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Comparative phase I randomized open-label pilot clinical trial of Gynophilus® (Lcr regenerans®) immediate release capsules versus slow release muco-adhesive tablets

  • Laboratoires Lyocentre

Abstract and Figures

Gynophilus® (Lcr regenerans®) is a live biotherapeutic product (LBP) that contains the live biotherapeutic microorganism Lactobacillus rhamnosus Lcr35®, which is indicated to restore vaginal health. The aim of the study was to compare the safety, ease of use, and compliance of two formulations (immediate release: IR capsule and slow release: SR muco-adhesive tablets) as well as the colonization of Lcr35® in healthy women. This phase I study (Comprigel) is a parallel, randomized, 4-arm, and open-label clinical trial evaluating an IR daily capsule formulation vs. a SR tablet administered every 3, 4, or 5 days for 21 days. Self-collected vaginal swabs were used to quantify Lcr35® and characterize the composition and structure of the vaginal microbiota. Both LBPs were well-tolerated, and no severe adverse effects were reported. All groups had Lcr35® vaginal concentrations over 10⁷ colony forming unit per milliliter of vaginal secretion on each day in the study. The new Gynophilus® slow release tablets administered either every 3, 4, or 5 days provided vaginal concentrations that were not significantly different from those of classic Gynophilus® (capsule) once-a-day regimen. The LBPs and the different regimens did not adversely influence the abundance of native Lactobacillus spp. and indeed tended to favor their growth and reduce colonization by non-Lactobacillus spp. This study illustrates that the SR muco-adhesive LBP tablet (Gynophilus® SR) administered every 3 or 4 days as a safe, well-tolerated, and efficacious alternative to a more demanding IR daily capsule and could protect women’s healthy vaginal microbiome by promoting endogenous Lactobacillus spp. Electronic supplementary material The online version of this article (10.1007/s10096-018-3321-8) contains supplementary material, which is available to authorized users.
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Comparative phase I randomized open-label pilot clinical trial
of Gynophilus
(Lcr regenerans
) immediate release capsules
versus slow release muco-adhesive tablets
Caroline Dausset
&Stéphane Patrier
&Pawel Gajer
&Claudia Thoral
&Yann Lenglet
&Jean-Michel Cardot
Philippe Judlin
&Jacques Ravel
&Adrien Nivoliez
Received: 2 March 2018 /Accepted: 2 July 2018 /Pu blished online: 21 July 2018
#The Author(s) 2018
(Lcr regenerans
) is a live biotherapeutic product (LBP) that contains the live biotherapeutic microorganism
Lactobacillus rhamnosus Lcr35
, which is indicated to restore vaginal health. The aim of the study was to compare the safety,
ease of use, and compliance of two formulations (immediate release: IR capsule and slow release: SR muco-adhesive tablets) as
well as the colonization of Lcr35
in healthy women. This phase I study (Comprigel) is a parallel, randomized, 4-arm, and open-
label clinical trial evaluating an IR daily capsule formulation vs. a SR tablet administered every 3, 4, or 5 days for 21 days. Self-
collected vaginal swabs were used to quantify Lcr35
and characterize the composition and structure of the vaginal microbiota.
Both LBPs were well-tolerated, and no severe adverse effects were reported. All groups had Lcr35
vaginal concentrations over
colony forming unit per milliliter of vaginal secretion on each day in the study. The new Gynophilus
slow release tablets
administered either every 3, 4, or 5 days provided vaginal concentrations that were not significantly different from those of classic
(capsule) once-a-day regimen. The LBPs and the different regimens did not adversely influence the abundance of
native Lactobacillus spp. and indeed tended to favor their growth and reduce colonization by non-Lactobacillus spp. This study
illustrates that the SR muco-adhesive LBP tablet (Gynophilus
SR) administered every 3 or 4 days as a safe, well-tolerated, and
efficacious alternative to a more demanding IR daily capsule and could protect womens healthy vaginal microbiome by
promoting endogenous Lactobacillus spp.
Keywords Live biotherapeutic product .Lcr35 .Vaginal infections .Va gina l mic rob i ota .Slow release .Muco-adhesive tablet .
The healthy vaginal microbiota is dominated by Lactobacillus
spp. which play important roles in protecting women, partic-
ularly against vaginal infections [1,2]. Bacterial vaginosis
(BV) and vulvovaginal candidiasis (VVC) are the most prev-
alent vaginal infections in women of reproductive age [3,4].
These infections have a negative impact on a womansquality
of life and represent a significant cost to the healthcaresystem,
especially due to medical consultations and antimicrobial
treatments. In addition, recurrence is common and can lead
to multiple relapses over time [5,6]. The use of probiotic
products or live biotherapeutic products (LBPs) represent an
alternative or complement to traditional treatment regimens to
help control and/or re-establish a beneficial vaginal microbio-
ta [7,8]. Indeed, LBPs are thought to stimulate the
Electronic supplementary material The online version of this article
( contains supplementary
material, which is available to authorized users.
*Caroline Dausset
Research and Development Department, BIOSE, Aurillac, France
Institute for Genome Sciences, University of Maryland School of
Medicine, Baltimore, MD, USA
Gynecology and Obstetrics Department, Jacques Lacarin Hospital
Center, Vichy, France
Biopharmaceutical Department, UMR MEDIS, Faculty of Pharmacy,
University of Clermont Auvergne, Clermont-Ferrand, France
Gynecology and Obstetrics Department, Nancy University Hospital,
Nancy, France
European Journal of Clinical Microbiology & Infectious Diseases (2018) 37:18691880
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
recolonization of endogenous Lactobacillus spp., which can
inhibit the growth of pathogens such as Gardnerella vaginalis
and Candida albicans [7,8]. LBPs have been used success-
fully as an adjunct to traditional antibiotics for BV and as an
antifungal for VVC to improve the cure rates and prevent
recurrence by driving the restoration of beneficial commensal
microbiota [3,9,10].
LBP Gynophilus immediate release (IR) capsule, contain-
ing Lactobacillus rhamnosus Lcr35
, is commonly recom-
mended for preventive therapies for gynecological indica-
tions. Indeed, several clinical trials validated its efficiency
for preventing recurrent VVC and BV [1113].
LBPs were first delivered in the form of vaginal dosage
capsules because vaginal administration affects vaginal health
more quickly than does oral LBP and enhances the viability of
the live biotherapeutic microorganism (LBM) [14]. To be ef-
ficacious, a sufficient amount of the probiotic bacteria must be
delivered locally. Previous studies have shown that in healthy
women, the concentration of Lactobacillus spp. is greater than
or equal to 10
CFU/ml of vaginal secretion [15,16]. Capsule
administration results in an immediate release of all the LBMs
that are linked to the natural vaginal secretions induced by the
daily elimination of approximately 10
to 10
CFU per day
and therefore requires daily administrations [17]. To limit this
rapid loss, Gynophilus
SR tablet was developed to ensure the
continuous release and presence of the LBM in sufficient
quantities for many days while conserving its in vitro intrinsic
characteristics (viability, stability, growth, and pathogen inhi-
bition) [18,19]. For the first time, a LBM was formulated as
slow release tablet for local vaginal administration to enhance
womens quality of life by spacing LBP intake [14,20].
The objective of this pilot phase I clinical trial was to de-
termine the optimal posology for the new tablet form (SR)
compared to the daily capsule (IR). The following criteria
were analyzed (i) safety, (ii) ease of use of two galenic forms,
(iii) vaginal concentration of the LBM L. rhamnosus Lcr35
in healthy women, and (iv) impact of the products on the
vaginal microbiota.
Materials and methods
Live biotherapeutic products
Two industrial LBPs, provided by BIOSE (Aurillac, France),
were used for this study: Gynophilus
(immediate release
capsule), and Gynophilus
SR (slow release tablet), both of
which were administered vaginally. Gynophilus
contains 350 mg administered daily and the new muco-
adhesive Gynophilus
SR vaginal tablet contains 1000 mg.
LBPs batch release correspond to L. rhamnosus Lcr35
centration greater than 10
CFU per dosage forms (capsule
and tablet). The LBPs and their corresponding characteristics
are shown in Table 1. In this article, the LPBs are called by
their respective commercial names: Gynophilus
Study design
The study was designed to include at least 32 female volun-
teers. Following the management of the recruitment centers,
the cohort comprised of 35 healthy reproductive age women
(> 18 years old). All women were not pregnant (negative urine
pregnancy test) and used adapted contraception throughout
the trial. Exclusion criteria included, in addition to the classi-
cal criteria, gynecological bacterial, fungal, or viral infection
in the month prior to or at time of enrollment; use of vaginal or
oral probiotics in the last 30 days; or allergy to one of the
active ingredients or one of the excipients in the products.
Further, additional specific exclusion criteria included an in-
ability to comply with the constraints of the protocol, currently
breastfeeding, being post-menopausal (no menstruation in the
last 6 months), menstrual bleeding lasting more than 8 days,
participated in a clinical study in the last 3 months, severe
acute or chronic conditions deemed incompatible with partic-
ipation in the trial by the clinician, and immunosuppression.
At enrollment, 1 day after the last day of menstruation, each
participant completed a medical history questionnaire and was
examined by a clinician who collected cervico-vaginal sam-
ples to test for Trichomonas vaginalis, Chlamydia
trachomatis, Neisseria gonorrhoeae,andCandida spp. A
clinical evaluation was performed at Alfred Fournier
Institute according to the Amsel criteria [21]. A second vagi-
nal swab was also collected using the Copan ESwab system
(Cat# 480C) bythe clinician and stored at BIOSE at 80 °C in
1 ml of Amies transport medium for L. rhamnosus Lcr35
quantification and vaginal microbiota analysis by 16S rRNA
gene amplicon sequencing.
Among the 35 volunteer women, one of them had taken a
prohibited treatment before the inclusion, and one other wom-
an did not take the test drug after inclusion because of men-
struation. Therefore, after obtaining written consent and en-
rollment, 33 women were randomized to one of four arms:
capsules administered daily which served as
the reference arm (REF, n= 9) or Gynophilus
SR tablets
administered either every 3 (TRT1, n= 8), 4 (TRT2, n=9),
or 5 (TRT3, n= 7) days. Randomization was stratified within
enrollment centers (Centre Hospitalier of Aurillac or Vichy,
Table 1 Industrial LBPs and their characteristics
LBP commercial name Dosage form Dosage LBM Application
Capsule 350 mg Lcr35
SR Tablet 1000 mg Lcr35
1870 Eur J Clin Microbiol Infect Dis (2018) 37:18691880
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
France). The randomization list was prepared using the SAS
software version 9.3.
Women self-administered the first LBPs according the
product package insert on the day of enrollment and continued
for 21 days according to their assigned regimen. Each day,
women self-collected a vaginal swab (Copan ESwab system)
and stored the sample at 4 °C in their home fridge. Volunteers
delivered all self-collected vaginal swabs to the clinic at the
second visit. This second clinical visit occurred within 4 days
of the last administration of the assigned LBP. A clinical eval-
uation similar to that performed at enrollment was performed
and a vaginal swab was collected by the clinician using a
Copan ESwab. All sample collected were stored at 80 °C
at BIOSE until additional analysis.
DNA extraction from vaginal samples
An optimized and standardized DNA extraction protocol ded-
icated to bacterial DNA extraction from swab samples has
been used (Genoscreen, Lille, France). ESwabs were thawed
on ice and a total of 500 μl of cell suspension in Amies trans-
port medium was processed using the Nucleospin 96 tissue kit
(Macherey Nagel, Germany) including a bead-beating step, as
recommended by the manufacturer. DNA quantification was
performed using SYBR green (Life Technologie, Paisley,
UK). A 16S rRNA gene PCR amplification was performed
using 2 μl of extracted DNA to confirm the presence of bac-
terial DNA using standard 16S rRNA gene PCR. DNA ex-
traction and quantification steps were performed by
GenoScreen Lille, France.
Quantification of L. rhamnosus Lcr35
by qPCR
Quantification of L. rhamnosus Lcr35
was estimated by a
specific qPCR run in triplicate as previously described
(Darbaky et al. 2016). L. rhamnosus Lcr35
quantities were
expressed in CFU/ml using a standard curve correlating Ct
values to colony forming unit (CFU) from in vitro culture in
De Man, Rogosa, and Sharpe (MRS) medium.
Quantification of total 16S rRNA copies
The number of 16S rRNA gene copies was measured using the
BactQuant qPCR assay as previously reported [22]. Estimates
of taxa absolute abundance were obtained by multiplying the
relative abundance of a specific taxa with the 16S rRNA gene
copy number in a sample (Online Resources 1and 2).
Vaginal microbiota characterization
The V3-V4 regions of the 16S rRNA gene were amplified
from 50 ng of DNA from each sample using the methods of
Fadrosh et al. [23]andsequencedonanIlluminaMiSeq
(Illumina, San Diego, CA, USA) using the 300-bp paired-
end protocol. Raw sequence reads were processed using in
house scripts and QIIME version 1.6.0 [24] to remove the
amplification primer sequences and quality screen was per-
formed according the following criteria: sequence reads with
average quality score of less than 20 over a 30-bp sliding
window were truncated at the first base pair of the window
and evaluated for length. If the trimmed read was < 75% of its
original length, it was discarded. Paired sequences were as-
sembled according to Fadrosh et al. [23] and each sequence
was assigned to a bacterial taxonomy using the PECAN soft-
ware [25]. Community state types (CST) according to the
previously reported method [26], taxa relative abundance
and CST assignments are shown in Online Resources 1and 2.
Statistical analysis
Data are presented as the mean and standard deviation for
continuous variables and as numbers or proportions (%) for
categorical variables. Comparisons between groups were per-
formed by using the Kruskal-Wallis test or Fisher exact test for
categorical variables. To compare the mean concentration of
over time between treatment and reference arms, the
Wilcoxon test was used. All clinical statistical analyses were
performed using the SAS software (SAS
institute Cary, NC,
USA,; pvalues < 0.05 were considered
statistically significant.
Inter-group differences in numbers of 16S rRNA copies
and microbiota were assessed using a Kruskal-Wallis test.
Theses statistical analyses were carried out using the
GraphPad Prism 5 software (; p
values < 0.05 were considered statistically significant.
As a classic pilot study, small arm population induces a low
power calculation so the statistical analysis was focused on
midpoint and variability.
Volunteer population
A total of 35 volunteer women were enrolled, and 34 were
randomized into 4 treatment arms; 33 women completed the
study (Fig. 1). Two women were excluded because of use of
treatment before product initiation or menstruation during the
The population characteristics and statistic results are
shown in Table 2. The median participant age was 32 years
(32.3 ± 7.7 years). A variability was observed in the median
participants age among the 4 treatment arms (TRT1, TRT2,
TRT3, and REF) (p= 0.02). However, all women were be-
tween 21 and 52 years of age. Body mass index (BMI) was
not significantly different (p= 0.60) between each arm, with a
Eur J Clin Microbiol Infect Dis (2018) 37:18691880 1871
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
mean of 23 ± 5 (kg/m
). Overall, 54.5% of the participants had
at least one previous live birth. The mean number of children
was 2 for the entire cohort, varying from 1 in TRT2 to 3 in
TRT1 (Table 2).
Safety of Lcr regenerans
No severe adverse events were observed (Table 3). Ten
adverse events (AE) were reported, but no differences
(p= 0.40) in the frequency of AEs were detected among
the 4 arms (Table 3). All AEs were considered not serious.
One of the AEs in TRT2 was deemed to be of severe in-
tensity with vulvar itching. Other reported AEs included
three that were linked to product use, and the women re-
ported vulvar itching, brown discharges, and vulvovaginal
discomfort after administration of the first tablet. However,
none of the AEs led to permanent or temporary withdrawal
from the study (Table 3).
Clinical tolerance was evaluated at the last visit by the study
clinician through questioning and examination of the partici-
pants. Factors evaluated were onset of clinical signs and/or
urogenital symptoms (Table 4). The products were well-
tolerated (score: excellent) by half the subjects and were tol-
erated in the other half (score: good). Specific criteria evalua-
tion (tingling, dryness, burning, itching, and pelvic pain) was
rarely reported, and no difference in these reported factors
between arms was observed (Table 5).
Table 2 Demographic characteristics of the populationFAS population (N=33
Parameter Statistics TRT1 (1 tab/3 days)
(N = 8)
TRT2 (1 tab/4 days)
(N = 9)
TRT3 (1 tab/5 days)
(N = 7)
REF (1 caps/ day)
(N = 9)
p(< 0.05)
Age at inclusion (years) Mean ± SD 39.4 ± 6.5 28.9 ± 4.8 32.4 ± 9.7 29.4 ± 5.7 0.0220**
Body mass index (kg/m
)Mean ± SD 24.53 ± 4.95 22.67 ± 6.19 22.47± 3.21 22.44 ± 4.29 0.5988**
No n(%) 2 (25.0%) 5 (55.6%) 3 (42.9%) 5 (55.6%) 0.6115*
Yes n(%) 6 (75.0%) 4 (44.4%) 4 (57.1%) 4 (44.4%)
If yes, number of children Mean ± SD 2.7 ± 0.5 1.0 ± 0.0 2.0 ± 0.8 1.5 ± 0.6 0.0652**
*Fishers exact test
**Kruskal-Wallis test
N= 33 because only 33 received the treatment
Fig. 1 Study design of
CompriGel pilot clinical trial
1872 Eur J Clin Microbiol Infect Dis (2018) 37:18691880
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Administration and dosage regimen demonstrated strong
satisfaction (Table 6). The tablet regimen showed significantly
higher acceptance after the 3-week administration, especially
in the less restrictive arms, in which the tablets were taken
every 5 days compared to the daily capsule (Table 6).
Women self-collected a daily vaginal swab that was used to
measure the concentration of Lactobacillus rhamnosus
in each arm (Fig. 2). The average vaginal Lcr35
concentration showed no major difference among the four
arms (p= 0.77). A decrease in the daily Lcr35
was observed post-tablet administration as the frequency of
administration increased from every 3 to every 5 days (Fig. 2).
Although the daily Lcr35
concentration decreased post-ad-
ministration, it remained greater than 10
CFU/ml in TRT1
and TRT2, with the exception of 1 day in TRT2. In TRT3,
5 days post-administration, the Lcr35
concentration was ap-
proximately 10
Effect of Gynophilus
formulations on the vaginal
The daily composition and absolute abundance of the
vaginal microbiota were evaluated using 16S rRNA
gene amplicon sequencing and quantitative PCR. No
significant difference (p= 0.12) in the concentration of
Lactobacillus spp. was observed before
treatment (D0), during treatment and at the end of treat-
ment (D21) (Fig. 3a). The overall composition in
Lactobacillus spp. remained consistent during and after
The vaginal microbiota was classified into six distinct
community state types (CSTs) based on the microbiota
bacterial composition and abundance. The before and af-
ter treatment CST frequencies are shown in Table 7,
where CST-I is dominated by L. crispatus, CST-II is dom-
inated by L. gasseri, CST-III is dominated by L. iners,
CST-V is dominated by L. jensenii, CST-IV is character-
ized by a paucity of Lactobacillus spp. and a diverse set
of strict and facultative anaerobes, and CST-VI is domi-
. The frequency of CSTs was
not different between visit 1 and visit 2, indicating that
treatments did not disturb the indigenous
vaginal microbiota. Only one on 35 women is classified
as CST-VI (dominance Lcr35
) because the last tablet
was administrated just before the V2. So, Lcr35
not colonize and replace the endogenous microbiota.
Moreover, the CST proportions were not drastically mod-
ified which suggest that Lcr35
did not promote only one
CST type.
Table 3 Safety analysisadverse events during the treatment period (N=33
Volunteer with at least one TRT1 (1 tab/3 days)
(N = 8)
TRT2 (1 tab/4 days)
(N = 9)
TRT3 (1 tab/5 days)
(N = 7)
REF (1 caps/ day)
(N = 9)
(N = 33)
p*(< 0.05)
SAE (n) 00000NA
AE (n) 4 1 2 3 10 0.4017
AE of severe intensity (n)01000NA
AE linked to administration of the trial
treatment (n)
AE that led to permanent or temporary
discontinuation of study treatment (n)
*Fishers exact test
N= 33 because only 33 received the treatment
Table 4 Overall tolerance (N=33
Volunteer evaluation TRT1 (1 tab/3 days)
(N = 8)
TRT2 (1 tab/4 days)
(N = 9)
TRT3 (1 tab/5 days)
(N = 7)
REF (1 caps/day)
(N = 9)
Tot al
(N = 33)
Very good tolerance 4 6 2 4 16 0.5446
Good tolerance 4 3 5 4 16
Average tolerance 0 0 0 0 0
Poor tolerance 0 0 0 0 0
*Fishers exact test
N= 33 because only 33 received the treatment
Eur J Clin Microbiol Infect Dis (2018) 37:18691880 1873
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Representative vaginal microbiota profiles for each
study arm and the absolute abundance of Lcr35
showninFig.4and highlight the absence of a rapid
change in the composition and structure of the vaginal
microbiota during treatment. Of note, it was observed that
the Escherichia coli present at visit 1 was rapidly elimi-
nated after the initiation of treatment and that the indige-
nous Lactobacillus spp. re-colonized the vagina (Fig. 4a).
Moreover, E. coli species was detected at least once dur-
ing the study in vaginal samples of 28 women. For 21 of
them, E. coli is eliminated quickly after treatment (Online
Resource 3). Overall, after the initiation of Gynophilus
treatments, Lactobacillus spp. abundance remained stable
or promoted (Fig. 4).
LBPs aim to re-establish a Lactobacillus-dominated vag-
inal microbiota by promoting the recolonization of the
indigenous Lactobacillus spp., thereby restoring the pro-
tection against infections [7,8,27,28]. The LBP
is vaginally delivered and is indicated to
prevent recurrent VVC and BV by restoring vaginal
health [1113]. This LBP contains L. rhamnosus
, which was previously reported to have potent
antimicrobial properties [18,19,2932]. Gynophilus
(Lcr regenerans
) LBP formulated in vaginal capsules
was shown to be well-tolerated and significantly enhanced
the quality of life of women after treatment [13]. A muco-
adhesive slow release tablet formulation (SR) was
developed to limit the rapid loss of the LBP associated
with natural vaginal secretions and ultimately enhance the
ease of use by minimizing the frequency of administration
[14,1820] resulting in an increased compliance.
CompriGel is a pilot phase I clinical trial, in which 35
volunteers were randomized to four arms to compare the
LBP vaginal concentrations between daily IR capsule ad-
ministration and SR tablets taken every 3, 4, or 5 days for
21 days. As most of the pilot clinical studies, the power
calculation is limited due to the small size population but
minimize the risks in healthy subjects while allowing se-
lection of an interesting posology. So, this pilot study was
designed to determine the more adapted posology of the
new SR tablet.
colonization between SR tablets administered every 3 or
4 days and daily capsules. Importantly, the mean con-
centration of L. rhamnosus Lcr35
in all treatment arms
remained greater than 10
CFU/ml, which is the neces-
sary minimal concentration for activity and, ultimately,
to prevent vaginal infections [17]. The Lcr35
tion was quantified by molecular biology. This method
was not used to differentiate viable and dead microor-
ganisms and we know that the delivered LBM concen-
tration is at least 1.10
CFU/posology and we observe a
quickly remove of the LBM probably induced by the
vaginal secretions [17]. So, administration of tablets ev-
ery 3 or 4 days maintained a mean Lcr35
tion greater than 10
CFU/ml, similar to that obtained
with the daily capsules. This finding supports the pos-
sibility of a clinical regimen in which Gynophilus
Table 5 Satisfaction of female volunteers with regard to treatment tolerance
Parameter Statistics TRT1
(1 tab/3 days)
(N = 8)
(1 tab/4 days)
(N = 9)
(1 tab/5 days)
(N = 7)
(1 caps/day)
(N = 9)
Tot al
(N = 33)
Global p value**
(< 0.05)
Tingling Mean ± SD 0.43 ± 0.69 1.13 ± 3.18 0.67 ± 1.43 0.28 ± 0.22 0.63 ± 1.77 0.5856
0 = no tingling
10 = severe tingling
Dryness Mean ± SD 0.30 ± 0.38 0.11 ± 0.15 0.50 ± 0.98 0.29 ± 0.19 0.29 ± 0.50 0.3568
0 = no dryness
10 = severe dryness
Burning Mean ± SD 0.29 ± 0.38 0.14 ± 0.25 0.14 ± 0.18 0.23 ± 0.19 0.20 ± 0.26 0.5970
0 = no burning
10 = severe burning
Itching Mean ± SD 0.66 ± 0.86 1.22 ± 3.26 0.97 ± 2.35 1.37 ± 3.24 1.07 ± 2.56 0.5747
0 = no itching
10 = severe itching
Pelvic pain Mean ± SD 0.29 ± 0.34 1.18 ± 2.41 0.11 ± 0.15 0.48 ± 0.82 0.55 ± 1.35 0.6258
0 = no pelvic pain
10 =severe pelvic pain
**Kruskal-Wallis test
1874 Eur J Clin Microbiol Infect Dis (2018) 37:18691880
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tablets are administered every 3 or 4 days while main-
taining maximum efficacy.
The formulation of the muco-adhesive Gynophilus
SR tablet was developed to provide a three-fold increase
in the quantity of LBM brought in one dosage form to
reduce the rapid loss of LBM Lcr35
delivered by a cap-
sule. Moreover, this new dosage form ultimately im-
proved the comfort and ease of use, as the controlled
muco-adhesive vaginal formulation affords a prolonged
residence time of the LBM at efficacious concentrations
with less frequent administration. Slow release delivery
strategies have been successfully developed for antifungal
and antibacterial drugs and for other vaginal LBPs using
different muco-adhesive tablets or vaginal rings [3337].
The main goal of slow release strategies is to promote
compliance when the recommended treatment duration is
longer than 23 days and, ultimately, to improve the
comfort and ease of use by reducing the burden on wom-
en through spacing administrations. The results presented
have confirmed that over a 3-week treatment period,
SR tablets administered every 3 or 4 days
were reported to be convenient and less burdensome than
were daily Gynophilus
capsules (Table 6). Daily treat-
ment schedules generally induce poor compliance over
long administration periods. Gynophilus
SR promoted
compliance and improved treatment adherence. This find-
ing supports a benefit of the LBP for treating recurrent
vulvovaginal infections, which have been shown to re-
quire a 3-week treatment [13]. While compliance and ease
of use are important factors, the safety of the product is of
the utmost importance. In this phase I clinical trial, no
severe adverse events (AE) and only a few AEs were
reported; these AEs were reported equally in all arms of
the study. None of the AEs led to temporary
Table 6 Satisfaction of female volunteers with regard to administration and dosage regimen
Parameter Statistics TRT1
(1 tab/3 days)
(N = 8)
(1 tab/4 days)
(N = 9)
(1 tab/5 days)
(N = 7)
(1 caps/day)
(N = 9)
Tot al
(N = 33)
p value**
(< 0.05)
Administration of the treatment Mean ± SD 0.84 ± 0.61 1.04 ± 1.11 1.00 ± 1.20 1.00 ± 1.20 0.92 ± 0.86 0.9740
0 = easy administration
10 = difficult administration
Size of the administered capsules/tablets Mean ± SD 1.33 ± 2.45 1.08 ± 0.97 1.61 ± 2.50 0.58 ± 0.36 1.12 ± 1.70 0.5983
0 = an appropriate size
10 = an inappropriate size
Use of intravaginal administration
of gynecological-related
Mean ± SD 0.91 ± 0.93 2.01 ± 1.59 1.43 ± 1.41 1.99 ± 1.82 1.62 ± 1.50 0.2635
0 = is practical
10 = is restrictive
Administration of capsules/tablets Mean ± SD 0.59 ± 0.72 1.52 ± 1.66 0.79 ± 0.54 1.12 ± 1.12 1.03 ± 1.14 0.5565
0 = an appropriate shape
10 = not practical
Use of the capsule/tablet Mean ± SD 0.84 ± 0.79 2.50 ± 1.66 1.47 ± 1.18 3.09 ± 2.82 2.04 ± 1.97 0.1381
0 = is ideal
10 = is restrictive
Administration of a capsule every
day/every 3, 4, and 5 days
Mean ± SD 2.33 ± 3.48 2.61 ± 2.38 0.96 ± 1.46 5.38 ± 3.35 2.95 ± 3.15 0.0270
0 = is not restrictive
10 = is restrictive
The 3-week period of administration Mean ± SD 2.94 ± 3.32 2.39 ± 1.41 1.27 ± 1.53 5.61 ± 2.95 3.16 ± 2.86 0.0364
0 = is not restrictive
10 = is restrictive
Release of the capsule/tablet Mean ± SD 3.20 ± 2.83 4.16 ± 3.63 3.49 ± 3.06 2.88 ± 2.72 3.43 ± 2.98 0.8958
0 = complete Bdisintegration^of the
10 = no Bdisintegration^of the
administered capsule/tablet which
was found completely expelled
from the vagina
**Kruskal-Wallis test
Eur J Clin Microbiol Infect Dis (2018) 37:18691880 1875
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discontinuation or withdrawal from the study. Overall, the
tolerance of the LBPs was reported to be excellent in half
of the participants and good in the other half and was
associated with an overall strong satisfaction with the
use of the products. These results are in line with previous
clinical trials for the prevention of recurrent VVC and BV
with various Gynophilus
formulations [11,13].
SR appears to be a well-accepted, safe, and
easy-to-use LBP with high compliance that delivers an
adequate concentration of LBM Lcr35
post-administration. The efficacy of Gynophilus
must be confirmed in a large-scale study with the final
selected dose.
The impact of Gynophilus
LBP formulation and treat-
ment frequency on the composition and structure of the
vaginal microbiota was evaluated. The results showed that
at study entry, 54.6% of the volunteers vaginal microbi-
ota harbored microorganisms that were phylogenetically
related to Lactobacillus spp. as the numerically dominant
members (Table 7). The frequency of vaginal CSTs in
these otherwise healthy French women is similar to that
observed by Ravel et al. in North American women [26,
38]. In this phase I clinical study, Gynophilus
and SR tablet administration did not disturb the endoge-
nous Lactobacillus spp. and trends towards an increase in
the abundance of indigenous Lactobacillus spp. without
colonization (Fig. 3and Fig. 4). This finding sup-
ports a beneficial effect of treatment by restoring a
healthy Lactobacillus-dominated vaginal microbiota.
However, because all participants are healthy and disease
free, a clinical trial designed to evaluate treatment efficacy
in women with VVC or BV is warranted to confirm that
SR administered every 3 or 4 days will also
promote the restoration of a resilient Lactobacillus spp.-
dominated microbiota while efficiently treating the vagi-
nal infections.
Even if statistical results showed no differences be-
tween both galenic forms, it has to be remind that low
number of subject does not allow any extrapolation to
the global population. This pilot clinical trial will afford
1876 Eur J Clin Microbiol Infect Dis (2018) 37:18691880
Fig. 2 Mean vaginal concentrations of Lactobacillus rhamnosus Lcr35
over time in each arm measured by the targeted qPCR method. Delivery of 1
tablet every 3 days (a), 1 tablet every 4 days (b), and 1 tablet every 5 days (c) were compared to the reference treatment of 1 capsule per day
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
statistical power calculation to design a larger and more
robust clinical trial to confirm the Gynophilus
SR effi-
cacy on vaginal infections.
In conclusion, this study showed that the SR formula-
tion of Gynophilus
administered every 3, 4, or 5 days is
well-tolerated, easy-to-use, and less burdensome than the
capsule form. More importantly, the findings support the
conclusion that the muco-adhesive Gynophilus
SR ad-
ministered every 3, 4, or 5 days is a safe, well-tolerated,
well-accepted, and efficient alternative to provide a daily
Fig. 3 Composition of the
vaginal microbiota in all
treatment arms. aEffect of all
treatments combined on the
estimates of Lactobacillus spp.
absolute abundance at visit 1,
during treatment and at visit 2. b
Community state type distribution
over all samples collected in the
study based on the species
composition and abundance, as
determined by the heatmap of
percentage abundance of
microbial taxa found in the
vaginal microbial communities of
all samples
Table 7 CST frequency at visit 1
Visit 1 (D 0) n(%) 10 (30.3%) 2 (6.1%) 6 (18.2%) 15 (45.4%) 0 (0.0%) 0 (0.0%)
Visit 2 (D21) n(%) 10 (30.3%) 2 (6.1%) 4 (12.1%) 16 (48.5%) 0 (0.0%) 1 (3.0%)
Eur J Clin Microbiol Infect Dis (2018) 37:18691880 1877
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Fig. 4 Representative longitudinal vaginal microbiota profiles of women
enrolled in atreatment 1; btreatment 2. Lactobacillus casei (pink)
indicates the live biotherapeutic microorganism Lcr35
. Vertically,
each column represents one sampling day. Horizontally, community
state type (CST) distribution for all samples collected by women was
determined by the abundance of phylotype composition represented in
the taxa relative abundance histogram. CST reflect the dominant
microorganisms, CST-I is dominated by L. crispatus,CST-IIbyL.
gasseri,CST-IIIbyL. iners, CST-V by L. jensenii, CST-VI by L. casei
), and CST-IV is characterized by a diverse set of strict and
facultative anaerobes. The vaginal microbiota study of each volunteer
women is presented in Online Resource 3
1878 Eur J Clin Microbiol Infect Dis (2018) 37:18691880
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
vaginal concentration of LBM greater than 10
while maintaining and even favoring a womansindige-
nous Lactobacillus spp. Thus, Gynophilus
SR adminis-
tered every 3 or 4 days is an efficacious alternative for
patients with poor compliance profiles.
Acknowledgements We wish to thank all gynecologists and volunteers
who have participated to the CompriGel clinical trial. Thanks to all those
who contributed in the clinical trial, in particular Richard Boissiere for the
Funding This pilot CompriGel study was supported by BIOSE.
Compliance with ethical standards
Conflict of interest Adrien Nivoliez, Caroline Dausset, Claudia Thoral,
and Stéphane Patrier have an institutional affiliation with BIOSE. Jean-
Michel Cardot, Philippe Judlin, and Yann Lenglet have a consultancy
contract with BIOSE, the financial and logistic support of CompriGel
Ethical approval The protocol for CompriGel clinical trial was designed
according to the recommendations of the ICH Steering Committee rec-
ommendations (ICH E6), Good Clinical Practice guidelines, the declara-
tion of Helsinki and the French legislation. Then this study was evaluated
favorably by the Ethics Committee South-East IV and approved by the
Competent Authority (ANSM: Agence Nationale de Sécurité du
Médicament [French National Agency for Medicines and Health
Products Safety]) which granted the authorization. This clinical trial
was registered under 2014-001746-21 EudraCT Number.
Informed consent In accordance with the law of 6 January 1978 mod-
ified, the woman volunteer was informed in the information leaflet and
gave her written consent for the processing of her personal data imple-
mented as part of this study and to enable analysis of the research results.
Before inclusion in the study, the investigator provided the woman vol-
unteer with all the information about the study. When the woman volun-
teer gives her consent, she and the investigator signed and dated the
consent form.
Open Access This article is distributed under the terms of the Creative
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distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a link
to the Creative Commons license, and indicate if changes were made.
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... GYNOPHILUS (Lcr REGENERANS) LBP contains Lactobacillus rhamnosus Lcr35, a LBM whose in vitro and in vivo characteristics are well-documented 11-15 . This LBP is recommended in preventive and curative therapies for gynecological indications, mostly vulvovaginal candidiasis [16][17][18] . ...
... Figure 5b presents the average aromagram obtained by compiling the aromagrams of the four samples points out 24 odor zones. Out of them, 15 odor zones were classified in one of the dairy (1-5, 6, 10), fruity floral (7,9,11,15,18), grass-vegetable (13) or mushroom (16,21) odor poles whereas the 9 remaining ones were less consensually described by the panelists. Cross analyses of these odor zones with significant MS data at corresponding retention time enabled the tentative identification of most odor-active compounds (Fig. S5). ...
Full-text available
Bacterial flagellin can elicit production of TLR5-mediated IL-22 and NLRC4-mediated IL-18 cytokines that act in concert to cure and prevent rotavirus (RV) infection. This study investigated the mechanism by which these cytokines act to impede RV. Although IL-18 and IL-22 induce each other's expression, we found that IL-18 and IL-22 both impeded RV independently of one another and did so by distinct mechanisms that involved activation of their cognate receptors in intestinal epithelial cells (IEC). IL-22 drove IEC proliferation and migration toward villus tips, which resulted in increased extrusion of highly differentiated IEC that serve as the site of RV replication. In contrast, IL-18 induced cell death of RV-infected IEC thus directly interrupting the RV replication cycle, resulting in spewing of incompetent virus into the intestinal lumen and causing a rapid drop in the number of RV-infected IEC. Together, these actions resulted in rapid and complete expulsion of RV, even in hosts with severely compromised immune systems. These results suggest that a cocktail of IL-18 and IL-22 might be a means of treating viral infections that preferentially target short-lived epithelial cells.
... 126 With a sustained-release mechanism, the drug dissolves slowly and gradually in the bloodstream, enabling a slower release from the tablet or capsule over time than immediate-release formulation. 127 These systems are known to increase patients' adherence to a certain medication. In fact, compliance and patient satisfaction with switching from sodium valproate, an immediate-release antiepileptic drug, to Depakine Chrono (a sustained-release formulation of valproate) were reported in patients with epilepsy. ...
Retinoblastoma is the most common primary intraocular malignancy in children. Although traditional chemotherapy has shown some success in retinoblastoma management, there are several shortcomings to this approach, including inadequate pharmacokinetic parameters, multidrug resistance, low therapeutic efficiency, nonspecific targeting, and the need for adjuvant therapy, among others. The revolutionary developments in biomaterials for drug delivery have enabled breakthroughs in cancer management. Today, biomaterials are playing a crucial role in developing more efficacious retinoblastoma treatments. The key goal in the evolution of drug delivery biomaterials for retinoblastoma therapy is to resolve delivery-associated obstacles and lower nonlocal exposure while ameliorating certain adverse effects. In this review, we will first delve into the historical perspective of retinoblastoma with a focus on the classical treatments currently used in clinics to enhance patients' quality of life and survival rate. As we move along, we will discuss biomaterials for drug delivery applications. Various aspects of biomaterials for drug delivery will be dissected, including their features and recent advances. In accordance with the current advances in biomaterials, we will deliver a synopsis on the novel chemotherapeutic drug delivery strategies and evaluate these approaches to gain new insights into retinoblastoma treatment.
... In the present review, most of the available clinical trials published between 2015 and 2020 were included, because previous trials were analyzed before. 86,142 In non-pregnant, fertile women (Table 1, white panel), probiotic strains were assayed to: evaluate their safety, and to improve the VM of healthy women 129,139,143,151 ; restore the abnormal VM 129,140,159,165 ; prevent recurrent UGTI 141,166 ; as adjunct treatment to BV, 37,160,161,167 AV 160 antimicrobial therapy, recurrent-VVC (R-VVC), 152,162 and TV in BV presence 144 ; as BV and R-VVC subsequent treatment 141,162,169 ; ...
Full-text available
Lactobacilli are the predominant microorganisms of the healthy human vagina. A novel alternative for the prevention and treatment of female urogenital tract infections (UGTI) is the inclusion of these microorganisms as active pharmaceutical ingredients in probiotic formulas, and more recently in female hygienic products. Probiotics are defined as "live microorganisms that, when administered in adequate amounts, confer a health benefit on the host." A list of requirements must be considered during the development of probiotic product/formula for the female urogenital tract (UGT). This review aims to resume the requirements, probiotic characteristics, and clinical trial applied to determine the effect of probiotic and potentially probiotic strains on different woman's physiological and pathological conditions, and in preterm birth prevention. A revision of female hygienic products available in the world market is included, together with novel studies applying nanotechnology for Lactobacillus incorporation in hygienic products. Further studies and well-designed clinical trials are urgently required to complement the current knowledge and applications of probiotics in the female UGT. The use of probiotic formulas and products will improve and restore the ecological equilibrium of the UGT microbiome to prevent and treat UGTI in women under different conditions.
... The decrease in the number of lactobacilli could play a role in the effectiveness of the product. Furthermore, the timing of probiotic use, sample collection and subsequent visits, as well as dietary habits and daily routines, could also alter the results of the trial (Dausset et al., 2018;Marcotte et al., 2019). Moreover, the antifungal medication prescribed to 11 participants who reported vaginal itching or burning and were diagnosed with vulvovaginal candidiasis in the trial, could have some effect on faecal and vaginal microbiome, and this may also indicate the limitation of the study. ...
Full-text available
The purpose of this study was to evaluate the effectiveness of metronidazole and oral probiotics adjunct to metronidazole in the treatment of bacterial vaginosis (BV). One hundred and twenty-six Chinese women with BV were enrolled in this parallel, controlled trial, and were randomly assigned into two study arms: the metronidazole group, which was prescribed metronidazole vaginal suppositories for 7 days, and the adjunctive probiotic group, which received Lacticaseibacillus rhamnosus GR-1 and Limosilactobacillus reuteri RC-14 orally for 30 days as an adjunct to metronidazole. Clinical symptoms and Nugent scores at the initial visit, 30 days and 90 days were compared. There was no significant difference of the 30-day total cure rate between the adjunctive probiotic group (57.69%) and the metronidazole group (59.57%), with an odds ratio (OR) of 0.97 (95% confidence interval (CI), 0.70 to 1.35, p-value = 0.04), or of the 90-day total cure rate (36.54% vs. 48.94%, OR, 0.75; 95% CI, 0.47 to 1.19; p-value = 0.213). Also, no significant difference of the vaginal and faecal microbial diversity and structure between the two groups at 0, 30 or 90 days were shown based on 16S rRNA sequences. The probiotic species were rarely detected in either the vaginal microbiota or the faecal microbiota after administration which may revealed the cause of noneffective of oral probiotics. No serious adverse effects were reported in the trial. The study indicated that oral probiotic adjunctive treatment did not increase the cure rate of Chinese BV patients compared to metronidazole.
... d'essais cliniques(de Champs et al. 2003 ;Petricevic and Witt 2008 ; Bohbot and Cardot 2012a ;Dapoigny et al. 2012 ;Dausset et al. 2018). ...
Full-text available
Les antibiotiques et antifongiques constituent une des plus grandes découvertes de la médecine et ont participé à sauver des millions de vies. Cependant, leur efficacité est menacée du fait de l’adaptation des microorganismes qui deviennent résistants à leurs actions. Ce phénomène est en particulier lié à la consommation anormalement élevée de molécules antimicrobiennes, notamment en France. En dépit du fait que ces résistances soient acquises majoritairement par des bactéries, les levures pathogènes comme le genre Candida n’échappent pas à la règle. Dès lors, la communauté scientifique et les services de santé doivent mettre en place au plus vite des alternatives aux médicaments traditionnels. Parmi ces alternatives, l’utilisation de microorganismes probiotiques dont le potentiel antifongique a déjà été démontré à l’aide de modèles précliniques (cultures cellulaires, animaux de laboratoire) et d’études cliniques est prometteuse. Ceci est notamment le cas du Live Biotherapeutic Microorganism Lactobacillus rhamnosus Lcr35® dont l’activité anti-C. albicans a été prouvée lors de travaux précédents sans toutefois parvenir à décrire les mécanismes d’actions. Les comprendre est devenu un besoin stratégique pour le développement de nouveaux traitements pour l’homme. Une approche expérimentale innovante, utilisant le modèle nématode Caenorhabditis elegans, a été mise en œuvre. Celle-ci visait à simuler une infection fongique et à évaluer l’effet de Lcr35® par des approches préventive et curative. Les impacts ont été suivis au moyen de tests de longévité et de survie de l’hôte ainsi que par l’étude de son transcriptome (de manière ciblée et globale), le tout en lien avec le niveau d’activité d’un facteur de transcription central, DAF-16. Nous avons ainsi démontré que Lcr35® induisait une survie significativement augmentée de l’hôte y compris après infection par Candida. L’analyse du transcriptome de C. elegans et l’utilisation de souches mutantes ont montré l’implication des voies de signalisations p38 MAPK et DAF-2/DAF-16 impliquées dans la longévité et la lutte anti-pathogène. De plus, des tests in vitro sur cellules intestinales Caco-2 ont montré une inhibition significative de la croissance et de l’adhésion du pathogène par Lcr35®. Ces résultats suggèrent que la bactérie Lcr35® a une action directe sur le pathogène en entraînant sa mort, mais également en modulant la réponse transcriptionnelle de l’hôte via des voies de signalisation hautement conservées. Une étude plus approfondie ciblant notamment le métabolome de l’hôte permettrait une compréhension plus fine des mécanismes afin d’adapter le criblage et la conception industrielle de LBM selon la cible thérapeutique.
In the last few years, the concept of happiness economics has gained massive popularity among researchers and policy-makers. Taking GDP as an indicator that reflects the economic welfare of countries indicated “dematerializing” of the economy, also known as the coupling effect. However, the viability of GDP as the sole and unambiguous economic measure has been severely impacted. Moreover, an increased inclination toward measuring the economic welfare and not just the economic output has captured more attention paving way to happiness economics. The aim of the study is to review the research work done in the last 35 years (1987–2022) in the area pertaining to “beyond GDP.” The study includes 144 research papers from the Scopus database through a reference searching approach and identified keywords. A bibliometric-based review approach using VOSviewer and RStudio software will be used to trace and review the most influential authors, journals, and top keywords. Finally, a conceptual framework and future research avenues are suggested.KeywordsBeyond GDP Happiness economy Well-being economy Sustainability Bibliometric analysis
Microbiomes live in symbiosis with their hosts at all stages of their life cycles, forming holobionts. The gut microbiome contributes to absorbing energy and affects the immune system and provides intense chemical communication and coordination of host physiological functions, characterizing the gut-brain axis. The human lifestyle promotes alterations in ecological relationships between the host and microbiome, as the non-rational use of antibiotics, biocides, and processed food, decreasing microbiome diversity and affecting gut homeostasis. This dysbiosis leads to disease development, as colitis, obesity, metabolic syndromes, diabetes mellitus, cancer, and liver, cardiovascular, and neurodegenerative diseases. Probiotic bacterial strains have been used in different dairy products to modulate the structure of the intestinal microbiome and recover a part of the lost functional balance, but a deep scientifical background is necessary to shift the focus of this product consumption, from food to pharmaceutical industry. Next-generation probiotic species have been sought with preventive and therapeutic characteristics; the main concern is efficiency and safety, which is the reason for the new category of live biotherapeutic products need to be standardized as drugs to be commercially viable, to search for intestinal homeostasis recovery and reducing dysbiosis and a chain of adverse effects that could culminate in severe and chronic diseases.KeywordsHealthy microbiomeDysbiosisIntestinal homeostasisGut microbiomeBacterial diversity
Dysbiosis of the vaginal microbiome as a result of overgrowth of anaerobic bacteria, such as Gardnerella vaginalis, and low levels of "healthy" lactobacilli leads to bacterial vaginosis (BV), usually associated with a low-grade inflammatory process. Despite appropriate antibiotic treatment, G. vaginalis-associated BV is characterized by significant recurrence. The use of probiotics could be an interesting alternative therapy due to their ability to rebalance vaginal microbiota. In this study, we investigated the effects of a well-characterized probiotic strain, Lacticaseibacillus rhamnosus Lcr35, on epithelial vaginal and dendritic cell (DC) immune responses after G. vaginalis infection. In an in vitro coculture model with human monocyte-derived dendritic cells and a vaginal epithelial cell (VEC) monolayer, the Lcr35 strain induced DC activation, as evidenced by the induction of maturation and synthesis of interleukin-8 (IL-8) and CCL-20 chemokines upon apical challenge of the VECs by G. vaginalis. Analysis of the vaginal epithelial response showed that the presence of Lcr35 significantly increased the production of the proinflammatory cytokines IL-8 and IL-1β and human β-defensin 2 (HBD-2), whereas the concentration of secretory leukocyte protease inhibitor (SLPI) was decreased in G. vaginalis-infected vaginal epithelial cells. Treatment with recombinant SLPI was associated with upregulation of Lcr35-stimulated IL-8 and HBD-2 production. These results suggest that inhibition of SLPI by Lcr35 in vaginal epithelial cells contributes to the host defense response against G. vaginalis infection.
Lactobacilli are the predominant microorganisms in the vaginal microbiota of healthy women, maintain the ecological equilibrium, and act in the prevention of infections. Their protective role is exerted through different mechanisms: adhesion/permanence in epithelium/mucosa, competitive exclusion against pathogens, production of antimicrobial compounds, and/or host´s immunomodulation. Therefore, probiotic products with vaginal lactobacilli constitute a novel strategy to restore vaginal microbiota. In the design of probiotic products, different criteria are applied according to the requirements of regulatory organisms, including host-tract-specificity origin of strains, their phenotypic/genetic identification; functional characterization and mechanisms of action; in-vitro and in-vivo safety evaluation; technological characterization (production, formulation, and shelf-life); efficacy/effectiveness in clinical trials; and label-health claims. This chapter is aimed to review the requirements, probiotic characteristics, and in vitro and in vivo trials published to evidence the effect of probiotic and potentially probiotic strains in vagina.
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Background: Few data are available on how women manage recurring bacterial vaginosis (BV) and their experiences of the clinical care of this condition. This study aimed to explore women's recurrent BV management approaches and clinical care experiences, with a view to informing and improving the clinical management of BV. Methods: A descriptive, social constructionist approach was chosen as the framework for the study. Thirty-five women of varying sexual orientation who had experienced recurrent BV in the past 5 years took part in semi-structured interviews. Results: The majority of women reported frustration and dissatisfaction with current treatment regimens and low levels of satisfaction with the clinical management of BV. Overall, women disliked taking antibiotics regularly, commonly experienced adverse side effects from treatment and felt frustrated at having symptoms recur quite quickly after treatment. Issues in clinical care included inconsistency in advice, misdiagnosis and inappropriate diagnostic approaches and insensitive or dismissive attitudes. Women were more inclined to report positive clinical experiences with sexual health physicians than primary care providers. Women's frustrations led most to try their own self-help remedies and lifestyle modifications in an attempt to treat symptoms and prevent recurrences, including well-known risk practices such as douching. Conclusion: In the face of considerable uncertainty about the cause of BV, high rates of recurrence, unacceptable treatment options and often insensitive and inconsistent clinical management, women are trying their own self-help remedies and lifestyle modifications to prevent recurrences, often with little effect. Clinical management of BV could be improved through the use of standardised diagnostic approaches, increased sensitivity and understanding of the impact of BV, and the provision of evidence based advice about known BV related risk factors.
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Bacterial vaginosis (BV) is a common vaginal disorder in women of reproductive age. Since the initial work of Leopoldo in 1953 and Gardner and Dukes in 1955, researchers have not been able to identify the causative etiologic agent of BV. There is increasing evidence, however, that BV occurs when Lactobacillus spp., the predominant species in healthy vaginal flora, are replaced by anaerobic bacteria, such as Gardenella vaginalis, Mobiluncus curtisii, M. mulieris, other anaerobic bacteria and/or Mycoplasma hominis. Worldwide, it estimated that 20-30 % of women of reproductive age attending sexually transmitted infection (STI) clinics suffer from BV, and that its prevalence can be as high as 50-60 % in high-risk populations (e.g., those who practice commercial sex work (CSW). Epidemiological data show that women are more likely to report BV if they: 1) have had a higher number of lifetime sexual partners; 2) are unmarried; 3) have engaged in their first intercourse at a younger age; 4) have engaged in CSW, and 5) practice regular douching. In the past decade, several studies have provided evidence on the contribution of sexual activity to BV. However, it is difficult to state that BV is a STI without being able to identify the etiologic agent. BV has also emerged as a public health problem due to its association with other STIs, including: human immunodeficiency virus (HIV), herpes simplex virus type 2 (HSV-2), Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG). The most recent evidence on the association between BV and CT/NG infection comes from two secondary analyses of cohort data conducted among women attending STI clinics. Based on these studies, women with BV had a 1.8 and 1.9-fold increased risk for NG and CT infection, respectively. Taken together, BV is likely a risk factor or at least an important contributor to subsequent NG or CT infection in high-risk women. Additional research is required to determine whether this association is also present in other low-risk sexually active populations, such as among women in the US military. It is essential to conduct large scale cross-sectional or population-based case-control studies to investigate the role of BV as a risk factor for CT/NG infections. These studies could lead to the development of interventions aimed at reducing the burden associated with bacterial STIs worldwide.
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The human body is the residence of a large number of commensal (non-pathogenic) and pathogenic microbial species that have co-evolved with the human genome, adaptive immune system, and diet. With recent advances in DNA-based technologies, we initiated the exploration of bacterial gene functions and their role in human health. The main goal of the human microbiome project is to characterize the abundance, diversity and functionality of the genes present in all microorganisms that permanently live in different sites of the human body. The gut microbiota expresses over 3.3 million bacterial genes, while the human genome expresses only 20 thousand genes. Microbe gene-products exert pivotal functions via the regulation of food digestion and immune system development. Studies are confirming that manipulation of non-pathogenic bacterial strains in the host can stimulate the recovery of the immune response to pathogenic bacteria causing diseases. Different approaches, including the use of nutraceutics (prebiotics and probiotics) as well as phages engineered with CRISPR/Cas systems and quorum sensing systems have been developed as new therapies for controlling dysbiosis (alterations in microbial community) and common diseases (e.g., diabetes and obesity). The designing and production of pharmaceuticals based on our own body's microbiome is an emerging field and is rapidly growing to be fully explored in the near future. This review provides an outlook on recent findings on the human microbiomes, their impact on health and diseases, and on the development of targeted therapies.
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The influence of the industrial process on the properties of probiotics, administered as complex manufactured products, has been poorly investigated. In the present study, we comparatively assessed the cell wall characteristics of the probiotic strain Lactobacillus rhamnosus Lcr35® together with three of its commercial formulations with intestinal applications. Putative secreted and transmembrane-protein-encoding genes were initially searched in silico in the genome of L. rhamnosus Lcr35®. A total of 369 candidate genes were identified which expressions were followed using a custom Lactobacillus DNA chip. Among them, 60 or 67 genes had their expression either upregulated or downregulated in the Lcr Restituo® packet or capsule formulations, compared to the native Lcr35® strain. Moreover, our data showed that the probiotic formulations (Lcr Lenio®, Lcr restituo® capsule and packet) showed a better capacity to adhere to intestinal epithelial Caco-2 cells than the native Lcr35® strain. Microbial (MATS) tests showed that the probiotic was an electron donor and that they were more hydrophilic than the native strain. The enhanced adhesion capacity of the active pharmaceutical ingredients (APIs) to epithelial Caco-2 cells and their antipathogen effect could be due to this greater surface hydrophilic character. These findings suggest that the manufacturing process influences the protein composition and the chemical properties of the cell wall. It is therefore likely that the antipathogen effect of the formulation is modulated by the industrial process. Screening of the manufactured products' properties would therefore represent an essential step in evaluating the effects of probiotic strains.
When most people think of human development, they tend to consider only human cells and organs. Yet there is another facet that involves human-associated microbial communities. A microbial perspective of human development provides opportunities to refine our definitions of healthy prenatal and postnatal growth and to develop innovative strategies for disease prevention and treatment. Given the dramatic changes in lifestyles and disease patterns that are occurring with globalization, we issue a call for the establishment of 'human microbial observatories' designed to examine microbial community development in birth cohorts representing populations with diverse anthropological characteristics, including those undergoing rapid change.
Introduction: Probiotics are a complementary and integrative therapy useful in the treatment and prevention of urogenital infections in women. This study extends the work of researchers who systematically investigated the scientific literature on probiotics to prevent or treat urogenital infections. Methods: A systematic review was conducted to determine the efficacy of probiotics for prevention and/or treatment of urogenital infections in adult women from January 1, 2008, through June 30, 2015. We searched in CINAHL, MEDLINE, Cochrane Central Register of Controlled Trials, Web of Science, Dissertations and Theses, and Alt-HealthWatch. After removing duplicates and studies that did not meet inclusion criteria, 20 studies were reviewed. All included at least one species of Lactobacillus probiotic as an intervention for treatment or prevention of urogenital infections. Data extracted included samples, settings, study designs, intervention types, reported outcomes, follow-up periods, and results. We evaluated all randomized controlled trials for risk of bias and made quality appraisals on all studies. Results: Fourteen of the studies focused on bacterial vaginosis (BV), 3 on urinary tract infections (UTIs), 2 on vulvovaginal candidiasis, and one on human papillomavirus (HPV) as identified on Papanicolaou test. Studies were heterogeneous in terms of design, intervention, and outcomes. Four studies were of good quality, 9 of fair, and 7 poor. Probiotic interventions were effective for treatment and prevention of BV, prevention of recurrences of candidiasis and UTIs, and clearing HPV lesions. No study reported significant adverse events related to the probiotic intervention. Discussion: The quality of the studies in this systematic review varied. Although clinical practice recommendations were limited by the strength of evidence, probiotic interventions were effective in treatment and prevention of urogenital infections as alternatives or co-treatments. More good quality research is needed to strengthen the body of evidence needed for application by clinicians.
Perinatally, and between menarche and menopause, increased levels of estrogen cause large amounts of glycogen to be deposited in the vaginal epithelium. During these times, the anaerobic metabolism of the glycogen, by the epithelial cells themselves and/or by vaginal flora, causes the vagina to become acidic (pH similar to 4). This study was designed to test whether the characteristics of acid production by vaginal flora in vitro can account for vaginal acidity. Eight vaginal Lactobacillus isolates from four species-L. gasseri, L. vaginalis, L. crispatus, and L. jensenii-acidified their growth medium to an asymptotic pH (3.2 to 4.8) that matches the range seen in the Lactobacillus-dominated human vagina (pH 3.6 to 4.5 in most women) (B. Andersch, L. Forssman, K, Lincoln, and P. Torstensson, Gynecol. Obstet. Investig. 21:19-25, 1986; L. Cohen, Br. J. Vener. Dis. 45:241-246, 1969; J. Paavonen, Scand. J. Infect. Dis. Suppl. 40:31-35, 1983; C. Tevi-Benissan, L. Belec, M. Levy V. Schneider-Fauveau, A. Si Mohamed, M.-C. Hallouin, M. Matta, and G. Gresenguet, Clin. Diagn. Lab. Immunol. 4:367-374, 1997). During exponential growth, all of these Lactobacillus species acidified their growth medium at rates on the order of 10(6) protons/bacterium/s. Such rates, combined with an estimate of the total number of lactobacilli in the vagina, suggest that vaginal lactobacilli could reacidify the vagina at the rate observed postcoitally following neutralization by the male ejaculate (W. H. Masters and V. E. Johnson, Human sexual response, p. 93, 1966). During bacterial vaginosis (BV), there is a loss of vaginal acidity, and the vaginal pH rises to >4.5. This correlates with a loss of lactobacilli and an overgrowth of diverse bacteria. Three BV-associated bacteria, Gardnerella vaginalis, Prevotella bivia, and Peptostreptococcus anaerobius, acidified their growth medium to an asymptotic pH (4.7 to 6.0) consistent with the characteristic elevated vaginal pH associated with BV. Together, these observations are consistent with vaginal Bore, rather than epithelial cells, playing a primary role in creating the acidity of the vagina.
Vaginal infections are extremely prevalent, particularly among reproductive aged women. Although not resulting in high mortality, these infections are associated with high levels of anxiety and depreciation of low quality of life. In most cases, topical treatment of vaginal infections has been shown to be at least as effective as oral treatment, resulting in higher local drug concentrations, with less drug interactions and adverse effects. Furthermore, the emergence of microbial resistance to chemotherapeutics and the difficulties in managing infection recurrences sustain the need for more effective local treatments. However, conventional dosage forms have been associated with low retention in the vagina and discomfort issues. Formulation strategies such as development of bioadhesive, thermogelling systems and micro or nanotechnologic approaches have been proposed to improve delivery of traditional drugs while other treatments modalities such as new drugs, plant extracts and probiotics are being studied. This paper reviews the recent strategies studied to improve the treatment and prevention of the most common vaginal infections, namely vaginal bacteriosis, aerobic vaginitis, vulvovaginal candidosis and trichomoniasis; through the intravaginal route. Copyright © 2015. Published by Elsevier B.V.
Numerous previous studies of nonspecific vaginitis have yielded contradictory results regarding its cause and clinical manifestations, due to a lack of uniform case definition and laboratory methods. We studied 397 consecutive unselected female university students and applied sets of well defined criteria to distinguish nonspecific vaginitis from other forms of vaginitis and from normal findings. Using such criteria, we diagnosed nonspecific vaginitis in up to 25 percent of our study population; asymptomatic disease was recognized in more than 50 percent of those with nonspecific vaginitis. A clinical diagnosis of nonspecific vaginitis, based on simple office procedures, was correlated with both the presence and the concentration of Gardnerella vaginalis (Hemophilus vaginalis) in vaginal discharge, and with characteristic biochemical findings in vaginal discharge. Nonspecific vaginitis was also correlated with a history of sexual activity, a history of previous trichomoniasis, current use of non-barrier contraceptive methods, and, particularly, use of an intrauterine device. G. vaginalis was isolated from 51.3 percent of the total population using a highly selective medium that detected the organism in lower concentration in vaginal discharge than did previously used media. Practical diagnostic criteria for standard clinical use are proposed. Application of such criteria should assist in clinical management of nonspecific vaginitis and in further study of the microbiologic and biochemical correlates and the pathogenesis of this mild but quite prevalent disease.
IntroductionBacterial vaginosis (BV) is a common clinical condition that affects millions of women annually. Serious sequelae exist from untreated infection. Recurrent BV (RBV) is also common with few approved clinical treatment modalities. Review of the current recommendations yields practical tips to aid busy professionals.AimTo review the current treatment recommendations for recurrent bacterial vaginosis.MethodsA literature review was conducted using the keywords: bacterial vaginosis, recurrent bacterial vaginosis, vaginal probiotics, vaginal reacidifiers, and trichomoniasis.Main Outcome MeasurePatients with RBV should be treated with the approved suppressive antimicrobial regimen, but new modalities and adjuncts are currently under review and appear safe; however, rates of efficacy still need to be established.ResultsThere is no defined etiology of RBV, and thus, a curative treatment remains elusive. Sexual practices, hygiene practices, and the type of sexual partner all affect the rate of BV recurrence. Vaginal reacidifiers and probiotics may offer effective alternatives to the current antimicrobial regimens. Clinicians should obtain an in-depth history to have an accurate picture of the patient's pattern of infection, ensure they are using all clinical tools available to make the correct diagnosis, and educate the patient regarding simple behavioral changes they can make to prevent RBV.Conclusion More research is needed to explain and treat RBV. In the meantime, if clinicians maximize all current modalities, they will reduce the recurrence rate in certain patients. Marshall AO. Managing recurrent bacterial vaginosis: Insights for busy providers. Sex Med Rev **;**:**–**.