. PMID: 18559121.
Mashburn J. Vaginal infections update. J Midwifery Womens Health. 2012; 57(6): 629-34. doi:
1111/j.1542-2011.2012.00246.x. PMID: 23094602.
Burkman RT. Berek & Novak’s Gynecology. JAMA. 2012; 613; 308(5): 516-7.
Cherpes TL, Hillier SL, Meyn LA, Busch JL, Krohn MA. A delicate balance: risk factors for acquisition of
bacterial vaginosis include sexual activity, absence of hydrogen peroxide-producing lactobacilli, black race,
and positive herpes simplex virus type 2 serology. Sex Transm Dis. 2008; 35(1): 78-83. doi:
1097/OLQ.0b013e318156a5d0. PMID: 17989585.
Reichman O, Akins R, Sobel JD. Boric acid addition to suppressive antimicrobial therapy for recurrent
bacterial vaginosis. Sex Transm Dis. 2009; 36(11): 732-4. doi: 10.1097/OLQ.0b013e3181b08456. PMID:
Allsworth JE. Bacterial vaginosis-race and sexual transmission: issues of causation. Sex Transm Dis. 2010;
(3): 137-9. doi: 10.1097/OLQ.0b013e3181d36bdc. PMID: 20118829.
Ness RB, Hillier SL, Kip KE, Soper DE, Stamm CA, McGregor JA, et al. Bacterial vaginosis and risk of
pelvic inflammatory disease. Obstet Gynecol. 2004; 104(4): 761-9. doi:
1097/01.AOG.0000139512.37582.17. PMID: 15458899.
Riggs M, Klebanoff M, Nansel T, Zhang J, Schwebke J, Andrews W. Longitudinal association between
hormonal contraceptives and bacterial vaginosis in women of reproductive age. Sex Transm Dis. 2007;
(12): 954-9. doi: 10.1097/OLQ.0b013e318074e565. PMID: 18077845.
Klebanoff MA, Nansel TR, Brotman RM, Zhang J, Yu KF, Schwebke JR, et al. Personal hygienic
behaviors and bacterial vaginosis. Sex Transm Dis. 2010; 37(2): 94-9. doi:
1097/OLQ.0b013e3181bc063c. PMID: 19823112, PMCID: PMC2811217.
Koumans EH, Sternberg M, Bruce C, McQuillan G, Kendrick J, Sutton M, et al. The prevalence of
bacterial vaginosis in the United States, 2001-2004; associations with symptoms, sexual behaviors, and
reproductive health. Sex Transm Dis. 2007; 34(11): 864-9. PMID: 17621244.
Schwebke JR, Desmond RA, Oh MK. Predictors of bacterial vaginosis in adolescent women who douche.
Sex Transm Dis. 2004; 31(7): 433-6. PMID: 15215700.
Bilardi JE, Walker S, Temple-Smith M, McNair R, Mooney-Somers J, Bellhouse C, et al. The burden of
bacterial vaginosis: women’s experience of the physical, emotional, sexual and social impact of living with
recurrent bacterial vaginosis. PloS one. 2013; 8(9): e74378. doi: 10.1371/journal.pone.0074378. PMID:
, PMCID: PMC3770676.
de Figueiredo Leite SR, de Amorim MM, Calábria WB, de Figueiredo Leite TN, de Oliveira VS, Ferreira
Júnior JA, et al. [Clinical and microbiological profile of women with bacterial vaginosis]. Rev Bras
Ginecol Obstet. 2010; 32(2): 82-7. PMID: 20305946.
Donders GG, Zodzika J, Rezeberga D. Treatment of bacterial vaginosis: what we have and what we miss.
Expert Opin Pharmacother. 2014; 15(5): 645-57. doi: 10.1517/14656566.2014.881800. PMID: 24579850.
Verstraelen H, Verhelst R. Bacterial vaginosis: an update on diagnosis and treatment. Expert Rev Anti
Infect Ther. 2009; 7(9): 1109-24. doi: 10.1586/eri.09.87. PMID: 19883331.
Löfmark S, Edlund C, Nord CE. Metronidazole is still the drug of choice for treatment of anaerobic
infections. Clin Infect Dis. 2010; 50(Suppl 1): 16-23. doi: 10.1086/647939. PMID: 20067388.
Ferris DG, Litaker MS, Woodward L, Mathis D, Hendrich J. Treatment of bacterial vaginosis: a
comparison of oral metronidazole, metronidazole vaginal gel, and clindamycin vaginal cream. J Fam Pract.
; 41(5): 443-9. PMID: 7595261.
Rafiean-Kopaei M, Baradaran A, Maghsoudi AR, Ghobadi Sh, Nasri H. Helicobacter pylori infection and
serum homocysteine in hemodialysis patient. Life Sci J. 2012; 9(4): 3696-3702.
Sharafati-chaleshtori R, Rafieian-kopaei M. Screening of antibacterial effect of the Scrophularia Striata
against E. coli in vitro. J HerbMed Pharmacol. 2014; 3(1): 31-4.
Amirmohammadi M, Khajoenia S, Bahmani M, Rafieian-Kopaei M, Eftekhari Z, Qorbani M. In vivo
evaluation of antiparasitic effects of Artemisia abrotanum and Salvia officinalis extracts on Syphacia
obvelata, Aspiculoris tetrapetra and Hymenolepis nana parasites. Asian Pac J Trop Dis. 2014; 4(1): 250- 254. doi: 10.1016/S2222-1808(14)60449-7.
Bahmani M, Rafieian-Kopaei M. Medicinal plants and secondary metabolites for leech control. Asian Pac J
Trop Dis. 2014; 4(4): 315-6. doi: 10.1016/S2222-1808(14)60580-6.
Shirzad H, Taji F, Rafieian-Kopaei M. Correlation between antioxidant activity of garlic extracts and
WEHI-164 fibrosarcoma tumor growth in BALB/c mice. J Med Food. 2011; 14(9): 969-74. doi:
1089/jmf.2011.1594. PMID: 21812650.
Ghasemi Dehkordi N.A, Sajadi S.E, Ghanadi A.R, Amanzadeh Y, Azadbakht M, Asghari GH.R, et al.
Iranian herbal pharmacopoeia (IHP). HAKIM. 2003; 6(3): 63-9.
Sobel JD. Bacterial vaginosis. Annu Rev Med. 2000; 51: 349-56. doi: 10.1146/annurev.med.51.1.349.
PMID: 10774469.
Simbar M, Azarbad Z, Mojab F, Majd HA. A comparative study of the therapeutic effects of the Zataria
multiflora vaginal cream and metronidazole vaginal gel on bacterial vaginosis. Phytomedicine. 2008;
(12): 1025-31. doi: 10.1016/j.phymed.2008.08.004. PMID: 18824338.
Rabiei Z, Rafieian-Kopaei M, Heidarian E, Saghaei E, Mokhtari S. Effects of Zizyphus jujube extract on
memory and learning impairment induced by bilateral electric lesions of the nucleus Basalis of Meynert in
rat. Neurochem Res. 2014; 39(2): 353-60. doi: 10.1007/s11064-013-1232-8. PMID: 24379110.
Sobel JD, Ferris D, Schwebke J, Nyirjesy P, Wiesenfeld HC, Peipert J, et al. Suppressive antibacterial
therapy with 0.75% metronidazole vaginal gel to prevent recurrent bacterial vaginosis. Am J Obstet
Gynecol. 2006; 194(5): 1283-9. doi: 10.1016/j.ajog.2005.11.041. PMID: 16647911.
Imanshahidi M, Hosseinzadeh H. Pharmacological and therapeutic effects of Berberis vulgaris and its
active constituent, berberine. Phytother Res. 2008; 22(8): 999-1012. doi: 10.1002/ptr.2399. PMID:
Han Y, Lee JH. Berberine synergy with amphotericin B against disseminated candidiasis in mice. Biol
Pharm Bull. 2005; 28(3): 541-4. PMID: 15744087.
Soffar SA, Metwali DM, Abdel-Aziz SS, el-Wakil HS, Saad GA. Evaluation of the effect of a plant
alkaloid (berberine derived from Berberis aristata) on Trichomonas vaginalis in vitro. J Egypt Soc
Parasitol. 2001; 31(3): 893-904. PMID: 11775115.
Oh KB, Oh MN, Kim JG, Shin DS, Shin J. Inhibition of sortase-mediated Staphylococcus aureus adhesion
to fibronectin via fibronectin-binding protein by sortase inhibitors. Appl Microbiol Biotechnol. 2006;
(1): 102-6. PMID: 16010573.
Danforth DN, Gibbs RS. Danforth's obstetrics and gynecology: Lippincott Williams & Wilkins; 2008: 783.
Kupeli E, Kosar M, Yesilada E, Husnu K, Baser C. A comparative study on the anti-inflammatory,
antinociceptive and antipyretic effects of isoquinoline alkaloids from the roots of Turkish Berberis species.
Life sciences. 2002; 72(6): 645-57. PMID: 12467905.
Kuo CL, Chi CW, Liu TY. Modulation of apoptosis by berberine through inhibition of cyclooxygenase-2
and Mcl-1 expression in oral cancer cells. In vivo. 2005; 19(1): 247-52. PMID: 15796182.
Shamsa F, Ahmadiani A, Khosrokhavar R. Antihistaminic and anticholinergic activity of Berberis vulgaris
fruit (Berberis vulgaris) in the guinea-pig ileum. J Ethnopharmacol. 1999; 64(2): 161-6. PMID: 10197751.
Godarzi F, Abaspour Z, Abaspour MR, Momeni A, Zandi K. The Effect of Vitamin C Vaginal Tablets on
Amsel Criterion in Patients with Bacterial Vaginosis. Armaghane Danesh. 2011; 16(4): 372-80.
Petersen EE, Magnani P. Efficacy and safety of Vitamin C vaginal tablets in the treatment of non-specific
vaginitis: A randomised, double blind, placebo-controlled study. Eur J Obstet Gynecol Reprod Biol. 2004;
(1): 70-5. doi: 10.1016/j.ejogrb.2004.02.032. PMID: 15474248.
Masoudi M, Miraj S, Rafieian-Kopaei M. Comparison of the Effects of Myrtus Communis L, Berberis
Vulgaris and Metronidazole Vaginal Gel alone for the Treatment of Bacterial Vaginosis. J Clin Diagn Res.
; 10(3): 4-7. doi: 10.7860/JCDR/2016/17211.7392. PMID: 27134945, PMCID: PMC4843330
Seyyedi F, Rafiean-Kopaei M, Miraj S. Comparison of the Effects of Vaginal Royal Jelly and Vaginal
Estrogen on Quality of Life, Sexual and Urinary Function in Postmenopausal Women. J Clin Diag Res.
; 10(5): 1-5. doi: 10.7860/jcdr/2016/17844.7715. PMID: 27437306, PMCID: PMC4948482.
Miraj S, Kiani S. Menstrual diseases as stated in canon fil-Tibb. Der Pharmacia Lettre. 2016; 8(6): 261-8.
Farage MA, Miller KW, Ledger WJ. Determining the cause of Vulvovaginal symptoms. Obstet Gynecol
Surv. 2008; 63(7): 445-64. doi: 10.1097/OGX.0b013e318172ee25. PMID: 18559121.
Mashburn J. Vaginal infections update. J Midwifery Womens Health. 2012; 57(6): 629-34. doi:
1111/j.1542-2011.2012.00246.x. PMID: 23094602.
Burkman RT. Berek & Novak’s Gynecology. JAMA. 2012; 613; 308(5): 516-7.
Cherpes TL, Hillier SL, Meyn LA, Busch JL, Krohn MA. A delicate balance: risk factors for acquisition of
bacterial vaginosis include sexual activity, absence of hydrogen peroxide-producing lactobacilli, black race,
and positive herpes simplex virus type 2 serology. Sex Transm Dis. 2008; 35(1): 78-83. doi:
1097/OLQ.0b013e318156a5d0. PMID: 17989585.
Reichman O, Akins R, Sobel JD. Boric acid addition to suppressive antimicrobial therapy for recurrent
bacterial vaginosis. Sex Transm Dis. 2009; 36(11): 732-4. doi: 10.1097/OLQ.0b013e3181b08456. PMID:
Allsworth JE. Bacterial vaginosis-race and sexual transmission: issues of causation. Sex Transm Dis. 2010;
(3): 137-9. doi: 10.1097/OLQ.0b013e3181d36bdc. PMID: 20118829.
Ness RB, Hillier SL, Kip KE, Soper DE, Stamm CA, McGregor JA, et al. Bacterial vaginosis and risk of
pelvic inflammatory disease. Obstet Gynecol. 2004; 104(4): 761-9. doi:
1097/01.AOG.0000139512.37582.17. PMID: 15458899.
Riggs M, Klebanoff M, Nansel T, Zhang J, Schwebke J, Andrews W. Longitudinal association between
hormonal contraceptives and bacterial vaginosis in women of reproductive age. Sex Transm Dis. 2007;
(12): 954-9. doi: 10.1097/OLQ.0b013e318074e565. PMID: 18077845.
Klebanoff MA, Nansel TR, Brotman RM, Zhang J, Yu KF, Schwebke JR, et al. Personal hygienic
behaviors and bacterial vaginosis. Sex Transm Dis. 2010; 37(2): 94-9. doi:
1097/OLQ.0b013e3181bc063c. PMID: 19823112, PMCID: PMC2811217.
Koumans EH, Sternberg M, Bruce C, McQuillan G, Kendrick J, Sutton M, et al. The prevalence of
bacterial vaginosis in the United States, 2001-2004; associations with symptoms, sexual behaviors, and
reproductive health. Sex Transm Dis. 2007; 34(11): 864-9. PMID: 17621244.
Schwebke JR, Desmond RA, Oh MK. Predictors of bacterial vaginosis in adolescent women who douche.
Sex Transm Dis. 2004; 31(7): 433-6. PMID: 15215700.
Bilardi JE, Walker S, Temple-Smith M, McNair R, Mooney-Somers J, Bellhouse C, et al. The burden of
bacterial vaginosis: women’s experience of the physical, emotional, sexual and social impact of living with
recurrent bacterial vaginosis. PloS one. 2013; 8(9): e74378. doi: 10.1371/journal.pone.0074378. PMID:
, PMCID: PMC3770676.
de Figueiredo Leite SR, de Amorim MM, Calábria WB, de Figueiredo Leite TN, de Oliveira VS, Ferreira
Júnior JA, et al. [Clinical and microbiological profile of women with bacterial vaginosis]. Rev Bras
Ginecol Obstet. 2010; 32(2): 82-7. PMID: 20305946.
Donders GG, Zodzika J, Rezeberga D. Treatment of bacterial vaginosis: what we have and what we miss.
Expert Opin Pharmacother. 2014; 15(5): 645-57. doi: 10.1517/14656566.2014.881800. PMID: 24579850.
Verstraelen H, Verhelst R. Bacterial vaginosis: an update on diagnosis and treatment. Expert Rev Anti
Infect Ther. 2009; 7(9): 1109-24. doi: 10.1586/eri.09.87. PMID: 19883331.
Löfmark S, Edlund C, Nord CE. Metronidazole is still the drug of choice for treatment of anaerobic
infections. Clin Infect Dis. 2010; 50(Suppl 1): 16-23. doi: 10.1086/647939. PMID: 20067388.
Ferris DG, Litaker MS, Woodward L, Mathis D, Hendrich J. Treatment of bacterial vaginosis: a
comparison of oral metronidazole, metronidazole vaginal gel, and clindamycin vaginal cream. J Fam Pract.
; 41(5): 443-9. PMID: 7595261.
Rafiean-Kopaei M, Baradaran A, Maghsoudi AR, Ghobadi Sh, Nasri H. Helicobacter pylori infection and
serum homocysteine in hemodialysis patient. Life Sci J. 2012; 9(4): 3696-3702.
Sharafati-chaleshtori R, Rafieian-kopaei M. Screening of antibacterial effect of the Scrophularia Striata
against E. coli in vitro. J HerbMed Pharmacol. 2014; 3(1): 31-4.
Amirmohammadi M, Khajoenia S, Bahmani M, Rafieian-Kopaei M, Eftekhari Z, Qorbani M. In vivo
evaluation of antiparasitic effects of Artemisia abrotanum and Salvia officinalis extracts on Syphacia
obvelata, Aspiculoris tetrapetra and Hymenolepis nana parasites. Asian Pac J Trop Dis. 2014; 4(1): 250- 254. doi: 10.1016/S2222-1808(14)60449-7.
Bahmani M, Rafieian-Kopaei M. Medicinal plants and secondary metabolites for leech control. Asian Pac J
Trop Dis. 2014; 4(4): 315-6. doi: 10.1016/S2222-1808(14)60580-6.
Shirzad H, Taji F, Rafieian-Kopaei M. Correlation between antioxidant activity of garlic extracts and
WEHI-164 fibrosarcoma tumor growth in BALB/c mice. J Med Food. 2011; 14(9): 969-74. doi:
1089/jmf.2011.1594. PMID: 21812650.
Ghasemi Dehkordi N.A, Sajadi S.E, Ghanadi A.R, Amanzadeh Y, Azadbakht M, Asghari GH.R, et al.
Iranian herbal pharmacopoeia (IHP). HAKIM. 2003; 6(3): 63-9.
Sobel JD. Bacterial vaginosis. Annu Rev Med. 2000; 51: 349-56. doi: 10.1146/annurev.med.51.1.349.
PMID: 10774469.
Simbar M, Azarbad Z, Mojab F, Majd HA. A comparative study of the therapeutic effects of the Zataria
multiflora vaginal cream and metronidazole vaginal gel on bacterial vaginosis. Phytomedicine. 2008;
(12): 1025-31. doi: 10.1016/j.phymed.2008.08.004. PMID: 18824338.
Rabiei Z, Rafieian-Kopaei M, Heidarian E, Saghaei E, Mokhtari S. Effects of Zizyphus jujube extract on
memory and learning impairment induced by bilateral electric lesions of the nucleus Basalis of Meynert in
rat. Neurochem Res. 2014; 39(2): 353-60. doi: 10.1007/s11064-013-1232-8. PMID: 24379110.
Sobel JD, Ferris D, Schwebke J, Nyirjesy P, Wiesenfeld HC, Peipert J, et al. Suppressive antibacterial
therapy with 0.75% metronidazole vaginal gel to prevent recurrent bacterial vaginosis. Am J Obstet
Gynecol. 2006; 194(5): 1283-9. doi: 10.1016/j.ajog.2005.11.041. PMID: 16647911.
Imanshahidi M, Hosseinzadeh H. Pharmacological and therapeutic effects of Berberis vulgaris and its
active constituent, berberine. Phytother Res. 2008; 22(8): 999-1012. doi: 10.1002/ptr.2399. PMID:
Han Y, Lee JH. Berberine synergy with amphotericin B against disseminated candidiasis in mice. Biol
Pharm Bull. 2005; 28(3): 541-4. PMID: 15744087.
Soffar SA, Metwali DM, Abdel-Aziz SS, el-Wakil HS, Saad GA. Evaluation of the effect of a plant
alkaloid (berberine derived from Berberis aristata) on Trichomonas vaginalis in vitro. J Egypt Soc
Parasitol. 2001; 31(3): 893-904. PMID: 11775115.
Oh KB, Oh MN, Kim JG, Shin DS, Shin J. Inhibition of sortase-mediated Staphylococcus aureus adhesion
to fibronectin via fibronectin-binding protein by sortase inhibitors. Appl Microbiol Biotechnol. 2006;
(1): 102-6. PMID: 16010573.
Danforth DN, Gibbs RS. Danforth's obstetrics and gynecology: Lippincott Williams & Wilkins; 2008: 783.
Kupeli E, Kosar M, Yesilada E, Husnu K, Baser C. A comparative study on the anti-inflammatory,
antinociceptive and antipyretic effects of isoquinoline alkaloids from the roots of Turkish Berberis species.
Life sciences. 2002; 72(6): 645-57. PMID: 12467905.
Kuo CL, Chi CW, Liu TY. Modulation of apoptosis by berberine through inhibition of cyclooxygenase-2
and Mcl-1 expression in oral cancer cells. In vivo. 2005; 19(1): 247-52. PMID: 15796182.
Shamsa F, Ahmadiani A, Khosrokhavar R. Antihistaminic and anticholinergic activity of Berberis vulgaris
fruit (Berberis vulgaris) in the guinea-pig ileum. J Ethnopharmacol. 1999; 64(2): 161-6. PMID: 10197751.
Godarzi F, Abaspour Z, Abaspour MR, Momeni A, Zandi K. The Effect of Vitamin C Vaginal Tablets on
Amsel Criterion in Patients with Bacterial Vaginosis. Armaghane Danesh. 2011; 16(4): 372-80.
Petersen EE, Magnani P. Efficacy and safety of Vitamin C vaginal tablets in the treatment of non-specific
vaginitis: A randomised, double blind, placebo-controlled study. Eur J Obstet Gynecol Reprod Biol. 2004;
(1): 70-5. doi: 10.1016/j.ejogrb.2004.02.032. PMID: 15474248.
Masoudi M, Miraj S, Rafieian-Kopaei M. Comparison of the Effects of Myrtus Communis L, Berberis
Vulgaris and Metronidazole Vaginal Gel alone for the Treatment of Bacterial Vaginosis. J Clin Diagn Res.
; 10(3): 4-7. doi: 10.7860/JCDR/2016/17211.7392. PMID: 27134945, PMCID: PMC4843330
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