Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/02—Bacterial antigens
  • A61K39/04—Mycobacterium, e.g. Mycobacterium tuberculosis
• • 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
  • A61K31/00—Medicinal preparations containing organic active ingredients
• • 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
  • A61K31/04—Nitro compounds
• • 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
  • A61K35/745—Bifidobacteria
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/02—Bacterial antigens
  • A61K39/05—Actinobacteria, e.g. Actinomyces, Streptomyces, Nocardia, Bifidobacterium, Gardnerella, Corynebacterium; Propionibacterium
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/02—Bacterial antigens
  • A61K39/07—Bacillus
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/02—Nasal agents, e.g. decongestants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants

Definitions

• the invention relates to a method for prophylaxis or treatment of sleep related conditions in a subject using an agent for reducing or inhibiting colonisation of Staphylococcus aureus of the nasal cavity of the subject.
• Snoring arises from oscillation of the oropharangeal soft tissues and is a widespread phenomenon amongst the general population with some reports suggesting that at least 20% of people snore. It is most common in middle aged males although women become more prone to snoring after menopause. Snoring has also been associated with adverse health outcomes including fatigue and hypertension, and the more serious conditions of ischemic heart disease and brain ischemia.
• snoring indicates that it commonly has more than one cause and a number of risk factors have been identified including smoking, alcohol, obesity, physiological causes such as deviated nasal septum and other abnormalities in internal nasal structures, chronic nasal congestion, congestion of throat tissues, lack of fitness and muscle tone, hypertrophy of the tonsils and/or adenoids and tongue enlargement.
• Medications such as benzodazepines and tranquilisers can also result in muscle relaxation thereby increasing the risk and/or tendency for snoring.
• Snoring can be divided into a number of categories ranging from mild snoring to severe snoring involving hypopnea during which a person's breathing may become abnormally slow and shallow, and apneic events during which breathing stops.
• obstructive sleep apnea involving complete airway closure.
• Chronic nasal congestion at night has been reported as a risk factor for habitual snoring, including snoring without frank sleep apnea (Young et al, 2001).
• Congestion due to allergies was not found to be a stronger predictor of snoring than other causes such as deviated septum.
• Various treatments are available for snoring ranging from the use of decongestants and adhesive nasal strips which are adhesively fastened to the bridge and the tip of the nose to open the nasal passages, to masks connected to air pumps that act to apply a continuous positive air pressure to maintain the breathing passage open.
• Streptococcus thermophilus Lactobacillus acidophilus and Bifidobacterium sp. has been reported to reduce nasal colonisation of the potentially pathogenic bacteria (PPB) Staphylococcus aureus, Streptococcus pneumoniae and -hemolytic streptococci (Gl ⁇ ck and Gebbers, 2003).
• PPB pathogenic bacteria
• Antiseptic regimens had been suggested as potentially being crucial for infection control of patients carrying PPB after major operations on, or injuries to, the head, nasal sinuses, or lungs, and possibly also for diabetic patients and persons receiving haemodialysis, in intensive care units, or with impaired immunity, and that study was undertaken to test the possible effect of the ingestion of probiotics on the bacterial flora of the nose.
• Staphylococcus aureus is a bacterial pathogen commonly found on the skin and in the nasal cavity (e.g., the nares), and can cause pus-forming infections such as pimples, styes, boils, impetigo and abscesses in the skin as well as serious infections in the bloodstream and joints including meningitis, lung pneumonia, endocarditis (infection of heart valves) and septic phlebitis if it enters the body through cuts, abrasions or wounds.
• Localised host responses to S. aureus can involve inflammation of tissues. Several strains of antibiotic resistant S.
• aureus e.g., methicillin resistant
• S. aureus strains are frequently susceptible to a range of commonly used antibiotics.
• patients, hospital workers and persons in the general public can become colonised by the pathogen and serve as a reservoir for transmission of the pathogen. It has been suggested that up to 2 out of every 10 persons may be colonised by the pathogen.
• the invention stems from the recognition that S. aureus infection or colonisation of the nasal cavity may impact on breathing during sleep and be associated with snoring. While snoring has detrimental effects such as fatigue and drowsiness in the sufferer, not all episodic upper airway resistance causes snoring (which may be multifactorial in nature) but nevertheless, can result in brief arousals from sleep. This phenomenon is known as "respiratory effort related arousals", which can lead to more serious sleep disorders and/or sleep related breathing disorders, and may also cause fatigue and drowsiness.
• the invention relates to the administration of an agent for reducing or inhibiting infection or colonisation of the nasal cavity of the subject by Staphylococcus aureus to alleviate respiratory effort related arousals during sleep and/or improve the quality of sleep in the subject.
• a method for prophylaxis or treatment of respiratory effort related arousals during sleep of a subject comprising administering to the subject an effective amount of an agent for reducing or inhibiting infection or colonisation of the nasal cavity of the subject by S. aureus.
• the respiratory related sleep arousals may or may not be associated with snoring.
• embodiments of the invention have particular application to prophylaxis or treatment of snoring.
• a method for prophylaxis or treatment of snoring by a subject comprising administering to the subject an effective amount of an agent for reducing or inhibiting infection or colonisation of the nasal cavity of the subject by S. aureus.
• the agent will inhibit infection or colonisation by S. aureus of the nares of the nasal passage.
• the agent may be any therapeutic agent that can directly or indirectly reduce or effect the inhibition of S. aureus infection or colonisation in the nasal passage and can, for example, be selected from the group consisting of antibiotics and immuno stimulants.
• antibiotics and immuno stimulants refers to an agent that stimulates a specific or non-specific immune response in the subject against S. aureus and includes probiotics.
• the probiotic can be a whole (viable/alive or killed) cell or part thereof for stimulating the immune system against S. aureus.
• the probiotic will stimulate the common immune system of the subject and stimulate a ThI immune response and/or suppress a Th2 immune response in the subject.
• the immuno stimulant can be a preparation of S. aureus antigen for generating a specific immune response against infection or colonisation of the nasal cavity by the pathogen.
• a method for improving sleep quality of a subject comprising administering to the subject an effective amount of an agent for reducing or inhibiting infection or colonisation of the nasal cavity of the subject by S. aureus.
• S. aureus for prophylaxis or treatment of respiratory effort related arousals during a sleep of the subject.
• an agent for reducing or inhibiting infection or colonisation of the nasal cavity of a subject by S. aureus for improving quality of sleep in the subject.
• an agent for reducing or inhibiting infection or colonisation of the nasal cavity of a subject by S. aureus for prophylaxis or treatment of snoring by the subject.
• the subject can be any mammalian animal model for snoring or a human being. Typically, the subject will be a human.
• Figure 1 shows changes in a male chronic carrier of s. aureus in relation to snoring and in associated factors of sleep disorder after a single dose of Mupirocine ointment was administered to the nostril regions of the subject. There was an initial dramatic effect on each parameter recorded which lasted about 3 days. Symptoms then began to return but had not returned to baseline levels after 2 weeks; and
• Figure 2 shows the changes in nasal blockage in the male chronic carrier of S. aureus in snoring and in associated factors of sleep disorder during daily treatment with probiotic (Lactobacillus acidophilus v 'Bifidobacterium animalis).
• probiotic Lactobacillus acidophilus v 'Bifidobacterium animalis
• the invention extends to the use of antibiotics and immuno stimulants (e.g., probiotics and S. aureus antigen preparations) to reduce or inhibit colonisation of the nasal passage by S. aureus for prophylaxis or treatment of snoring.
• antibiotics and immuno stimulants e.g., probiotics and S. aureus antigen preparations
• antibiotics Any of a range of antibiotics can be employed in a method embodied by the invention. Many strains of S. aureus are now resistant to penicillin primarily because the bacteria produce the enzyme -lactamase which degrades penicillin destroying its antibacterial activity. Although penicillin can still be used to treat S. aureus strains responsive to it, other antibiotics will generally be employed including, but not limited to, methicillin, flucloxacillin, mupirocin (e.g., BactrobanTM nasal), erythromycin, ciprofloxacin (e.g., Ciproxin ), vancomycin and teicoplanin (e.g., Targocid ).
• MRSA Methicillin resistant strains of S. aureus are known as MRSA. MRSA may still be treated with mupirocin or, for example, vancomycin or teicoplanin.
• the selected antibiotic can be administered orally, intravenously or to mucosa of the nasal cavity.
• the antibiotic is applied topically to the nares of the subject in a topically acceptable carrier (e.g., as a cream or ointment). Topical application of the antibiotic is preferred as extended oral use of antibiotics can impact on intestinal bacterial flora populations and have unintended side effects including diarrhoea.
• probiotic encompasses bacteria and yeast, and parts thereof (e.g., fraction(s) or specific cell surface components of the probiotic) which act to reduce or inhibit infection or colonisation of the nasal cavity by S. aureus.
• the probiotic can be a killed or viable (live) whole cell.
• the probiotic will be viable whole cells.
• Particularly suitable bacterial probiotics include strains of the genera
• Yeast probiotics that may have application in embodiments of the invention include strains of the genera Sacchromyces such as Sacchromyces boulardii.
• Examples of bacterial probiotics include, L. acidophilus, L. fermentum, L. casei, L. plantarum and L. rhamnosus, M. vaccae, B. breve, P. jensenii.
• the probiotic can be taken as a food (which can be a fermented or non-fermented food) or as a probiotic supplement preparation such as a concentrated probiotic drink or in capsule form or in tablet form.
• Probiotics in capsule form are widely commercially available and are particularly suitable for use in methods as described herein.
• tablets containing whole killed probiotic cells (e.g., heat killed) or parts thereof can be taken orally.
• the capsules and tablets will may be enterically coated for passage of the probiotic through the acid environment of the stomach and release in the small intestine.
• the capsule or tablet may also contain prebiotic as well as probiotic.
• the prebiotic can, for example, be selected from carbohydrates, monosaccharides and oligosaccharides although non-carbohydrate prebiotics are not precluded.
• prebiotic monosaccharide and oligosaccharides examples include fructooligosaccharides (FOS), xylooligosaccharides (XOS), polydextrose, galactooligosaccharides (GOS) and the monosaccharide tagatose.
• FOS fructooligosaccharides
• XOS xylooligosaccharides
• GOS galactooligosaccharides
• Orally administered probiotics can be taken up by lymphoid nodes known as Peyer's patches in the small intestine where they are processed and probiotic antigen is presented (i.e., by dendritic cells and macrophages) to effector immune cells.
• the effector cells migrate via efferent lymphatics to distant mucosal sites including respiratory and nasal cavity mucosal surfaces where they can exert a non-specific cellular-mediated immune response providing mucosal protection against S. aureus infection or colonisation.
• administration of probiotic(s) via the oral route can stimulate an immune response at remote mucosal surfaces, this system being known as the "common mucosal system" (see for example International Patent Application No. PCT/AUOl/00726).
• Effector T lympocytes are responsible for the cell-mediated immune responses of adaptive immunity and may be broadly categorised into three groups namely, cytotoxic T cells, ThI cells and Th2 T-cells.
• ThI cells stimulate antibacterial mechanisms of phagocytic cells such as neutrophils and macrophages, and release cytokines that attract phagocytic cells to the site of infection/colonisation.
• Th2 cells have a role in activating B-cells for generating antibodies against bacterial and other antigens.
• the probiotic(s) or part(s) thereof utilised in a method of the invention will typically generate a ThI immune response and/or down-regulate/suppress Th2 responses.
• any adjuvant(s) added to the immuno stimulant will also typically be selected to generate a ThI immune response.
• Cytokines typically secreted by ThI cells include ⁇ -interferon ( ⁇ -IFN), IL- 12 and TNF- ⁇ .
• ⁇ -IFN is the main phagocytic cell activating cytokine.
• TNF- ⁇ is directly cytotoxic for some cells.
• Th2 cells secrete IL-4, IL-5, IL-IO, IL- 13, TGF- ⁇ and other cytokines. While both ThI and Th2 cells both secrete IL-3, GM-CSF and for instance TNF- ⁇ , the overall cytokine profiles of each type of cell are different.
• a ThI response can be detected by up-regulated secretion of a cytokine or combination of cytokines characteristic of a ThI immune response such as ⁇ -IFN and/or IL- 12.
• a Th2 immune response may be characterised by up-regulated expression of a cytokine or combination of cytokines characteristic of a Th2 response such as IL-4 or IL-IO.
• Immuno stimulants that can be employed in methods embodied by the invention include preparations of S. aureus antigen (e.g., attenuated, whole killed or particulate antigen) which can generate a specific and/or systemic immune response against the pathogen. While it is desirable that the immune response be specific against S. aureus it is not essential, and antigen from other bacteria or sources that generate a non-specific immune response that reduces or inhibits S. aureus infection or colonisation of the nasal cavity can also be used.
• the immuno stimulant may include an adjuvant such as may be selected from, for instance, cholera toxin B subunits and conventionally known alum adjuvants.
• Particularly suitable immuno stimulants include immunizing preparations of S. aureus clumping factor B (CIfB) which has been shown to reduce nasal colonisation of S. aureus in a murine model (Schaffer et al., 2006).
• CIfA clumping factor A
• CIfB or sortase A showed reduced colonisation.
• mice immunised systemically or intranasally with a recombinant vaccine composed of domain A of CIfB were found to exhibit reduced nasal colonisation by S. aureus, as were mice passively immunised with a monoclonal antibody (MAb) against CIfB.
• MAb monoclonal antibody
• CIfB is abundantly expressed in the log growth phase when capsule is not present but not in the stationary phase when capsule is present.
• S. aureus expressing CIfB for use as antigen as described herein should be harvested in the log growth phase when CIfB is expressed.
• the nose of the mouse is known to contain a high density of immune nodes equivalent to the Peyer's patches in humans. Such nodes are also found in the nasal passageway of humans, and administration of S. aureus antigen as described above intranasally (e.g., by spray) or orally offers a mechanism for stimulating an immune response against the pathogen.
• Cellular fractions of probiotics and S. aureus can also be employed in methods embodied by the invention.
• the fraction can be prepared by disrupting killed or viable microorganism(s), and filtering the resulting product to obtain cellular material within a discrete size range. Any suitable method which achieves an appropriate level of cellular disruption can be employed including dissolution of cells utilising appropriate surfactants and agitation. Generally, the microorganism(s) will be subjected to sonication.
• probiotic cellular debris may include natural adjuvant(s) which helps stimulate a mucosal immune response against S. aureus.
• the natural adjuvant(s) may for example comprise lipopolysaccaride and CpG oligodeoxynucleotides.
• the sonication step can be repeated a number of times in order to obtain the desired degree of disruption of the microorganism and the release or generation of appropriate sized soluble antigen/cellular material.
• the number of cycles and length of each may be determined by repeating the process a number of times employing a different number of cycles each time. Alternatively, or as well, the length of time the microrganism is sonicated may be varied.
• the collected fraction can then be tested for ability to produce an immune response against S. aureus.
• An immuno stimulant as described herein will comprise sufficient antigen such that an effective dosage will be delivered to the subject for the generation of the immune response taking into account the proposed mode of delivery and added adjuvant(s) (if any) as can be determined using well accepted principles in the art of immunisation.
• the dosage of an immuno stimulant comprising S. aureus antigen will typically be in a range of about 10 9 to about 10 12 viable or killed bacteria, and more usually in a range of from about 10 10 to about 10 11 viable or killed bacteria.
• the optimum dosage of the antigen may be determined by administering different dosages to different groups of test mammals, prior to subsequently intransally infecting the animals in each group with S.
• the immuno stimulant can be administered in accordance with any regimen suitable for generating an effective immune response against S. aureus infection or colonisation of the nasal cavity.
• a single dose of the immuno stimulant can be administered.
• One or more "booster" doses administered at an interval of a number of weeks or months may also be given.
• any suitable formulations, preparations, delivery forms and /or compositions suitable for the delivery, consumption or administration of the agent for reducing or inhibiting the infection or colonisation of S. aureus in the nasal cavity can be utilized.
• a probiotic can be taken in a concentrated capsule form or tablet form.
• whole live probiotic in a range of from about 2x10 9 to 3xlO u cells will be taken be orally by the subject on a daily basis for about a 1 day to 2 weeks to stimulate the non-specific mucosal immune response against S. aureus.
• the subject can then be administered an ongoing daily maintenance dosage of IxIO 9 to IxIO 11 probiotic cells.
• probiotics can also be consumed as a fermented or non-fermented food, the food being consumed over a sufficient period (e.g., weeks) for generation of a non-specific mucosal immune response to reduce or inhibit infection or colonisation of S. aureus in the nasal cavity.
• Fermented probiotic food contains live probiotic micro-organisms which have grown in the food and produced a fermented product.
• Non-fermented probiotic food contains probiotic microorganisms or their components which have been added to the food.
• Fermented probiotic foods include probiotic dairy foods such as yoghurt including drinking yoghurt, and fermented milks.
• the invention also extends to the use of mixed cultures of two or more probiotic organisms and includes cultures of lactobacillus with one or more of bifidobacterium, brevibacterium, and/or propionibacterium strains.
• Probiotic and immuno stimulant preparations as described herein can also contain one or more anti-caking agents and preservatives (e.g., thimerosal) suitable for the proposed mode of administration, stabilisers such as amino acids and/or sugar moieties, sweetening agents such sucrose, lactose or saccharin, surfactants, pH buffering agents and pH modifiers such as monosodium phosphate and/or disodium phosphate, a pharmaceutically acceptable carrier such as physiologically saline, solvents and dispersion media.
• stabilisers such as amino acids and/or sugar moieties, sweetening agents such sucrose, lactose or saccharin, surfactants, pH buffering agents and pH modifiers such as monosodium phosphate and/or dis
• EXAMPLE 1 Effect of antibiotic ointment on snoring and sleep quality
• the subject had been identified as having nares chronically colonised with Staphylococcus aureus (methicillin sensitive S. aureus) prior to the commencement of the study.
• Mupirocine ointment (BactrobanTM, GlaxoSmithKline) was applied at the base of each nostril of the subject as well as just inside his nostrils.
• the subject's sleeping partner (wife, aged 46 years) was unwilling to not use ear plugs that night.
• follow up observations were recorded over the subsequent 16 day period, and the degree of nasal blockage and snoring of the subject as well as morning freshness of he and his wife was assessed. Mupirocine ointment was not administered to the subject during the 16 day observation period.
• Table 3 Concomitant medication taken by subject 2. Sleep history of subject
• the subject awoke feeling refreshed with clear nares in the early hours of the morning following the administration of the Mupirocine ointment. Both the subject and his wife reported that he did not snore during the night.
• the subject's wife recorded scores of 6 for all parameters measured despite her wearing ear plugs.
• the subject's wife woke about 5.00am due the subject's "shuffling" in bed which impacted on her freshness in the morning. She was not aware of any snoring by the subject during the night.
• EXAMPLE 2 Effects of probiotics L. acidophilus /Bifidus animalis on snoring and sleep quality
• Example 1 The subject (male) described in Example 1 has a history of snoring, sleep disturbance and daytime fatigue. This contributes to sleep disturbance of his sleeping partner (wife). As outlined in Example 1, investigations have shown that the subject's nares are chronically colonised with Staphylococcus aureus (methicillin sensitive
• Probiotics L. acidophilus/ Bifidus animalis
• probiotics L. acidophilus/ Bifidus animalis
• a study was conducted to determine whether oral treatment of the male subject with probiotic (L. acidophilus /Bifidus animalis) would reduce nasal colonisation by S. aureus and improve the snoring and sleep patterns of the subject.
• the subject was given an initial dose of 2 capsules containing the probiotic orally 3 times daily for 9 days (white capsules containing Lactobacillus acidophilus /bifidus animalis, 10 9 cells/capsule; Blackmore's, Warriewood, NSW, Australia)), then a maintenance dose of the probiotic of 1 capsule, 3 times daily for 14 days. Observations were recorded daily during the study period, and parameters including the degree of nasal blockage and snoring of the subject as well as morning freshness of he and his wife was self assessed. Observations were also recorded on the day (Day 0) prior to commencement of the study. Self assessment parameters recorded by the subject were scored on a scale of 1 to 7, with 1 being very good and 7 being very poor. The subject's results are presented below.
• probiotic and post-treatment scores were consistent whether measured by t-test or Confidence intervals.
• Benefit occurred on the first day of treatment although maximum benefit occurred by day 3.
• the benefits lasted while treatment was maintained (14 days) after which there was no statistical difference between post-treatment and pre- treatment scores.
• the subject reported reduced nasal blockage and improved sleep patterns during the course of the study and his daily scores for the initial 9 days of the study period are shown graphed in Fig. 2. In each parameter assessed there was an initial dramatic effect which lasted about 3 days, which then stabilised during the treatment period.
• the spike shown at day 8 in Fig. 2 was associated with a particularly stressful event reported by the subject.
• the subject's wife also reported substantial reductions in the snoring of the subject as well as the loudness of the snoring.
• EXAMPLE 3 Dose-response effects of probiotics L. acidophilus I Bifidus animalis on snoring and sleep quality
• the subject (male) described in Examples 1 and 2 was assessed in a third study for dose-response to probiotic treatment, to determine whether oral treatment of the subject with probiotic (L. acidophilus I Bifidus animalis) doses of 2 x 10 9 and 5 x 10 9 bacteria reduced nasal colonisation by S. aureus and improved the snoring and sleep patterns of the subject.
• probiotic L. acidophilus I Bifidus animalis
• the subject was given an initial dose of 5 capsules containing the probiotic orally (white capsules containing Lactobacillus acidophilus /bifidus animalis, 10 9 organisms/capsule; Blackmore's, Warriewood, New
• the subject reported a dose-response effect in relation to nasal blockage with S. aureus and each symptom of snoring.
• the study shows that daily probiotic (acidophilus/bifidus) reduces snoring and improves sleep quality, and that there is a dose-dependent effect on effectiveness, time to onset of effect and duration of effect.
• the study shows that the daily administration of probiotic (acidophilus/bifidus) reduces snoring and improves sleep quality
• the study shows that daily administration of probiotic (acidophilus/bifidus) reduces snoring and improves sleep quality.
• Example 5 The 52 year old male described in Example 5 had suffered from chronic congestion, snoring and sleep disturbance and had been maintained on capsules containing L. acidophilus/B. Animalis. The individual was treated with 1 x probiotic (L. fermentum; >lxl ⁇ 9 bacteria) every evening before going to bed.
• 1 x probiotic L. fermentum; >lxl ⁇ 9 bacteria

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