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THl; COUNCIL FOR TOBACCO R~SEARCH - U.S.A • 88s TIUMD AV'ENIIE =4+I1TTEE: . NE{V YORK. N. Y. 10017 Dr. Catte~, Chm6 Dr. Bing Dr. Jacobson Application FonResearch Grant Date3rAugust, 1967 of Urology; Peregrina Labay, M.D. , Research~Associate in Urology 2. Institution & Address: Division of Urology, Department of Surgery Duke University Medical Center Durham, North Carolina 27706 3. Short file of Project: Nicotine Effect on Ureter in Man: A Possible Therapy for Hydronephrosis. 1. MlameofInvestigator(s):(includeTitteandDegrees) Saul Boyarsky, M.D.,Prof. of Urology, Director, Urological Research; James F. Glenn, M. D. ,Prof. of Urology, Chairman Division 4. Proposed Starting Date: December 1, 1967 S.AnticipatedDurationofthisSpecificStudy: Three years C Q Brief Descripton of Objectives or Specific Aims: In recent animal experiments we have demonstrated conclusively that nicotine accelerates the peristaltic rate of the normal and abnormal ureter and increases the force of contraction. The renal pelvis and ureter are thereby emptied super- normally by nicotine action. This nicotine effect' has been demonstrated in our laboratory by several in vivo techniques, cinefluorography, peristaltic pressures, surgical observation, as well as in vitro and in abnormal ureter such as diverted'y ligated' and pharmacologically- blocked ureters. Nicotine proditces these effects whether administered by the intravenous, intiraarterial, pulmonary or topical routes. The drug releases catecholamines from sympathetic nerve endings and the adrenal gland in addition to its cholinergic action, and its release of antidiuretic hormone. Hence, cigarette smoking may be a "natural" for the treatment of hydronephrosis which is characterized by depressed motility of the renal' pelvis and ureter, and excessive collection of urine in the renali pelvis. The human uretea resembles the dog ureter pharmacologicalUy in every respect we have had an opportunity to study. Our assays of surgical specimens have shown that the dog and human ureters have a similar catecholamine content. The humann ureter responds in vitro to the same spectrum of drugs as the dog ureter. 7. GiveaBriefStatementofyourWorkingNypothesii: Since nicotine accelerates ureteral'peristalisis in dogs, and the human and dog ureter are similar pharmacologically, the effect of nicotine on the normal and hydronephrotic human ureter would be eXpected' to stimulate peristalsis and to restore tone. C~

8. Details of!Experimental Design and Procedures: (Attach Separate Pages) It is proposed to study normali voluntee: s and urologic patients by cinefluorography to determine the effect of nicotine and tobacco smoke upon ureteral peristalsis in . ~ health and disease. laboratories in related fields provides the background for this study in a university Duke University Medical Center with its library, faculty and plenitude of research passed also. 9. Physical Facilties Available (Where Other than Administering Organization Indicate Geographical location)', metric pressure. studies of peristalsis will' be performed whenever catheters are catecholamine assays of surgically excised ureters and renal pelves; and c) mano- -in terms of rate, rhythm and character of bolus progression. contrast medium willi allow us to describe ureteral peristalsis and pelvic peristalsis ' 1) Observation of the ureter during a slow intravenous infusion of concentrated 2) The effect of nicotine administration and'tobacco smoking upon this control rate will be determined. 3) Patients with ureteral obstruction, hydronephrosis, dilated' renal pelves and surgical lesions of the pelvis will then be studied t'o note the effect of nicotine upon ureteral and pelvic function in these patients. 4) Ancillary studies will include a) in vitro motility studies; b) fluorozrnetric C medical center. See addendum Page 2a, 10i Additional Requirements: This proposal is actually for a part of our total needs. The requested unit' will be an integral part of several larger projects mentioned above and already in progress. _ Salaries, supplies and staff are available through these projects. The annual budget is actually between 2 to 3 times the amount of the present request. Our present need' is for this equipment, not salaries or supplies. The salaries needed to use the equipment are being funded from other sources, so that the budgetary deletions would represent a "savings" in one sense to the Council for Tobacco Research. ( 11, Biographical sketches of oil principal and professional personnel (append) ' 12. list of publications: (Five most recent as pertinent) (append)

Council for Tobacco Research Saul Boyarsky, M. D. Addendum to No. 9, Physical Facilities Available ,.: Three hospital services, the Duke Medical Center, Durharn Veterans Administration Hospital and the affiliated Watts community Hospital provides some 80-100 urologic beds. :;.The research laboratories include 2200 sq. ft. in~ the new Clinical Research II Building and some 1200 sq. ft. in the Bell Building animal laboratories and the ~ Yeterans Administration Hospital adjacent to the Duke campus. `; At present these laboratories are complete for animal cinefluorography (obsolete for patient use), animal surgery, electrornanometry, chemical, histo= '. logic and physiologic studies. However, we have not yet fund'ed the cinefluorographic unit for which adequate space has been provided in our new laboratories. These laboratories will pass from the contractor to Duke University within the next 6-8 weeks. ~. The research staff is one of the largest in any urology department in the country We have a full-time research professor who is the principal investigator of thils . project, a full-time research associate, a pha"rmacologist and a bioengineer in the ` Division of Urology, a half-time radiologist as well as a collaborating biochernist, ;r (Dr. Norman Kirshner of catecholamine fame) and a physiatrist, Dr. Robert Gregg .' A USPHS academic urology training program supports three pre-residency ~ research fellows and two post-residency research fellow s at present engaged in r'? research (three full-time an6 two half-time). We have five research technicians, ~; two research secretaries, and two research nurses in the urology research laboratory "As will be d'etailed, below under the additional research support section and in the presentations section, active research programs are in progress in surgical .physiology of the ureter, in the area of catecholamine biochemistry, in ureteral neurology, in human diagnostic cinefluorography of the ureter, ureteral reconstruction and pyelonephriitis. Funds are needed for the cinefluorographic unit so that patients can be studied in the urologic facility properly, rather than when an opening on a unit located in the Radiology Department becomes available. Backing from Dr. Richard Lester, Professor and Chairman of Radiology, is enthusiastic as is evidenced' in part by his assignment of Dr. William Barry, Associate Professor of Radiology to Uroradiology.

4~ : ` Council for Tobacco Research Saul Boyarsky, M. D. ' Addendum to No. 12, List of Publications ,Boyarsky, S. , Labay, P. , Kirshner, N., and Gerber, C. : Does the Ureter Have Nervous Control?, J of Urol., 97:627, 1967 (April). The Neurogenic Bladder, Saul Boyarsky, M. D. (Ed. ) The Williams and . Boyarsky, S., Kirshner, N. and Catacutan-Labay, P. : Catecholamine Monographs of.the Surgical Sciences, Vol. I, pp. 173-2:1i3, June, 1964. No. 2 -Wilkins Co., Baltimore, Maryland, March, 1967. Boyarsky, S'. , Labay, P., and Kirshner, N. : Accelexation~ of Ureteral Peristalsis by Adrenal Compression, Science,, 154:669, 1966. Content of the Normal Dog Ureter, Invest. Urol. , 4:97, 1966. . Boyarsky, S. : Surgical Physiology of the Renal Pelvis and Ureter,

r A. Salaries (Personnel by names) Professional B. Consumable Suppiies(list by categories) i % time Amount ' Sub-Total Sub-Total :Saul Boyarsky, M. D. 'Duke Utiiv Med Ctr D. Permanent Equipment (itemize) $61, 950 61 50 Hydradjust Table 9'r image intensifier Vidicon with 500 MA generator cinefluorographic unit C Saiaries Consumable SupplJ Other Expenses Permanent Equip. C . 13. Budget: (lst year) It is understood that the applicant and'institutional officers in applying for a grant have read'and found acceptable the Council's "Statement of Po6icyLontaining Conditions and Terms Under Which Project Grants Are hSode." Signature ttAJ _ 2 681 b D~ <rlorosvroi«t , 919) rJ ~ , _~ Teiephone ~ ~ ~/ Signature BuePnns Obflkecof th<.IhstiluNon S.; C. Harward ComtrolLer Telephone 111111CM1111111111111 `_

4. Other Sources of Financial Support List financial support for research from all sources, including own institution, for this and/or related research projects. Current ritle of Projed Pathophysiology of the Scarred Ureter in Dogs Pathophysiology of Ureteral Obstruction in Man The Ureter in Pyelonephritis Workshop on the Optimal Care of the Neurogenic Bladder Patient In Vitro Studies of the Ureter Ureteral Pharmacology Toxicology and Pharmacology of Ureteropelvic Motility Source NIH NIH NIH NIH Vocational Rehabilitation n Administration NIH NII-I' Army Amount Duration 17, 500 7/1/67 - 6/30/68 17,000 7/1/67- 12/31/67 14,565 7/1/67- 6/30/68 20, 410 8/1/67- 7/31/68 14,966 8/1/67- 7/31/68 36,828 7/1/67- 6/31/70 20,614 7 /1/ 67- 6/30/73 19,248 7/1/67- 6/30/68

• Saul Boyarsky, M. D, Duke University Med Ctr Progress Report: lnclude in sufficient detail, for, purposes of evaluation, accomplishments related -`; to the original goals of this project, and information concerning any new , lines of investigation which have been followed. (Tables and figures may be included.) Attach additional pages as required. ;;Effect of Nicotine: r The effect of nicotine upon the function of the renal pelvis and ureter has een established. Ureteral peristaltic frequency is accelerated by a factor of 2 to 5 under optimal doses. This has been demonstrated by the methods of peristaltie` ~.~.- . pressures, cinefluorography, and direct' observation at laparotomy in the dog. Our studies show that nicotine reaches ureteral receptors whether administered topically intravenously, intraaortically, or by inhalatirn . The classical biphasic effect of r~ ° nicotine is observed on the ureter as well as elsewhere, that of preliminary excit- afion followed by a longer lasting depression of activity. Dose-response curves have not been established completely and definitely yet; work is underway to gather this `~ data. r z s`. Localization to Ureter: Yl.~ Critical experiments have demonstrated that the nicotine effect is entirely. ;4separate from that of any antidiuretic effect which may be also introduced. In vitro °.~tudies have demonstrated inconstant, unpredictable and weak effect of the drug ~ acting d'irectl'y on the srnooth muscle of the ureter. These studies are continuing. Nicotine Analogues and Metabolites: With, the cooperation of Dr. Charles H. Jarboe, Assistant Dean and Associate Professor of Pharmacology, University of. Louisville, School of Medicine, we have ' instituted pilot studies on the ef2•c cts of nicot:n-_ moaon-lethiod'ide and other analogues. here does seem to be ureteral activity inherent in, these compounds. , , ; .. a; ~ ~~.:. .. . ..: ~ . . ~ r;%. . . . . .. . . . Studies with a batch of cotlinine, kindly supplied by Dr. Herbert McKennis, Professor of Pharmacology, the Medical College of Virginia, has shown that these breakdown products of nicotine are inactive. Mechanisin of Action: The rrech3nism, of action of nicotine on the ureter is under investigation. Studies on the adrenallectornizcd dog and reserpinized dog, are continuing in order to demonstrate the rolie of intrinsic c vechoian-Lines, vis-a-vis the role of systemic catecholartiines secre'ed by the adrenal gland. Correlati•,n \srith Re:nal F,ffects: ~The long series of experinler.t:i oni tht:~ different:all effect of topical and nicotinic • nerve stimulation has shown that thore are overlapping effects between ureteral perist'alsis and renal secretion of uri:1e. 1003547078

AMA Progress Report `° Effect of Nicotine, on, the Urtnary Trae-t ~ Ureteral Peristalsis Sau1 Boyarsky, M.D. :;. . 'At present problems remaining to be investigated include: e74effect of adrenal cortical hormones in supporting muscular contraction role of the cholinergic system in ureteral peristalsis.. ontimuing-call-c-cti~on-of data to fill out dose-response curves ~,r;:<; Elucidation of the renal pelvis and ureter as a delicate neurornuscular .mechanisrn -rather than an autonomous muscular tube represents a fundamental advance in Urology and in U'seteral Physiology which should have far reaching s `..diagnostic and therapeutic effects. The rapy: Therapeutic uses are suggested by present research and should be welcome. One of the objects of our research is to develop drugs which can be used in the . reatment of ureteral colic and similar disorders. =Other Benefits of Research: .~ _ he Tesult of this project on our laboratory has been most beneficial. Our g1'oup ha`s`grown-to embrace bioengineer, pharmacologist, and radiologist in addition '.to the Urolo y research fellows. The additional equipment has increased the efficiency of.our efforts, particularly the tape recorder which has allowed immediate analysis ;~,.of cinefluorographic experiments and longer periods of observation, at lesser expense than was previously possible with cinefluorographic film alone. Does the Ureter Have Nervous Control?, Physiologic, Pharmacologic and Biochemical _ Evidence for Sympathetic Innervation, Peregrina Labay, American Physiological Society, Houston, Texas, August29-Sept 2, 1966. ftecent Advances in Ureteral Physiology, Saul Boyarsky, Pan Pacific Surgical Association Annual Meeting, Honolulu, Hawaii, Sept 20-28, 1966. ~: Symposium on Urologic Education, Saul Boyarsky, Landmark Inn, Duke University Sponsor, Div. of Urology, Durham, N. C. August 29-Sept. 2, 1966.

~~.Ureteral Pharmacology and Toxicology, Saul Boyarsky, Edgewood Army Arsenal, Edgewood Arsenal, Maryland (March 24, 1967)~. re Ureteral Nerves Functional?, N. Kirshner, S. Boyarsky, P Labay, C ,,Gerber .,~ and J.. F._ Glenn, American Heart Association, New York, New York -' Oct•ober 21-23, 1966. urther Ureteral Neurophysiology Explorations -- Evidence for Nerve Influence 11 on Ureteral Peristalsis, Saul Boyarsky, Spinal Cord Injury Conference, West Roxbury, Massachusetts, Nov. 7-9, 1966. Ureteral Peristalsis from Conduit to Control Mechanism (Taylor Lecture) Saul `' : Boyarsky, University of Oklahoma, Oklahoma City, Okla., Nov. 17-19, 1966. >, -Is There a Physiologic Basis for Ureteral Pharmacology?, Saul Boyarsky, Physiology Pharmacology Seminar, University of Oklahoma, Oklahoma City, Okia. Nov. 17-19, 1966. EXHIBIT: Physiologic Diagnosis Through Urodynamics, R. D. Ensor, S. Boyarsky,.*; 1 and J. F. Glenn, Southeastern Section of American Urological Association, y; Hollywood Beach, Florida, April 9-13, 1967. 'reteral Peristaltic Acceleration by Renal Nerve Stimulation, Peregrina Labay and- .;: }, Saul Boyarsky, American Physiological Society, FASEB, Chicago, Illinois, April18-19, 1967. More Evidence for Ureteral Nerve Function and Its Therapeutic Implications, Saul Boyarsky, Peregrina Labay and J. F. Glenn, Annual Meeting of the Society of Genito-Urinary Surgeons, Rye, New York, May, 1967. EXHIBIT- Physiologic Diagnosis Through Urodynamics, R. Dale Ensor, Saul Boyarsky, and James F. Glenn, American Urological Association, New York May 1967, lst Prize. In Vitro Studies of Ureteral Smooth Muscle, J. Malin, S. Boyarsky, and P. Labay, American Urological Association, New York, May 1967. The Effect of Topical Nicotine on Ureteral Peristalsis, Peregrina Labay, and Saul Boyarsky, American Medical Association 116th Annual Convention, Atlantic City, New Jersey, June 18-22, 1967.

~ ..A.~ ...,V-~. . r ~.• - ~ ... ~ ~`~ A i L ma , n ` G. June Yiautz, Yerzgrina Labay anr! Saul 13oyarsky MOVIE - 'The Effect of Nicotine on Ureteral Peristalsis - The Experirnental. presented at the following meetings: . Symposium on Urologic Education, Landmark Inn, Duke Univ. Division o Urology, Sponsor, Durham, N. C. , Sept. 1966. American Urological Association, Annual Meeting, New York, May, 1967 .116th Annual Convention of the American Medical Association, Atlantic City, New Jersey, June 18-22, 1967 n Does the Ureter Have Nervous Control?, Saul Boyarsky, Peregrina Labay, Norman Kirshner, and Carl Gerber, J. of Urol. , 97:627, 1967 (april) AMA Prot rens Report Effect of Nicotine on the Urinary Tract: ~~Ureteral Peristalsis Saul Boyarsky,-M: D. _ The Effect of Topical Nicotine on Ureteral Peristalsis, Peregrina Labay . and Saul Boyarsky, JAMA, 200:209, 1967.