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because of inflation in the level of equal dollar value available for support of research and training by this Institute.
This is particularly significant because during this time several areas of categorical research for this Institute have been mandated by Congress. These have been in the area of digestive diseases with which you are quite familiar, and also diabetes and arthritis.
This plan in support is true of two other Institutes, and I hope that this year you may find it possible and within your best judgment to try to reverse this. This
year is particularly important, we think, because two national commissions, one on diabetes and the other on arthritis, will be presenting their findings to you. These findings are going to be such that I feel sure you will be compelled to add some programs to this Institute's already heavy load.
It is such a diverse Institute-arthritis, metabolism, kidney disease but unless we are able to catch up some this year, I fear that the chance will be lost for getting the Institute in a position to handle its many responsibilities.
These deficiencies are both in the area of money and also in positions. I want to transmit to you the concerns we have that with ceilings that have been established on manpower, that unless this Institute gets additional positions it won't be able to continue its diverse programs and to expand them in the event hopefully that you provide some of the budgets we have requested.
So both moneys and positions are needed and I have been given figures in the range of 71 new positions that the Institute feels it needs during fiscal 1977.
Why the plea for money and positions? I would like to return to a pattern of testimony that we have used in previous years in which we report on recent reassessment efforts supported by your committee. Mr. Chairman, you know that about 9 years ago the digestive disease community had a national conference and developed a coherent pattern for research, patient care, and education. This has resulted in our presenting during the past 5 years proposals to you gentlemen, oftentimes in quite specific terms.
These specific terms related to areas that we felt were ready for rapid advances with adequate support.
I would like to review for you some of the things you have accomplished. First, the area of gallstones. You began supporting this program in 1973, 1974, 1975. We now have a natural bioacid that is capable of dissolving most of the gallstones that occur so commonly in the American public.
This program is moving. Now the animal studies have been done to insure proper safety for studying patients.
Ten centers have been set up over the country and are now and have been since last October enrolling patients in a study to see how rapidly this bile salt works, how safe it is, whether it can be used for prevention as well as for cure.
In 1974 you gave us funds to extend the research and the clinical activities using fibroendoscopes. Three grants have been made with these moneys, and as a consequence it is now possible to diagnose virtually all of the patients who have upper gastrointestinal hemorrhage at precisely the site of origin of the bleeding.
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Now three different approaches are being taken to stem this bleeding: one with laser beams, another with the application of an electrical energy, and also with physical factors such as clips.
, Finally last year we told you of a need for pure hormones to be used in studying the effect of gastrointestinal hormones on the digestive system. You provided moneys, and as a consequence a Swedish investigator, Dr. Viktor Mutt, has been synthesizing these hormones and providing them to our scientists for clinical studies.
We would like to suggest to you that during the coming year an area of which could be of critical importance is further additional funding for studies in the area of gastrointestinal hormones.
You might ask, what does that mean in terms of illness? The greatest practicability at the moment might be in the area of peptic ulcer. There has been developed a drug, cimetidine, which is the third of the drugs in this general category that can inhibit or stop the secretion of the acid, and this acid secretion is driven in part by gastrointestinal hormones.
Further support of the area of research in gastrointestinal hormones could well within the next 2 or 3 years provide a drug that will be extremely useful, perhaps of critical importance, in the treatment of peptic ulcer disease.
I would like to close by saying that the proposed citizens budget which will be introduced to you on April 6 is one that we can sincerely endorse, and we feel includes much needed funds for this Institute's progress and almost its survival in an effective manner during the coming year.
Second, we would favor the addition of positions. Whether this involves some modification in manpower ceilings or authorizations, I am not clear, but I do know that this is of critical importance where this Institute has so many diverse activities.
Finally, on the part of, to use the common approach of people testifying before you, the 18 million people in the country with digestive diseases, I would hope that the support of gastrointestinal hormone research would be most productive if you saw fit to endorse it.
Thank you so much. (Dr. Sessions complete statement follows:) Mr. Chairman, I am very pleased to testify today on behalf of the American Gastroenterological Association. I am Dr. John T. Sessions, chief of gastroenterology at the University of North Carolina School of Medicine.
A little more than a month ago, we wrote to you in support of your effort to have the House override the veto by the President of the HEW appropriations bill. That veto, if sustained, would have caused very serious problems for research in digestive diseases, at a time when we are obtaining singular success in advancing our research efforts in several areas.
The President's proposed budget for fiscal year 1977 would do the same. In particular, the National Institute of Arthritis, Metabolism, and Digestive Disease would be very severely affected.
Mr. Chairman, for a number of years the NIAMDD has suffered an actual decline in the number of real dollars available to it for research. In fact, it is, I understand, only one of three institutes which has less research funding available in fiscal year 1976 than it had in 1967. I ask you now to study this chart which shows in graphic form this decrease. The blocks show appropriated dollars; the line shows actual dollars devaluated for inflation, the unusual peak occurring in fiscal 1973–74 resulted from the release of impounded funds.
The American Gastroenterological Association supports most strongly the citizens budget for this institute to be proposed formally on April 6 to this committee. The total available would be $224 million.
over the past several years : since 1972 there have been three major health laws
I have inserted in my testimony at this point an outline of the proposed citizens' budget, and request your support of it.
Mr. Chairman, you have heard from witnesses for the past several years from the American Gastroenterological Association testifying about digestive diseases research, and the impact of the diseases upon 18 million Americans. I would now like to report on how our research is going in three areas of research, which could not have been possible if you had not specifically named them in your bill report language as areas worthy of vigorous research efforts.
1. Efforts directed toward gallstone therapy (responding to language in the
House appropriations bill report 1973, 1974, 1975) A. National cooperative gallstone study (chenodeoxycholic acid).—Even though accurate figures are not available, gallstones are estimated to be present in approximately 10 percent of the total population and 30 percent of the population over the age of 65. In the United States, about 85 percent of the gallstones are of the cholesterol type and about 15 million people in the United States have this type. In 1972, a group of researchers at Mayo Clinic showed that the oral administration of the natural bile acid, chenodeoxycholic acid, could dissolve cholesterol gallstones. In 1973, the National Institute of Arthritis, Metabolism and Digestive Diseases initiated a large-scale effort to evaluate the usefulness and safety of this agent, chenodeoxycholic acid, in dissolving gallstones. Two years of effort were required to test the agent in a wide variety of animal species, to select the 10 treatment centers throughout the United States which would treat patients, to work out methods of procedure and protocol so that all of the patients could be treated in a uniform manner and to insure that all safety precautions were observed.
In October 1975, the clinical phase of the study began at the 10 centers (CedarsSinai, Los Angeles, Calif. ; Cornell, New York, N.Y. ; Duke, Durham, N.C.; Emory, Atlanta, Ga.; Mayo, Rochester, Minn. ; University of Minnesota, Minneapolis, Minn.; University of Pennsylvania, Philadelphia, Pa.; University of California, San Francisco, Calif.; Scott & White Clinic, Temple, Tex. ; and Yale, New Haven, Conn.). Fifty patients have currently received the initial screening and of these, 31 were found eligible for further testing. Most of these will then be randomized into one of the three groups being studied : placebo, 375 milligrams per day chenodeoxycholic acid and 750 milligrams per day chenodeoxycholic acid. It is estimated that approximately 2 years will be required for screening and performing the necessary testing of the 1,000 patients who will eventually be studied. Each patient will receive the medication for 2 years or until the gallstones dissolve, whichever occurs first.
B. Other agents.-Ursodeoxycholic acid, an unusual bile acid found in bear bile and which closely related to chenodeoxycholic acid, is being tested in a small trial supported by the Institute. This agent has the potential advantage of not having to be converted in the intestine to a product which is harmful to the liver, if present in high concentrations.
Phenobarbital, a commonly used sedative, can cause an increase in the flow of bile and some decrease in the cholesterol saturation of the bile. While this agent, given for periods up to 1 year, was not able to dissolve gallstones alone, it is being tested by Institute grantees to see if it may improve the dissolution of gallstones when given together with bile acid.
B-glycerophosphate has recently been reported to decrease cholesterol saturation in patients with gallstones, but its efficacy in dissolving stones has not yet been tested. II. Efforts directed toward gallstone prevention
Cholesterol-saturated bile is a prerequisite for the formation of cholesterol gallstones and the incidence of gallstones within a population seems to be correlated with the prevalance of saturated bile. If populations at risk could be identified by the saturated bile, such as has been seen in young American Indian women, it might be possible to use agents prophylactically ; i.e., to prevent stones from forming.
As a followup to the national cooperative gallstone study, plans are being formulated for a followup study on those patients in whom gallstones are dissolved with chenodeoxycholic acid. If chenodeoxycholic acid proves to be completely safe as well as effective, then there will be a need to determine the indications for its prophylactic and therapeutic application and the need for continued or intermittent treatment after existing stones have been dissolved.
EFFORTS DIRECTED AT UNDERSTANDING PROCESSES OF GALLSTONE FORMATION AND
In addition to the main clinical trial, a number of important ancillary studies are being performed simultaneously in some of the patients participating in the trial to learn more about the disease. The following are some examples :
1. Studies to determine if we can predict in advance which gallstone patients will benefit from drug administration; for example, bile samples are being collected from patients in the trial to see if the amount of desaturation of the bile will indicate the degree of success of stone dissolution.
2. Studies to determine if we can predict in advance which patients may experience side effects from the drug; for example, by analyzing the bile for a degradation product which may cause side effects, the drug could be stopped before any problem could occur.
3. Studies to see whether unusual bile acids are found in bile of patients on the drug, and if these have any predictive value.
4. Studies to see whether cholesterol metabolism is changed in gallstone patients and whether key liver enzymes are modulated by the drug to correct any inbalance.
The marked stimulation of research in this area has caused the development of vital information in our understanding of the disease process.
For example, as a result of recent funding by the NIAMDD, there have been very elaborate, detailed, and definitive studies which have shown that obesity is clearly related to gallstone formation and the mechanism by which this occurs has been elucidated.
As another example, it has been found that women on birth control pills, and postmenopausal women on estrogens have a 2 or 212 times risk of gallstone disease over that of control groups, and recent research has shown that the pills produce lithogenic bile, which causes gallstones. That raises a further important question, which is just how this process occurs.
These examples point up the very great value of congressional interest, and in particular, the interest of your committee, in this field, and what the support of the NIAMDD has produced.
There are several other questions that are being looked into:
About 15 percent of gallstones are of the bilirubinate pigment type in the United States. What is the triggering factor(s) in this type of stone formation ? In Japan, the predominate type of stone is the pigment stone. Why?
GASTROINTESTINAL HORMONE RESOURCE (RESPONSE TO HOUSE APPROPRIATIONS BILL
REPORT LANGUAGE, 1975) It has become increasingly evident over the past few years that the functions of the stomach, intestines, gallbladder, and pancreas, are greatly influenced by hormones. Disorders of a hormone, that is too much or too little, may well be related to disease. In fact, one condition in which patients have recurring peptic ulcers has been shown to be due to an excess of a hormone, Gastrin. With the advanced biochemical, immunological, and radioisotope techniques that are now available, investigators are able to identify hormones that were never recognized before and to assay and study the activities of the known hormones. From such studies, it is hoped that we can learn more about the relationship between hormones and disease.
However, pure hormones are present in the body of men and experimental animals in very small quantity, and one of the factors that has delayed the progress of investigation has been the lack of pure hormones for study. Some of the best preparations were obtained from the Karolinska Institute in Sweden where a former grantee of the NIH made them available to a few investigators out of courtesy. But, with the increasing demand it was impossible for him to supply hormones to all investigators without support. When a committee of ex