Information on Secretin

Information on Secretin
Letter to the editor in the New England Journal of Medicine April 20, 2000

My colleagues and I began evaluating children with autism and gastrointestinal problems in 1997 and reported our findings initially in 1998. (1) The main secretin-related observation was a significant increase in the volume of pancreaticobiliary fluid after intravenous injection of secretin during endoscopy in 75 percent of the 36 autistic children we studied. (2) Most of the children had gastrointestinal changes after a single dose of secretin. The majority of these patients had gradual improvements in social and behavioral skills after repeated injections. Of course, to prove scientifically that secretin is beneficial in the treatment of autism, randomized, double-blind, placebo-controlled studies should be conducted.

The lack of benefit from a single injection of secretin in the study by Sandler et al. (Dec. 9 issue) (3) is not surprising. It is unusual for a single dose of a drug to result in full recovery from a chronic disease. In addition, the age range, diagnosis, and absence of serious gastrointestinal problems in the study sample were all predictive factors for a negative result. We studied younger, nonverbal patients with autism who had gastrointestinal symptoms and a low level of functioning. Many of our patients with diarrhea had an immediate improvement in stool consistency after a single injection of secretin; however, marked responses in terms of behavior were rare.

It was striking to read that, despite learning of the negative study results, 63 percent of the parents of children in the secretin group were interested in further treatment with secretin injections. In the early stage of our studies, we became aware of the poor sensitivity of the various diagnostic behavioral tests used in children with autism. These tests were designed to diagnose autism, not to assess drug-induced changes. In our initial case studies, secretin was administered intravenously during endoscopy. After meals, several gastrointestinal hormones are released. one or more of these hormones may antagonize the effects of secretin. Sandler et al. did not report whether their patients had fasted.

Karoly Horvath, MD, Ph.D.
University of Maryland at Baltimore
Baltimore, MD 21201-1595

(1) Horvath K, Stefanatos G, Sokolski KN, Wachtel R, Nabors L, Tildon JT.
Improved social and language skills after secretin administration in patients with autistic spectrum disorders. J Assoc Acad Minor Phys 1998;9:9-15.

(2) Horvath K, Papadimitriou JC, Rabsztyn A, Drachenberg C, Tildon JT.
Gastrointestinal abnormalities in children with autistic disorder. J Pediatr 1999;135:559-63.

(3) Sandler AD, Sutton KA, DeWeese J, Girardi MA, Sheppard V, Bodfish JW.
Lack of benefit of a single dose of synthetic human secretin in the treatment of
autism and pervasive developmental disorder. N Engl J Med 1999;341:1801-6.

Added by Brenda Denzler

REPLIGEN INITIATES PHASE II TRIAL OF SECRETIN

If you are interested in participating in the clinical trial, please complete Repligen's online form at www.repligen.com/Corporate/contactform.html. If you have already completed this form but wish to update the information, please provide the new information and indicate that it is an "update request."

Largest Clinical Trial in Autism to be Conducted at Four U.S. Sites

NEEDHAM, MA -- March 29, 2000 -- Repligen Corporation (Nasdaq: RGEN) today announced it has initiated a Phase II clinical trial with the hormone secretin in children with autism. The double-blind, placebo-controlled study will involve up to 140 autistic children aged 3 to 6. After extensive documentation of their autistic and gastrointestinal symptoms, each patient will receive three treatments and a thorough follow-up evaluation over a 10-week period.

The primary objective of the study is to determine if secretin improves the social and communicative deficits of autism. These symptom changes will be evaluated with multiple assessment tools including video taping of structured play sessions, clinical and parent evaluations using accepted tools and a daily diary of symptoms. A secondary objective is to assess changes in the patients' gastrointestinal symptoms following treatment. The trial will include an endoscopic examination of the gastrointestinal tract for patients for whom this evaluation is deemed appropriate.

The Phase II trial sites will include the Mayo Clinic, the University of Rochester Medical Center and the Southwest Autism Research Center in collaboration with Phoenix Children's Hospital. The study is expected to be completed by year's end.

Repligen has also initiated a significant research effort to better understand the biology of secretin and its mechanism of action in autistic patients. Analysis of patient samples to date has demonstrated physiological changes in some children treated with secretin. Similar analyses will be conducted on patients enrolled in the clinical trial which will be correlated with changes in autism symptomatology.

"We believe this to be the largest and most comprehensive clinical trial ever carried out in autism," commented Walter C. Herlihy, Ph.D., President and CEO of Repligen. "By correlating changes in physiology with changes in the symptoms of autism, we hope to define the biological characteristics associated with response to secretin."

Secretin is currently approved by the FDA to diagnose gastrinoma and assess pancreatic function. Anecdotal reports from "off-label" use of secretin in pediatric autism suggest that it may improve both physiological and behavioral symptoms associated with autism, a disorder characterized by severely impaired communication, social skills and development. There are no drugs currently approved for the treatment of autism.

Repligen Corporation develops new drugs for autism, organ transplant and cancer. Repligen also manufactures and markets a set of patented products based on Protein A which are used by the pharmaceutical industry to produce therapeutic antibodies. Its corporate headquarters are located at 117 Fourth Avenue, Needham, MA 02494. Additional information may be requested from www.repligen.com.

This press release contains forward-looking statements based on current management expectations. There are certain key factors which could cause future results to differ materially from those anticipated by management. Such factors include, but are not limited to: uncertainty in the realization of future revenues, the uncertain timeline for clinical activity, results of pending or future clinical trials, the Company's ability to continue to establish collaborative arrangements with third parties; the Company's ability to maintain financial stability; the technical risks associated with development and manufacture of clinical products; the fact that there can be no assurances that patents relating to the Company's potential products will afford adequate protection to the Company, the risks of technological change and competition, and the competitive environment of the biotechnology and pharmaceutical industries. These factors are more fully discussed in the Company's periodic filings with the Securities and Exchange Commission.

UPDATE ON PHARMACOLOGIC TREATMENT STUDIES IN AUTISM
Please visit http://www.autism-info.com/990322nt.html

The Use of Secretin for the treatment of Autism

Disclaimer: This website was copied/mirrored in response to media attention surrounding the use of secretin as an intervention for autism. The authors stress that any information contained on this site does not at this time constitute a recommendation for the use of secretin.

What is Secretin ?

Secretin is a polypeptide hormone involved in the regulation of gastric function. It is prepared from the duodenal mucosa of pigs. Following administration by intravenous injection, it causes an increase in the secretion of the pancreas of water and bicarbonate into the duodenum. It is used alone or in conjunction with pancreozymin or cholecystokinetic agents as a test for exocrine pancreatic function, and in the diagnosis of biliary-tract disorders.

Comments from Paul Shattock, Autism Research Unit.

Readers of the "Observer" and/or "Mail" and listeners to Radio will be aware that there has been interest in the potential use of a hormone "Secretin" for the treatment of autism. Perhaps a bit more background information would be useful. Secretin has been known for at least 20 years and it has a variety of functions but not much in the way of medical uses. One thing it has been used for is to test pancreatic function in other words to see if the pancreas is functioning correctly. A small amount is injected and the amount of "bicarbonate" which appears in the bloodstream is measured a short time afterwards. The bicarbonate secretion is required in order to neutralise the acid from the stomach and allow the enzymes in the duodenum to function. As well as secreting bicarbonate, the pancreas secretes many other enzymes including lipases and especially peptidases. These peptidases will break down the peptides which, according to proponents of the opioid excess theories of autism, may be responsible for the problems. One way to diminish the problems caused by these potentially harmful peptides is the remove them from the diet. That is why people experiment with gluten and casein free diets. Since secretin will stimulate the pancreas to produce these enzymes it could ameliorate the symptoms by this mechanism. It could, also or alternatively, be acting in the brain itself or in the intestinal wall (if it acts at all). There are numerous anecdotal reports (a hundred or so) of the benefits of this form of therapy from parents whom I have met and others with whom I have "talked" on the net. I have also discussed the effects with 5 physicians in the US all of whom are enthusiastic about what they have seen.

Some caveats.

There have been no proper trials to prove efficacy although there has been a brief report published by Karoly Horvath. The drug is not licenced for this purpose so it would take a fairly daring physician top prescribe this medication, in the UK, for this purpose and at this time. The drug without side effects does not exist. Secretin has not been used over periods of time so we don't know what will happen when it is. With products as complex as this we should expect them to occur. The benefits/advantages ratio will have to be taken into account. There are some children with whom no effects are seen anyway. This could be a significant contribution or it could turn out to be yet another gross disappointment. We will have to wait and see on this one.

Conclusion

There is no doubt that this is an interesting development but we will have to see if it pans out. There is a biomedical plausibility about the mechanism and results seem promising. Since the material is not readily available and it is not licenced for this particular use at the moment anyway, we have little alternative than to monitor progress with interest and some cautious optimism.

Paul Shattock

Karoly Horvath, M.D., Ph.D. Associate Professor of Pediatrics Pediatric Gastroenterology and Nutrition 22 S Greene Street, N5W70, Box 140 Baltimore, Maryland 21201-1595

References

Improved Social and Language Skills After Secretin Administration in Patients with Autistic Spectrums Disorders Karoly Horvath, MD, PhD, Gerry Stefatos, DPhil, Kenneth N. Sokolski, MD, Renee Wachtel, MD, Laura Nabors, PhD, and J. Tyson Tildon, PhD.

Autistic Behavior and Secretin. Journal of the Association for Academic Minority Physicians. January, 1998. Vol. 9, No.1. pp.9-15.

Abstract: We report three children with autistic spectrum disoreder who underwent upper gastrointestinal endoscopy and intravenous administration of secretin to stimulate pancreaticobiliary secretion. All three had an increased pancreaticobiliary secretory response when compared with nonautistic patients (7.5 to 10 mL/min versus 1 to 2 mL/min). Within 5 weeks of the secretin infusion, a significant amelioration of the children's gastrointestinal symptoms was observed, as was a dramatic improvement in their behavior, manifested by improved eye contact, alertness, and expansion of expressive language. These clinical observations suggest an association between gastrointestinal and brain function in patients with autistic behavior.

Additional References

Regulation of tyrosine hydroxylase activity in rat PC12 cells by neuropeptides of the secretin family.

Roskoski R Jr, White L, Knowlton R, Roskoski LM

Department of Biochemistry and Molecular Biology, Louisiana State University Medical Center, New Orleans.

Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, is subject to regulation by the cAMP as well as the calcium and cGMP second messenger systems. Treatment of intact rat PC12 cells with neuropeptides including secretin and vasoactive intestinal polypeptide (VIP) stimulated tyrosine hydroxylase activity 2 to 3-fold in vitro. Secretin (EC50 = 10 nM) was about 3 orders of magnitude more potent than VIP (EC50 = 3 microM). A combination of several protease inhibitors failed to enhance the potency of either peptide. Other members of the secretin family including glucagon and peptide histidine isoleucine (PHI) stimulated tyrosine hydroxylase activity to a lesser extent. Somatostatin, which is not homologous to secretin, was ineffective. The maximal response of tyrosine hydroxylase activation to 1 microM secretin occurred within 6-15 sec. Secretin, VIP, and forskolin also enhanced tyrosine hydroxylase activity (3,4-dihydroxyphenylalanine production) in intact cells, as determined by high performance liquid chromatography and electrochemical detection. Secretin, VIP, PHI, and glucagon increased the levels of cAMP in PC12 cells more than 10-fold, as determined by radioimmunoassay. We also demonstrated that cAMP is released from the cells into the incubation medium following secretin treatment. Secretin and VIP treatment also enhanced the activity of cAMP-dependent protein kinase in a concentration-dependent fashion, as measured subsequently in vitro. Based on the greater potency of secretin in comparison with VIP, PHI, and glucagon, we suggest that the PC12 cells contain a secretin-preferring receptor that increases cAMP levels and brings about an activation of tyrosine hydroxylase activity through the stimulation of cAMP-dependent protein kinase.

Added by Steve Cory October 22, 1998 at 00:31

More Secretin Information

Secretin may be something wonderful, but I have problems with the present experiments.Below is what I think. I must say I am deeply worried because not even the most elementary animal tests with repeated injections has been done.

The structure of human secretin is:
H-S-D-G-T-F-T-S-E-L-S-R-L-R-E-G-A-R-L-Q-R-L-L-Q-G-L-VNH2
Porcine
H-S-D-G-T-F-T-S-E-L-S-R-L-R-D-S-A-R-L-Q-R-L-L-Q-G-L-V NH2

The sequence E-G-A is replaced with D-S-A which may or may not be enough to induce antibodies.

Human synthetic secretin can be obtained from Bachem, AG, CH-4416 Bubendorf, Switzerland. E-mail: sales.ch@bachem.com for information.
If you therefore use porcine secretin there should be tests for antibodies against secretin included in the protocol. This is important, because antibodies would cross react with human endogenous secretin. (Destroy endoegnous secretin effects and gradually injected supply too). I am not disputing effects, but want to be safer. (No behavioural tests have been done before and after, only subjective judgement). There is a vast difference between removing something and repeatedly injecting a compound not studied at all with repeated injections over probably years. I would therefore not use this before some elementary studies on IV use repeatedly has been done in animals. I would also make sure I only used the human secretin before the possibility of inducing antibodies has been excluded. The present preparation is only to be used once for diagnostic purposes, no one anywhere knows what repeated injections will do. After all this is more pharmacological than physiological conditions. So many hormones also have trophic effects (eg. cancer inducing ???). In fact this is a series of human first experiments.

I really do not know, but I am worried and would at least be very cautious.

All the best
KLReichelt

K. Reichelt
Pediatric Research Institute
N-0027 Oslo, Norway

Autism Meeting on Secretin

I thought that I'd summarize an information session that Dr. Leve and his wife Barbara was kind enough to host at their house the other night regarding the use of Secretin in the treatment of Autism.

I'm sure everyone watched the Dateline show which sent the message that Secretin helps more than 60% of the autistic children that have been given the infusion. Well, some local parents who recently attended the autism seminar in NJ (a portion of which focused on secretin) gave the material to Dr. Leve and he researched some of the facts (he is an endocrinologist and has an autistic grandchild) and asked some parents to share their understanding of secretin in a gathering that he hosted Sunday evening at his house.

Present were about 40 parents along with Dr Leve, his wife Barbara, and Dr. Foster. About three of the parents present have already been giving their autistic children secretin and all have had positive results so far. Other parents were there to share information and to learn more about it...

Dr Leve explained how secretin is a normal hormone in humans, but the chemical being used for infusion is made from swine cells (which result in a close resembelence to human... only 2 amino acids are different). He said that the hormone creates energy which helps particular cells do their job better and that some of these cells are neurotransmitters and can help in brain functions. Researchers have discovered secretin levels in the brain, but its main purpose is to aid digestion of food. Research is going on at several universities...Maryland, Arizona, UCLA, Texas, etc.

Caution...

Not much known on secretin. No big studies done yet in proper scientific format. Some autistic kids have been helped, most that have also had GI problems, and most have had severe ear problems in their past. Some past studies using pig intestine (not secretin though) turned out bad for kids, and one study in Skandanavia tried growth hormone which also did not turn out well (after initial encouraging results). Recently one secretin study showed 3 out of 4 kids developed a bad rash and were hypersensitive. All of these low volume studies are hard to draw conclusions from until the data is shared and proper research trials are conducted.

Secretin Manufacture

It is made by a company in Skandanavia with HQ in NYC. Not making much...very hard to get proper amounts from them. Drug is approved by FDA, but NOT FOR TREATMENT OF AUTISM. Johnson & Johnson is said to be doing some research and doctors are trying to get together to share information soon. Secretin has to be infused (slow injection) into the bloodstream right now although some work is being done using a patch, cream, and maybe a nasal spray. Pills are not viable since the acid in the stomach seems to break it down and it gets digested.

Experience of Parents

All 3 parents who are giving their kids secretin were pleased with the short term results. A 5 year old, a 7 year old and a 9 year old (all relatively low functioning) have taken doses of secretin and had better verbal communication, eye contact, and and were able to do multiple tasks for the first time. One child has been on secretin for a year and is doing well. Most improve within 24 hours from their first infusion. Infusions are normally given 4-6 weeks apart (effect starts wearing off in 3 weeks) and cost about $200-$300 each (although some Drs. charge much more and some less). A list of doctors giving secretin around the US was distributed, but most Dr.'s hesitate to give it for autism because it is not supported by the FDA. Other doctors who may be giving it have not made it known yet.

Diets low in gluten and casein seem to help autistic kids...all of the kids on secretin are also on these diets. Thought is that digesting gluten and casein may be part of the problem. Yeasts are also problems for kids. Most kids WILL NOT show an allergic test reaction to gluten and casein, but they re still problems because they will not be digested thoroughly and may form other compounds (morphine, etc.) from time to time. Autistic kids may have adequate volume of secretin in their blood, but it may not be "good" secretin and thus be ineffective. You can't just screen a kid for secretin to see if there is a problem.

Conclusion:

Dr Leve is attending a "physicians interested in secretin" meeting in Nov. and will update us on new information when he returns.

These are my own notes, so please just use them for rough information on what transpired at the meeting. A book recommended was: Biological Treatments for Autism and PDD by William Shaw. Also the Beck's (Dateline family featured) own booklet is out and can be purchased from the Autism Research International.

Hope this helps.
Mike Gorman MikeJG222@aol.com

Added by Steve Cory March 26, 1999 at 21:50

Finding a Doctor

The following is from http://www.autism.com/ari/secretin2.html ...
...
Finding a doctor: Many requestors ask for a list of doctors administering secretin. We have no list at this time. We have received hundreds of requests, and orders for Victoria Beck's secretin book from physicians, and after they have had a chance to read it, and as soon as we can make some extra time, we will write to all of these physicians to see if they are willing to be placed on a referral list. We cannot do that without their permission. We hope to have a list in January.

However, there really is no need for such a list in most cases, since administering the secretin is not a difficult procedure. It is generally given intravenously and takes only a few minutes to do (an IV "push" rather than an IV "drip"). Any physician can do it, if he or she wishes to. The secretin book contains all the information presently available.

Added by Steven Cory March 9, 1999 at 21:21

Secretin and Autism: The Role of Cysteine

By Susan L. Connors M.D. and Dorothy E. Crowell

Reprints: Susan L. Connors M.D., 38 Daniels Street, Hopedale, MA 01747
Much interest has recently developed in the possibility that secretin infusions may be of some therapeutic value in the cognitive and communicative functioning of autistic individuals. Whether or not the peptide can act directly on the CNS to contribute to the effects reported, or remains peripheral, with clinical advances somehow secondary to improved digestion, is unknown. The information accumulated to date is anecdotal, and no controlled safety or efficacy studies in children have been conducted. While secretin infusions have not yet been proven to produce any positive long-term effects, it must also be noted that there is more than one ingredient in the secretin preparation. Researchers have failed to consider that cysteine hydrochloride, added to stabilize secretin, is a biologically active compound in the central and peripheral nervous systems. There is a possibility that cysteine and its metabolite taurine could be responsible for some of the changes alleged to follow secretin therapy. Medical literature indicates that cysteine, given in the amount contained in an infusion of secretin, can have a significant impact on behavioral and immunological functions in children. We will focus here on the role that cysteine and taurine may play in reported improvements in autistic patients.

Cysteine is a sulfur-containing amino acid. It is obtained directly from the diet and by synthesis from two other amino acids, methionine and serine. Its functions include the synthesis of glutathione, and the formation of taurine (Stipanuk et al., 1994). By its incorporation into the tripeptide glutathione, cysteine acts as a detoxicant in most tissues. Clinically it is used to treat acetamenophen overdoses as N-acetylcysteine (Windholz et al., 1983).

Cysteine's concentration in human plasma is the lowest of the protein forming amino acids (Droge et al., 1991). The plasma concentration of cysteine depends upon blood volume, which is determined by body weight. Cysteine is commonly incorporated into pharmacological preparations as a stabilizer for peptides such as secretin.

Standard chemical calculations (available from the authors) show that a rapid infusion of 1.0 mg. cysteine HCl, as contained in a vial of porcine secretin, will produce a significant increase in the plasma concentration of cysteine. Since secretin is not currently given in a weight dependent manner, the lower the weight of an individual, the greater the increase in cysteine's plasma concentration. The increase in the cysteine level from one vial of secretin is negligible in adults, but almost doubles the plasma concentration in a 30 lb. child.

The mechanism by which secretin may influence the functioning of autistic patients, if it does, is unknown. It has been suggested that the peptide is acting centrally through a variety of neurotransmitter influences. However, in order to have a direct action in the CNS, secretin must cross the blood-brain barrier in sufficient quantity to produce an effect.

The blood-brain barrier is a specialized microvasculature that effectively limits the passage of molecules into the brain to those that are very small, e.g. oxygen, water and carbon dioxide, or those that are lipid-soluble. These brain capillaries also contain 'transport systems' which serve to bring specific nonlipid-soluble and large molecules through the cells lining them to the tissue spaces of the brain (Begley, 1994). Whether or not secretin itself crosses the blood-brain barrier remains to be proven. The peptide and its receptor have been found in the CNS in some studies (Leiter et al., 1994; Patel et al., 1995; Samson et al., 1982). However, secretin is a 27 amino acid water-soluble peptide, without a known transporter.

There is a possibility that secretin can enter the brain in the areas of the circumventricular organs (CVO), specialized tissues which lack a blood-brain barrier (Carpenter, 1991). The ratio of the total surface area of the vessels in the CVO compared to that of the blood-brain barrier vessels is small, only 1:5000. Certain peptides have been shown to enter the CNS at these locations in the rat brain (Begley, 1994). Studies have shown that receptors for some peptides do exist within the circumventricular organs of the rat (Ermisch et al., 1993), but secretin and its receptors have not so far been part of these studies. Whether or not secretin can cross the blood-brain barrier in sufficient quantities at the CVO to have an effect on the brain is therefore unknown. Cysteine, however, crosses the blood brain barrier using a specific transport system (Bannai, 1984; Wade & Brady, 1981).

Cysteine possesses excitatory neurotransmitter properties, acting centrally and peripherally at NMDA (N-methyl-D-aspartate) type glutamate receptors (Parsons et al., 1997). This effect in the CNS may be responsible for hyperactivity reported by some parents soon after a child receives secretin. In the presence of bicarbonate ions in the GI tract (such as the bicarbonate-rich pancreatic fluid induced by secretin) cysteine becomes a potent excitotoxin (Williams et al., 1991) which could account for anecdotal reports of loose stools or diarrhea a few days after a secretin infusion.

Cysteine and its metabolite taurine can also have inhibitory effects on the central and peripheral nervous systems. Cysteine serves an important regulatory function in the immune system. During T lymphocyte activation cysteine is produced by macrophages, is released into the extracellular space at a controlled and varied rate, and is taken up by the lymphocytes where it regulates the functional response of those cells. Later phases of T cell activation are heavily influenced by small variations in the extracellular cysteine supply, with an increase in the cysteine level strongly favoring interleukin-2 production by lymphocytes (Droge et al., 1991). Interleukin-2 easily crosses the blood brain barrier (Hanisch & Quirion, 1996), and in the central nervous system produces an analgesic effect which is mediated by a direct action on opioid receptors (Jiang et al., 1995). This narcotic type action may be responsible for some of the calming effects reported in autistic children after secretin therapy.

Through two enzymatic steps in the CNS and periphery cysteine is metabolized to hypotaurine, which spontaneously oxidizes to taurine (Weinstein et al., 1988). Taurine itself can influence physiologic functioning, acting as an inhibitory neuromodulator in the nervous system and muscle. By decreasing the intracellular concentration of calcium and inhibiting the release of other neurotransmitters, taurine modulates the membrane excitability of neurons and has a general depressant effect on the CNS (Hayes & Sturman, 1981).

Neuroanatomic studies (Bauman and Kemper, 1994) have shown findings consistent with a halt in maturation of certain brain areas in autistic children. Taurine is important as a neuronal regulator in immature brain tissue. A number of studies have indicated that developing axons use taurine throughout synaptogenesis to help stabilize the electrical properties of the axons until formation is complete (Sturman 1993). If any true benefits are being realized after secretin therapy, they may be due in part to the effects of taurine in immature brain regions, contributing to synaptogenesis and electrical stability, and to an inhibiting modulatory effect of taurine on the nervous system overall.

There exist anecdotal reports of normalization of stool patterns after secretin therapy, in autistic children with chronic diarrhea. While the mechanism for this is unknown, it is of some interest that taurine supplementation of preterm infants improves fat absorption and decreases steatorrhea (Sturman, 1993). This effect may contribute to reported GI improvements after secretin infusions.

In conclusion, it is possible that some autistic individuals might benefit from the metabolic and immunologic influences of the cysteine component of secretin preparations. Cysteine and its metabolite taurine clearly have been shown to have independent actions in the central and peripheral nervous systems. Cysteine is known to cross the blood brain barrier. It is not clear (and is unlikely) that secretin can cross. A placebo should be developed which incorporates the same concentration of cysteine as is found in the investigational compound. This would help delineate which effects reported in autistic children, if verified in controlled studies, are secondary to secretin and which are due to cysteine. If cysteine proves to be the active ingredient in the secretin preparation its effects and metabolism in autistic children must be carefully studied. Cautious administration of this amino acid would be necessary since cysteine has been shown at excess levels in vitro to be toxic to certain human neuronal cell lines (Parsons et al., 1997). The duration of the improvements and potential negative side effects of both compounds should also be examined.

REFERENCES

Bannai, S. (1984), Transport of cystine and cysteine in mammalian cells. Biochimica et Biophysica Acta, 779: 289-306.

Bauman, M. L. & Kemper, T. L. (1994), Neuroanatomical observations of the brain in autism. In M. L. Bauman & T. L. Kemper (Eds.), The Neurobiology of Autism (pp. 119-145). Baltimore: The Johns Hopkins University Press.

Begley, D. J. (1994), Peptides and the blood-brain barrier: the status of our understanding. Annals of the New York Academy of Sciences, 739: 89-100.

Carpenter, M. B. (1991), Core Text of Neuroanatomy (pp. 20-21). Baltimore: William and Wilkins.

Droge, W., Eck, H. P., Gmunder H., & Mihm, S. (1991), Modulation of lymphocyte functions and immune responses by cysteine and cysteine derivatives. American Journal of Medicine, 91, (Suppl. 3C): 140S-144S.

Ermisch, A., Brust, P., Kretzschmar, R., & Ruhle, H-J. (1993), Peptides and blood-brain barrier transport. Physiology Reviews, 73: 489-527.

Hamburger, A. & van Gelder, N. M. (1993), Metabolic manipulation of neural tissue to counter the hypersynchronous excitation of migraine and epilepsy. Neurochemical Research, 18: 503-509.

Hanisch, U. K., & Quirion, R. (1996), Interleukin-2 as a neuroregulatory cytokine. Brain Research Reviews, 21: 246-284.

Hayes, K. C., & Sturman, J. A. (1981), Taurine in metabolism. Annual Reviews in Nutrition, 1: 401-425.

Jiang, C. L., Lu, C. L., & Liu, X. Y. (1995), Multiple actions of cytokines on the CNS. Trends in Neuroscience, 18: 296.

Leiter, A. B., Chey, W. Y., & Kopin, A. S. (1994), Secretin. In J. H. Walsh & G. J. Dockray (Eds.), Gut Peptides: Biochemistry and Physiology (pp. 147-173). New York: Raven Press, Ltd.

Parsons, R. B., Waring, R. H., Ramsden, D. B., & Williams, A. C. (1997), Toxicity of cysteine and cysteine sulphinic acid to human neuronal cell-lines. Journal of Neurological Sciences, 152, (Suppl. 1): 562-566.

Patel, D. R., Kong, Y., & Sreedharan, S. P. (1995), Molecular cloning and expression of a human secretin receptor. Molecular Pharmacology, 47: 467-473.

Samson, W. K., Lumpkin, M. D., Vijayan, E., & McCann, S. M. (1982), Gastrointestinal hormones: Central nervous system localization and sites of neuroendocrine actions. Endocrinologia Experimentalis, 16: 177-189.

Stipanuk, M. H., Bagley, P. J., Hou, Y-C., Bella, D. L., Banks, M. F., & Hirschberger, L. (1994), Hepatic regulation of cysteine utilization for taurine synthesis. In R. Huxtable and D. V. Michaik (Eds.) Taurine in Health and Disease (pp. 79-89). New York: Plenum Press.

Sturman, J. A., (1993), Taurine in development. Physiological Reviews, 73: 119-143.

Wade, L. A., & Brady, H. M. (1981), Cysteine and cystine transport at the blood-brain barrier. Journal of Neurochemistry, 37: 730-734.

Weinstein, C. L., Haschemeyer, R. H., & Griffith, O. H., (1988), In vivo studies of cysteine metabolism. Journal of Biological Chemistry, 263: 16568-16579.

Williams, A. C., Stevens, G. B., Sturman, S., & Waring R. H. (1991), Hereditary variation of liver enzymes involved with detoxification and neurodegenerative disease. Journal of Inherited Metabolic Disorders, 14: 431-435.

Windholz, M., Budavari, S., Blumetti, R. F., & Otterbein, E. S. (Eds.). (1983), The Merck Index. Rahway, N. J.:Merck and Company, Incorporated.

Added by Benjamin Linson April 8, 1999 at 21:45

Information on Cysteine Hydrochloride

By Susan L. Connors M.D. and Dorothy E. Crowell Submitted but not published

March 24, 1999

Letters to the Editor

Wall Street Journal

200 Liberty Street

New York, NY 10281

Dear Editor,

As parents of autistic children and as professionals who treat these children on a daily basis, we find it necessary to respond to your article of March 10, 1999, " New Hampshire Mother Overrode Doubts on New Use of Old Drug". We are concerned that a reputable, high-caliber publication such as the Wall Street Journal would add to the sensationalism surrounding the purported therapeutic use of Secretin for children with autism. This "therapy" lacks published controlled studies to support its use, though many such studies are under way. In addition, although Secretin has been used for years as an aid in diagnosing gastrointestinal disturbances, and is approved as such for adults, its safety and efficacy in children have never been tested. Nothing is known of the potential long-term negative effects of Secretin. The hormone was first promoted on the basis of anecdotal reports of a child who has never been formally diagnosed with autism (Parker Beck). The fact that this subject appears at all in The Wall Street Journal tends to serve as an endorsement for Secretin, making it seem a legitimate and valid therapy. Parents who read the article may have little knowledge of the necessity for controlled studies in the scrutiny of new treatments.

We are also concerned about what parents are NOT told during their inquiries regarding secretin:

1) The reported improvements are, for the most part, temporary, and may not be measurable by standard cognitive, social and language testing methods.

2) Since Secretin is a porcine product, there is a possibility that repeated doses in humans could lead to antibody formation against Secretin by the immune system (as was the case with Insulin) and eventual lack of effect.

3) There is a theoretical potential for long-term adverse effects from Secretin such as pancreatic "burnout" due to repeated intravenous doses which are high compared to physiologic levels.

4) Secretin is currently prepared in Sweden following the same methods used in the 1970's when it was first extracted from porcine intestines. Although it is relatively safe to say that Secretin is free from viruses endemic to pigs, it is also true that the preparation cannot be "pure", that other smaller pieces of proteins are contained in the vial. These extraneous proteins would be an added burden to the child's immune system, which may react to them.

5) Secretin is not the sole physiologically active ingredient in the infusion. It requires a stabilizer, cysteine hydrochloride. This cysteine component is also biologically active in the central and peripheral nervous systems. The amount of cysteine in one vial of secretin is negligible for adults, but is significant for children. This fact will become a problem for "practitioners" administering three and four vials at a time since cysteine acts as an excitatory neurotransmitter and has been shown to be toxic at high concentrations.

6) After three to five days much of the cysteine injected is metabolized to taurine, a compound which has a generalized depressant effect on the nervous system, and may be responsible for the calming parents have reported after Secretin therapy.

7) People are assuming that Secretin has a direct action in the central nervous system, but it has never been shown that this hormone crosses from the bloodstream into the brain at all. Secretin's stabilizer, cysteine, however, does cross into the brain.

The events surrounding Secretin have mirrored the history of autism "research" in that parents, at great emotional and financial expense, are encouraged to try some new "therapy" that has no real data to support its use. Most therapies have turned out to have little or no effect. It would help legitimate research efforts if highly regarded newspapers could avoid adding to the feeding frenzy of Secretin. The shortage of this hormone created by the publicity of the "Dateline" broadcast last October pushed the black market price of one vial to $5000, as reported in the Canadian "National Post", even though the cost to manufacture and ship, according to Ferring Pharmaceuticals, is $175. Until positive and lasting results are shown by controlled studies, great caution should be exercised in advocating or using Secretin. The off-label use of Secretin has become a money-making venture for "practitioners" preying on a desperate population of parents.

Respectfully,

Susan L. Connors M.D., Hopedale, MA

Dorothy E. Crowell, Housatonic, MA

Deborah Fein Ph.D, University of Connecticut

William Chey M.D., University of Rochester Medical Center

Peter Murad, Somerville, MA

Gina Green Ph.D., New England Center for Children, Southborough, MA

Steve Auster, M.D., Worcester, MA

P.S. The information on cysteine is scheduled to be published as a Letter to the Editor in the July issue of The Journal of the American Academy of Child and Adolescent Psychiatry.

Added by Peter@Secretin-Cysteine.com http://www.secretin-cysteine.com/ March 24, 1999