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The original negative
seretin study can be viewed by clicking
here.
Dr. Horvath (the first physician in the world to use secretin
for autism) writes:
The lack of benefit
from a single injection of secretin in the study by Sandler et al. (Dec.
9 issue) 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.
Dr. Rimland (one of the pioneers in natural autism therapy and founder
of the Autism Research Institute) writes:
As the father of an
adult son with autism, I commend Sandler et al. for their report on the
administration of secretin in children with autism and related disorders.
I am impressed with their straightforward acknowledgment of several major
limitations of their study and their candor in revealing that many parents
continued to be interested in secretin after being told of the negative
study results. A number of parents whose children participated in the
study have informed me that their children have continued to receive secretin,
with noteworthy improvement.
In sharp contrast
to the appropriately temperate position of Sandler et al., Volkmar, in
an editorial accompanying the report, displays an unseemly eagerness to
discard secretin. He overlooks a major deficiency in the study: the lack
of instruments designed to evaluate the effectiveness of treatments for
autism. Volkmar is coeditor of the Handbook of Autism and Pervasive Developmental
Disorders, (2) which includes the statement that diagnostic checklists,
such as those used by Sandler et al., are not sensitive enough "to
measure change in response to treatment." Sandler et al. acknowledge
this limitation, but in his editorial, Volkmar does not.
We are in the top
of the first inning -- it is much too early to reach a negative conclusion.
There is a great deal to learn, and a great deal to be gained, from the
continued intensive study of the effects of secretin on autism.
Dr. Herlihey (president of Repligen, the company that has the patent
on the new secretin which is not yet available) writes:
The study by Sandler
et al. has numerous critical limitations. As the authors note, only a
single dose of secretin was evaluated over a period of one month, an unrealistically
short assessment period for a chronic disease. A second limitation was
the divergent diagnoses and variations in the severity of disease. Fully
33 percent of the children did not meet the diagnostic criteria for autism,
and the variance in severity was statistically equivalent to the full
range of functioning found in autism.
A third limitation
was the use of the Autism Behavior Checklist as a primary method of assessing
changes in autistic symptoms. This checklist was designed as a screening
tool to distinguish children with autism from those with mental retardation
or emotional disturbances. The checklist consists of 57 symptoms, which
are graded as present or not present. Each symptom is assigned a weight
of one to four in the calculation of the overall score. For example, "Does
not follow simple commands given once (e.g., sit down)" has a weight
of one, whereas "Speech is atonal and arrhythmic" has a weight
of four. Atonal speech is more heavily weighted because it better distinguishes
autism from other disabilities. Such weighting is not justified when assessing
change, particularly in the context of a study in which compliance with
commands is an anecdotally reported benefit in some children and a change
in speech patterns is not.
In addition, the Autism
Behavior Checklist assesses various levels of symptoms, including many
that are appropriate to evaluate only in persons with a relatively high
level of functioning. "Has pronoun reversals (e.g., you for I)"
is an inappropriate assessment for a nonverbal child. Of the 13 items
in the language section, only 2 assess the emergence of expressive language,
which has been anecdotally reported in some children treated with secretin.
Furthermore, several items on the checklist involve historical facts,
which by definition are unresponsive to drug treatment.
Given the limitations
of the single dose, the heterogeneity of the patients, and the problems
with the primary assessment tool, is it any surprise that many parents
and Dr. Sandler himself continue to express an interest in the evaluation
of multiple doses of secretin in patients with autism?
Drs. Said and Bodanszky write:
We find it difficult
to ignore the numerous, albeit mostly anecdotal findings of other investigators,
who noted dramatic improvement after a single injection of secretin. Although
the apparent improvement could indeed have resulted from a placebo effect,
we believe the discrepancy between the negative results reported by Sandler
et al. and the positive results reported by others may be due to the fact
that two different preparations were used. The positive effects were observed
with the use of secretin isolated from hog intestines, whereas the negative
effects were reported with the use of a synthetic preparation of human
secretin.
It is conceivable,
though unlikely, that the small difference between the sequences of human
and porcine secretin (a difference in 2 of 27 amino acid residues) accounts
for the strikingly different results. It is possible that the natural
material contained an active "impurity" -- for instance, another
peptide, most likely vasoactive intestinal peptide. This peptide is closely
related to secretin, and the two are present together in the same peptide
fractions during the process of isolation from intestinal extracts. Vasoactive
intestinal peptide and its receptors are widely distributed in many organs,
especially the brain, where the actions of the peptide include the protection
of neuronal cells against a variety of insults.
The possibility that
the synthetic preparation was not intact secretin should also be considered.
The amino acid sequence of secretin is conducive to the conversion of
the two aspartyl residues to aminosuccinyl residues, with the possible
subsequent formation of inactive (beta)-aspartyl peptides. Investigators
experienced in the synthesis of secretin have reported the occurrence
of this process during its synthesis and purification or storage. Sandler
et al. did not characterize the synthetic material with respect to its
homogeneity, its amino acid composition and sequence, its conformation,
or its biologic activity on the basis of the stimulation of pancreatic
bicarbonate secretion.
The
New England Journal of Medicine -- April 20, 2000 -- Vol. 342, No.
16
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