US20080058282A1 - Use of lactulose in the treatment of autism - Google Patents
Use of lactulose in the treatment of autism Download PDFInfo
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- US20080058282A1 US20080058282A1 US11/468,379 US46837906A US2008058282A1 US 20080058282 A1 US20080058282 A1 US 20080058282A1 US 46837906 A US46837906 A US 46837906A US 2008058282 A1 US2008058282 A1 US 2008058282A1
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- lactulose
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- IDONTDZDDGYSFP-MKGWWZIKSA-N OCC1O[C@@](O)(CO)C(O)[C@@H]1COC[C@@H]1OC(CO)[C@H](O)[C@@H](O)C1O Chemical compound OCC1O[C@@](O)(CO)C(O)[C@@H]1COC[C@@H]1OC(CO)[C@H](O)[C@@H](O)C1O IDONTDZDDGYSFP-MKGWWZIKSA-N 0.000 description 1
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- 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
- A61K31/7016—Disaccharides, e.g. lactose, lactulose
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
-
- 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
- A61K31/7012—Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the invention relates to a treatment for autism, and more particularly, to the use of lactulose in the treatment of autism.
- Autism is the most prevalent of a subset of disorders organized under the umbrella of pervasive developmental disorder (PDD).
- PDD pervasive developmental disorder
- Autism is a serious developmental disorder characterized by profound deficits in language, communication, and socialization, resistance to learning, and displays of stereotypical behavior including perseveration.
- a spectrum disorder ASD
- Autism is a life-long developmental disorder affecting as many as 1 in 500 children. Recent studies have indicated that the prevalence is closer to 1 in 166 live births. The causes of this profound disorder are largely unknown.
- Recent research has uncovered pathology in the gastrointestinal tract of autistic children. The pathology is reported to extend from the esophagus to the colon.
- Lactulose is presently used in the treatment of constipation and hepatic encephalopathy.
- the efficacy of lactulose in these conditions is based on its fermentation in the colon by certain bacteria and the increase of the biomass of these bacteria in the colon.
- the products of fermentation are mainly organic acids, such as lactic acid and small-chain fatty acids, which, by exerting a local osmotic effect in the colon, result in increased fecal bulk and stimulation of peristalsis.
- the higher doses used for hepatic encephalopathy lower the colonic pH, and ammonia, in the form of ammonium ions, is used by the bacteria for amino acid and protein synthesis. This lowers the serum ammonia levels and improves mental function.
- Increased or high levels of ammonia in the blood stream can produce toxicity to the cells of the body especially to the cells of the nervous system. This neurotoxicity can alter brain function and cause other neurological diseases, including autism. Thus, decreasing the levels of ammonia in the blood would decrease the levels of ammonia in the brain thereby reducing the neurotoxic effects.
- Augmentin® amoxicillin+clavulanate potassium
- Augmentin® amoxicillin+clavulanate potassium
- lactulose has been used for years as a treatment for constipation and hepatic encephalopathy. However, lactulose has not previously been used as a treatment for autism or autism prevention. Presently, there exists no other pharmaceutical or biological treatment for autism. Since there is no pharmaceutical or biological treatment for autism, other than psychotropic medications for symptoms, only behavioral and educational solutions have been offered. Behavioral treatments, such as applied behavioral analysis and TEACCH (Treatment and Education of Autistic and related Communication Handicapped Children) and others, have some value in the treatment of these children but do not address the physiological, specifically gastrointestinal, problems encountered by them.
- TEACCH Treatment and Education of Autistic and related Communication Handicapped Children
- It is a goal of the present invention provide a treatment for autism that addresses the physiological symptoms of the disorder.
- lactulose is used to bind ammonia in the gastrointestinal tract, the bloodstream, and the nervous system.
- FIG. 1 is a block diagram illustrating the mechanism of the function of lactulose in the colon.
- Lactulose is a semisynthetic disaccharide comprised of the sugars D-galactose and D-fructose. It is not found naturally. The sugars are joined by a beta glycosidic linkage making it resistant to hydrolysis by human digestive enzymes. There is no disaccharidase in the microvillus membrane of small intestine enterocytes that can hydrolyze lactulose; nor is the disaccharide absorbed from the small intestine. Lactulose is, however, fermented by a limited number of colonic bacteria. This can lead to changes in the colonic ecosystem in favor of some bacteria, such as lactobacilli and bifidobacteria, which may confer some health benefits.
- Lactulose is a solid substance that is very soluble in water and has a sweet taste. It is sweeter than lactose but not as sweet as fructose. Lactulose is also known as 4-O-beta-D-galactopyranosyl-D-fructofuranose. Its molecular formula is C 12 H 22 O 11 , and its molecular weight is 342.30 daltons. The structural formula is:
- Lactulose has an inhibiting action on ammonia production in the ileum and reduces the ammonia level in portal circulation.
- lactulose molecules pass through the stomach and ileum unsplit.
- the lactulose is fermented by certain bacteria, which supplies carbohydrates and energy. This results in an increase of the biomass of these bacteria in the colon.
- the products of fermentation are mainly organic acids, such as lactic acid and small-chain fatty acids, which, by exerting a local osmotic effect in the colon, result in increased fecal bulk and stimulation of peristalsis.
- the fermentation process lowers the colonic pH, and ammonia, in the form of ammonium ions, is used by the bacteria for amino acid and protein synthesis. This lowers the serum ammonia levels and improves mental function.
- Augmentin® amoxicillin-clavulanate
- urea or another available ammonia source to a fermentation broth. This additional ammonia represses the number of enzymes involved in the metabolism of nitrogen, including urease, which catalyzes the conversion of urea to ammonia and carbon dioxide.
- urease which catalyzes the conversion of urea to ammonia and carbon dioxide.
- Urea and/or nitrogen poisoning has a two-fold effect in humans: 1) a neurotoxic effect on brain tissue and 2) a corrosive effect on the digestive tract, specifically damage to the secretory cells of the small intestine, due to the highly alkaline nature of NH 3 .
- Signs of urea poisoning include colic, bloating, diarrhea, muscle tremors, difficulty with coordination, weakness, and poor appetite.
- 206 children with autism not related to a known genetic condition, birth trauma, or known neurological disease were examined and a detailed case history was obtained.
- the 206 children tested had a mean number of 9.96 instances of otitis media with a standard error of the mean of ⁇ 1.83. This represented a sum total for the 206 children under age three of 2052 bouts of otitis media.
- These children received a mean number of 12.04 courses of antibiotics with a standard error of the mean of ⁇ 0.13.
- the total number of courses given to all of the children in the study was 2,480. Of those courses, 893 were Augmentin®, with 362 of those courses of Augmentin® being administered to children under age one.
- the treatment has a formulation of 0.4 g/kg lactulose and 0.1 g/kg mannitol. In another embodiment, the treatment has a formulation of 0.3 g/kg lactulose. In either embodiment, the treatment is administered two to five times per day.
- the lactulose may be administered in the form of a powder, liquid solution, or syrup.
Abstract
A treatment for autism in which an effective amount of lactulose is administered in order to bind excess ammonia in the gastrointestinal tract, the bloodstream, and the nervous system in order to prevent or reverse ammonia poisoning caused by the administration of certain antibiotics. Lactulose molecules in the colon are fermented by certain bacteria. The fermentation process lowers the colonic pH, and ammonia, in the form of ammonium ions, is used by the bacteria for amino acid and protein synthesis. This lowers the serum ammonia levels and reduces neurotoxicity.
Description
- This application claims the benefit of U.S. Provisional Application No. 60/712,551, filed Aug. 30, 2005. This application is herein incorporated in its entirety by reference.
- The invention relates to a treatment for autism, and more particularly, to the use of lactulose in the treatment of autism.
- Autism is the most prevalent of a subset of disorders organized under the umbrella of pervasive developmental disorder (PDD). Autism is a serious developmental disorder characterized by profound deficits in language, communication, and socialization, resistance to learning, and displays of stereotypical behavior including perseveration. Known now as a spectrum disorder (ASD), it includes a myriad of behavioral, emotional, and physiological symptoms. Autism is a life-long developmental disorder affecting as many as 1 in 500 children. Recent studies have indicated that the prevalence is closer to 1 in 166 live births. The causes of this profound disorder are largely unknown. Recent research has uncovered pathology in the gastrointestinal tract of autistic children. The pathology is reported to extend from the esophagus to the colon.
- Lactulose is presently used in the treatment of constipation and hepatic encephalopathy. The efficacy of lactulose in these conditions is based on its fermentation in the colon by certain bacteria and the increase of the biomass of these bacteria in the colon. The products of fermentation are mainly organic acids, such as lactic acid and small-chain fatty acids, which, by exerting a local osmotic effect in the colon, result in increased fecal bulk and stimulation of peristalsis. The higher doses used for hepatic encephalopathy lower the colonic pH, and ammonia, in the form of ammonium ions, is used by the bacteria for amino acid and protein synthesis. This lowers the serum ammonia levels and improves mental function.
- Increased or high levels of ammonia in the blood stream can produce toxicity to the cells of the body especially to the cells of the nervous system. This neurotoxicity can alter brain function and cause other neurological diseases, including autism. Thus, decreasing the levels of ammonia in the blood would decrease the levels of ammonia in the brain thereby reducing the neurotoxic effects.
- Certain drugs such as Augmentin® (amoxicillin+clavulanate potassium) have been known to leave an ammonia residue in the gastrointestinal tract. The increased levels of ear infections in children with autism and the use of Augmentin® to treat these and other infections makes the child vulnerable to the potential buildup of ammonia in the digestive system as well as the blood, thus leading to a potential neurotoxic state. By giving lactulose immediately following the administration of Augmentin® or other ammonia producing substances, the potential for a neurotoxic disease is reduced.
- It can be appreciated that lactulose has been used for years as a treatment for constipation and hepatic encephalopathy. However, lactulose has not previously been used as a treatment for autism or autism prevention. Presently, there exists no other pharmaceutical or biological treatment for autism. Since there is no pharmaceutical or biological treatment for autism, other than psychotropic medications for symptoms, only behavioral and educational solutions have been offered. Behavioral treatments, such as applied behavioral analysis and TEACCH (Treatment and Education of Autistic and related Communication Handicapped Children) and others, have some value in the treatment of these children but do not address the physiological, specifically gastrointestinal, problems encountered by them.
- What is needed, therefore, is a treatment for autism that works by preventing the build up of ammonia in the gastrointestinal tract, the bloodstream, and the nervous system.
- It is a goal of the present invention provide a treatment for autism that addresses the physiological symptoms of the disorder.
- It is another goal of the present invention to provide a treatment for autism that works by preventing the build up of ammonia in the gastrointestinal tract, the bloodstream, and the nervous system.
- It is a further goal of the present invention to provide a treatment for autism that reverses the effects of ammonia poisoning on the gastrointestinal tract, the bloodstream, and the nervous system caused by certain antibiotics.
- In one embodiment, lactulose is used to bind ammonia in the gastrointestinal tract, the bloodstream, and the nervous system.
- The features and advantages described herein are not all-inclusive and, in particular, many additional features and advantages will be apparent to one of ordinary skill in the art in view of the drawings, specification, and claims. Moreover, it should be noted that the language used in the specification has been principally selected for readability and instructional purposes, and not to limit the scope of the inventive subject matter.
-
FIG. 1 is a block diagram illustrating the mechanism of the function of lactulose in the colon. - Lactulose is a semisynthetic disaccharide comprised of the sugars D-galactose and D-fructose. It is not found naturally. The sugars are joined by a beta glycosidic linkage making it resistant to hydrolysis by human digestive enzymes. There is no disaccharidase in the microvillus membrane of small intestine enterocytes that can hydrolyze lactulose; nor is the disaccharide absorbed from the small intestine. Lactulose is, however, fermented by a limited number of colonic bacteria. This can lead to changes in the colonic ecosystem in favor of some bacteria, such as lactobacilli and bifidobacteria, which may confer some health benefits.
- Lactulose is a solid substance that is very soluble in water and has a sweet taste. It is sweeter than lactose but not as sweet as fructose. Lactulose is also known as 4-O-beta-D-galactopyranosyl-D-fructofuranose. Its molecular formula is C12H22O11, and its molecular weight is 342.30 daltons. The structural formula is:
- Lactulose has an inhibiting action on ammonia production in the ileum and reduces the ammonia level in portal circulation. Referring to
FIG. 1 , lactulose molecules pass through the stomach and ileum unsplit. Once in the colon, the lactulose is fermented by certain bacteria, which supplies carbohydrates and energy. This results in an increase of the biomass of these bacteria in the colon. The products of fermentation are mainly organic acids, such as lactic acid and small-chain fatty acids, which, by exerting a local osmotic effect in the colon, result in increased fecal bulk and stimulation of peristalsis. The fermentation process lowers the colonic pH, and ammonia, in the form of ammonium ions, is used by the bacteria for amino acid and protein synthesis. This lowers the serum ammonia levels and improves mental function. - It has been postulated that there is a relationship between the use of the antibiotic Augmentin® and autism. Many autistic children suffer from chronic otitis media (ear infections) prior to age three. Otitis media is generally by two strains of bacteria, Streptococcus pneumoniae and Hemophilus influenzae. Augmentin® (amoxicillin-clavulanate) is a frequently prescribed antibiotic for this condition because it is effective against both of these strains. However, the process of manufacturing Augmentin® involves the addition of urea or another available ammonia source to a fermentation broth. This additional ammonia represses the number of enzymes involved in the metabolism of nitrogen, including urease, which catalyzes the conversion of urea to ammonia and carbon dioxide. Thus, there is the possibility of urea and/or nitrogen poisoning.
- Urea and/or nitrogen poisoning has a two-fold effect in humans: 1) a neurotoxic effect on brain tissue and 2) a corrosive effect on the digestive tract, specifically damage to the secretory cells of the small intestine, due to the highly alkaline nature of NH3. Signs of urea poisoning include colic, bloating, diarrhea, muscle tremors, difficulty with coordination, weakness, and poor appetite.
- In a study conducted by the inventor, 206 children with autism not related to a known genetic condition, birth trauma, or known neurological disease were examined and a detailed case history was obtained. The 206 children tested had a mean number of 9.96 instances of otitis media with a standard error of the mean of ±1.83. This represented a sum total for the 206 children under age three of 2052 bouts of otitis media. These children received a mean number of 12.04 courses of antibiotics with a standard error of the mean of ±0.13. The total number of courses given to all of the children in the study was 2,480. Of those courses, 893 were Augmentin®, with 362 of those courses of Augmentin® being administered to children under age one.
- The increased levels of ear infections in children with autism combined with the use of Augmentin® to treat these infections has the potential to make these children vulnerable to the buildup of ammonia in the gastrointestinal tract, the bloodstream, and the nervous system, leading to a neurotoxic state. By administering lactulose subsequent to a course of treatment with Augmentin® or other antibiotics that leave an ammonia residue in the gastrointestinal tract, the potential for a neurological disease, such as autism, is reduced.
- In one embodiment of the present invention, the treatment has a formulation of 0.4 g/kg lactulose and 0.1 g/kg mannitol. In another embodiment, the treatment has a formulation of 0.3 g/kg lactulose. In either embodiment, the treatment is administered two to five times per day. The lactulose may be administered in the form of a powder, liquid solution, or syrup.
- The foregoing description of the embodiments of the invention has been presented for the purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed. Many modifications and variations are possible in light of this disclosure. It is intended that the scope of the invention be limited not by this detailed description, but rather by the claims appended hereto.
Claims (20)
1. A method for treating an individual exhibiting one or more symptoms of autistic disorder, the method comprising administering an effective amount of lactulose to the individual.
2. The method of claim 1 , wherein one of the symptoms is selected from a group consisting of a gastrointestinal disorder, a neurological disorder, and a combination thereof.
3. The method of claim 1 , wherein the effective amount of lactulose comprises about 0.4 g/kg lactulose and 0.1 g/kg mannitol per dose.
4. The method of claim 1 , wherein the effective amount of lactulose comprises about 0.3 g/kg lactulose per dose.
5. The method of claim 1 , wherein the effective amount of lactulose is administered approximately two to five times per day.
6. The method of claim 1 , wherein the effective amount of lactulose is administered in a form selected from the group consisting of a powder, liquid solution, syrup, and a combination thereof.
7. The method of claim 1 , wherein the effective amount of lactulose includes an amount of lactulose sufficient to decrease ammonia levels in the blood of the individual.
8. The method of claim 1 , wherein the effective amount of lactulose includes an amount of lactulose sufficient to decrease ammonia levels in the gastrointestinal tract of the individual.
9. The method of claim 1 , wherein the effective amount of lactulose includes an amount of lactulose sufficient to decrease ammonia levels in the nervous system of the individual.
10. The method of claim 1 , wherein the effective amount of lactulose includes an amount of lactulose sufficient to reverse ammonia poisoning caused by the administration of antibiotics that leave a residue in the gastrointestinal tract of the individual.
11. A composition for treating autism and the symptoms thereof in an individual comprising an effective amount of lactulose.
12. The composition of claim 11 , wherein one of the symptoms is selected from a group consisting of a gastrointestinal disorder, a neurological disorder, and a combination thereof.
13. The composition of claim 11 , wherein the effective amount of lactulose comprises about 0.4 g/kg lactulose and 0.1 g/kg mannitol per dose.
14. The composition of claim 11 , wherein the effective amount of lactulose comprises about 0.3 g/kg lactulose per dose.
15. The composition of claim 11 , wherein the effective amount of lactulose is administered approximately two to five times per day.
16. The composition of claim 11 , wherein the effective amount of lactulose is manufactured in a form selected from the group consisting of a powder, liquid solution, syrup, and a combination thereof.
17. The composition of claim 11 , wherein the effective amount of lactulose includes an amount of lactulose sufficient to decrease ammonia levels in the blood of the individual.
18. The composition of claim 11 , wherein the effective amount of lactulose includes an amount of lactulose sufficient to decrease ammonia levels in the gastrointestinal tract of the individual.
19. The composition of claim 11 , wherein the effective amount of lactulose includes an amount of lactulose sufficient to decrease ammonia levels in the nervous system of the individual.
20. The composition of claim 11 , wherein the effective amount of lactulose includes an amount of lactulose sufficient to reverse ammonia poisoning caused by the administration of antibiotics that leave a residue in the gastrointestinal tract of the individual.
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/468,379 US20080058282A1 (en) | 2005-08-30 | 2006-08-30 | Use of lactulose in the treatment of autism |
US12/049,613 US20080161265A1 (en) | 2005-08-30 | 2008-03-17 | Use of lactulose in the treatment of autism |
US13/204,881 US8673877B2 (en) | 2005-08-30 | 2011-08-08 | Use of lactulose in the treatment of autism |
US14/087,930 US9345721B2 (en) | 2005-08-30 | 2013-11-22 | Use of lactulose in the treatment of autism |
US15/089,842 US10350229B2 (en) | 2005-08-30 | 2016-04-04 | Use of lactulose in the treatment of autism |
US16/422,079 US11033563B2 (en) | 2005-08-30 | 2019-05-24 | Use of lactulose in the treatment of autism |
US17/306,614 US20210252031A1 (en) | 2005-08-30 | 2021-05-03 | Use of lactulose in the treatment of autism |
Applications Claiming Priority (2)
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US71255105P | 2005-08-30 | 2005-08-30 | |
US11/468,379 US20080058282A1 (en) | 2005-08-30 | 2006-08-30 | Use of lactulose in the treatment of autism |
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US12/049,613 Division US20080161265A1 (en) | 2005-08-30 | 2008-03-17 | Use of lactulose in the treatment of autism |
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US11/468,379 Abandoned US20080058282A1 (en) | 2005-08-30 | 2006-08-30 | Use of lactulose in the treatment of autism |
US12/049,613 Abandoned US20080161265A1 (en) | 2005-08-30 | 2008-03-17 | Use of lactulose in the treatment of autism |
US13/204,881 Active US8673877B2 (en) | 2005-08-30 | 2011-08-08 | Use of lactulose in the treatment of autism |
US14/087,930 Active US9345721B2 (en) | 2005-08-30 | 2013-11-22 | Use of lactulose in the treatment of autism |
US15/089,842 Active US10350229B2 (en) | 2005-08-30 | 2016-04-04 | Use of lactulose in the treatment of autism |
US16/422,079 Active US11033563B2 (en) | 2005-08-30 | 2019-05-24 | Use of lactulose in the treatment of autism |
US17/306,614 Abandoned US20210252031A1 (en) | 2005-08-30 | 2021-05-03 | Use of lactulose in the treatment of autism |
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US13/204,881 Active US8673877B2 (en) | 2005-08-30 | 2011-08-08 | Use of lactulose in the treatment of autism |
US14/087,930 Active US9345721B2 (en) | 2005-08-30 | 2013-11-22 | Use of lactulose in the treatment of autism |
US15/089,842 Active US10350229B2 (en) | 2005-08-30 | 2016-04-04 | Use of lactulose in the treatment of autism |
US16/422,079 Active US11033563B2 (en) | 2005-08-30 | 2019-05-24 | Use of lactulose in the treatment of autism |
US17/306,614 Abandoned US20210252031A1 (en) | 2005-08-30 | 2021-05-03 | Use of lactulose in the treatment of autism |
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US20020081628A1 (en) * | 2000-11-16 | 2002-06-27 | Fallon Joan M. | Methods for diagnosing pervasive development disorders, dysautonomia and other neurological conditions |
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US20140187512A1 (en) | 2014-07-03 |
US20160213697A1 (en) | 2016-07-28 |
US11033563B2 (en) | 2021-06-15 |
US10350229B2 (en) | 2019-07-16 |
US9345721B2 (en) | 2016-05-24 |
US20080161265A1 (en) | 2008-07-03 |
US20120004192A1 (en) | 2012-01-05 |
US20210252031A1 (en) | 2021-08-19 |
US20190275066A1 (en) | 2019-09-12 |
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