WO2022096336A1 - Use of a combination of lactic acid bacteria with probiotic action, cranberry extract and d-mannose for prevention of post coital cystitis - Google Patents

Use of a combination of lactic acid bacteria with probiotic action, cranberry extract and d-mannose for prevention of post coital cystitis Download PDF

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WO2022096336A1
WO2022096336A1 PCT/EP2021/079770 EP2021079770W WO2022096336A1 WO 2022096336 A1 WO2022096336 A1 WO 2022096336A1 EP 2021079770 W EP2021079770 W EP 2021079770W WO 2022096336 A1 WO2022096336 A1 WO 2022096336A1
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mannose
cystitis
combination
lactic acid
acid bacteria
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French (fr)
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Stefano Colombo
Anna Porchetti
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Montefarmaco Otc S.P.A.
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Priority to CN202180073348.1A priority Critical patent/CN116507221A/en
Publication of WO2022096336A1 publication Critical patent/WO2022096336A1/en

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/45—Ericaceae or Vacciniaceae (Heath or Blueberry family), e.g. blueberry, cranberry or bilberry
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Definitions

  • the present invention relates to the use of a combination of lactic acid bacteria with probiotic action, cranberry extract and D-mannose in preventing post coital cystitis.
  • a urinary tract infection is defined as recurrent with the appearance of two or more episodes of uncomplicated lower urinary tract infection in the last 6 months or more episodes in the last year (20-30% of women from the first episode).
  • Post coital cystitis represents a particular form of cystitis because of post-traumatic origin on which bacterial superinfection is established.
  • a fundamental pathophysiological element is represented by mechanical urethro-bladder trauma facilitated in case of vaginal dryness (4 times higher risk) and/or hypertonicity of the pelvic floor muscles (7 times higher risk).
  • Penetration pain is the most powerful inhibitor of the vaginal lubrication reflex and genital congestion associated with sexual arousal.
  • the urethra is surrounded by a dense network of blood vessels, which congest with excitement, forming a shock-absorbing sleeve, a sort of "airbag", which protects the urethra and the bladder trigone from the mechanical trauma of sexual intercourse, especially if prolonged.
  • the traumatic potential is even higher if the vaginal introitus is sub-stenotic due to an hypertone of the pelvic floor muscles, further
  • vestibular hypersensitivity (vestibulodynia).
  • the object of the present invention is a combination of lactic acid bacteria with probiotic action, cranberry extract and D-mannose for use in preventing post coital cystitis.
  • Lactobacillus paracasei LC11 as lactic acid bacteria with probiotic action.
  • the combination is effective in preventing post coital cystitis thanks to the synergistic action of its components.
  • probiotics based on lactobacilli act in rebalancing vaginal dysmicrobism while D-mannose and cranberry extract act by preventing the adhesion of uropathogenic germs in the bladder and strengthening the so-called "bladder coating", a urothelial barrier characterized by glucosaminoglycans and proteoglycans.
  • the bladder coating is the first line of defense of the bladder wall, neutralizing toxic compounds, inhibiting the passage of small molecules and inhibiting the adhesion of uropathogens.
  • the combination used in preventing post coital cystitis is the supplement marketed under the name LACTOFLORENE® CIST which contains the combination of Lactobacillus paracasei LC11, cranberry extract and D-mannose in a suitable mixture with maltodextrin, sorbitol, anti-caking agent, silicon dioxide, sucralose, citric acid, flavours and colouring agents.
  • LACTOFLORENE®CIST is already known as an adjuvant to antibiotic therapy in the treatment of UTIs.
  • the combination of lactic acid bacteria with probiotic action, cranberry extract and D-mannose is administered to patients suffering from post coital cystitis after antibiotic treatment of the acute phase of the disorder.
  • the combination is administered orally for a period of at least three months, to prevent recurrence of post coital urinary infection.
  • the preferred dose is a combination of Lactobacillus paracasei LC11 1 mid CFU, cranberry extract in quantity corresponding to a proanthocyanidin content of 36 mg and D-mannose 1000 mg, corresponding to the content of a sachet of LACTOFLORENEOCIST, for 10 days a month for at least three months.
  • the LACTOFLORENEOCIST product has been administered to patients aged 18-30 years with a diagnosis of post coital cystitis.
  • the menstrual cycle has been regular due to the intake of an estrogen-progestin contraceptive preparation (Ethinyl Estradiol 20mcg + Drospirenone 3mg) for about 2 years and is nulliparous.
  • an estrogen-progestin contraceptive preparation Ethinyl Estradiol 20mcg + Drospirenone 3mg
  • the general objective examination is negative (Pa 120/70, Temperature 36.5°C) with particular absence of pain in the lumbar area (Jordan negative).
  • the abdominal palpation shows a discreet dolorability in the supra pubic area.
  • the objective gynecological examination shows normal external genitalia with the exception of a slight thinning of the vestibular mucosa with notes of dryness.
  • Uterus and appendages are apparently normal, a finding confirmed by transvaginal ultrasound office performed in succession.
  • a urinalysis + urine culture test is prescribed which demonstrates culture positivity for high concentration E. coli.
  • Patient A is diagnosed with acute UTI in a context of recurrent urinary infections.
  • Therapy with ciprofloxacin 500 mg, 1 tablet every 12 hours for 5 days, is prescribed, as indicated in the antibiogram, and the following treatment program is established for the prevention of relapses:
  • Patient A. did not have relapses of post coital urinary infection for the entire duration of the treatment.

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Abstract

The use of a combination of lactic acid bacteria with probiotic action is described, in particular Lactobacillus paracasei LC11, cranberry extract and D-mannose for the prevention of post coital cystitis.

Description

USE OF A COMBINATION OF LACTIC ACID BACTERIA WITH PROBIOTIC ACTION, CRANBERRY EXTRACT AND D-MANNOSE FOR PREVENTION OF POST COITAL CYSTITIS
**************************
DESCRIPTION
5 The present invention relates to the use of a combination of lactic acid bacteria with probiotic action, cranberry extract and D-mannose in preventing post coital cystitis.
It is estimated that in their lifetime at least 30-40% of women have suffered at least once from a urinary tract infection (UTI) episode.
A urinary tract infection is defined as recurrent with the appearance of two or more episodes of uncomplicated lower urinary tract infection in the last 6 months or more episodes in the last year (20-30% of women from the first episode).
The following factors make women more vulnerable to recurrent UTIs: anatomical factors: relative brevity and placement in the vestibular seat of the urethral outlet
15 sexual intercourse hypoestrogenism
Post coital cystitis represents a particular form of cystitis because of post-traumatic origin on which bacterial superinfection is established.
In fact, post-coital UTIs in women generally appear 24-72 hours after sexual
20 intercourse and represent up to 60% of relapsing forms. A fundamental pathophysiological element is represented by mechanical urethro-bladder trauma facilitated in case of vaginal dryness (4 times higher risk) and/or hypertonicity of the pelvic floor muscles (7 times higher risk). Penetration pain is the most powerful inhibitor of the vaginal lubrication reflex and genital congestion associated with sexual arousal. The urethra is surrounded by a dense network of blood vessels, which congest with excitement, forming a shock-absorbing sleeve, a sort of "airbag", which protects the urethra and the bladder trigone from the mechanical trauma of sexual intercourse, especially if prolonged. The traumatic potential is even higher if the vaginal introitus is sub-stenotic due to an hypertone of the pelvic floor muscles, further
30 accentuated by vestibular hypersensitivity (vestibulodynia).
To date, the prevention of post coital cystitis is represented by antibiotic prophylaxis. Post coital treatment involves taking the antibiotic within 2 hours of sexual intercourse. Although generally effective, taking antibiotics has several drawbacks related to possible allergic reactions and the development of resistance (Shawn Dason et al., Guidelines for the diagnosis and management of recurrent urinary tract infection in women, CUAJ, October 201 1 , volume 5, issue 5).
There is therefore a need for non-antibiotic treatment in preventing post coital cystitis. We have now found that a combination of lactic acid bacteria with probiotic action, cranberry extract and D-mannose are effective in preventing post coital cystitis.
Therefore, the object of the present invention is a combination of lactic acid bacteria with probiotic action, cranberry extract and D-mannose for use in preventing post coital cystitis.
Particularly preferred is the use of Lactobacillus paracasei LC11 as lactic acid bacteria with probiotic action.
Even more preferred is the use of a combination of Lactobacillus paracasei LC11 1 mid CPU, cranberry extract in an amount corresponding to a proanthocyanidin content of 36 mg (according to European Pharmacopoeia 6.0 1/2008: 1220) and D-mannose 1000 mg.
The combination is effective in preventing post coital cystitis thanks to the synergistic action of its components. In particular, probiotics based on lactobacilli act in rebalancing vaginal dysmicrobism while D-mannose and cranberry extract act by preventing the adhesion of uropathogenic germs in the bladder and strengthening the so-called "bladder coating", a urothelial barrier characterized by glucosaminoglycans and proteoglycans. The bladder coating is the first line of defense of the bladder wall, neutralizing toxic compounds, inhibiting the passage of small molecules and inhibiting the adhesion of uropathogens.
In a particularly preferred practical embodiment of the present invention, the combination used in preventing post coital cystitis is the supplement marketed under the name LACTOFLORENE® CIST which contains the combination of Lactobacillus paracasei LC11, cranberry extract and D-mannose in a suitable mixture with maltodextrin, sorbitol, anti-caking agent, silicon dioxide, sucralose, citric acid, flavours and colouring agents.
It is significant that LACTOFLORENE®CIST is already known as an adjuvant to antibiotic therapy in the treatment of UTIs.
This adjuvant use does not in any way suggest, indeed it makes it even more surprising, the preventive effectiveness of the combination of lactic acid bacteria with probiotic action, cranberry extract and D-mannose in preventing post coital cystitis. ln its preferred embodiment, the combination of lactic acid bacteria with probiotic action, cranberry extract and D-mannose is administered to patients suffering from post coital cystitis after antibiotic treatment of the acute phase of the disorder. The combination is administered orally for a period of at least three months, to prevent recurrence of post coital urinary infection.
The preferred dose is a combination of Lactobacillus paracasei LC11 1 mid CFU, cranberry extract in quantity corresponding to a proanthocyanidin content of 36 mg and D-mannose 1000 mg, corresponding to the content of a sachet of LACTOFLORENEOCIST, for 10 days a month for at least three months.
For the prevention of recurrence of post coital urinary infection, it may also be useful to take a diet rich in fiber and an adequate quantity of fluids to regularize intestinal function as well as perform appropriate exercises to re-educate the muscles of the pelvic floor.
Although the use according to the present invention is in preventing post coital urinary infections, it is intended that the combination of lactic acid bacteria with probiotic action, cranberry extract and D-mannose can also be used as an adjuvant in the antibiotic treatment of post coital cystitis.
To demonstrate the clinical efficacy of the combination of lactic acid bacteria with probiotic action, cranberry extract and D-mannose in preventing post coital cystitis, the LACTOFLORENEOCIST product has been administered to patients aged 18-30 years with a diagnosis of post coital cystitis.
An exemplary clinical case is reported below.
Clinical case 1
Patient A., 27 years old, has been complaining for 12 hours:
- dysuria (burning urination)
- stranguria (painful and intermittent emission of urine)
- pollakiuria (high frequency of urination)
- urinary urgency
- pelvic pain with persistent suprapubic weight after urination.
The complaints appeared about 48 hours after sexual intercourse.
Past medical history. Patient A. has no relevant family problems, does not smoke, does not consume alcohol, denies allergies to drugs or substances and has a tendentially constipated alvo. She complains of an inconstant appearance of abdominal pain and bloating after an abundant intake of milk and dairy products, in the absence of laboratory tests that have confirmed a lactose intolerance.
The menstrual cycle has been regular due to the intake of an estrogen-progestin contraceptive preparation (Ethinyl Estradiol 20mcg + Drospirenone 3mg) for about 2 years and is nulliparous.
She reports at least 3 episodes of lower urinary tract infections (UTIs) in the last 6 months, confirmed in 2 episodes by performing a urine culture test. She also complains about 6 months pain on sexual penetration with sensation of vaginal dryness.
Objective examination and clinical management. The general objective examination is negative (Pa 120/70, Temperature 36.5°C) with particular absence of pain in the lumbar area (Jordan negative). The abdominal palpation shows a discreet dolorability in the supra pubic area. The objective gynecological examination shows normal external genitalia with the exception of a slight thinning of the vestibular mucosa with notes of dryness. There is a discreet painful hypertone at the palpation of the pubococcygei muscular bundles and a marked dolorability to the trigonal acupressure in the intravaginal area. Uterus and appendages are apparently normal, a finding confirmed by transvaginal ultrasound office performed in succession.
A urinalysis + urine culture test is prescribed which demonstrates culture positivity for high concentration E. coli.
Diagnosis and therapeutic management.
Patient A. is diagnosed with acute UTI in a context of recurrent urinary infections. Therapy with ciprofloxacin 500 mg, 1 tablet every 12 hours for 5 days, is prescribed, as indicated in the antibiogram, and the following treatment program is established for the prevention of relapses:
- LACTOFLORENEOCIST: 1 sachet for 10 days per month for 3 months
- Regularization of intestinal function (e.g., fibers, hydration)
- Re-education of the pelvic floor muscles
Patient A. did not have relapses of post coital urinary infection for the entire duration of the treatment.

Claims

- 5 -
1) A combination of lactic acid bacteria with probiotic action, cranberry extract and D-mannose for use in preventing post coital cystitis. 2) Combination according to claim 1 wherein the lactic acid bacteria with probiotic action are Lactobacillus paracasei LC11.
3) Combination according to claim 1 or 2 composed of Lactobacillus paracasei LC11 1 mid CFU, cranberry extract in an amount corresponding to a content of proanthocyanidin of 36 mg e D-mannose 1000 mg. 4) Combination according to claim 1 , 2 or 3 in admixture with maltodextrin, sorbitol, an anti-caking agent, silicon dioxide, sucralose, citric acid, flavours and colouring agents.
5) Combination according to anyone of the preceding claims for oral administration for a period of at least 3 months.
PCT/EP2021/079770 2020-11-06 2021-10-27 Use of a combination of lactic acid bacteria with probiotic action, cranberry extract and d-mannose for prevention of post coital cystitis WO2022096336A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2906109A1 (en) * 2006-09-22 2008-03-28 Physcience Soc Par Actions Sim Food supplements, useful to prevent or combat urinary tract infections, comprise first preparation made of cranberry extract comprising proanthocyanidins and second preparation made of probiotics
US20090180999A1 (en) * 2008-01-11 2009-07-16 U.S. Nutraceuticals, Llc D/B/A Valensa International Method of preventing, controlling and ameliorating urinary tract infections using cranberry derivative and d-mannose composition
US20110064706A1 (en) * 2008-01-11 2011-03-17 U.S. Nutraceuticals, Llc D/B/A Valensa International Method of preventing, controlling and ameliorating urinary tract infections and supporting digestive health by using a synergistic cranberry derivative, a d-mannose composition and a proprietary probiotic blend
EP2996700B1 (en) * 2013-05-14 2020-10-28 Probiotical S.p.A. Composition comprising lactic acid bacteria for use in the preventive and/or curative treatment of infections and/or inflammations of the urinary tract and/or bladder

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2906109A1 (en) * 2006-09-22 2008-03-28 Physcience Soc Par Actions Sim Food supplements, useful to prevent or combat urinary tract infections, comprise first preparation made of cranberry extract comprising proanthocyanidins and second preparation made of probiotics
US20090180999A1 (en) * 2008-01-11 2009-07-16 U.S. Nutraceuticals, Llc D/B/A Valensa International Method of preventing, controlling and ameliorating urinary tract infections using cranberry derivative and d-mannose composition
US20110064706A1 (en) * 2008-01-11 2011-03-17 U.S. Nutraceuticals, Llc D/B/A Valensa International Method of preventing, controlling and ameliorating urinary tract infections and supporting digestive health by using a synergistic cranberry derivative, a d-mannose composition and a proprietary probiotic blend
EP2996700B1 (en) * 2013-05-14 2020-10-28 Probiotical S.p.A. Composition comprising lactic acid bacteria for use in the preventive and/or curative treatment of infections and/or inflammations of the urinary tract and/or bladder

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE GNPD [online] MINTEL; 24 September 2020 (2020-09-24), ANONYMOUS: "Probiotic Live Lactic Ferments Supplement", XP055823987, retrieved from https://www.gnpd.com/sinatra/recordpage/8132181/ Database accession no. 8132181 *
FRANCO VICARIOTTO: "Effectiveness of an Association of a Cranberry Dry Extract, D-mannose, and the Two Microorganisms Lactobacillus plantarum LP01 and Lactobacillus paracasei LPC09 in Women Affected by Cystitis A Pilot Study", 1 January 2014 (2014-01-01), XP055720798, Retrieved from the Internet <URL:https://journals.lww.com/jcge/Fulltext/2014/11001/Effectiveness_of_an_Association_of_a_Cranberry_Dry.26.aspx> [retrieved on 20200806], DOI: 10.1097/MCG.0000000000000224 *
GUAY DAVID R P: "Contemporary management of uncomplicated urinary tract infections", DRUGS, ADIS INTERNATIONAL LTD, NZ, vol. 68, no. 9, 1 January 2008 (2008-01-01), pages 1169 - 1205, XP008108663, ISSN: 0012-6667, DOI: 10.2165/00003495-200868090-00002 *
SHAWN DASON: "Guidelines for the diagnosis and management of recurrent urinary tract infection in women", CUAJ, vol. 5, no. 5, October 2011 (2011-10-01)

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