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WO1999058133A2 - Antidiarrheique et procede d'utilisation dudit produit - Google Patents

Antidiarrheique et procede d'utilisation dudit produit Download PDF

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Publication number
WO1999058133A2
WO1999058133A2 PCT/US1999/010049 US9910049W WO9958133A2 WO 1999058133 A2 WO1999058133 A2 WO 1999058133A2 US 9910049 W US9910049 W US 9910049W WO 9958133 A2 WO9958133 A2 WO 9958133A2
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WO
WIPO (PCT)
Prior art keywords
dna
streptococcus
egg
type
streptococcus pyogenes
Prior art date
Application number
PCT/US1999/010049
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English (en)
Other versions
WO1999058133A3 (fr
Inventor
Hellen Chaya Greenblatt
Orn Adalsteinsson
David A. Brodie
Hank Jacoby
Original Assignee
Dcv, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dcv, Inc. filed Critical Dcv, Inc.
Priority to NZ508133A priority Critical patent/NZ508133A/en
Priority to JP2000547984A priority patent/JP2002514604A/ja
Priority to CA002331314A priority patent/CA2331314A1/fr
Priority to AU38905/99A priority patent/AU772785B2/en
Priority to KR1020007012463A priority patent/KR20010043426A/ko
Priority to EP99921785A priority patent/EP1075269A2/fr
Publication of WO1999058133A2 publication Critical patent/WO1999058133A2/fr
Publication of WO1999058133A3 publication Critical patent/WO1999058133A3/fr

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    • 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
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/48—Reproductive organs
    • A61K35/54—Ovaries; Ova; Ovules; Embryos; Foetal cells; Germ cells
    • 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
    • A61K35/56—Materials from animals other than mammals
    • A61K35/57—Birds; Materials from birds, e.g. eggs, feathers, egg white, egg yolk or endothelium corneum gigeriae galli
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/02—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from eggs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to a product and method for treating and preventing diarrhea. More particularly, this invention relates to a natural food product which, when administered to a subject animal, treats and prevents diarrhea in that subject animal.
  • Diarrhea is a worldwide problem for individuals of all ages. Diarrhea is a common condition, which at the very least is life disrupting and can be life threatening. Acute diarrhea can be produced by a variety of pathological organisms, functional disruptions of intestinal function and as a drug-related side effect.
  • diarrhea e.g., rotavirus- induced
  • childhood diarrhea e.g., childhood diarrhea
  • organism induced diarrhea i.e. food poisoning
  • most gastrointestinal disorders i.e. food poisoning
  • diseases which affect the gastrointestinal system indirectly.
  • Infants and children suffering from diarrhea have a major problem since they can become severely dehydrated and require fluids and medication.
  • Diarrhea is also common in cancer patients and may interfere with cancer treatment (Ippoliti, 1998). Chemotherapy, radiation therapy, surgery, graft- versus-hot disease (GVHD), bone marrow transplantation, or infection may induce diarrhea.
  • GVHD graft- versus-hot disease
  • Bacterial pathogens may also produce diarrheal symptoms with a spectrum of effects ranging from severe tissue damage to a lack of perceptible damage.
  • Enterotoxigenic Escherichia coli which causes acute and severe diarrhea, does so by producing potent toxins, which act by altering the biological activity in epithelial cells.
  • potent toxins which act by altering the biological activity in epithelial cells.
  • Current treatment of diarrhea consists of antibiotic treatment of the causafive organisms or pharmacological intervention in pathophysiological function.
  • Antidiarrheal drugs reduce the symptoms of diarrhea (loose stool consistency, frequency of defecation and excessive stool weight) by effects on intestinal transit, mucosal transport or luminal contents (Schiller, 1995).
  • Opioids such as loperamide are the most useful antidiarrheal agents and act by a combination of inhibition of intestinal transit, pro-absorptive and anti-secretory effects.
  • pharmacological therapies include use of alpha-adrenergic agonists such as clonidine and somatostatin analogues. These drugs may modify mucosal transport in addition to slowing transit but have limited clinical utility due to nonspecificity of action.
  • Adsorbents Kaopectate
  • bismuth Pepto-Bismol
  • stool texture modifiers are used frequently as over the counter medication, but their efficacy, other than Pepto-Bismol, is largely unproven.
  • a safe and effective natural anti-diarrheal agent would be very useful in therapy of acute and chronic diarrheal conditions.
  • the invention is based upon the inventors' discovery that there is anti-diarrheal activity in egg or egg products and particularly in egg products obtained from hyperimmunized avians, which when administered to a subject animal, prevents or reduces diarrhea in that subject animal.
  • the invention is directed to a method of treating and preventing diarrhea in a subject animal suffering from or susceptible to diarrhea, the method comprising administering to the subject animal an effective amount of an egg product.
  • the invention is also directed to a composition containing beneficial properties that prevent or reduce diarrhea in a subject animal who is suffering from or susceptible to diarrhea, the composition comprising a product obtained from an animal that has been hyperimmunized with at least one immunogen.
  • the hyperimmune egg product of the invention when administered to a subject animal, is useful for the treatment and prevention of diarrheal diseases in that subject animal.
  • diarrhea means abnormal frequency and liquidity of fecal discharges resulting from an imbalance between absorption and secretion in the intestine.
  • hyperimmunization means exposure to one or more immunogenics such that an immune response is elevated and maintained above the natural unexposed state.
  • egg or "egg product” each mean any whole egg (table, hyperimmunized or otherwise) or any product or fraction derived therefrom.
  • table egg or “table egg product” each mean a whole egg, or any product or fraction derived therefrom, obtained from egg-producing animals which are not maintained in a hyperimmune state.
  • immunogen means a substance that is able to induce a humoral antibody and/or cell-mediated immune response rather than immunological tolerance.
  • the term signifies the ability to stimulate an immune response as well as react with the products of it, e.g., antibody.
  • combinatorial derived immunogens refers to a novel process of generating molecular diversity among immunogenics by way of combinatorial synthesis.
  • bioengineered immunogens refers to immunogens which are obtained through the process of gene cloning technologies and genetic rearrangements which allow the insertion of encoding nucleotides which can give rise to molecules having immunogenicic properties.
  • genetic vaccine refers to a nucleic acid vaccine which is generally produced by recombinant technologies and which may elicit an immune response.
  • treatment means that the onset of the symptoms (including pain) of the disorder and/or pathogenic origin of the disorder be delayed or completely prevented, or, if present, the symptoms be ameliorated or completely eliminated.
  • the hyperimmune egg product treats arthritis and/or an autoimmune disease not only by suppressing the symptoms of the disorder in humans and other mammals, but also by acting as a prophylactic agent to counteract the presence of the disorder in the recipient.
  • prevention means that the progression of the disease is reduced and/or eliminated, or that the onset of the disease is eliminated.
  • administer means any method of providing a subject with a substance, including orally, intranasally, parenterally (intravenously, intramuscularly, or subcutaneously), rectally or topically.
  • animal means the animal kingdom definition.
  • target animal refers to an animal which functions as the egg or egg product producing animal.
  • subject animal refers to the animal which is administered the egg or egg product produced by the target animal.
  • the hyperimmune egg product of the invention when administered to a subject animal, is useful in treating and preventing diarrhea in the subject animal.
  • the product and method of the invention relate particularly to the use of hyperimmune egg product, which is a natural food product, in the treatment and prevention of diarrhea and related disorders in a subject animal. Being natural, this food product can be used to treat and prevent diarrhea and related disorders without the fear of side effects. Those allergic to eggs or having an intolerance to eggs may not be able to ingest the hyperimmune egg product in certain administerable forms.
  • the invention comprises a hyperimmune egg or egg product which is obtained from an egg-producing animal, and more preferably, an avian, which has been hyperimmunized with at least one immunogen.
  • the hyperimmune egg product is one which is preferably administered orally to the subject animal although the hyperimmune egg or egg product can be further separated into more potent fractions which can subsequently be administered to a subject animal in a variety of forms.
  • the hyperimmune egg or egg product of the invention when administered to a subject animal, is effective in treating and preventing all forms of diarrhea and related disorders, in that subject animal, including, but not limited to, acute and chronic diarrheal diseases such as infant diarrhea (e.g. including those diarrheas that are viral or bacteria induced), childhood diarrhea, adult organism induced, and gastrointestinal disorder induced diarrhea, among others.
  • acute and chronic diarrheal diseases such as infant diarrhea (e.g. including those diarrheas that are viral or bacteria induced), childhood diarrhea, adult organism induced, and gastrointestinal disorder induced diarrhea, among others.
  • the hyperimmune egg product can be produced by any egg-producing animal. It is preferred that the animal be a member of the class Aves or, in other words, an avian. Within the class Aves, domesticated fowl are preferred, but other members of this class, such as turkeys, ducks, and geese, are a suitable source of hyperimmune egg product.
  • This special state of hyperimmunization is preferably achieved by administering an initial immunization, followed by periodic boosters with sufficiently high doses of specific immunogens or mixtures of immunogens.
  • the preferred dosage of booster should be equal to or greater than 50% of the dosage necessary to produce primary immunization of the avian.
  • the hyperimmune state is preferably produced by any immunogen or combination of immunogens. Hyperimmunization is preferably achieved by multiple exposures to multiple immunogens, multiple exposure to single immunogens, or single exposures to libraries of immunogens.
  • immunization may also be accomplished using immunogens which are synthetically derived by combinatorial chemistries.
  • the basic strategy is to assemble multiple combinations of chemical building blocks for producing a population of molecules with diversity.
  • Several methods have recently been developed for solid and solution phase combinatorial synthesis of libraries of oligomers (Fodor, S. et al., Science 251:767 (1991); Houghton, R. et al., Nature 354:82 (1991) as well as small organic molecules (Bunin, B. & Ellman, J., J. Am. Chem. Soc. 114:10997 (1992)). Rapid multiple peptide and oligomer synthesis can serve as a source for combinatorial derived immunogens.
  • an alternative strategy would allow the addition of organic building blocks in combinatorial fashion to a backbone molecule for improved immunogenicity.
  • any DNA construct (generally consisting of a promoter region and an immunogen encoding sequence) will trigger an immune response.
  • Genetic vaccines consist of immunogenic-coding vectors, fragments of naked DNA, plasmid DNA, DNA-RNA immunogens, DNA-protein conjugates, DNA-liposome conjugates, DNA expression libraries, and viral and bacterial DNA delivered to produce an immune response.
  • Methods of DNA delivery include particle bombardment, direct injection, viral vectors, liposomes and jet injection, among others. When applying these delivery methods, much smaller quantities may be necessary and generally result in more persistent immunogen production.
  • the preferred method for introducing DNA into avians is through intramuscular injection of the DNA into the breast muscle.
  • Methods of DNA delivery include but are not limited to, particle bombardment, direct injection, liposomes, jet injection (Fynan, E.F. et al., Proc. Natl. Acad. Sci. USA 90: 11478-11482 (1993)).
  • the nucleic acids that code for known or unknown immunogens, promoter regions (notably CMV cauliflower mosaic virus) and SV40 bacterial origin can be replicated in bacteria to produce plasmid DNA for use in DNA injections.
  • promoter regions notably CMV cauliflower mosaic virus
  • SV40 bacterial origin can be replicated in bacteria to produce plasmid DNA for use in DNA injections.
  • the preferred method is intramuscular injection to the breast muscle.
  • Vaccine trials are carried out in egg laying avians, preferably chickens. Repeated immunizations are given at one to two week intervals for up to six months.
  • the amounts of DNA used are generally in the order of 50-300 ⁇ g of DNA in saline for direct injection.
  • 4 - 100 ⁇ g of DNA co-precipitated onto gold beads by the addition of 2.5 M CaCl 2 are preferred. Repeated immunizations can be given intradermally by this method of accelerating DNA coated particles into the live animal.
  • Step 1 Any immunogenic or combination of immunogens may be employed as a vaccine.
  • the immunogenics can be bacterial, viral, protozoan, fungal, cellular, or any other substances to which the immune system of an egg- producing animal will respond.
  • the critical point in this step is that the immunogen(s) must be capable of inducing immune and hyperimmune states in the egg-producing animal.
  • one preferred vaccine is a mixture of polyvalent bacterial and fungal immunogens selected from the following immunogenic families: the enteric bacilli and bacteroides, pneumococci, Pseudomonas, Salmonella, Streptococci, bacilli, Staphylococci, Neisseria, Clostridia, Mycobacteria, Actinomycetes Chlamydiae, and Mycoplasma.
  • Viral immunogens are preferably selected from the following immunogenic families: adenoviruses, picomaviruses and herpes viruses, although other viral immunogenic families will work.
  • S- 100 a polyvalent vaccine referred to as Series 100 (S- 100) is used.
  • the bacteria included in the S-100 vaccine are listed in table 1 of Example 1. This vaccine has been previously described in US patent Nos. 5,106,618 and 5,215,746, both assigned to Stolle Research and Development Corporation.
  • the vaccine can be either a killed or live-attenuated vaccine and can be administered by any method that elicits an immune response. It is preferred that immunization be accomplished by administering the immunogens through intramuscular injection.
  • the preferred muscle for injection in an avian is the breast muscle. Dosage is preferably 0.05-5 milligrams of the immunogenic vaccine.
  • Other methods of administration include intravenous injection, intraperitoneal injection, intradermal, rectal suppository, aerosal or oral administration. When DNA techniques are used for the hyperimmunization process, much smaller quantities are required, generally 300 micrograms.
  • the hyperimmune state is preferably induced and maintained in the target animal by repeated booster administrations of an appropriate dosage at fixed time intervals.
  • the time intervals are preferably 2-8 week intervals over a period of 6-12 months. However, it is essential that the booster administrations do not lead to immune tolerance.
  • Such processes are well known in the art.
  • hyperimmunization maintenance procedures or combination of procedures such as, for example, intramuscular injection for primary immunization and intravenous injection for booster injections.
  • Further procedures include simultaneously administering microencapsulated and liquid immunogen, or intramuscular injection for primary immunization, and booster dosages by oral administration or parenteral administration by microencapsulation means.
  • the eggs from these animals are collected and processed to produce a hyperimmune egg product in administerable form. Subsequently, the hyperimmune egg product can be administered to the subject.
  • the egg and/or egg product of the present invention is administered to a subject animal by any means that treats or prevents diarrhea in the subject animal. It is preferred that administration occurs by directly feeding the egg or any derivative of the egg.
  • Egg and egg yolk are natural food ingredients and are non-toxic and safe.
  • the egg product of the invention is integrated into a dietary supplement.
  • One preferred method for preparing the egg of the invention to be incorporated into a dietary supplement involves drying the egg into an egg powder.
  • spray drying is a preferred method.
  • the process of spray drying eggs is well known in the art.
  • the dried egg powder can be incorporated into a variety of administerable forms, such as drinks in the form of, for example, protein powders, power building drinks, protein supplements and any other nutritional, athlete-associated products.
  • the egg powder can be used in bake mixes, power bars, candies, cookies, etc.
  • the egg powder can be placed in a capsule form and administered as such.
  • Other examples of egg processing include making an omelet, soft or hard-boiling the egg, baking the egg, or, if desired, the egg can be eaten raw or processed as liquid egg.
  • the yolk and/or white fractions contain the agent or agents responsible for the beneficial properties observed and referred to above.
  • further separation could provide more potent fractions or elimination of undesirable components, and would allow for other modes of administration such as administering egg product parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, intranasally, orally or topically.
  • Such further separation will provide for the ability to make encapsulated products and pharmaceutical compositions with said egg or fraction thereof.
  • Inhibition of castor oil induced diarrhea has been used as an animal model for the development of antidiarrheal agents such as diphenoxylate and loperamide and has been shown to be a good predictor of anti-diarrheal activity in humans for at least 25 years (Awouters et al, 1974).
  • the present study indicates that acute dosing with egg obtained from chickens immunized against a variety of immunogens can inhibit castor oil induced diarrhea.
  • the mechanism of the diarrheogenic activity of castor oil is complex. Castor oil must first be metabolized to ricinoleic acid in the lumen of the intestinal tract. Ricinoleic acid then produces a marked increase in net secretion of fluid and electrolytes in the intestine resulting in diarrhea.
  • the mechanism of action of castor oil has been studied recently by Mascolo N et al who found an activation of Platelet Activating Factor (PAF) in duodenal tissue by nitric oxide (NO) released in response to cast
  • Example 2 The study detailed in Example 2 shows that long periods of pretreatment are not needed for showing activity of the hyperimmune egg product and that the hyperimmune egg product is effective when given orally in a bolus dose.
  • hyperimmune egg product is a safe and effective therapy for alleviation of acute or chronic diarrhea irrespective of cause and may be a valuable addition to therapy in diarrheal conditions.
  • the study showed that when hyperimmune egg product is given by oral bolus doses for two days, it will significantly inhibit castor oil-induced diarrhea in a mouse.
  • the hyperimmune egg product is preferably administered to the subject in an amount that is immunologically effective in treating and preventing the particular disorder.
  • a dose-related effect was seen when doses of 1,2 and 4 grams/kg were administered in the castor oil study. Dosage and duration of the administration, however, will depend upon the particular condition, whether it is present, and, if so, the advancement of the condition in the subject. It is preferred that the hyperimmune egg product is provided in whatever amount is necessary and effective in treating and/or preventing the condition and the symptoms of the condition.
  • hyperimmune eggs or hyperimmune egg products containing the equivalent of less than one to several whole, hyperimmune eggs
  • More potent fractions can be separated and concentrated by methods well-known in the art, from several hundred eggs.
  • the egg product of this invention has been shown to be safe, non-toxic, ideal for long term use and has no side effects other than on humans allergic to eggs.
  • the egg product can be orally administered either alone or in combination with drug therapy, for long term use for diarrhea- related disorders.
  • the bacterial cells were harvested by centrifugation of the suspension for 20 minutes to remove the media.
  • the bacterial pellet obtained was resuspended in sterile saline solution and the bacterial sample was centrifuged three times to wash the media from the cells. After the third sterile saline wash, the bacterial pellet was resuspended in a small amount of double distilled water.
  • the media-free bacterial suspension was killed by placing the suspension in a glass flask in an 80 C water bath overnight. The viability if the broth culture was tested with a small amount of killed bacteria, incubated at 37 C for five days and checked daily for growth to certify that the bacteria had been killed. The killed bacteria were lyophilized until dry. The dry bacteria were then mixed with sterile saline solution to a concentration of 2.2 x 10° bacterial cells/mL saline (1.0 optical density reading at 660 nm). Bacteria contained in S-100 vaccine are listed in Table 1 below.
  • Escherichia coli Escherichia coli Klebsiella pneumoniae Pseudomonas aeruginosa Salmonella typhimurium Salmonella dysenteriae Salmonella enteriditis Salmonella epidermis Salmonella simulans Streptococcus pyogenes, type 1 Streptococcus pyogenes, type 3 Streptococcus pyogenes, type 5 Streptococcus pyogenes, type 8 Streptococcus pyogenes, type 12 Streptococcus pyogenes, type 14 Streptococcus pyogenes, type 18 Streptococcus pyogenes, type 22 Pseudomonas vulgaris Streptococcus agalactiae Streptococcus mitis Streptococcus mutans Streptococcus salavarius Streptococcus sanguis Streptococcus sanguis Str
  • a killed preparation of pathogens was prepared as described above.
  • the bacteria were mixed with complete Freund's adjuvant, and 5.6 mg of bacterial material were injected into the breast muscle of a chicken.
  • the bacterial preparation was mixed with incomplete Freund's adjuvant and injected into the chickens at two week intervals for six months.
  • mice The purpose of these tests was to identify, characterize, and document the preventative actions of hyperimmune egg product in an experimental model of diarrhea in mice. In this model using mice, diarrhea is induced by oral administration of castor oil.
  • This test is a standard test for anti-diarrheal agent for human use and was used for the discovery of the two most utilized anti-diarrheal agent, loperamide and diphenoxylate.
  • mice Male mice weighing 25-30 grams were obtained from Ace Laboratories, Boyertown, Pennsylvania. They were quarantined for at least 5 days and then randomized into groups of 10 and placed in plastic boxes with bedding. Treatments were all administered by gavage to fed mice on two consecutive days between 8:00 and 9:00 A.M. Mice were given 4.0 grams/kg po of either powdered immune or powdered control egg in 20 mL/kg distilled water. Spray-dried hyperimmune egg powder was provided by DCV, Inc., Wilmington, DE. It was obtained from eggs of chickens that have been repeatedly vaccinated with large amounts of killed enteric pathogens of human origin. Sprayed-dried table eggs were used as the control.
  • Test A Mice were dosed with:
  • Test B Mice were dosed with: 1. Distilled water - 20 mL/kg PO 2. Hyperimmune egg - DCV Product B-98-06-Jan ID #3059 lot 96298VOFP PSL 80108 4D - 1.0 grams/kg PO
  • Results were analyzed using an all or none criterion, with ano-genital staining and soft stools counting as diarrhea. Results are given as percentage of mice with diarrhea at each time and the cumulative number of positives over the 6 hour period. Percent inhibition was calculated by comparison to the appropriate control. Statistical analysis was done using the chi square test.
  • Results of the study are shown in Table 2. Data is presented as percent of mice with diarrhea and as percent inhibition compared to control for studies 1 and 2.
  • the initial study (Test A) comparing hyperimmune egg to control egg showed a significant difference in the ability to inhibit castor oil induced diarrhea by the hyperimmune egg.
  • Four grams/kg of hyperimmune egg significantly blocked castor oil induced diarrhea in the test subjects at the 4 hour observation period when compared to normal egg. No diarrhea was noted at the 2 hour period and the smallest amount of diarrhea was found in all groups at the 6 hour period.
  • a significant inhibition in the cumulative occurrence of diarrhea over the entire 6 hours was noted in hyperimmune egg-treated groups.
  • Hyperimmune egg administered at 1 gram/kg did not show significant anti-diarrheal activity at any time period.
  • Hyperimmune egg, administered at 2 grams /kg showed significant activity at the 6 hour period but not at 2 or the cumulative 0-6 hour period.
  • Hyperimmune egg administered at 4 grams per kg had significant effects at all time periods in which diarrhea was noted in the control period.
  • Percent inhibition for castor oil diarrhea over the 0-6 hour period was dose related with 38% inhibition with 1 gram/kg, 43% with 2 grams/kg and 62% with 4 grams/kg. An estimated 50% effective dose would be between 2 and 4 grams/kg. Discussion
  • Hyperimmune egg product showed significant dose related activity against castor oil induced diarrhea. Four grams/kg orally as a bolus dose was effective in both studies and appears to be a reasonable therapeutic dose. The mechanism of hyperimmune egg activity against castor oil is not known but may be related to potential intestinal anti-secretory activity. Hyperimmune egg was not effective in previous studies in which it was administered in the diet. This may have been due to a lack of an effective concentration of hyperimmune egg at sites of activity.
  • Hyperimmune egg may find use as acute therapy as an antidiarrheal in both animals and humans. This study shows that long periods of pretreatment are not needed for showing activity and that it is effective when given orally in a bolus dose.
  • Control Egg 4 0/10 0 9/10 90 3/10 30 12/30 40
  • HIV positive male subjects (as documented by ELISA and Western Blot analysis) ranging in age from 18-50 years and suffering from gastrointestinal problems were recruited from the Jamshedji Jeejiboy (J.J.) Hospital, Mumbai, India. These individuals had been previously diagnosed with one or more of the AIDS defining secondary conditions (refs). None had participated in any investigational drug tests within the last 60 days or had been exposed to any innumomodulator or vaccine for the past 90 days. Subjects who had frequent changes in dosing or types of medication to control clinical symptoms, alcohol or substance abusers, history of allergy towards eggs or any other ingredient in the test article were excluded from the study.
  • the open-label study testing of a dietary supplement fortified with hyperimmune egg in spray dried form was conducted for a total of 12 weeks.
  • the dietary supplement beverage was freshly prepared and consumed as a liquid once a day for 8 weeks.
  • test article was no longer consumed for the rest of the 1 month duration of the study.
  • the same physician monitored subjects at four week intervals for the entire length of the study and drew blood samples. All subjects maintained their normal diets and medication and were monitored during the 60-day trial period and 30 days thereafter, for any untoward signs or symptoms.
  • the severity, onset date, duration, frequency, study product relationship, action taken and outcome of each adverse experiences were recorded.
  • Subject # 2 was admitted with a weight of 53 kg. He complained of respiratory distress and abdominal pain and was treated for Koch's infection. Subject had tested HIV positive for last 6 years and had taken sporadic doses of ayurvedic medicines for chest congestion and cough. Subject was also provided antibiotics and cough syrup.

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Abstract

L'invention concerne un produit alimentaire et un procédé de prévention et de traitement de la diarrhée chez un animal de destination souffrant de diarrhées ou sensible à la diarrhée. Le procédé consiste à administrer à l'animal de destination un produit à base d'oeufs obtenu d'un ovocyte hyperimmunisé.
PCT/US1999/010049 1998-05-08 1999-05-07 Antidiarrheique et procede d'utilisation dudit produit WO1999058133A2 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
NZ508133A NZ508133A (en) 1998-05-08 1999-05-07 Anti-diarrheal and method for using the same
JP2000547984A JP2002514604A (ja) 1998-05-08 1999-05-07 下痢止め薬およびそれを使用するための方法
CA002331314A CA2331314A1 (fr) 1998-05-08 1999-05-07 Antidiarrheique et procede d'utilisation dudit produit
AU38905/99A AU772785B2 (en) 1998-05-08 1999-05-07 Anti-diarrheal and method for using the same
KR1020007012463A KR20010043426A (ko) 1998-05-08 1999-05-07 지사제 및 그의 사용 방법
EP99921785A EP1075269A2 (fr) 1998-05-08 1999-05-07 Antidiarrheique et procede d'utilisation dudit produit

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US8476598P 1998-05-08 1998-05-08
US60/084,765 1998-05-08

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WO1999058133A2 true WO1999058133A2 (fr) 1999-11-18
WO1999058133A3 WO1999058133A3 (fr) 2000-01-06

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104288769A (zh) * 2014-09-17 2015-01-21 陕西建华生物制药有限公司 一种西药外用膏剂及其制备方法
CN113016714A (zh) * 2021-03-04 2021-06-25 湖南中医药大学 一种泄泻食滞胃肠证动物模型的制备方法及评价泄泻食滞胃肠证动物模型的方法

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US5106618A (en) * 1987-07-02 1992-04-21 Stolle Research And Development Corporation Method of treating protozoal gastrointestinal disorders by administering hyperimmune milk product
JPH0813755B2 (ja) * 1988-04-13 1996-02-14 太陽化学株式会社 ウイルス性下痢症予防剤
WO1996010420A1 (fr) * 1994-10-04 1996-04-11 Sotomayor, Tevic, Emar Composition et traitement d'hyperimmunisation a l'aide de bacteries non tuees thermiquement
US5772999A (en) * 1996-07-30 1998-06-30 Dcv Biologics, L.P. Method of preventing, countering, or reducing NSAID-induced gastrointestinal damage by administering milk or egg products from hyperimmunized animals

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104288769A (zh) * 2014-09-17 2015-01-21 陕西建华生物制药有限公司 一种西药外用膏剂及其制备方法
CN113016714A (zh) * 2021-03-04 2021-06-25 湖南中医药大学 一种泄泻食滞胃肠证动物模型的制备方法及评价泄泻食滞胃肠证动物模型的方法
CN113016714B (zh) * 2021-03-04 2023-08-22 湖南中医药大学 一种泄泻食滞胃肠证动物模型的制备方法

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EP1075269A2 (fr) 2001-02-14
JP2002514604A (ja) 2002-05-21
AU3890599A (en) 1999-11-29
CA2331314A1 (fr) 1999-11-18
WO1999058133A3 (fr) 2000-01-06
CN1308540A (zh) 2001-08-15
KR20010043426A (ko) 2001-05-25
AU772785B2 (en) 2004-05-06
NZ508133A (en) 2003-10-31

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