<pre style="white-space: pre-wrap">xt76dj58d94c https://exploreuk.uky.edu/dips/xt76dj58d94c/data/mets.xml Lexington, Kentucky University of Kentucky 19830410 minutes English University of Kentucky Contact the Special Collections Research Center for information regarding rights and use of this collection. Minutes of the University of Kentucky Board of Trustees Minutes of the University of Kentucky Board of Trustees, 1983-04-mar10-ec. text Minutes of the University of Kentucky Board of Trustees, 1983-04-mar10-ec. 1983 2011 true xt76dj58d94c section xt76dj58d94c 


   Minutes of the Special Called Meeting of the Executive
Committee of the Board of Trustees of the University of Kentucky,
Thursday, March 10, 1983.


    The Executive Committee of the Board of Trustees of the
University of Kentucky met in a Special Called Meeting in the
Board Room on the 18th floor of the Patterson office Tower on the
Lexington Campus at 11 a.m. (Eastern Standard Time) on Thursday,
March 10, 1983.

    A.   Meeting opened and Roll Called

    Mr. William B. Sturgill, Chairman, called the meeting to
order at 11:10 a.m. and the invocation was pronounced by Mr.
William R. Black.

    The following members of the Executive Committee of the Board
of Trustees answered the call of the roll: Mr. William B.
Sturgill (Chairmany, Mr. William R. Black, Mr. Tracy Farmer, and
Mr. John C. Darsie (Assistant Secretary, ex officio, of the
Executive Committee). Absent from the meeting were Mr. Albert G.
Clay and Mr. A. Stevens Miles. Members of the Board of Trustees
attending the meeting were Mr. James W. Dinkle, Mrs. Edythe Jones
Hayes, Mr. W. Terry McBrayer, and Professor William F. Wagner.
The University administration was represented by President Otis
A. Singletary; Dr. Donald B. Clapp, Vice President for
Administration; Chancellors Peter P. Bosomworth, Art Gallaher,
and Charles T. Wethington; Dr. Raymond R. Hornback, Vice
President for University Relations; Mr. Henry Clay Owen,
Controller and Treasurer; Mr. David I. Carter, Special Assistant
for Business and Financial Affairs; Dr. Paul G. Sears, Special
Assistant for Academic Affairs; and Dr. Wimberly C. Royster, Vice
Chancellor for Research and Dean of the Graduate School. Members
of the various news media were also in attendance. The Secretary
reported a quorum present, and the Chairman declared the meeting
officially open for the conduct of business at 11:13 a.m.

    B.   Adoption of Resolution Accepting the Successful Bid for
the University of Kentucky Consolidated Educational Buildings
Revenue Bonds, Series H (PR 3A)

    Thereupon, a motion was made by Mr. Farmer and seconded by
Mr. Black that the following titled Resolution, which was read in
summary form to the Executive Committee, be adopted:

    A RESOLUTION RELATING TO THE $8,500,000 UNIVERSITY OF
    KENTUCKY CONSOLIDATED EDUCATIONAL BUILDINGS REVENUE
    BONDS, SERIES H.


    (The full Resolution being attached to these Minutes as
Exhibit 1.)


-2-


    Upon a vote being taken on the motion, the result was as
follows:

         Yeas                                      Nays

   William B. Sturgill                             None
   William R. Black
   Tracy Farmer

   Thereupon, the Chairman declared that the motion had carried
and that the Resolution had been passed and adopted and directed
that the same be recorded in the Minutes of the Executive
Committee of the Board of Trustees.  (See PR 3A at the end of the
Minutes.)

    C.   Scientific Advisory Committee Report, Tobacco and Health
Research Institute

    President Singletary reminded the Trustees of the appointment
several months ago of a Scientific Advisory Committee, Tobacco
and Health Research Institute.  The Committee has submitted its
first report and President Singletary said he wished to share it
with members of the Board. He then called on Chancellor Gallaher
who made introductory comments and introduced Dr. Layten Davis,
Director of the Tobacco and Health Research Institute. Dr. Davis
summarized the report, a copy of which is appended to the
Minutes.

    The Chairman indicated the Board's approval and support of
the Institute and complimented President Singletary, Dr. Davis,
and the administration on the progress being made at the
Institute. Mr. Sturgill then accepted the report of the
Scientific Advisory Committee, Tobacco and Health Research
Institute.

    D.   Meeting Adjourned

    There being no further business to come before the meeting,
the Chairman declared the meeting officially adjourned at 11:35
a.m.

                             Respectfully s mitted,


                             ohn C. Darsie
                             Assistant Secretary, Ex Officio
                             Executive Committee
                             Board of Trustees


          (PR 3A (Exhibit 1) and the THRI Scientific Advisory
Committee Report which follow are official parts of the Minutes
of the meeting.)


                                                                        (EXHIBIT 1)

                                                              Office of the President
                                                              March 10, 1983


Members, Executive Committee, Board of Trustees:


                    RESOLUTION ACCEPTING THE SUCCESSFUL BID
                                    FOR THE
                      UNIVERSITY OF KENTUCKY CONSOLIDATED
                 EDUCATIONAL BUILDINGS REVENUE BONDS, SERIES H


Recommendation: That the Executive Committee approve a Resolution
accepting the bid of Seasongood and Mayer with a net interest cost
of 8.435319%             for the purchase of $8,500,000 Consolidated
Educational Buildings Revenue Bonds, Series H, dated March 1, 1983.


Action:  Approved      X


Disapproved


Other


Date:     March 10


, 198 3


EXHIBIT 1


            RESOLUTION RELATING TO THE
        $8,500,000 UNIVERSITY OF KENTUCKY
        CONSOLIDATED EDUCATIONAL BUILDINGS
             REVENUE BONDS, SERIES H

WHEREAS, the Executive Committee of the Board of
Trustees of the University of Kentucky ("the Board") at
its meeting on January 25, 1983, passed and adopted two
Resolutions, entitled, respectively,

     A   RESOLUTION   AUTHORIZING   THE    ISSUANCE   OF
     $8,500,000 UNIVERSITY OF KENTUCKY CONSOLIDATED
     EDUCATIONAL BUILDINGS REVENUE BONDS, SERIES H, OF
     THE BOARD OF TRUSTEES OF THE UNIVERSITY OF KEN-
     TUCKY

                       - and -

     A   RESOLUTION   AUTHORIZING   THE    ISSUANCE   OF
     $8,500,000 UNIVERSITY OF KENTUCKY CONSOLIDATED
     EDUCATIONAL BUILDINGS REVENUE BONDS, SERIES H, OF
     THE BOARD OF TRUSTEES OF THE UNIVERSITY OF KEN-
     TUCKY AND THE ISSUANCE OF $8,500,000 UNIVERSITY OF
     KENTUCKY   CONSOLIDATED   EDUCATIONAL    BUILDINGS
     REVENUE BOND ANTICIPATION NOTES, SERIES H, OF THE
     BOARD OF TRUSTEES OF THE UNIVERSITY OF KENTUCKY IN
     ANTICIPATION OF THE ULTIMATE ISSUANCE OF SAID
     SERIES H BONDS,

said Resolutions being referred to herein, respec-
tively, as "the Series H Resolution" and "the Alternate
Series H Resolution;" and

WHEREAS, pursuant to Section 5.3 of the Alternate
Series H Resolution, on or about February 15, 1983, the
Treasurer of the Board duly polled each member of the
Finance Committee of the Board, all of whom preferred
the issuance of the Series H Bonds authorized by the
Series H Resolution to the issuance of the Series H
Notes authorized by the Alternate Series H Resolution;
and

WHEREAS, pursuant to Section 2.10 of the Series H
Resolution, the Treasurer has caused to be published a
Notice of Bond Sale with respect to the Series H Bonds
for the information of potential bidders and has
furnished copies of an Official Statement and Official
Terms and Conditions of Bond Sale to interested persons
requesting the same; and


WHEREAS, under the terms of the Notice of Bond Sale and
the Official Terms and Conditions of Bond Sale, it is
provided that proposals for purchase of the Series H
Bonds would be received by the Board until 10:30 a.m.
on March 10, 1983; and

WHEREAS, the following proposals for purchase of the
Series H Bonds have been received in due time and
acceptable form:


Seasongood & Mayer
Cincinnati, Ohio

       -  Aggregate
          Principal
          Amount
          Sought

          $1,255 ,000
            310,000
            340,000
            365,000
            400,000
            435,000
            475,000
            525,000
            575 ,000
            630,000
          3,190,000


Coupon
Rate
Offered

6.75%
7.00%
7.20%
7.40%
7.60%
7.80%
8.00%
8.20%
8.40%
8.60%
8.70%


  Net
Interest
  Cost

8.435319%


B. Bidder:   Smith Barney, Harris Upham & Co.,
            New York, New York

                       Aggregate
  Bonds               Principal


Maturing
May 1,

1986-1990
    1991
    1992
    1993
    1994
    1995
    1996
1997-1998
1999-2000
200 1-2003


Amount
Sought


$1,255,000
  310,000
  340,000
  365,000
  400,000
  435,000
  475,000
  1, 100,000
  1,320,000
  2,500,000


Incorporated


Coupon
Rate
Offered

7.00%
7. 20%
7 .40%
7.70%
8.00%
8.20%
8.40%
8.60%
8.75%
9.00%


2


A. Bidder:


   Bonds
Maturing
May 1,

1986-1990
     1991
     1992
     1993
     1994
     1995
     1996
     1997
     1998
     1999
2000-2003


  Net
Interest
  Cost

8.699996%


C. Bidder: Blyth Eastman Paine Webber, Inc.
             New York, New York


  Bonds
Maturing
May 1,

1986-1988
     1989
     1990
     1991
     1992
     1993
     1994
     1995
     1996
     1997
     1998
1999-2003


Aggregate
Principal
Amount
Sought

$ 700,000
   265,000
   290,000
   310,000
   340,000
   365,000
   400,000
   435,000
   475,000
   525,000
   575,000
 3,820,000


D. Bidder: Johnston, Brown, Burnett
             Inc., Prudential - BachE
             Lexington, Kentucky


   Bonds
Maturing
May 1,

1986-1989
     1990
     1991
     1992
     1993
     1994
     1995
     1996
     1997
     1998
     1999
2000-2003


Aggregate
Principal
  Amount
  Sought

$ 965,000
   290,000
   310,000
   340,000
   365,000
   400,000
   435,000
   475,000
   525,000
   575,000
   630,000
 3,190,000


& Knight, Inc., John Nuveen & Co.,
e Securities, Inc. and Associates


Coupon
Rate
Offered

6.65%
6.90%
7.15%
7.40%
7.65%
8.00%
8.20%
8.40%
8.60%
8.75%
9.00%
9.10%


  Net
Interest
  Cost

8.7934%


3


  Net
Interest
  Cost

8.7376%


Coupon
Rate
Offered

6.40%
6.70%
6.90%
7. 10%
7.40%
7.70%
7.90%
8.20%
8.40%
8.60%
8.80%
9.00%


E. Bidder: Morgan Guaranty Trust Company of New York
            New York, New York


  Bonds
Maturing
May 1,

1986-2003


Aggregate
Principal
Amount
Sought

$8,500,000


Coupon
Rate
Offered

8.75%


  Net
Interest
  Cost

8.&8154%


WHEREAS, the Executive Committee has considered
the matter of which bid is most advantageous to
the Board;


NOW, THEREFORE, THE EXECUTIVE COMMITTEE HEREBY
RESOLVES AS FOLLOWS:

1.   that the proposal of Seasongood & Mayer, as
follows, for the purchase of the $8,500,000
"University of Kentucky Consolidated Educational
Buildings Revenue Bonds, Series H," dated March 1,
1983 ("the Series H Bonds") is hereby accepted as
the highest and best bid:


  Bonds
Maturing
May 1

  1986
  1987
  1988
  1989
  1990
  1991
  1992
  1993
  1994
  1995
  1996
  1997
  1998
  1999
  2000
  2001
  2002
  2003


Coupon
Rate

6. 75%
6. 75%
6. 75%
6. 75%
6. 75%
7 . 00%
7 . 20%
7. 40%
7 . 60%
7. 80%
8. 00%
8.20%
8 . 40%
8.60%
8. 70%
8. 70%
8. 70%
8. 70%


Aggregate
Principal
Amount

$215,000
235,000
250,000
265,000
290,000
310,000
340,000
365,000
400,000
435,000
475,000
525,000
575,000
630,000
690,000
755,000
830,000
915,000


Net Interest Cost = 8.435319%


4


2.   that the interest rates on the Series H Bonds
are hereby fixed at the rates set out in the said
accepted proposal;

3.   that the Series H Bonds as identified in the
Series H Resolution shall be delivered by the
officers of the Board in accordance with the terms
of the Series H Resolution as soon as ready;

4.   that the confirmation of the said accepted
proposal subjects the Board to no liability if it
is unable to obtain the final approving legal
opinion of Wyatt, Tarrant & Combs, Louisville,
Kentucky, Bond Counsel, or if the interest on the
Series H Bonds should become subject to federal or
Kentucky income taxation, or if the Series H Bonds
should become subject to Kentucky ad valorem
taxation, prior to the delivery of the Series H
Bonds; but also that the purchaser shall not be
required to take up the Series H Bonds without the
final approving legal opinion of Bond Counsel
aforesaid or if the Series H Bonds or interest
thereon should become so subject to taxation;

5.   that this Resolution shall be in full force
and effect from and after its adoption.


5


SCIENTIFIC ADVISORY COMMITTEE REPORT, TOBACCO AND HEALTH RESEARCH INSTITUTE


Submitted to: Dr. D. Layten Davis, Director. University of Kentucky

               Tobacco and Health Research Institute


Subject:       Report of the Scientific Advisory Committee, Tobacco and

               Health Institute concerning site visit held December 15-16,

               1982 at the University of Kentucky, Lexington, Kentucky


Scientific Advisory Committee:


               Leo G. Abood, Professor, Center for Brain Research, University

                 of Rochester Medical Center, Rochester, NY 14642


               Donald Heistad, Professor of Medicine, University Hospital,

                 Iowa City, IA 52242


               Aaron Janoff, Professor of Pathology, State University of New

                 York at Stony Brook, Stony Brook, NY 11794


               Fred Bock, Senior Scientist, Papanicolaou Cancer Research

                 Institute, Miami, FL 33101


               Thurston J. Mann, Assistant Director, North Carolina

                 Agricultural Research Service, North Carolina University,

                 Raleigh, NC 27650


SUMMARY OF THE REVIEW


     It was the Committee's view that the aims of the research program of the

University of Kentucky Tobacco and Health Research Institute (THRI) address

many timely and important issues relating to tobacco and the health

consequences of smoking.   The program is a broad-based one involving a number

of capable investigators from numerous departments throughout the University

of Kentucky whose interests range from the neurobehavioral and cardiovascular-

pulmonary effects of smoking to matters dealing with product modification and

passive exposure to the constituents of smoke.   In addition to contributing to

a better understanding of the basic mechanisms associated with the health

consequences of smoking, the investigations were appropriately directed

towards the missions of    1) identifying and reducing the health hazards in

both the smoking and non-smoking population,     2) emphasizing numan studies,

and   3) attempting to develop appropriate animal models for research on

smoking.  The research program is unique in its scope and the concentration of

qualified investigators devoted to research on smoking.


     In summary, the Committee concluded that the research program of the THRI

is comprised of a number of projects of high scientific merit, is clearly

relevant to the issues of tobacco health, and is being effectively

administered.


                  COMMENTS ON THE INDIVIDUAL RESEARCH PROJECTS


     The  majority   of   the  research   projects   were   highly  meritorious,


particularly  1) The involvement of elastase-antielastase in emphysema, 2) the

chemistry and function of a1 -protease inhibitor;3ithe neurobehavioral projects

dealing with multiple nicotine receptors and their neuroanatomical loci of

action; 4) the cardiovascular program, particularly the studies on ventilatory

mechanisms, the studies on the use of non-invasive techniques to evaluate

high-risk cardiovascular patients, the studies on drug disposition, and those

on thromboxane-prostacyclin production; 5) a number of the projects dealing

with passive smoking-smoke components, particularly those on nicotine-derived

nitrosamines, the role of methylation in nicotine toxicity,  and on the growth

and coagulation of tobacco smoke aerosols; 6) the projects on product

modification within the College of Agriculture, particularly those on nicotine

metabolism on modification of the tobacco plant and on viral gene expression

in tobacco cells.    All of the principal investigators responsible for these

projects were considered to be highly competent and productive, while the

projects themselves were in the forefront of research on smoking and tobacco

health.


     There were some projects that were considered to be satisfactory but

could be improved by a revision of experimental procedures.   Included in this

group were the projects 1) aimed at developing a model of lung injury induced

by chronic exposure to cigarette smoke coupled with steroid treatment, 2)

examining the relationship between the accumulation of tobacco smoke and

pulmonary  emphysema,  3)  determining  the  effects  of  passive  smoking  on

interferon production, and 4) determining the effect of cigarette smoking and

age on drug disposition in man.


2


     Other projects were somewhat less promising and/or productive.    Included

in this group were the projects on the early detection of and susceptibility

to smoking-related emphysema, at the treatment of emphysema, the studies

attempting to develop a smoking induced model of lung injury, the project on

cutaneous blood flow in man, the project on the tissue distribution of smoke

carcinogens, and the project concerned with the cholinergic system of brain

synaptosomes. Some of the projects were often lacking in tenable hypotheses,

originality, and potential for disclosing new, significant findings.


                             I. Pulmonary Program


1.  The underlying hypothesis behind one study is that amines in. cigarette

smoke are avidly bound by lung cells or extracellular receptors, leading to

phospholipid    accumulation    in    pulmonary   macrophages.        Macrophage

phospholipidosis, in turn, is thought to cause cell death with attendant

release  of  elastase  and  destruction  of  adjacent  pulmonary   tissue.    No

mechanism is suggested for the accumulation of phospholipids in macrophages

due to amine-binding in the lung, nor is it made clear why such accumulations

should cause macrophage death.   Some data were presented showing that labelled

imipramine,  preloaded  into  animal   lungs,  is  partly  displaced   following

subsequent in vivo exposure of these animals to cigarette smoke inhalation,

thus supporting the suggestion that amines in smoke may bind to amine

receptors in lung tissue.


           (a) The bulk of the data are derived from an in-vitro isolated lung

perfusion model, in which amine-containing fractions of smoke-condensate are

                                        3


added to the perfusate and efflux of labelled imipramine is then measured.

The physiological relevance of such experiments is questionable, since uptake

of smoke amines by pulmonary endothelium in the investigator's model may be

very different from uptake by pulmonary epithelium in smoking animals or man.

Why not ventilate the isolated, perfused lung with cigarette smoke so as to

bring the in vitro and in vivo experiments onto a common footing?


          (b)   If phospholipid accumulation    in macrophages   (or some other

effect of amine-binding on these cells) causes macrophage death and

dissolution, this is unlikely to lead to significant elastase release in the

lung.   Macrophages do not store elastase in their lysosomes,        rather they

continuously  synthesize   and  secrete   it  into  their  medium.     Therefore,

macrophage death is associated with decreased, not increased, elastase

production.    It  was  shown  that alveolar macrophages sequester neutorphil

elastase and that this enzyme is released by injured macrophages (e.g.,

severely anoxic cells).   Is this the mechanism of lung injury proposed by one

of the investigators?   A more detailed exposition of the working hypothesis is

needed to help clarify these and other questions.


2.   A second project proposes to synthesize 14C-labelled carbamates to be

used as elastase-specific substrates and to use such reagents in a screening

program to detect smokers at risk of developing emphysema.       The rationale is

that  high-risk   smokers   may  have  increased   lung   elastolytic  activity.

Aerosolizations of the labelled substrate into the lung, then, may permit

detection of such individuals by measurement of exhaled 14CO2.     Alternatively,

the assay may be used to measure elastase activity in plasma.

                                         4


          (a)   Smokers with emphysema are likely to have derangements in

ventilation, such that the inhaled substrate-aerosol may not be adequately

exposed to lung regions where higher than normal elastase activity is present

(diseased regions).


          (b)   Detection of increased plasma or serum elastase activity in

high-risk smokers is very unlikely, because of the overwhelming concentration

of  al-croteinase  inhibitor   in plasma.    It is more feasible to measure

neurtroph1il elastase in plasma by immunological techniques, since neutrophil

elastase  retains  its   antigenicity  in   a 1-proteinase  inhibitor   complex.

Indeed, screening of smoking populations using such measurements (RIA, other)

are already in progress in several laboratories.


          (c) Other non-invasive chemical tests are currently being developed

and have already been reported in the literature, which may be more promising

for detection of high-risk smokers.     These tests include ELISA for elastin-

peptides in serum (Darnule et al., Anal. Biochem. 1982, 122:302) and RIA for

desmosine in urine (Harel et al., Am. Rev. Respir. Dis. 1980, 122:769).


3.   A third study seeks to develop desmosine analogues to inhibit monocyte

chemotactic responses to desmosine-containing elastin-peptides.       Such drugs

would hopefully blunt the further recruitment of monocytes (macrophages?) to

regions of smokers' lungs containing degraded elastin, thus reducing the risk

of developing emphysema.


     This work is largely based on earlier published work by Senior et al.

                                        5


showing that elastin-peptides are chemotactic for monocytes and suggesting

that the chemotactic fragments were enriched in desmosine cross-links (J.

Clin.  Invest., 1980, 66:859).   Recently, however, Senior has observed that

non-cross-linked tropoelastin and also desmosine-free synthetic peptides (with

amino acid sequences characteristic of repeating peptides in elastin) are

chemotactic for human monocytes.   He mentions these observations in a second

paper (Senior et al., J. Olin. invest., 1982, 70:614) and concludes:         'tit

appears that cross links are not necessary for chemotactic activity of elastin

peptides. t


4.  A  fourth study   of the   Pulmonary Program is conducting an extensive

correlation   designed   to   evaluate   the   protease-antiDrotease   imbalance

hypothesis  of  pulmonary  emphysema.     Parameters  being  explored  include:

smoking history, individual smoking habits (puff-volume, puff-duration, etc.)

plasma    thiocyanate     and     carboxyhemoglobin     levels,    number     of

polymorphonucleocytes (PMN) in the circulation, elastase and myeloperoxidase

contents of PMN, total plasma a 1-proteinase inihibitor (immunological assay),

ratio of trypsin-inhibitory to elastase-inhibitory activities of plasma

(functional assay of al-proteinase inhibitor), complement levels in plasma,

neutrophil chemotactic responses to zymosan-activated plasma and to n-formyl-

methionyl-peptides, and pulmonary function tests including spirometry and

single-breath nitrogen washout.


     Preliminary results on 50 matched subject pairs (smokers vs. non-smokers)

were presented at the visit.    Statistically significant negative correlations

were found between pulmonary function and levels of complement,, neutrophil

                                        6


myeloperoxidase and numbers of circulating neutrophils.     These data suggest

that  increased  inflammatory  mediators  and  attendant  increases   in  total

neutrophil protease "burden" may be important pathogenetic determinants of

lung injury in smokers.   Of special interest is the observation of increased

neutrophil myeloperoxidase in high-risk smokers, since this enzyme has been

implicated by other workers in the oxidative inactivation of a 1-proteinase

inhibitor.


     The group working on protease-antiprotease imbalance is a hard-working,

impressive one, who is fully competitive with the best in its field at other

lung research centers.    Moreover, the group has made an exensive effort to

characterize their smoking subjects in terms of mg tar per cigarette, depth of

inhalation,  puff  retention  time,  puff  volume  and  number   of  puffs  per

cigarette, in addition to the usual indices of packs per day x years of

smoking.   They should now take greater advantage of available statistical

resources at THRI to examine possible correlations between parameters of

inflammation, protease-antiprotease balance, and Individual smoking habits.


5.   Another study seeks to develop a model of lung-injury induced by chronic

cigarette smoke exposure coupled with steroid treatment to suppress the

pulmonary macrophage response to cigarette smoke.       In the absence of the

normal macrophage pool in the lung, cigarette smoke exposure is observed to

cause severe accumulation of phospholipid-protein complexes (tubular myelin

arrays) in the alveoli, resembling those seen in human alveolar proteinosis.

It is clear that emphysematous (destructive) changes also take place in this

model.   It was hypothesized    that,  in the absence of normal numbers of

                                        7


phagocytic macrophages, secretory products (perhaps augmented in smoking

animals) cannot be properly removed from the alveoli.


          (a)  The dose of steroid employed to produce the above effect in

animals is extraordinarily high and has no physiological relevance.    The dose

corresponds to 35,000 mg/day/70 kg man as opposed to the usual clinical dose

of 100-200 mg/day.  (The lazter is, itself, a pharmacological dose as opposed

to a physiological dose.)  At the dose level- used in the animal studies, there

is a 30% mortality from the steroid alone.  Under these conditions, little can

be said regarding the mechanism of action of the steroid-smoke combination,

since steroids have wide-ranging effects even at physiologic doses.


          (b)  In view of these potential problems in data interpretation, a

recent study has initiated experiments using lower doses of the drug combined

with  smoking.    However,   even  this  current   dose  is  about  1Ox  higher

(corresponding to 1,750 mg/day/70 kg man) than the usual clinical dosage.

Data on lung effects of this modified regimen were not available at the time

of the site-visit.


6.   A study is being undertaken on the in vitro and in vivo studies of the

chemical and biological changes in alPi induced by oxidizing agents and by

cigarette smoke. Data were summarized at the site-visit showing that 4 out of

6 tyrosine residues in the free inhibitor molecule are normally suscpetible to

nitrosylation with resultant loss of pancreataic elastase-inhibitory activity.

However, a lPi complexed to trypsin or to pancreataic elastase appears

conformationally altered, so that these same 4 tyrosine residues are no longer

                                       8


susceptible to nitrosylation.   Furthermore, and perhaps of greater relevance

to the smoking and health issue, mild oxidation of a lPi converts 2 of 8

methionine residues in the inhibitor to their sulfoxides with loss of

elastase-inhibitory activity (as observed by others); whereas stronger

oxidizing  conditions  lead   to  conversion   of  4  methionine  residues  to

methionine-sulfoxide.   Under these conditions, reductants cannot reactivate

clPi , but they can do so when only 2 methionine sulfoxides are present.  This

information  is  new  and  potentially  of  great   importance,  since  chronic

cigarette smoking has been reported to convert half of the a lPi in the lung

to an oxidized form containing 4 methionine sulfoxide residues per molecule

(Carp et al., PNAS, 1982, 79:2041).


     Studies are now in progress dealing with chemical changes and activity

measurements for a lPi treated with cigarette smoke fractions in vitro, as

well as for inhibitor recovered from lung fluids and plasma of animals

following  acute cigarette   smoke  inhalation.    Longer-range  plans  include

structure-function studies of    lPi obtained from chronic smoking animals and

humans.


     The studies of ventilatory mechanics in unanesthetized dogs is certainly

an  appropriate  preparation.    Preliminary  observations   that nicotine  may

stimulate airway receptors are provocative and potentially important. It will

be important in those studies    1) to obtain simple hemodynamic measurements,

such as arterial pressure, which may have important effects on ventilation,

and 2) to perform systematic pharmacological evaluation to determine whether

the airway receptors that are activated are indeed nicotinic receptors.

                                       9


II. Neurobehavioral Program


    The main objective of this program is to explore the mechanisms and the

various sites of action of nicotine in rats and dogs with a view toward

elucidating the role of nicotine in smoking health and behavior. The group is

attempting to characterize the physiologic and pharmacologic nature of the

various receptors for nicotine within the central and peripheral nervous

system employing an extensive battery of pharmacodynamic, electrophysiologic,

psychophysical, and biochemical techniques.


     The overall objectives of the program were well-delineated and addressed

important issues related to tobacco health, while the experimental design and

protocol was well-conceived   and  appropriate.     During a   relatively short

period, many experimental procedures were developed and refined, which were

required to accomplish the objectives, and also significant data was generated

concerning the nature and function of multiple nicotine binding sites within

the brain.  Among the significant findings were those demonstrating that low

concentrations of nicotine may enhance nicotine binding and that the analgetic

action of nicotine involved the medulla oblongata rather than the opioid

system.


     Convincing data was presented showing that nicotine is self-administered

(i.e., reinforcing) when administered directly into rat lateral hypothalamus,

while being adversive when administered into the pons-medulla. Although other

studies  have   demonstrated   that   nicotine   is   reinforcing   when   given

systemically, this study is the first to show that it is self-administered

                                       10


into a brain area, specifically the lateral hypothalamus.         Such studies

contribute to our knowledge of why people smoke and help elucidate the brain

sites and mechanisms involved in nicotine's action.


     In summary, the projects have considerable relevance to the stated

objectives of THRI and are in competent, experienced hands.     The progress to

date has been very good and is expected to continue to be so.


Neurochemical Studies:


     This project dealt with the effects of chronic nicotine administration on

the cholinergic system of synaptosomes isolated from rat and mouse brain and

on the transport of 14C-isoaminobutyric acid (AI) transport across the mouse

placenta.    The  likelihood  that the synaptosomal studies will result in

significant new findings concerning mechanism of the action of nicotine is not

great, since this approach has been used by innumerable investigators in the

past and to little avail.    Although effects of chronic nicotine on placental

transport are worth investigating, the rationale behind the studies on AIB

transpor</pre>