WO2007057748A2

WO2007057748A2 - Use of colostrum for the prophylaxis of influenza syndromes

Info

Publication number: WO2007057748A2
Application number: PCT/IB2006/003222
Authority: WO
Inventors: Umberto Cornelli
Original assignee: Umberto Cornelli
Priority date: 2005-11-18
Filing date: 2006-11-15
Publication date: 2007-05-24
Also published as: ITMI20052204A1; WO2007057748A3

Abstract

Use of colostrum as an active principle for preparing pharmaceutical compositions for the prevention of influenza syndromes.

Description

USE OF COLOSTRUM FOR THE PROPHYLAXIS OF INFLUENZA SYNDROMES

FIELD OF THE INVENTION

The present invention relates to the use of colostrum as an active principle for preparing pharmaceutical compositions for the prevention of influenza syndromes.

STATE OF THE ART

Influenza is caused by RNA viruses of the Orthomyxoviridae family. Three different types of influenza viruses are known, namely A, B and C, which are considered responsible for common influenza episodes of varying severity (1).

Type A viruses are those which cause the most aggressive forms in man, although types B and C are also pathogens though responsible for milder clinical forms. Moreover, form A is that which develops more frequently, that is to say annually between autumn and spring, whereas form B tends to appear with periods of dormancy lasting a few years, as does form C.

Form A is the most antigenically variable, hence during common periods of infectivity it changes typology (antigenic drift) and when antigenic modifications are considerable, true pandemics occur because the human antibody set is not suited to dealing with the mutated viral strain (1). If the antigenic modifications are small then annual influenza epidemics are more territorially limited and with slightly milder clinical manifestations.

Influenza is transmitted from person to person via respiratory droplets. Types A and B cause fever, shivers, unwell feeling, muscular pains, cough, blocked nose and dryness of the mouth and throat. However, in patients affected by influenza

(2) complications can occur which result in viral and also bacterial pneumonias.

These events are more often manifested in older people and in subjects affected by chronic cardiovascular and lung diseases, as well as other chronic diseases

(diabetes) when they are not sufficiently controlled.

These subjects are defined as being at risk in that during the influenza episode there is a steady worsening of the concurrent chronic pathology (3) and an actual increase in mortality.

Vaccination (2, 3) is considered to be the most effective treatment for influenza, utilizing vaccines adapted for the mutated influenza virus (antigenic drift) which are produced at the first appearance of the virus. Vaccination is therefore a prophylactic treatment because on the appearance of clinical influenza phenomena, only symptomatic treatment can be undertaken. As well as prophylactic treatment with vaccines, antiviral drug treatment has also been used, particularly neuraminidase inhibitors but also amantadine and rimantadine which are usually used in subjects affected by immunosupression. These subjects cannot take full advantage of vaccination since, due to their immunosuppressed state, they are unable to produce antibodies which are stimulated by the vaccination.

Unfortunately, both vaccination and antivirals can have drawbacks and cause side effects (4, 5); it is therefore necessary to provide substances with antiviral action or which strengthen immune defences in a natural manner enabling them to be administered in cases where vaccines are not indicated or when vaccines are not yet ready.

Colostrum is a substance produced in mammary glands within the first 48-72 hours post-parturition. This period is so important that, without it, many newborn mammals could not survive. For various reasons, human colostrum cannot easily be used nor can it constitute a primary source of usable product. In the last decade bovine colostrum has been identified as the most effective alternative production source - both in terms of quality and quantity - for administration to man. As well as being an important source of proteins, fats, carbohydrates, vitamins and minerals, human colostrum contains many biologically active molecules which are essential for immune functions and growth (6). The factors, also present in bovine colostrum, are practically identical to those found in human colostrum, but many are found in greater and more pharmacologically interesting amounts (for example some immunoglobulins and growth factors are present in quantities about 4 times greater than those found in human colostrum).

The most important components in colostrum are immune factors and various growth factors. The immune factors provide generic immunity and protection against infections in the first few weeks of life, while growth factors stimulate development of the newborn. After puberty the quantity of immune and growth factors present in our body begins to decline. Subsequently with advancing years we become generically more vulnerable to diseases, energy levels diminish, skin begins to lose elasticity, weight tends to increase and muscle tone declines. Furthermore, considering that we live in a "toxic" environment full of polluting and allergenic elements under conditions that are different from those of our evolutionary design, and combined with a substantial series of accumulated factors (sugars, fats and salt in particular), a general reduction in immune efficiency could be at the basis of a number of diseases and disfunctions. Various research studies have shown that colostrum possesses a natural immune capacity and growth factors that bring about a state of homeostasis, a natural state of well-being and good health in the body. Colostrum supports a natural immune function and enables us to respond to the damaging effects of pollutants and allergens when we come into contact with them. Also, the growth factors present in colostrum create a sort of positive "side effect" in the healthy body, an increased capacity to metabolise or burn fats, and a greater ability to increase muscle mass and "rejuvenate" muscles and skin.

There are more than 90 constituent components in colostrum. The main ones are immune and growth factors. Colostrum also contains a precise balance of vitamins, minerals and amino acids. All these factors act in perfect synergy to reestablish and maintain a good state of health.

Immune factors. It has been demonstrated that the factors present in colostrum help the body to repel viruses, bacteria and fungi. Each factor plays a specific role in the defence of our body. In addition, colostrum contains more than 20 specific antibodies including those for E. coli, Salmonella, Rotavirus, Candida, Streptococcus, Staphylococcus, Haemophilus, Helicobacter and others. Various studies - both in vitro and clinical - have shown that in addition to immunoglobulins, colostrum comprises a factor that strengthens a poorly active immune system, while it tends to balance a hyperactive immune system such as that present in autoimmune diseases.

Growth factors. Growth factors help to build and heal bones, muscles, nerve and connective tissue, skin and cartilage. It has been demonstrated that these factors increase muscle mass, help the body to burn fats and supports wound healing. Finally, it has been suggested that growth factors actually slow down ageing by diminishing signs of age. Growth factors present in colostrum can:

- influence cerebral metabolism by regulating some mediators to improve mood,

- help to regenerate and improve normal growth of aged muscles, bone, cartilage, skin, collagen and damaged or nerve tissue,

- promote the use of fats for energy in place of muscle tissue in cases of fasting (dieting) and build and preserve lean muscle (independently of diet),

- favour the regulation of blood glucose levels and levels of brain chemicals to increase attention and concentration,

- favour the healing of skin if applied locally,

- selectively repair RNA and DNA in our bodies.

Other useful components: certain vitamins and minerals which are essential nutrients for normal metabolism, growth and development and are indispensable for maintaining a good state of health are found in colostrum (also based on diet).

Different amino acids are also found in various colostrum types. These components of proteins are necessary for growth and development of the body.

They are divided into essential (not produced in our bodies) and non-essential

(can be produced in the body).

SUMMARY OF THE INVENTION

It has been surprisingly observed that in individuals subjected to vaccination as well as to colostrum and in those treated with colostrum alone (without vaccination) the results in terms of influenza syndrome prevention were the same, indicating that colostrum alone is sufficient in itself to prevent influenza episodes.

The present invention therefore provides the use of colostrum as an active principle for preparing pharmaceutical compositions for preventing influenza syndromes,

DETAILED DESCRIPTION OF THE INVENTION

Colostrum for use in accordance with the present invention is preferably colostrum of bovine type and is preferably administered in the form of oral compositions.

These compositions are preferably chewable tablets and in accordance with a particularly preferred embodiment they essentially consist of colostrum. Compositions of colostrum that can be suitable for the use according to the present invention are given by way of example.

The quantities of the various active principles relate to 1 gram of colostrum. TABLE 1 - FORMULATION 1

Product Quantity/gram Product Quantity /gram

Vitamins Amino acids

Vitamin A 4 -5 μg Alanine 40-45 μg

Vitamin B₁ 1-1.5 μg Arginine 35-40 μg

Vitamin B₂ 1-1.5 μg Aspartic acid 15-20 μg

Vitamin B₆ 0.25-0.5 μg β alanine 1-2.5 μg

Vitamin B₁₂ 0.5-1 ng β aminoisobutyric acid 6-8 μg

Vitamin B₉ 0.15 - 0.: 2 μg Citruliine 6-8 μg

Vitamin C 2.5-5 μg Cystine 1-2 μs

Vitamin D₃ 5-11 ng Glutamine 40-50 μg

Vitamin E 3-5 μg Glutamic acid 200-270 μg

Coenzyme Q10 0.1-0.2 μg Glycine 30-35 μg

Histidine 7.5-12.5 μg

Minerals lsoleucine 30-35 μg

Sodium 8.5 mg Leucine 60-85 μg

Potassium 126 mg Lysine 50-65 μg

Calcium 2,7 mg Methionine 6-9 μg

Magnesium 1.0 mg Ornithine 3-5.5 μg

Iron 0.0015 mg Phenylalanine 32.5-33 μg

Copper 0.00035 mg Phosphoethanolamine 150-225 μg

Zinc 0.0003 mg Phosphoserine 50-75 μg

Chromium 0.0001 mg Proline 35-60 μg

Selenium 0.00002 mg Serine 25-40 μg

Phosphoric acid 3 mg Taurine 0.6-0.12 mg

Threonine 17.5-27.5 μg

Immunoglobulins Tryptophan 40-60 μg

IgG 200-350 mg Tyrosine 17.5-27.5 μg

IgA 15-35 mg Valine 60-80 μg

IgM 5-10 mg Growth facors

GF 1 1-1.5 μg TABLE 2 - FORMULATION 2

Product Quantity/gram Product Quantity /gram

Vitamins Amino acids

Vitamin A 14-16 μg Alanine 11.7 mg

Vitamin Bi 6-7 μg Arginine 10.8 mg

Vitamin B₂ 25-35 μg Aspartic acid 5.4 mg

Vitamin B₆ 1.5-2 μg Citrulline 2.1 mg

Vitamin Bi₂ 5-8 ng Cystine 0.4 mg

Vitamin B₉ 0.6-0.7 μg Glutamine 12.9 mg

Vitamin C 31-33 μg Glutamic acid 87.2 mg

Vitamin D₃ 31-35 ng Glycine 60.8 mg

Vitamin E 3-5 μg Histidine 1.4 mg

Coenzyme Q10 0.5-0.8 μg lsoleucine 9.4 mg

Leucine 18.0 mg

Minerals Lysine 8.4 mg

Sodium 1.7 mg Methionine 2.3 mg

Potassium 3.4 mg Ornithine 1.2 mg

Calcium 5.5 mg Phenylalanine 9.7 mg

Magnesium 2.0 mg Proline 114.4 mg

Iron 0.003 mg Serine 10.0 mg

Copper 0.0007 mg Taurine 145.6 mg

Zinc 0.0006 mg Threonine 5.8 mg

Chromium 0.0002 mg Tryptophan 14.4 mg

Selenium 0.00004 mg Tyrosine 7.2 mg

Phosphoric acid 6 mg Valine 26.6 mg

Immunoglobulin Growth factors

IgG 300-600 mg IGF 1 15.0 μg

IgA 50-60 mg IGF2 1.5 μg

IgM 70-90 mg TGF-β 0.6 μg

Hormones Other factors

Prolactin 4 ng Creatine 2.0 mg

Testosterone 33.6 ng Creatinine 0.5 mg

Estradiol 2 ng Lactoferrin 9.2 mg

Progesterone 18 ng Transferrin 5.1 mg

Calcitonin 158 pg Phosphoethanolamine 57.6 mg

The Applicant has also unexpectedly found that the combination of specific components, such as vitamin D3, immunoglobulin and transition metal salts chosen from iron, copper and zinc phosphates or relative mixtures of said salts, is effective for preventing influenza syndromes. A further aspect of the present invention is therefore the use of a combination of:

I) vitamin D3

II) transition metal phosphates chosen from Fe, Cu and Zn and relative mixtures

III) immunoglobulins chosen from IgG, IgA, IgM and relative mixtures, and possibly

IV) lactoferrin, for preparing compositions for preventing influenza syndromes, in which the total quantity of I), II), III) and possibly IV) does not exceed 800 mg per gram of said composition, preferably being between 350 and 700 mg.

Compositions containing a combination of I), II), III) and possibly IV), can also contain other active principles chosen from the classes consisting of:

• vitamins chosen from vitamin A, vitamin B-i, vitamin B₂, vitamin B₆, vitamin Bi₂, vitamin Bg, vitamin C, vitamin E, coenzyme Q10 and relative mixtures,

• metal phosphates chosen from Na, K, Ca, Cr, Se and mixtures of said salts,

• hormones chosen from: prolactin, testosterone, estradiol, progesterone, calcitonin, osteocalcin, insulin.

• amino acids chosen from the class consisting of: alanine, arginine, aspartic acid, citrulline, cystine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, serine, taurine, threonine, tryptophan, tyrosine, valine and relative mixtures,

• growth factors chosen from the group consisting of 1GF1 , IGF2, TGF-β and relative mixtures, and

• other factors chosen from: creatine, creatinine, transferrin, phosphoethanolamine, phosphoserine.

In accordance with particularly preferred embodiments, the formulations particularly suitable for said use are those containing the aforesaid components I), II), III) and possibly IV) and the other components listed above in the quantities indicated in the aforesaid formulations 1 and 2 given above in tables 1 and 2 respectively.

The method followed and the results attained relating to the use of oral colostrum compared with the anti-influenza vaccine for preventing influenza illnesses in winter, are given hereinafter by way of non-limiting illustration, a group of subjects without prophylaxis having also been examined as reference.

MATERIALS, PATIENTS AND METHODS

INCLUDED SUBJECTS. Subjects between the ages of 30 and 80 were included in the study even if vaccinated (anti-influenza vaccine). The included subjects were divided into two groups (vaccinated and non-vaccinated) in order to have an identical distribution.

Exclusion criteria. Subjects with clinically significant diseases, those with chronic diseases not under therapeutic control and patients undergoing treatment or with potential intolerances were excluded.

Treatment. The subjects in the treatment group were treated with a colostrum tablet in the morning for 8 weeks.

Dose: chewable tablets or capsules were used (900 mg of AR₀ Colostrum,

Corcon, Guna srl, Milan) containing 900 mg of bovine colostrum. The choice of chewable tablets or capsules to be swallowed was left to the subjects. The subjects were treated for two months with a single daily dosage.

Overall assessment. The assessment was by examining: a- the presence and number of influenza episodes in the two months of treatment b- the presence and number of influenza episodes in a period of three successive months (two months of treatment and the month immediately after) c- the total number of indisposition days d- the expense resulting from loss of working days, bed rest and other potential costs as a result of the illness.

The data were collected on forms on which the name (initials), age and gender of the included subjects were indicated.

CONTROLS. The included subjects were assessed within a study of a population already under assessment in San Valentino (Pescara). This study, which is a repeat of the Framingham study but using different characteristics and based mainly on an ultrasound assessment of vascular walls, has been ongoing for ten years; nearly all the included subjects are in almost daily contact with the doctors of the study.

After inclusion the subjects were re-assessed by telephone (every 2 weeks) or, directly, with interviews and a questionnaire at least once a month. The study was undertaken in accordance with a registry model. STATISTICAL ANALYSIS. At the end of the study an analysis of variance was undertaken between the groups and compared with nonparametric tests (Mann- Whitney).

Intention-to-treat analysis (ITTA): an ITTA was also carried out. In brief, this test takes into consideration the difference between the number of negative events (influenza episodes) and also the number of drop-outs in the different groups. RESULTS

The groups assessed in the study proved to be comparable (Table 3) in age and gender distribution. The drop-outs were due to non-medical causes (failure to follow the therapy or control system, or non-appearance at the re-assessment appointments).

Table 3: groups examined (average age and standard deviation in brackets). 144 subjects were initially included, 137 of whom completed the 3-month follow-up. The 7 drop-outs were due to non-medical causes.

TABLE 3

Abbreviations: Compl.= subjects who completed the study

Untreated= untreated subjects

Vacc+colostrum= subjects treated with vaccination and colostrum

Vacc. alone= subjects treated with vaccination alone

F: M= female/male ratio

The following table 4 gives median values (range) per individual parameter influenced by vaccination or by prophylaxis with colostrum in the 4 subject groups under examination.

TABLE 4

ANALYSIS OF THE RESULTSATTAINED

EPISODES AND DAYS OF ILLNESS. In the subjects treated with colostrum the mean number of episodes over two months (0.335; range 0-3) was significantly lower than those recorded both in untreated subjects (25% of those recorded in the untreated group; P<0.05) and subjects treated with the vaccine alone (in the subjects who used colostrum the episodes were 30% of those vaccinated but without colostrum; P<0.05). The difference is substantial and significant (p<0.05) even when examined three months after inclusion, thus including the month following colostrum administration.

The number of days of illness was about 3 times greater in the untreated subjects and in those who were vaccinated but with no colostrum.

INTENTION-TO-TREAT (ITT) ANALYSIS:

The difference in the incidence of events (combined with drop-outs) between subjects treated with colostrum alone and untreated subjects was 4.2 (178/41.4); hence the incidence of events in the untreated proved to be 4.2 times greater

(P<0.05). The difference between subjects treated with colostrum alone and vaccine alone was 3.9 (163.8/41.4); hence the incidence of events in subjects treated with vaccine alone proved to be 3.9 times greater than that observed in the group with colostrum alone (P<0.05).

COSTS. Also the costs determined on the basis of lost working days, treatment required in case of influenza and any complications, followed the same pattern. In subjects treated with colostrum the cost due to days and episodes of feeling unwell was about 30% of that observed in the groups which did not use colostrum.

When allowing for convalescence days (only observed in subjects not treated with colostrum) which probably follow - particularly in older subjects - bronchopulmonary complications connected with the influenza episode, the difference in costs becomes truly substantial. There were no convalescences in subjects treated with colostrum.

TOLERABILITY. Tolerability was excellent and compliance was >88% (only less than 12% of the capsules or tablets were used inadequately or not used or the dosages not complied with). Self-administration by healthy subjects of a prophylaxis had a very positive compliance.

There were no differences in acceptance and tolerability between capsules and chewable tablets but 73% of the subjects reported a preference for chewable tablets.

DISCUSSION

Colostrum appears to modulate the immune system, stimulating it when the quantity (and even the quality) of certain elements is inadequate and regulating it should its composition change.

In conclusion, it is therefore important to observe that the problems of infection spread and the control of influenza manifestations must occur through improvement of the individual's generic immune defences, and colostrum, particularly in the formulation proposed, appears to have an important and well defined role.

The results of this study indicate a generic, poor efficacy of the vaccine and a good effect (with high tolerability and substantial cost-efficacy) of colostrum.

Bibliography

1. Couch RB. Prevention and treatment of influenza. N Engl J Med 2000;343:1778-87.

2. Belshe RB, Nichol KL, Black SB, Shinefield H, Cordova J, et Al. Safety, efficacy, and effectiveness of live, attenuated, cold-adapted influenza vaccine in indicated population aged 5-49 years. Clin Infect Dis. 2004 Oct 1 ; 39(7):920-7.

3. Thompson WW, Shay DK, Weintraub E, et Al. Influenza-associated hospitalizations in the United States. JAMA. 2004 Sept 15; 292(11):1333-40.

4. Hemingway CO, Poehling KA. Change in recommendation affects influenza vaccination among children 6 to 59 months of age. Pediatrics. 2004 Oct; 114(4);948-52.

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Claims

1. Use of colostrum as an active principle for preparing pharmaceutical compositions for the prevention of influenza syndromes.

2. Use as claimed in claim 1 wherein the colostrum is bovine.

3. Use as claimed in either of claims 1-2 characterized in that said compositions are suitable for oral administration.

4. Use as claimed in claim 3 characterized by their being chewable tablets.

5. Use as claimed in claim 4 characterized in that said tablets consist essentially of colostrum.

6. Use of a combination of:

I) vitamin D3

II) phosphates of transition metal cations chosen from Fe, Cu₁ and Zn and relative mixtures,

III) immunoglobulins chosen from IgG, IgA, IgM and relative mixtures, and possibly Vl) lactoferrin, for preparing compositions for the prevention of influenza syndromes, wherein the total quantity of I)₁ II), III) and possibly IV) does not exceed 800 mg per gram of said compositions.

7. Use as claimed in claim 6 characterized by their containing a combination of I), II), III) and possibly IV) in a total quantity of between 350 and 700 mg per gram of said compositions.

8. Use as claimed in either of claims 6 or 7 characterized by their containing other active principles chosen from the classes consisting of:

• vitamins chosen from vitamin A, vitamin Bi ,vitamin B₂, vitamin Be, vitamin B12, vitamin Bg₁ vitamin C, vitamin E, coenzyme Q10 and relative mixtures,

• phosphates of cations chosen from Na⁺, K⁺, Ca⁺⁺, Cr⁺⁺, Se²⁺ and mixtures of said salts,

• other factors chosen from: creatine, creatinine, transferrin, phosphoethanolamine, phosphoserine and mixtures thereof.