1. INTESTINNOVATION FOR YOUR HEALTH
LEKSIR. Ltd , Russia, Moscow, Krylatskie Kholmy 30, build  9 tel./fax (495)
INTESTINNOVATION FOR YOUR HEALTH

2. Expert appraisal. Initiative - basis for progress
Do You need friends?
Expert appraisal. Initiative - basis for progress
Leksir Company, Russia, is known as a reliable and dynamically developing company. It is a part of the international pharmaceutical group which includes "STI-MED-SORB“ manufacturing plant (Russia), “AVVA Pharmaceuticals AG” marketing company (Switzerland) and a pharmacy chain in Moscow. Leksir Ltd. has a wide distribution network in Russia and the CIS countries.
There are 55 items of pharmaceuticals in the portfolio of the company including original formulations and brand generics.
"Leksirъ“ Trademark . We aim at quality rather than quantity
"Leksir" Company specializes in development, manufacturing and marketing of innovative pharmaceuticals and food supplements in three therapeutic areas: gastroenterology, pediatrics and infectious diseases (improved antibiotics). The ready made products are presented in solid drug forms (tablets, capsules, powders and suppositories)

3. Do You need friends?
"STI-MED-SORB“ manufacturing plant . Modern manufacturing facilities are the base of high technologies
"Leksir" Company was founded in 1996 (Russia, Moscow). Manufacture of the pharmaceutical preparations is performed at its own plant, “STI-MED-SORB“, located 1000 km from Moscow in the ecologically pure Volga region.
The manufacturing facilities are located in two buildings which were constructed from the ground up with the total area m2 and m2.
The staff of the manufacturing plant includes 300 eminently qualified workers, experts
and managers.

4. “STI-MED-SORB”. Following high standards
Do You need friends?
“STI-MED-SORB”. Following high standards
Compliance with the requirements of GOST R (GMP EU) is confirmed by Certificate of conformity No issued as of by the Federal Agency on Technical Regulation and Metrology of the Russian Federation.
Manufacturing License - No dated issued by the Federal Service for Surveillance in Public Health and Social Development (former Ministry of Health of the Russian Federation)

5. Our manufacturing plant "STI-MED-SORB“. Modern manufacturing
Do You need friends?
Our manufacturing plant "STI-MED-SORB“. Modern manufacturing
facilities is the base of high technologies
First production site produces uncoated and coated tablets and pellets. Production capacity is 25 mln tablets/month.
Another production site is designed for pharmaceuticals in
solid gelatin capsules. Production capacity – 15 mln tablets/month.
And the third production site – production of pharmaceuticals based on hydrolyzed lignin. Production capacity – 24 mln tablets/month.
API production site – production of hydrolyzed lignin. Production capacity – 16 tons/month.
The plant has high-technology equipment. Complex
multilevel quality control system is introduced at the plant. "STI-MED-SORB" plant has its
own R&D laboratory which develops new
pharmaceuticals and their dosage forms.
The structure of the plant also includes
Central Plant Laboratory and Department of Quality Control.

6. “STI-MED-SORB”. Control and quality
Do You need friends?
“STI-MED-SORB”. Control and quality
Central Plant Laboratory (CPL)
was founded in 2005 to solve perspective tasks in the field of technology for ready made drug formulations and modernizing technological processes of existing manufacture. The staff (9 specialists) operate with the most advanced materials and methods from the leading pharmaceutical manufacturers.
Department of Quality Control
includes physical-chemical and microbiology laboratories which are equipped with modern devices for measuring and testing the quality of raw materials and ready-made products. Qualification of the staff (36 specialists) was confirmed by Certificate of Technical Competence No KK issued 28/08/2006 by Federal Service for Supervision in Public Health and Social Development

7. International cooperation
Do You need friends?
International cooperation
Our products are promoted in the CIS countries through Leksir subsidiaries and exclusive distributors. On far abroad markets we start our activity with marketing research and registration as well as establishing contacts with potential partners to set up outsourcing cooperation.
Russia, Armenia, Belarus, Moldova, Kazakhstan, Ukraine, Republic of Uzbekistan, Brazil, China, India, USA, Canada
Cooperation Tasks
Leksir Ltd. develops, manufactures and markets innovative food supplements and pharmaceuticals in gastroenterology. Main R&D areas: antibiotics with enhanced safety profile, prebiotics for treatment of alimentary intoxications and intestinal infections, composite prebiotics for treatment and prevention of intestinal microflora disbalance (total: 30 new compositions in pipeline). The company offers finished formulations, with further partnership in marketing on national and international markets (Strategic Distribution Alliance).

8. FILTRUM – protects from food intoxication and intestinal infections
Do You need friends?
INNOVATION PRODUCTS:
FILTRUM – protects from food intoxication and intestinal infections
LACTOFILTRUM – improves intestinal microflora and prevents from dysbacteriosis
New Antibiotics - antibiotics with enhanced safety profile for intestinal microflora

9. PRODUCT OFFER SUMMARY Do You need 3 000 000 000 friends?
Enterosorbent fibers of plant origin neutralizing a wide range of endo- and exogenous toxins and pathogenic microorganisms in the GI tract
Double power prebiotic improving intestinal microflora
Antibiotic with enhanced safety profile for intestinal microflora
Food and alcohol intoxication. Intestinal infections. Diarrhea syndrome
Microflora disorders, atopic dermatitis, antibiotic therapy
Durable antibacterial therapy by broad spectrum antibiotics
FILTRUM (Lignin) tablets, capsules
LACTOFILTRUM (lignin+lactulose) tablets, capsules
Combination “ANTIBIOTIC+prebiotic” tablets, capsules

10. Looking forward to cooperation: Strategic Distribution Alliance (SDA)
Do You need friends?
Looking forward to cooperation: Strategic Distribution Alliance (SDA)
AVVA Pharmaceuticals AG (Switzerland)
owner of the registration dossier
“STI-MED-SORB” (Russia)
Manufacturer of the ready made product
LEKSIR LTD. (Russia):
STI-MED-SORB operating company
PARTNER
1. AVVA Pharmaceuticals AG delivers reg. dossier and Territory license to the Partner on the basis of SDA agreement.
2. STI-MED-SORB manufactures the product (registered by the Partner in the Territory) on the basis of the Manufacturing Contract.
3. The Partner on its own behalf registers and promotes/distributes the product in the Territory.

11. Strategic Distribution Alliance
Do You need friends?
Strategic Distribution Alliance
AVVA Pharmaceuticals AG (owner of dossier)
Our Partner (registers the product)
Plant “STI-MED-SORB” (Contract Manufacturer)
dossier
places the order
exports the products
distributes
and
promotes
products
L o c a l M a r k e t

12. FILTRUM (0,45 g LIGNIN, TABS)
NEW GENERATION ENTEROSORBENT
Life free of toxins

13. FILTRUM INDICATIONS: Intoxication by poor food, alcohol, drugs.
Lignin fibres of plant origin to neutralize wide range of endo- and exogenous toxins and pathogenic microorganisms in GI tract
INDICATIONS:
Intoxication by poor food, alcohol, drugs.
Intoxication by detrimental substances accumulating at hepatic and renal insufficiency.
Acute intestinal diseases (dysentery, salmonellosis, rota-virus infections etc.)
Diarrhea syndrom of unspecified origin
Filtrum does not affect any tissues of the gastro-intestinal tract, is does not accumulate in any organs and is entirely eliminated from the intestines.

14. FILTRUM
COMPOSITION
Lignin is formed by removal of water from sugars to create aromatic structures.
These reactions are non reversible. There are many possible monomers of lignin, and the types and proportions depend on the source in nature. Some typical monomers are shown in the sketch :
The OH groups (either the alcoholic OH's on the chains or the phenolic OH's on the aromatic rings) can react with each other or with the aldehyde or ketone groups. When an OH reacts with another, an ether linkage is formed. As we see, an OH reacts with an aldehyde to form a hemiacetal. The reactions of OH groups with ketones forms ketals. An early stage in the condensation of various monomers to form lignin is shown in the next sketch :

15. FILTRUM / LIGNIN COMPOSITION
There are several groups shown in red that can react further. Some will simply extend the polymer while others would establish cross linking. The monomer that is shaded in orange has three of its functional groups linked to other monomers, so it is starting a branch or cross link. The large lignin molecules fill three dimensions and are heavily cross linked. Sometimes lignin is isolated as a brown powder, but more often it is a gummy mixture of lignins with a wide range of molecular weights.
Lignin resists attack by most microorganisms, and anaerobic processes tend not to attack the aromatic rings at all. Aerobic breakdown of lignin is slow and may take many days. Lignin is nature's cement along with hemicellulose to exploit the strength of cellulose while conferring flexibility.

16. FILTRUM / LIGNIN HISTORY AND BACKGROUND
1943 / Germany – original enterosorbent product Porlisan (on the basis of lignin) appeared as anti-diarrhea product for curing diarrhea syndrome of infection and non-infection nature
1970 / Russia – improved form of lignin was elaborated (lignin powder with higher absorbtion properties)
1997 / Russia – tableted formulation of medical lignin (Filtrum) was patented
There are many pores on the surface of Filtrum-sorbent: micro-, mezo- and macropores, which results in broad spectrum of absorbtion activity – from heavy metal ions to microbic cells and organic metabolits. Prevalence of mezopores enables Filtrum to neutralize middle- and long-chained molecules including endo- and exotoxins.

17. FILTRUM vs Activated Charcoal
Broad absorbtion spectrum
Narrow absorbtion spectrum
Neutralizes bacteria and its toxins
Low absorbtion of bacteria and its toxins
Binds gistamine and food allergens
Binds low spectrum of allergens
Negative influence on intestinal mucous surface
Reparative effect of lignin
on intestinal mucous surface

18. advantages in intoxication and acute intestinal diseases segment
FILTRUM
advantages in intoxication and acute intestinal diseases segment
Universal means of decreasing intoxication in case of intoxication of different etiology (poor food, acute intestinal diseases, alchogol overdosage etc.)
Neutrolizes pathogenic microflora and its toxins thus blocking the pathogenic mechanism (vs. loperamide)
No negative effect on normal microflora (vs. intestinal antiobiotics)
Does not form resistant stamps in pathogenic microflora.
High safety profile.
Can be used to prevent an assumed intoxication.

19. FILTRUM
Frequency of acute toxic infections symptoms in people %

20. FILTRUM Intoxication and acute intestinal diseases
According to marketing research 60% of people at least once a year suffered from the following symptoms:
1. Gastro-intestinal disorders caused by “food poisoning”
2. Alimentary toxic infection
3. Intestinal infection
4. Gastro-intestinal disorder of unspecified toxic origin
60%

21. FILTRUM
CLINICAL EVIDENCE Treatment of acute intestinal infections accompanied by diarrhea syndrome
Fig.1 Duration of main clinical symptoms in patients with acute dysentery
Control group (basic therapy): antimicrobials Furazolidon (nitrofurans) and ciprofloxacin (fluoroquinolones), and pathogenetic therapy – parenteral detoxification solutions (colloid and salt solutions), astringents, reparative drugs and adrenomimetics.
Filtrum group = standard therapy +Filtrum
Russian State Medical University (Moscow, 2001)

22. FILTRUM
Fig.2 Duration of main clinical symptoms in patients with gastrointestinal form of salmonellosis
Standard therapy (control group): parenteral and oral rehydration by salt solutions and adrenomimetics
Filtrum group: standard therapy Filtrum
Russian State Medical University (Moscow 2001)

23. FILTRUM
Fig.3 Duration of main clinical symptoms in patients with alimentary toxic infections
Standard therapy (control group): parenteral and oral rehydration by salt solutions and adrenomimetics
Filtrum group: standard therapy Filtrum
Russian State Medical University, 2001

24. FILTRUM Сlinical evidence
Conclusion 1:
Filtrum is highly effective for treatment of acute intestinal infections accompanied by diarrhea syndrome, e.g. acute dysentery, gastrointestinal form of salmonellosis and, particularly, gastroenteritic form of alimentary toxic infection. Filtrum therapy results in shortening of the major clinical signs statistical decrease (in days) over 30%.
Conclusion 2:
Filtrum can be recommended as a drug of choice for patients with mild alimentary toxic infections and salmonellosis as well as a component of combined therapy of moderate and severe dysentery, salmonellosis and alimentary toxic infections
DOSAGES:
Children under 6 months - 1/4 tablet 3-4 times a day
6 months - 1 year - 1/3 tablet 3-4 times a day
1-3 years - 1/2 - 1 tablet 3 times a day
4-7 years ,5 tablets 3 times a day
over 7 years - 2 tablets 3-4 times a day
1-1,5 hours before or 1-1,5 hours after meal

25. FILTRUM
Efficacy in combined treatment of acute intestinal infections in children
Patients characteristics
Etiology: Klebsiella, Salmonella, Campilobacter, Rotaviruses, Thoroviruses, Norwalk viruses, Unspecified
Characteristic
Filtrum (n=61)
Control (n=58)
Age (years)
3.420.44
4.220.79
Disease duration (days)
3.340.36
2.450.2
Filtrum STI addition to basic therapy of acute intestinal infections in children had beneficial effect on general toxicity and resulted in alleviation of fever, intoxication, nausea and vomiting and in improvement of appetite
Research Institute of Pediatric Infections (St.Petersburg, 2003)

26. FILTRUM
Fig.1 Duration of general infection symptoms in study and control patient groups
Days
(rehydration, diet)
Research Institute of Pediatric Infections (St. Petersburg, 2003)

27. FILTRUM Fig.2 Duration of local infection symptoms Days
Research Institute of Pediatric Infections (St.Petersburg, 2003)

28. FILTRUM
Clinical evidence conclusion: addition of intestinal sorbent Filtrum to standard therapy of acute intestinal infections significantly enhances treatment efficacy and results in a quicker clinical recovery. Good tolerability and significant therapeutic effect on the course of acute intestinal infections in children, including infants, allows giving Filtrum a positive opinion and recommendation towards a wider promotion of the drug into clinical practice
Research Institute of Pediatric Infections (St.Petersburg, 2003)

29. FILTRUM Positioning: key messages aspects
First aid natural means for protecting organism from alimentary intoxication
Multipurpose non-drug means for decreasing acute intoxication of different nature (food, intestinal infections, alcohol)
Universal anti-”Travellers diarrhea” protector
Convenient first aid supplement – always at hand in case of unexpected acute intoxication
Strengthens effect of the standard therapy in case of acute intestinal disorders
Accelerates rehabilitation after food intoxication

30. FILTRUM
R & D prospects
Product improvement for children audience: confectionery, various tastes
Different formulations: caplets, capsules, sache, gel, paste
Combination with additives giving detoxifying synergy effect for specific niche demands
Modifying absorption spectrum to increase neutralization of toxic or microbe agents of definite parameters and properties
Search for new enterosorbents with unique properties beneficial for health and treatment

32. Prehistory terminology
Probiotics/Prebiotics Lactulose
Food fibers Enterosorbents Lignin
Lactofiltrum
Probiotics are beneficial bacteria that can be introduced into the digestive system with food. They enhance immunity, help regulate hormone balance, protect from food poisoning, allergies, and perform other important functions.
Prebiotics are non-digestible carbohydrates that pass through the small intestine undigested and are fermented in the colon by beneficial bacteria thus activating their growth.
Enterosorbents are substances that bind and deduce exogenous and endogenous toxins as well as pathogenic microorganisms and their metabolites from the gastrointestinal tract .

33. Medicinal lignin fibers, mg
Composition
Medicinal lignin fibers, mg
375,0
Lactulose, mg
125,0
Moisture, %
5, 0
Total tablet weight, mg, + 5%
500,0
Specification of components:
Medicinal lignin by Russian manufacturers standard (approved by the Ministry of Health) FSP
Lignin active substance and Lactofiltrum (as finished product) are manufactured on the own plant in accordance with GMP standards. Lignin modified preparation technology and sterilization were elaborated on the basis of the own patent (1999).
Lactulose (complies with Lactulose Concentrate USP26)
Shelf life: 3 years
Lactofiltrum is patented in Expiry date 2019

34. New generation prebiotic for elimination of intestinal pathogenic microorganisms and their toxins as well as for activation of own bifidobacteria growth, which normalizes microflora balance
Indications:
Dysbacteriosis of different etiology (gastro- intestinal chronic and acute diseases, long-term therapy by anti-inflammatory non-steroids, immunosuppresants etc.)
Irritated bowel syndrome with a tendency to constipation and unstable stool
Rehabilitation of microflora disbalance after antibiotic therapy (incl. antibiotic-associated diarrhea)
In complex therapy of atopic dermatitis (diathesis) particularly in pediatric practice
Combined treatment of acute and chronic viral hepatitis and hepatic cirrhosis.
General improvement of intestinal microbiological ecology (for aging population)

35. Dysbacteriosis or microflora disbalance
Vital aspects of abnormal microflora in children
Dysbacteriosis or microflora disbalance:
Microflora disorders are diagnosed in 90% children
Slows down vitamins and minerals absorption thus negatively affecting development of bone, muscle and nervous systems as well as immunity
Often causes or aggravates atopic dermatitis
Has negative destructive influence on the intestinal mucosa causing various gastro-intestinal chronic diseases
Vital aspects of normal microflora in adults and aged people
Normal microflora
Prevents septic processes in intestines and colon
Results in decreasing internal intoxication
Improves absorption of vitamins and minerals preventing osteoporosis
Has beneficial effect on immunity and general physiological activity

36. 100 % Features Normalization of intestinal microflora
DOUBLE MECHANISM INFLUENCE ON MICROFLORA
Lignin - natural enterosorbent, adsorbs wide range of endo- and exogenous toxins and pathogenic microorganisms in the intestines
Lactulose - improves growth and activity of lacto - and bifidobacteria
100 %
Normalization of intestinal microflora

37. High safety profile: can be used for a long time without side effects
Аdvantages vs traditional probiotic therapy
LACTOFILTRUM®
(as prebiotic)
Bacterial colonies products (probiotics)
Direct absorption of pathogenic microflora and its toxins
Unable to absorb pathogens
Substantial loss of activity in intestines due to interference with aggressive stomach excretion
Free transit through gastro-intestinal tract with minimum efficacy loss
Direct stimulation of own normal microflora growth
Indirect influence on the normal microflora growth
Binds histamines and food allergens (in allergo-dermatosis therapy)
Unable to bind toxic organic metabolites
High safety profile: can be used for a long time without side effects
Ideal as preventive (prophylactic) means
Restrictions for durable usage
Prophylactic usage with cautions

38. Сlinical evidence Treatment of dysbacteriosis in children,
including those with functional and chronic gastrointestinal disturbances
Fig. 1 Improvement of clinical condition (treatment duration 14 days)
Efficacy, % patients
Research Institute of Pediatrics (Moscow, 2003)

39. Microflora composition
Lactofiltrum influence
on intestinal microflora
Fig. 2
Microflora composition
Normal
level
With Lactofiltrum
(n = 45)
Control (n = 15)
Before
After
Bifidobacteria
> 8
< 6
> 9
< 7
Lactobacteria
> 6
< 5 6
E.coli, weak fermentative
< 10 %
13% 5%
12% 9%
Hemolytic E.coli 5 2
Candida
< 3
> 5
< 4
Lactase-negative bacteria
< 5 % 7% 3%
Enterococcus
Research Institute of Pediatrics (Moscow, 2003)

40. Сlinical evidence CONCLUSIONS DOSAGES:
Children under 6 months - 1/4 tablet 3-4 times a day
6 months - 1 year - 1/3 tablet 3-4 times a day
1-3 years - 1/2 - 1 tablet 3 times a day
4-7 years ,5 tablets 3 times a day
over 7 years - 2 tablets 3-4 times a day.
1-1,5 hours before or 1-1,5 hours after meal.
Lactofiltrum treatment resulted in normalization of intestinal microflora composition, namely, in elimination of opportunistic bacteria, suppression of cocci and growth of Lacto- and Bifidobacteria.

41. CONCLUSIONS (cont.)
Lactofiltrum corrects both intestinal peristalsis and intestinal microflora composition.
Lactofiltrum is effective in pediatric patients with functional gastrointestinal disturbances like
Lactofiltrum can be used for conditioning therapy to enhance the effect of further decontamination against parasitic invasion (lambliasis)
Lacto- and Bifidobacteria-containing drugs can be reasonably used after 14-day conditioning by Lactofiltrum.
At least 14-day treatment by Lactofiltrum with further analysis of feces for dysbacteriosis appears obligatory after children are transferred from hospital to an orphanage. This measure aims at prevention of nosocomial infection in weak children by opportunistic microflora.

42. Lactofiltrum clinical study in patients with dysbacteriosis
Dynamics of clinical symptoms during Lactofiltrum treatment
RESULTS:
Improvement of clinical signs was associated by alleviation of intestinal dysbacteriosis.
State Medical University (Saratov, 2005)

43. Atopic dermatitis accompanied by intestinal disturbance with a tendency to constipation and unstable stool
Days
Treatment duration 14 days
Conclusions:
Lactofiltrum can be recommended for monotherapy of mild atopic dermatitis in the phase of incomplete remission of moderate disease, and for treatment of moderate atopic dermatitis in combination with local therapy.
Scientific Center of Children Health (Moscow, 2003)

44. Acute viral hepatitis (A, B, C)
Lactofiltrum addition to standard therapy of acute viral hepatitis results in significantly lesser duration and intensity of intoxication (fatigue, headache, low appetite, anorexia, fever), dyspepsia, pain and jaundice. Such
Treatment duration 21 days
Days
treatment is shown to accelerate normalization of liver and thickened gallbladder wall sizes and gallbladder clearance of the solids compared to control patients.
Federal Medico-Biological Agency (Moscow, 2005)

45. Microflora support during oral antibacterial therapy
Intestinal microflora components in patients with genitourinary chlamydiosis (lg CFU/g).
Control group: clarithromycin
Experimental group: clarithromycin + Lactofiltrum
Before treat.
1 - Lactobacillus spp.
3 - Escherichia coli
4 - Enterococcus spp.
2 - Bifidobacterium spp.
After treat.
Institute of Epidemiology and Microbiology (St.-Petersburg)

46. RESULTS
Decrease of lactobacilli and bifidum bacteria content was statistically significant in the control group (р<0.001 and p< 0.05 respectively).
Analysis did not reveal significant qualitative alteration of the studied microflora components in experimental patient group.
CONCLUSIONS
The study confirmed the efficacy of prebiotic Lactofiltrum administration for prevention of dysbacteriosis development during chlamydiosis treatment by macrolide antimicrobial clarithromycin.
Lactofiltrum administration concomitantly with antimicrobial treatment of chlamydiosis facilitates preservation of normal intestinal microflora and decreases the risk of intestinal colonization by Candida spp.
Lactofiltrum administration decreases the risk of antimicrobials-induced dyspepsia and allergic reactions.

47. support during parenteral antibacterial therapy
Microflora
support during parenteral antibacterial therapy
Lactofiltrum prevention of intestinal dysbacteriosis
in surgical patients with purulent conditions receiving
prolonged antimicrobial therapy (by CEPHAZOLIN, IMIPENEM, MAXIPIME)
Dysbacteriosis parameters
Study group
Control group
Before treatment
After treatment
Bifidobacteria (<107)
10% 5% -
20%
Lactobacteria (<105)
30%
Lactose-negative E. coli (> 5%)
50%
E. coli with low enzyme activity
(> 10%)
Hemolytic E. coli
40%
Proteus spp. (>103)
Staphylococcus aureus
Military hospital №42 (St.-Petersburg)

48. RESULTS
Potential prolonged antimicrobial therapy results in intestinal dysbacteriosis, decrease of bifidobacteria and lacrobacteria content and appearance of opportunistic and pathogenic microflora, including Candida spp.
Lactofiltrum administration allows prevention of intestinal dysbacteriosis during antimicrobial therapy.
Lactofiltrum administration decreases the risk of Candidosis development during antimicrobial therapy.
Lactofiltrum administration allows normalization of gastrointestinal tract condition even in patients with initial dysbacteriosis – normalization of microflora profile, stool frequency and consistence, pain, discomfort and meteorism relief.
CONCLUSION
Lactofiltrum inclusion into combined therapy schedule significantly alleviates both clinical and laboratory manifestations of dysbacteriosis during prolonged parenteral antimicrobial therapy.

49. Sales dynamics, Russia

50. Positioning: key messages aspects
Double power prebiotic for improvement of
intestinal microflora in case of gastrointestinal
disorders and atopic dermatitis
High safety profile prebiotic for all groups of
population
Microflora protector during antibiotic therapy
Strengthens standard therapy efficacy in case of
microflora disorders (synergy)

51. R & D prospects
Product improvement for children audience: confectionery, powders, various tastes
Miscellaneous formulations: caplets, capsules, sache, gel, paste
Combination with additives giving synergy positive effect for intestinal microflora
Modifying prebiotic component to reach better activation of definite spp.
Modifying enterosorbent component to gain more specific absorption of certain pathogens

52. INTESTINNOVATION FOR YOUR HEALTH
LEKSIR. Ltd , Russia, Moscow, Krylatskie Kholmy 30, build  9 tel./fax (495)
INTESTINNOVATION FOR YOUR HEALTH

53. Antibiotics with enhanced safety profile for intestinal microflora
Do You need friends?
Innovation product
Antibiotics with enhanced safety profile for intestinal microflora

54. Do You need friends?
Antibiotic + prebiotic combination: background and history of the development
1929 – A. Fleming extracted penicillin
The term “antibiotic” introduced
2000 – About 160 antibiotics used in practice
Antibiotic global sales $25 billion (13% of all drug sales)
1916 – the term “dysbacteriosis” first appeared in clinical practice.
1929 – lactulose was synthesized and described
1957 – lactulose bifidogenic effect was discovered
2006 – Innovation composition “Antibiotic+lactulose” was elaborated

55. Unsatisfied needs for elaboration of new antibiotics
Do You need friends?
Unsatisfied needs for elaboration of new antibiotics
Worldwide growth of infection diseases being cured by antibiotics resulted in intensive growth of antibiotic consumption.
Antibiotics therapy is the leading factor resulting in elimination of intestinal bifidobacteria and lactobacilla along with growth of pathogenic microflora.
Vast prevalence of the gastrointestinal diseases in the population leading to stable disbalance of intestinal micro-ecology.
4. Rehabilitation of the normal microflora after antibiotic therapy became standard practice
Antibiotics without side effect on intestinal microflora

56. The next generation Pharmaceutical forms
Do You need friends?
The next generation
You want to give your patients the most safety treatment by antibiotics. Innovation antibiotic formulations combine the well established power of widely used antibiotics with prebiotic microflora balance effect. This new formulation ensures microflora maintainance during antibiotic treatment.
Patent status:
Composition of improved antibiotics and its manufacturing technology were patented and international priority received.
Pharmaceutical forms
Tablet and capsule formulation
Powder for oral solution (sachets)
Suspension and syrup

57. Results AVOID DYSBACTERIOSIS DURING ANTIBIOTIC THERAPY
Do You need friends?
Results
Inclusion of lactulose into combination with antibiotics results in the following:
Bifidobacteria and Lactobacilla maintainance during antibiotic therapy
Tendency of Candida albicans elimination
No influence on anti-infective activity of antibiotic
(equal efficacy with
pure antibiotic control tests)
AVOID DYSBACTERIOSIS
DURING ANTIBIOTIC
THERAPY

58. Clinical approbations 1
Do You need friends?
Clinical approbations 1
Composition “Clarithromycin + lactulose”
in urogenital chlamidiosis therapy
Pasteur Scientific Research Institute of Epidemiology and Microbiology (St.-Petersburg, Russia, 2006)
Patients: urogenital infections caused by Clamidia trachomatis
Control group: clarithromycin 250 mg twice
a day, 14 days
Test group: clarithromycin
250mg+lactulose 300mg twice

59. Do You need friends?
Composition “Clarithromycin + lactulose” vs Claritromycin in urogenital chlamidiosis therapy
CFU/g
Control: clarithromycin Test: clarithromycin + lactulose

60. Results Do You need 3 000 000 000 friends?
The control group demonstrated a considerable (p< 0.05) 100-fold decrease of lactobacilli amount and a 20-fold decrease of bifidobacteria and enterococci. The amount of escherichia per 1 g of faeces virtually did not change.
In the test group (Clarithromycin + lactulose ) there is 10-fold less decrease of lactobacilli amount (p<0.1), than in the test group. The amount of other bacteria virtually does not change in combination with antibiotic therapy.

61. Do You need friends?
Conclusion
1. The research proves that even when using such a favorable antibiotic as clarithromycin for intestinal microecology, the amount of main representatives of obligate microbial flora shows statistical decrease even in patients with unaggravated gastroenterologic anamnesis.
2. Including lactulose prebiotic into the antibiotic composition allows to minimize these changes and protect obligate microflora from antibiotic negative effect.

62. Clinical approbations 2
Do You need friends?
Clinical approbations 2
Composition “amoxicillin + clavulanic acid” with lactulose” in treating gastroduodenitis.
Medical Pediatric Academy (St.-Petersburg, Russia, 2006)
Patients: Children with Helicobacter pylori-associated gastroduodenitis.
Control group: amoxicillin + clavulanic acid (675 mg) twice a day, 14 days.
Test group: amoxicillin + clavulanic acid (675 mg) + lactulose 300mg twice a day, 14 days.

63. “Amoxicillin+clavulanic acid” with and without lactulose”
Do You need friends?
“Amoxicillin+clavulanic acid” with and without lactulose”
CFU/g

64. Results Do You need 3 000 000 000 friends?
The control group (antibiotic) demonstrated a significant (p< 0,01) and substantial (from 10 to 50 times) decrease of the amount of escherichia, bifidobacteria and lactobacteria.
The amount of Candida albicans increased considerably (more than 10 times)
The test group (antibiotic+lactulose) showed (p>0,01) no change of Escherichia coli, increase of bifidobacteria and lactobacilli, virtually complete sanitation of the infection candida, as well as of proteus and klebsiella (р<0.001).

65. Do You need friends?
Conclusion
1) Administration of amoxicillin (with clavulanic acid) as an antibiotic, most favourable for the intestinal microecology, without prebiotic protection results in dysbiosis that is manifested in the patients in statistically significant decrease of the main representatives of obligate microflora (Bifidobacterium., Lactobacillus, Escherichia ) and considerable increase of Candida albicans.
2) Effectiveness of combined administration of the prebiotic preparation of lactulose in the pharmaceutical composition with amoxicillin has been proved. Introduction of lactulose into the complex therapy with amoxicillin allows to avoid microflora disbalance

66. Do You need friends?
Summary of results
Antibiotic + lactulose combination is likely to find a role as a safe, microflora favorable option in treatment of bacterial infections by oral antibiotics

67. Development status: dossier available Q3 - 2007
Do You need friends?
Development status: dossier available Q
clarithromycin
amoxicillin + clavulanic acid
azithromycin
Development status: dossier in pipeline Q
Spiramycin
Cefixime
Midecamycin
Ceftibuten
Roxithromycin
Minocycline
Rifampicin
Cefuroxime
Josamycin
Ciprofloxacin
Ofloxacin
Levofloxacin
Moxifloxacin
Natamycin
Fosfomycin
Nifuratel
Clindamycin
Thiamphenicol

68. Market prospects for improved antibiotics (ecobiotics):
Do You need friends?
Market prospects for improved antibiotics (ecobiotics):
Antibiotic market grows by 12% yearly
Cautious use of antibiotics due to microflora side effects
Awareness growth of the normal microflora role in human health
Growth of the probiotic and prebiotic market – loyalty increase towards microflora improving components
Positioning aspects
Antibiotic therapy in pediatric practice (microflora is unstable and sensitive to
antibiotics in children and infants)
Diseases requiring long term antibiotic
therapy by broad spectrum antibacterial preparations

69. Safe antibiotics / Ecobiotics
LEKSIR LTD
Antibiotics with enhanced safety profile for intestinal microflora
Safe antibiotics / Ecobiotics
Perorally Administrable Antimicrobial Composition

70. Abstract
Leksir Ltd (Russia) presents the innovative project Safe antibiotics.
The use of invention «Perorally Administrable Antimicrobial Composition» (PCT/RU 2005/ WO 2006/025767)
Allows to produce antibiotics with limited list of side effects:
safe antibiotics do not damage intestine beneficial bacteria (Bifidobacterium spp. Lactobacillus spp)
safe antibiotics prevent pathogenic microorganisms from spreading (Candida- , Proteus- and Klebsiella-associated infections)
Opens new business prospects for pharmaceutical companies:
new patent protection for the old (traditional) antibiotics
new opportunities of marketing strategy on the drug market
new competitive advantages on the drug market over producers of traditional forms of antibiotics

71. Problem
Almost any antibiotic possesses a broad spectrum of side effects
The main reason why of antibioticotherapy negative consequences is that:
antibiotics do not have selective damaging effect on the
pathogenic microflora only and destroy both pathogenic
organisms and protective (useful) intestinal microflora
death of protective intestinal microflora (Bifidobacterium spp. Lactobacillus spp) resulting from taking antibiotics is the basic reason for the dysbiosis
Under dysbiosis:
Development of the pathogenic organisms in the colon.
Intoxication as a result of the growing of pathogens.
Infringement of the motoric and secretion function of the colon.
Development of the anemies, hypovitaminosis, fermentopathies.
Depressed immunological status ….. etc
The use of invention «Perorally Administrable Antimicrobial Composition» can solve the problem of antibiotics-related dysbiosis

72. How does it work? Аntibiotics are administered perorally q
Pathogenic
organisms
Аntibiotics are administered perorally q
Antibiotic is absorbed from the stomach
Antibiotic eliminates pathogenic organisms
Non-absorbed part of antibiotic
go to the intestine
Antibiotic damage intestinal beneficial
microflora
As a result :
intestinal biocenose is destroyed
dysbiosis-related side effects manifest
themselves (antibiotic-induced colitis,
antibiotic-induced diarrhea, etc)1
Antibiotic eliminate pathogenic organisms
Intestinal
beneficial
microflora
Antibiotic damage intestinal beneficial
microflora

73. Solution Lactose Lactulose
Finished product of traditional antibiotics is produced according to the formula :
Antibiotics substance + Lactose or another excipient
Finished product of Safe antibiotics is produced according to the new formula :
Antibiotics substance + Lactulose
Innovative antibiotic compositions combine the well established power of widely
used antibiotics with prebiotic microflora balance effect. This new composition
ensures microflora maintainance during antibiotic treatment.
Antibiotics substance
Lactulose
Lactose

74. Lactulose
Lactulose is widely known and researched. In medicine, lactulose has a long track record as a successful therapy against constipation and portal hepatic encephalopathy.
The disaccharide lactulose is the ketonic analogue of lactose and consists of the two mono-saccharides galactose and fructose. Lactulose is not broken down by disaccharidases in the small intestine and is therefore not absorbed.
In the colon, undigested lactulose is the ideal nutri-
tional basis for health-promoting bacteria (bifidobac-
teria and lactobacilli).
In the colon lactulose is degraded by saccharolytic
bacteria which convert it into low-molecular organic
acids, mainly lactic acid.
Lactulose stimulates selectively the growth and vital
activity of protective intestinal microflora.
Dosage of lactulose, as a component of the finished form of antibiotic, is very small and do not induced constipation effect.
This dosage of lactulose enter the large intestine unaltered, where it stimulates the growth of beneficial bacteria only.

75. How does it work? Safe antibiotics are administered perorally q
Antibiotic is absorbed from the stomach
Antibiotic eliminates pathogenic organisms
Lactulose can not be digested and absorbed
through the stomach
Non-absorbed part of antibiotic and lactulose
goes to the intestine
Antibiotic can damage intestinal beneficial
microflora, but …
… lactulose stimulates the growth and vital
activity of intestinal beneficial microflora
Antibiotic
eliminate
pathogenic
organisms
Pathogenic
organisms
Intestinal
beneficial
microflora
Antibiotic can
damage intestinal
beneficial
microflora
lactulose stimulates the growth and vital
activity of intestinal beneficial microflora
As a result :
intestinal biocenose remains unchanged
there’s no dysbiosis- related side-effects

76. in Combination with Lactulose:
Start of project
Safe Antibiotics are produced by Leksir Ltd according to the new formula
in Combination with Lactulose:
Amoxicillin
Azithromycin
Cefixime
Cefuroxime
Ciprofloxacin
Clarithromycin
Clindamycin
Doxycycline
Fosfomycin
Levofloxacin
Midecamycin
Moxifloxacin
Nifuratel
Nifuroxazide
Ofloxacin
Roxithromycin
Spiramycin
Leksir Ltd has carried out clinical tests, confirming the efficacy of new class of antibiotics:
Clarithromicyn + Lactulose (2006)
Amoxiclav + Lactulose (2007)
Leksir Ltd plans to start the producing these antibiotics from

77. Design of trials
The random test sample included 30 children of both sexes aged 917 years with diagnosed Нр-associated gastrites. The initial diagnosis was substantiated by an urease test of antral gastric bioptats obtained upon fibroesophagogastroduodenoscopy (FEGDS).
Group № Group № Group № 3
Amoxiclav daily
dose: 1350 mg
Amoxiclav daily
dose: 1350 mg
Amoxiclav daily
dose: 1350 mg
Lactulose daily
dose: 200 mg
Lactulose daily
dose: 600 mg
Treatment course 14 days
№ patients in each of group - 10
Before and after implementation of antibiotic therapy, the intestinal
contents of all patients (n=30) were screened for dysbacteriosis.
Medical Pediatric Academy (St.-Petersburg, Russia, 2006)

78. Results. Group №1 (Amoxiclav 1350 mg)
Results of bacteriological analysis of intestinal microflora
Some characteristics of intestinal microbiocenosis in patients of the control group before and after treatment (lg CFU/g) 10
patients
Bifidobacterium spp.
Lactobacillus spp.
Candida albicans
Before treatment
After treatment
p or q
p or q
Average
8.7±1.5
7.1±1.1 q
6.8±0.9
5.8±0.7
1.1
2.4±0.2 p
Conclusions
The titers of bifidobacteria and lactobacilli were significantly decreased (p< 0.01), while those of Candida albicans were significantly increased.
1 - Bifidobacterium spp.
2 - Lactobacillus spp.
3 - Candida albicans

79. Results. Group №2 (Amoxiclav 1350 mg + Lactulose 200 mg)
Results of bacteriological analysis of intestinal microflora
Some characteristics of intestinal microbiocenosis in patients of the test group before and after treatment (lg CFU/g) 10
patients
Bifidobacterium spp.
Lactobacillus spp.
Candida albicans
Before treatment
After treatment
p or q
p or q
Average
8.2±1.2
8.1±1.1 tu
5.9±0.7
6.1±0.8
2.2 ±0.2
1.8±0.1 q
Conclusions
The titers of bifidobacteria and lactobacilli were similar both before and after treatment. The titers of Candida albicans sowed a tendency to decrease; however, this difference was insignificant.
1 - Bifidobacterium spp.
2 - Lactobacillus spp.
3 - Candida albicans

80. Results. Group №3 (Amoxiclav 1350 mg + Lactulose 600 mg)
Results of bacteriological analysis of intestinal microflora
Some characteristics of intestinal microbiocenosis in patients of the tests group before and after treatment (lg CFU/g) 10
patients
Bifidobacterium spp.
Lactobacillus spp.
Candida albicans
Before treatment
After treatment
p or q
p or q
Average
8.1±0.9
8.6±1.1 p
5.1±0.7
6.6±0.8
1.9±0.4
0.2 q
Conclusions
The titers of bifidobacteria and lactobacilli were significantly increased (p< 0.01), Candida-, Proteus- and Klebsiella-associated infections were fully eliminated.
1 - Bifidobacterium spp.
2 - Lactobacillus spp.
3 - Candida albicans

81. Conclusions
The monotherapy with Amoxiclav causes dysbiosis manifested as a statistically significant decrease in the titers of the major representatives of the obligate microflora (Bifidobacterium, Lactobacillus, Escherichia coli) and an increase in the titers of Candida albicans.
Combined therapy with the pharmaceutical composition Lactulose + Amoxiclav has a high therapeutic potential. Lactulose added to the treatment schedule improves the state of large intestinal microflora.
Lactulose has a dose-dependent protective effect. In Group 3 patients to whom the prebiotic was administered in the daily dose of 600 mg, this effect was more apparent than in Group 2 patients (daily dose = 200 mg).

82. Summary
Safe antibiotics are ecobiotics, that is the new class of drugs which do not destroy intestinal biocenosis eco-balance.
Ecobiotic = antibiotic + prebiotic
Ecobiotics:
possess all the antibacterial properties of traditional antibiotics (penicillins,
cephalosporins, tetracyclines, lincosamides, macrolides) and thus destroy
pathogenic microflora (in the same way)
acquire new properties, that is, unlike traditional antibiotics, they do not damage
beneficial intestinal microflora and therefore prevent the development of an
infection (Candida- , Proteus- and Klebsiella-associated infections) etc.
The use of ecobiotics:
reduces both the period of in-patient and out-patient treatment
reduces infection treatment costs
reduces recovery expenses after antibioticotherapy
As evidenced by the focus group, physicians prefer ecobiotics to traditional antibiotics.
Ecobiotics will be in great demand on the drug market. Independent experts estimate the ecobiotics market at about USD 4-5 billion.

83. Invitation Patent protection (PCT/RU 2005/000434 WO 2006/025767)
Leksir Ltd (pharmaceutical producer) cooperating with Fresenius Kabi (first-rate producer of lactulose) invites to collaboration pharmaceutical companies for producing safe antibiotics under licensing agreement.
Patent protection
(PCT/RU 2005/ WO 2006/025767)
Claim: An antimicrobial composition for peroral administration, characterized in that it contains an antibiotic drug selected from the group including broad-spectrum penicillins, cephalosporins, tetracyclines, lincosamides, macrolides, and lactulose at the active component ratio of 1:1-1:100, with the mean particle size of lactulose ranging from 100 nm to 200 µm »
Contacts:
Leksir Ltd
121614, Russia, Moscow, Krilatskie Holmy,30, build. 9.
tel/fax +7 (495)