Drug – bio-affecting and body treating compositions – Enzyme or coenzyme containing – Hydrolases
Reexamination Certificate
1999-10-01
2001-06-26
Naff, David M. (Department: 1651)
Drug, bio-affecting and body treating compositions
Enzyme or coenzyme containing
Hydrolases
C435S212000, C435S225000
Reexamination Certificate
active
06251391
ABSTRACT:
FIELD OF THE INVENTION
The field of the present invention is the inhibition of the opioid effects of casomorphins and gluteomorphins.
BACKGROUND OF THE INVENTION
Wheat products and dairy products are two of the primary, most prevalent foodstuffs in the world today. A primary protein in wheat products is gluten, while a primary protein in milk is casein. As a part of the digestion and metabolism of these proteins, they are cleaved (broken up into smaller parts) in the stomach and intestines. Analyses have found that, if not properly digested, each of these proteins can give rise to peptides (short chains of amino acids) known as exorphins. Whiteley et al.,
Autism,
3(1):45-55 (1999). The exorphins from gluten are known as gluteomorphins while the exorphins from casein are known as casomorphins. Id.; Reichelt et al.,
J. Applied Nutr.,
42(1):1-11 (1990).
These exorphins from wheat and milk are important, and problematic, because they mimic opiates when in the human body. Indeed, gluteomorphin and casomorphin are known as “opioids” because they have the opiate-type effects. This is also indicated by the “-morphin” suffix of the names, which shows their functional similarity to morphine, a strong opiate; casomorphin is also known as caseomorphine. For example, one molecule of gluten contains 15 opioid sequences, which may be released by the action of trypsin, chymotrypsin, and secretin. Reichelt et al.,
Dev. Brain Dysfunct,.
7:71-85 (1994).
Casomorphin and gluteomorphin have been implicated in a variety of human diseases, including schizophrenia and autism (Sun and Cade,
Autism,
3(1):85-95 (1995)), attention deficit disorder (ADD)/attention deficit hyperactivity disorder (ADHD) (as used herein, unless indicated otherwise, reference to ADD includes ADHD and vice-versa), epilepsy, and pervasive development disorder (PDD), which can also potentially be referred to as autistic spectrum disorders (ASDs) or, for some subtypes of PDD, multisystem neurological disorders. Reichelt (1990, 1991, and 1994); Ackerman (1997).
Autism is a one example of the types of effects that casomorphin and gluteomorphin can have on a person. Autism is a relatively rare syndrome of early childhood that affects between three and eight of every 10,000 school-aged children. Autism is a serious disease that seriously impairs the functioning and life-enjoyment of its victims. The disease can include language disorders with impaired understanding, echolalia, pronominal reversal (such as using “you” instead of “I” or “me” when referring to one's self), rituals and compulsive phenomena, and uneven intellectual development with mental retardation. Autism is about two to five times more common in boys than in girls. As noted above, autism appears to have ties to casomorphin and gluteomorphin, but the actual cause of autism is unknown. There are at least some important genetic factors, as indicated by the fact the concordance rate is significantly greater in monozygotic twins than dizygotic twins, which genetic factors provide one explanation for the ties to exorphins. Merck Manual, 17
th
edition, section 19, chapter 274 (1999); Autism Review, Lowell Ackerman, www.parentzone.com/autism/review.htm (1997). Other causitive factors may include rubella, problems during pregnancy, labor and delivery, cytomegalic inclusion disease, phenylketonuria, and fragile X syndrome. Autistic children are also at increased risk of developing seizure disorders, e.g., epilepsy, especially during their teen years.
Analysis of the urine of autistic children found hyperpeptiduria in the children, which means that the analysis found a significantly increased presence of peptides, in this case the exorphins casomorphin and gluteomorphin, in the urine of children. Reichelt et al. (1990); Reichelt et al.,
Brain Dysfunct.,
4:308-319 (1991); Reichelt et al. (1994). Reichelt et al. (1994) hypothesized that the peptiduria was caused by insufficient breakdown of casein and gluten. Reichelt et al. (1991), at 308, also hypothesized that the release of the opioid-like casomorphin (from casein) and gluteomorphin (from gluten) were caused by a defect of peptidases in the patient. Accordingly, Reichelt et al. proposed a strict gluten-free and casein-free diet (i.e., strictly wheat-free and dairy-free). Reichelt et al. (1990) found that such a diet ultimately resulted in increased social contact, decreased stereotypy, an end to self-mutilation like head banging, and a decrease in dreamy state periods. Also, alimentary problems generally improved. Reichelt et al. (1990) at 5; accord Reichelt et al. (1991); Reichelt et al. (1994).
Ackerman (1997) hypothesized that the addition of papain, bromelain, and chymotrypsin to the diet of the patient might be beneficial. However, Ackerman never reported the actual use of any such enzymes, and his proposed combination would not be expected to work because chymotrypsin, according to Reichelt et al. (1994) at 79, is one of the digestive enzymes (as well as trypsin and the hormone secretin) believed to release the detrimental opioid sequences. Papain and bromelain are, likewise, broad-spectrum digestive enzymes that would also have a reasonably high chance of actually increasing the amount of opioids, i.e., casomorphins or gluteomorphins, instead of reducing them (absent the additional use of an agent to specifically inhibit the casomorphin or gluteomorphin, as discussed further herein).
As noted above, Reichelt et al. found that a strict gluten-free and casein-free diet had beneficial effects for the patient. However, as described by Seroussi,
Frequently Asked Questions About Dietary Intervention For The Treatment Of Autism And Other Developmental Disabilities
, www.enabling.org/ia/celiac/aut/autgfffaq.html (1999), achieving and maintaining such a diet can be very difficult “Be careful. Removing all dairy means ALL milk, butter, cheese, cream cheese, sour cream, etc. It also includes product ingredients such as ‘casein’ and ‘whey,’ or words even containing the word ‘casein.’ Read labels—items like bread and tuna fish often contain milk products. Even soy cheese usually contains caseinate.” Failure to adhere to the strict diet can be seriously detrimental: “What you need to understand is that for certain children, these [dairy and wheat] foods are toxic to their brains. . . . You would never knowingly feed your child poison, but if he fits into this category, that is exactly what you could be doing.” Id.; see Reichelt et al. (1991) (abstract; those patients that remained on the diet had further improvement, while those that abandoned the diet showed regression).
Thus, there has gone unmet a need for improved methods of treating patients who exhibit the effects of exorphins such as gluteomorphin and casomorphin without requiring the patient to adhere to difficult dietary restrictions. Similarly, there has gone unmet a need to protect patients from inadvertent exposure to gluten and casein, typically in the form of dairy products and wheat products. The present invention provides these and other advantages.
SUMMARY OF THE INVENTION
The present invention provides compositions and methods that can reduce the effects of exorphins in a human patient. Briefly, the compositions and methods comprise administering an exorphinase and an exorphin ligand to a human patient in sufficient quantities to reduce the effects of the exorphin. When administered to human patients suffering from autism, without restriction on the normal diet of the patients, the compositions and methods reduced one or more symptoms of autism, such as increased eye contact, better enunciation and use of pronouns, less fatigue, singing a song for the first time with the melody and words together and the entire song understandable, playing with age appropriate friends for the first time, fewer tantrums, better sleep patterns, improved politeness and coordination, being more loving, acknowledging another individual's emotion, increased voice and word association and, in one case, noticing that a calendar needed changing. In addition, t
Houston Devin B.
Wilkinson Randall Eugene
Graybeal Jackson Haley LLP
Klaire Laboratories, Inc.
Meller Mike
Naff David M.
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