Transcript D.K. Zabolotny Institute of microbiology and virology of

XXXII Kongres Polskiego Towarzystwa Ginekologicznego
Łodz, September 3, 2015
Vaginal dysbiosis and its correction
with vaginal probiotic Neoprobio
Taras Lyaskovsky
PhD, Laboratory of Lactic Acid Bacteria
Zabolotny Institute of Microbiology and Virology
National Academy of Sciences, Kiev, Ukraine
email: [email protected]
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
• Institute is the main scientific organization in Ukraine in
the field of microbiology and virology research.
• 17 departments and labs
• State depositary of non-pathogenic microorganism
• Accredited laboratory in the sphere of control of
biological products in Ukraine
• Publish “Microbiological Journal”
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
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Department of Physiology of Industrial Microorganisms
Department of antibiotics
Department of General and soil microbiology
Department of Biochemistry microorganisms
Department of phytopathogenic bacteria
Department of Biology extremal microorganisms
Department of Physiology and Systematics of micromycetes
Department of Genetics of microorganisms
Department of phytopathogenic viruses
Department of microbiological processes on solid surfaces
Department mycoplasmology
Department of Molecular Genetics of Bacteriophages
Division problems interferon and immunomodulators
Department of Innovation and Technology Transfer
Laboratory of secondary metabolites micromycetes
Laboratory reproduction of viruses
Laboratory biological polymer compounds
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
Bacterial Vaginosis is the most common
vaginal infection in women ages 15-44.
http://www.cdc.gov/std/bv/stats.htm
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
Bacterial Vaginosis is the most common cause of vaginal symptoms among
women.
The prevalence in USA is estimated to be 21.2 million (29.2%) among women
ages 14–49.
Most women found to have BV (84%) reported no symptoms.
Women who have not had sex can still be affected by BV (18.8%), as can
pregnant women (25%), and women who have ever been pregnant (31.7%).
Prevalence of BV increases based on lifetime number of sexual partners.
Source: Koumans EH, Sternberg M, Bruce C, McQuillan G, Kendrick J, Sutton M, Markowitz LE. The prevalence of
bacterial vaginosis in the United States, 2001-2004; associations with symptoms, sexual behaviors, and reproductive
health. Sex Transm Dis. 2007 Nov;34(11):864-9.
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
What is Bacterial Vaginosis?
BV is a polymicrobial clinical syndrome resulting from replacement of
the normal hydrogen peroxide producing Lactobacillus sp. in the
vagina with high concentrations of anaerobic bacteria (e.g., Prevotella
sp. and Mobiluncus sp.), G. vaginalis, Ureaplasma, Mycoplasma, and
numerous fastidious or uncultivated anaerobes.
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
Factors promoting Bacterial Vaginosis
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uncotrollable drugs administration – mainly antibiotic
frequent use of contraceptive products
changes of hormonal status at menstrual cycle
stress
travelling
suppression of immune system
inflammation processes
other
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
Composition of the vaginal microbiota
in women of reproductive age
Genetic analysis with the use of 16S rRNA gene
and 16 quantitative bacterial species/genus-specific
real-time PCR assays for:
• healthy women
• intermediate
• Bacterial Vaginosis
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
Healthy women
Microorganism
Lactobacillus iners
Lactobacillus crispatus
Other Lactobacillus species
Gardnerella vaginalis
Atopobium vaginae
Eggerthella
Prevotella
BVAB 1
BVAB 2
Finegoldia magna
Megasphaera type 1
Megasphaera type 2
Sneathia sanguegens
Leptotrichia amnionii
BVAB-NV7
Mobiluncus curtisii/mulieris
Other non-Lactobacillus species
Other non-Lactobacillus species
Mobiluncus curtisii/mulieris
BVAB-NV7
Leptotrichia amnionii
Sneathia sanguegens
Megasphaera type 2
Megasphaera type 1
Finegoldia magna
BVAB 2
BVAB 1
Prevotella
Eggerthella
Atopobium vaginae
Gardnerella vaginalis
Other Lactobacillus species
Lactobacillus crispatus
Lactobacillus iners
0
10
20
30
40
50
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
%
38.1
43.2
5.4
7.2
0.6
0.001
0.2
0.02
0.01
0.1
0.2
0
0.1
0.1
0.002
0.002
4.8
Intermediate
Microorganism
Lactobacillus iners
Lactobacillus crispatus
Other Lactobacillus species
Gardnerella vaginalis
Atopobium vaginae
Eggerthella
Prevotella
BVAB 1
BVAB 2
Finegoldia magna
Megasphaera type 1
Megasphaera type 2
Sneathia sanguegens
Leptotrichia amnionii
BVAB-NV7
Mobiluncus curtisii/mulieris
Other non-Lactobacillus species
Other non-Lactobacillus species
Mobiluncus curtisii/mulieris
BVAB-NV7
Leptotrichia amnionii
Sneathia sanguegens
Megasphaera type 2
Megasphaera type 1
Finegoldia magna
BVAB 2
BVAB 1
Prevotella
Eggerthella
Atopobium vaginae
Gardnerella vaginalis
Other Lactobacillus species
Lactobacillus crispatus
Lactobacillus iners
0
10
20
30
40
50
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
%
43.9
1.2
6.1
30.5
1.5
0.2
0.9
0
0.5
0.1
4.2
0.001
0.2
2.4
0
0.01
8.3
Bacterial Vaginosis (BV)
Other non-Lactobacillus species
Mobiluncus curtisii/mulieris
BVAB-NV7
Leptotrichia amnionii
Sneathia sanguegens
Megasphaera type 2
Megasphaera type 1
Finegoldia magna
BVAB 2
BVAB 1
Prevotella
Eggerthella
Atopobium vaginae
Gardnerella vaginalis
Other Lactobacillus species
Lactobacillus crispatus
Lactobacillus iners
0
5
10
15
20
25
30
35
Microorganism
Lactobacillus iners
Lactobacillus crispatus
Other Lactobacillus species
Gardnerella vaginalis
Atopobium vaginae
Eggerthella
Prevotella
BVAB 1
BVAB 2
Finegoldia magna
Megasphaera type 1
Megasphaera type 2
Sneathia sanguegens
Leptotrichia amnionii
BVAB-NV7
Mobiluncus curtisii/mulieris
Other non-Lactobacillus species
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
%
6.6
0.3
0.3
29.1
7.1
1.2
13.2
6.1
6.3
0.1
9.8
0.1
4.3
6.8
0.8
0.2
7.9
Probiotic strain screening
Report of a Joint FAO/WHO Working Group on
Drafting Guidelines for the Evaluation
of Probiotics in Food London Ontario, Canada
April 30 and May 1, 2002
Food and Agriculture Organization of the United
Nations & World Health Organization
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
EVALUATION OF PROBIOTICS
• Strain identification
– Strain identification by phenotype (API test systems)
– Strain identification by genotype (sequencing)
• Functional characterization
– In vitro tests
– Animal studies
• Safety assessment
– In vitro and/or animal
– Phase 1 human study
• Clinical trials (Phase II (DBPC), Phase III
(effectiveness in comparing with standard treatment)
• Deposit strain in IMV culture collection
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
PROBIOTIC SCREENING
STRAIN IDENTIFICATION
• Study of phenotype characteristics of LAB
• Study of genotype characteristics of LAB
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
PHENOTYPE CHARACTERISTICS
Colony: size, surface, color
Cells: form, size, positioning,
Motion
Fermentation of 49 carbohydrate
substrates (API 50 CH)
Gas production from glucose,
NH3 from arginine
Higrolitic activity: gelatin,
eskuline
Acidification and the growth
in milk
Growth on different media
(substrates)
6,5% NaCl; pH 9,6; 40% bile
Growth at temperatures 150С,
300С, 370С, 450С, 500С
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
GENOTYPE CHARACTERISTICS
Electrophoregram of amplification products with the use of genus specific primers
The result of the sequence of amplification products of DNA
fragment of the strain L. plantarum 200 Д with primers
Lp3_sp and Lp2 ( 543 b.p. fregment)
Gel picture showing the PCR amplified product of
probiotic strains of lactic acid bacteria :
М- marker, 1- E.durans Sm, 2-E.faecium 77Д, 3Str.thermophilus S8, 4- L.plantarum 200 Д
[GGC TGC TGG CAC GTA GTT AGC CGT GGC TTT CTG
GTT AAA TAC CGT CAA TAC CTG ААС AGT TAC TCT CAG ATA TGT TCT
TCT TTA АСА АСА GAG TTT TAC GAG CCG AAA CCC TTC TTC ACT CAC
GCG GCG TTG CTC CAT CAG ACT TTC GTC CAT TGT GGA AGA TTC CCT
ACT GCT GCC TCC CGT AGG AGT TTG GGC CGT GTC TCA GTC CCA ATG
TGG CCG ATT ACC CTC TCA GGT CGG СТА CGT ATC ATT GCC ATG GTG
AGC CGT TAC CCC ACC ATC TAG СТА ATA CGC CGC GGG ACC ATC CAA
AAG TGA TAG CCG AAG CCA TCT TTC AAG CTC GGA CCA TGC GGT CCA
AGT TGT TAC GCG GTA TTA GCA TCT GTT TCC AGG TGT TAT CCC CCG
CTT CTG GGC AGG TTT CCC ACG TGT TAC TCA CCA GTT CGC CAC TCA
CTC AAA TGT AAA TCA TGA TGC AAG CAC CAA TCA ATA CCA GAG TTC
GTT CGA CTT GCA TGT ATT AGG CAC GCC GCC AGC GTT CGT CCT GAG
CCA GGA TCA ААС TCT ]
99% identical to gene 16S рРНК of L. plantarum, presented
in GenBank.
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
PROBIOTIC STRAIN SCREENING
FUNCTIONAL CHARACTERIZATION
• Adhesion Activity
• Antagonistic Activity
• Lysozyme Synthesis
• Vitamin Synthesis
• Interferon Induction
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
ADHESION ACTIVITY
Adhesion activity is studied in vitro on the model of pig enterocytes
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
LACTIC ACID BACTERIA ADHESION TO EPITHELIUM OF
DIFFERENT BIOTOPES OF HUMAN ORGANISM
BUCCAL
VAGINAL
INTESTINAL
x 4000
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
ANTAGONISTIC ACTIVITY
Escherichia coli ATCC
Bacillus cereus ATCC
11778
25922
Staph. epidermitis ATCC
Pseudomonas
aeruginosa ATCC
12228
9027
Pribiotic strains
of LAB
Candida albicans
ATCC 885-653
Klebsiella pneumonia ATCC
10031
Proteus vulgaris ATCC
6896
Staphylococcus aureus
ATCC 12228
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
ANTAGONISTIC ACTIVITY SYNERGISM
OF PROBIOTIC LAB
10
9
8
7
6
5
4
3
2
1
0
Pathogens growth inhibition zones, mm
10
9
8
7
6
5
4
3
2
1
0
+
L. plantarum 200D
E.durance Sm
Bacillus cereus
Escherichia coli
Proteus vulgaris
Staphylococcus aureus
Pseudomonas aeruginosa
Candida albicans
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
ANTAGONISTIC ACTIVITY
Growth inhibition of gas producing putrefactive microflora by LAB probiotic strains
TEST (Growth inhibition by LAB )
CONTROL
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
ANTAGONISTIC ACTIVITY
Number of gas producing putrefactive
microorganisms, %
Growth inhibition of gas producing putrefactive microflora by LAB probiotic strains
70
60
50
40
30
20
10
0
контроль
L.plantarum
L.plantarum200Д
200D Str.thermophilus
E.durance Sm
Control
(Sn+Sm)
(фіз.розчин)
Physiologic
solution
суміш
трьох
Blend
of
штамів
(1:1:1)
strains
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
Lyses of micrococcus zone diameter, mm
LYSOZYME SYNTHESIS
Micrococcus
lysodeikticus
lysozyme assay
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
VITAMIN SYNTHESIS
120
μg/ml
5
400
100
4
300
80
3
60
2
200
40
1
20
0
0
μg/ml
B1 (THIAMINE)
100
0
B2 (RIBOFLAVIN) B5 (NICOTINAMIDE)
1.2
1
1
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
0
0
B6 (PYRIDOXINE)
L. plantartum 3
L. plantartum 45
H (BIOTIN)
L. plantartum 200D
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
INTERFERON INDUCTION BY LACTIC ACID
BACTERIA IN EXPERIMENTS IN VITRO
Interferon activity INF AU/ml on media
Cultures
№5 (bean broth)
№7 (enzyme lysate cornmeal)
Streptococcus thermophilus Sn
0
320
E.durance Sm
1280
320
Str. thermophilus S24
640
1280
Str. thermophilus S8
160
640
E. faecium 77D
640
80
Lactobacillus plantarum 195D
0
0
L plantarum 200D
0
0
L. acidophilus 4356
0
0
Суміш: Sn +Sm + 200D
0
0
Полі {І}: полі {Ц}
2560
2560
Контроль середовища
0
0
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
OPTIMISED BLEND OF LAB
• Lactobacillus plantarum 200D
• Enterococcus faecium 77D
• Enterococcus durance Sm
Bacterial
vaginoses
Neoprobio
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
OPTIMISED BLEND OF LAB
• High adhesion activity (provide fast
colonization of vaginal canal)
• High antagonistic activity (provide
inhibition of growth of pathogenic
microflora)
• Synthesis of biologically active
substances (H2O2, lysozyme,
vitamins
Bacterial
vaginoses
Neoprobio
• Interferon induction
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
UNIQUE COMPOSITION
Lactic acid bacteria blend
Lactose
Ascorbic acid
Folic acid
Hard fat
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
FUNCTION OF EACH INGREDIENT
LACTIC ACID
BACTERIA (LAB)
BLEND
Probiotic
properties of the
product
LACTOSE
Starting and
protective
ingredient for
growth of lactic
acid bacteria
ASCORBIC ACID
Provide acidic
conditions which
create more
favorable
condition for the
growth of LAB
then other BV
microflora
FOLIC ACID
HARD FAT
Provide acidic
conditions and
makes positive
effect on vaginal
epithelium
regeneration.
Base of the
suppository and
protective media
for LAB. Slow
melting of the
suppository
provide
controlled
release of LAB
and effectively
colonies the
vaginal canal by
LAB
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
CLINICAL TRIALS OF VAGINAL
OVULES WITH PROBIOTIC LAB
BLEND
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
CLINICAL TRIALS
Name of the study
Clinical studies of efficacy and tolerability of
XXX (vaginal suppositories with probiotic lactic
acid bacteria) in treatment of patients with
vaginal disbacteriosis (Bacterial Vaginosis).
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
CLINICAL TRIALS
Clinical base:
Investigation
Product:
Type of study:
Study design:
Study methods:
Patients:
Number of
patients:
Efficacy criteria:
Objectives:
Ministry of Health of Ukraine, Shupik National Medical Academy of
post-graduate education Department of Obstetrics, Gynecology
and Reproduction, Hospital No 4
XXX (vaginal suppositories with probiotic lactic acid bacteria)
Under restricted program
Open, comparative, controlled, randomized study
Clinical study. General laboratory analysis, cytological, bacterioscopic,
bacteriological analysis of vagina discharge
Vaginal disbacteriosis in patients 18-40 years of age
Investigation group – 40 (Metronidazole+probiotic); Control group – 30
(Metronidazole);
- clinical symptoms normalization dynamics;
- dynamics of bacteriological, bacterioscopic, cytological analysis of
vaginal discharge for disbacteriosis.
- study the efficacy of the study medication in vaginal disbacteriosis
patients.
- study the tolerability of the product and possible adverse productrelated events.
- compare the findings of treatment between the investigating and
control groups.
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
CLINICAL TRIALS
Selection criteria for the patients
in the trial
• Clinical symptoms (vaginal discharge that is usually thin
and grayish white, vaginal odor (foul-smelling or
unpleasant fishy odor), itching irritation.
• Microbiological examination (dominative microflora is
Gardnerella vaginalis, Prevotella and other, Lactobacilli
in low quantities).
• pH greater than 4.5.
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
CLINICAL TRIALS
Treatment
• Metronidazole 500 mg orally twice a day for 7 days
• Vaginal ovules with probiotic LAB blend twice a day
for 10 days
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
CLINICAL TRIALS
Day 7 after start of the treatment
Microorganism
Lactobacillus iners
Lactobacillus crispatus
Other Lactobacillus
species
Gardnerella vaginalis
Atopobium vaginae
Prevotella
Investigation group
(Combined treatment
(Metronidazole + vaginal
ovules with probiotic LAB
blend)
Control group
(Metronidazole)
%
22
29.4
%
3.6
0.3
5.4
16.3
4.1
6.4
2.4
17.3
3.7
7
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
CLINICAL TRIALS
Day 20 after start of the treatment
Microorganism
Lactobacillus iners
Lactobacillus crispatus
Other Lactobacillus
species
Gardnerella vaginalis
Atopobium vaginae
Prevotella
Investigation group
(Combined treatment
(Metronidazole + vaginal
ovules with probiotic LAB
blend)
Control group
(Metronidazole)
%
%
25.4
36
7.9
3.5
7.2
14.3
5.1
5.8
8.4
16.4
3.9
6.2
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
CLINICAL TRIALS
Conclusions
Combined treatment (Metronidazole + vaginal suppositories
with probiotic LAB blend) was effective in achieving
therapeutic cure or in restoring healthy vaginal lactobacilli
• Fast colonization with beneficial microflora
• Decrease the risk of BV relapse
• Decrease the risk of local adverse events of standard
treatment
• Treatment with Metronidazole reduced colonization with
BV-associated bacteria, but was not effective in achieving
therapeutic cure or in restoring healthy vaginal lactobacilli
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
PRODUCTION OF LAB BLEND
LAB blend is produced by Nutraceutix Inc, USA at a GMP certified facility.
Guaranteed required quality parameters.
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
STRAINS INDENTIFICATION
As probiotic features of the lactic
acid bacteria are strain dependent
the strains for each batch of
production are re-identified before
and after the production to validate
that the LAB blend conceits of the
same probiotic strains. This
identification is done by DNA
sequencing technique.
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
MANUFACTURE OF FINAL PRODUCT
Neoprobio ovules are manufactured in Poland by FARMINA SP. Z O.O., KRAKÓW.
A unique technology of low temperature production has been specially developed
to allow safe processing of the LAB, keeping a therapeutic concentration of 109 to
107 of viable LAB cells per ovule.
The facility is regularly audited according to EU GMP standards.
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
NEOPROBIO IS NOT ANOTHER
VAGINAL PROBIOTIC!
NEOPROBIO IS UNIQUE!
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
UNIQUE OVULE FORM
Ovules provide controlled release of LAB and promote fast colonization of
healthy microflora.
Capsules are not the correct vaginal form (may cause individual reactions
to the compound of the capsule which contains unfavourable biological
material and the rest of cultivation media).
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
UNIQUE OVULE FORM
Ovules provide direct therapeutic concentrations of LAB to vaginal canal.
The use of oral tablets or capsules decreases concentration of LAB which
pass through the aggressive environment of the stomach and then depend
on an unproven mechanism of „finding their way” from from anal canal into
the vaginal canal.
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
UNIQUE LAB BLEND
LAB of the blend have been tested in vitro as well as in vivo and
possess main characteristics:
• High adhesion activity (provide fast colonization of vaginal canal)
• High antagonistic activity (provide inhibition of growth of pathogenic
microflora)
• Synthesis of biologically active substances (H2O2, lysozyme, vitamins
• Interferon induction
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
UNIQUE LAB BLEND
Unique composition helps create conditions for fast microflora balance
change.
API of Neoprobio consists of tested and scientifically proved probiotic
LAB according to WHO requirements. Validated technology of production
and testing ensure that exactly specific probiotic strains are incorporated
in the ovule.
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
UNIQUE MEDICAL EFFECTS
•
Neoprobio is indicated for the prevention and treatment of vaginal
dysbiosis of different etiologies.
•
Neoprobio is indicated following therapy with antibiotics, antifungal
and antiviral drugs to maintain and restore the balance of vaginal
flora.
•
Neoprobio is indicated for the prevention and elimination of dry
erosion of women of different age groups, as an aid to
epithelialization due to the components included in the product.
Indications are supported by positive clinical trials.
dr Taras Lyaskovsky | Zabolotny Institute of Microbiology and Virology NAS | Ukraine
Thank you!
FOR MORE INFORMATION PLEASE CONTACT:
Taras Lyaskovsky, PhD
email: [email protected]
or
Michał Szczęsny, MPharm
email: [email protected]
www.neoprobio.pl