Drug Discovery - ACS Publications

7 The Biological Knowledge Gap J. J. BURNS

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Hoffmann-La Roche Inc., Nutley, N. J. 07110 New drug development—so has

slowed

because

rapid during

advances

the past 20

in biological

failed to keep pace with those in medicinal spite

successes

matory

cited in psychotherapeutic

drug development,

is hampered

by

further

inadequate

and

Where

Parkinson's

developed research under

more adequate disease,

recently. in drug

way

Others

in the

avoid unnecessary

'"phe A

criteria

can

be

and

and industry

areas

fundamental existing

exists, as in gout drugs

expected

have

been

from

basic

molecular

biology

now

industry.

However,

delay in introducing

for evaluating

in these

of action of

new

pharmaceutical

sities, government, lating

important

anti-inflam-

of

knowledge

metabolism

De-

progress

disease processes and of the mechanism drugs.

have

chemistry. and

knowledge

years—

science

future drugs,

must cooperate

drug safety and

in

to

univerformu-

efficacy.

last 20 years h a v e seen the r a p i d d e v e l o p m e n t of n e w d r u g s ,

l a r g e l y because of the advances i n m e d i c i n a l c h e m i s t r y discussed i n

this v o l u m e . F u t u r e d e v e l o p m e n t , h o w e v e r , w i l l b e m o r e d i f f i c u l t . W h i l e m e d i c i n a l c h e m i s t r y has a d v a n c e d b y finding n e w methods f o r synthesizi n g c o m p l i c a t e d m o l e c u l e s a n d i s o l a t i n g a n d i d e n t i f y i n g the active substances f r o m plants, b a c t e r i a , a n d m a m m a l s , o u r b i o l o g i c k n o w l e d g e has f a i l e d to keep pace.

W e l a c k basic k n o w l e d g e of d r u g a c t i o n a n d of

disease processes i n m a n , a n d this l a c k is c e r t a i n to d e l a y f u t u r e advances, e s p e c i a l l y i n t r e a t i n g diseases s u c h as cancer, v i r a l infections.

c o n g e n i t a l disease, a n d

E v e n w h e n n e w d r u g s are d e v e l o p e d , their i n t r o d u c t i o n

is often d e l a y e d because m e d i c a l o p i n i o n s differ o n w h a t constitutes v a l i d safety a n d efficacy data.

I n short, w e are c o n f r o n t e d b y a w i d e n i n g

biological knowledge gap.

Progress in Developing Psychotherapeutic Agents T h e r a p i d d e v e l o p m e n t of p s y c h o t h e r a p e u t i c agents a n d their success i n t r e a t i n g m e n t a l a n d e m o t i o n a l disorders w a s one of the m o r e sig166

In Drug Discovery; Bloom, B., et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

7.

BURNS

The

Biological

nificant achievements decades.

Knowledge

167

Gap

of the p h a r m a c e u t i c a l

i n d u s t r y i n the

last

two

S i n c e c l i n i c i a n s first r e c o g n i z e d n e u r o l e p t i c , antidepressant, a n d

t r a n q u i l i z i n g effects of c e r t a i n d r u g s , l a b o r a t o r y scientists h a v e

sought

to u n d e r s t a n d t h e i r p s y c h o p h a r m a c o l o g y a n d to d e v e l o p t e c h n i q u e s

for

d i s c o v e r i n g i m p r o v e d d r u g s . T h e s e scientists d e v i s e d b e h a v i o r a l , electrop h y s i o l o g i c a l , a n d b i o c h e m i c a l concepts a n d t e c h n i q u e s a n d , i n d e e d , h a v e o b t a i n e d a w e a l t h of i n f o r m a t i o n o n h o w s u c h d r u g s interact w i t h b i o -


l o g i c a l systems.

B e h a v i o r a l p h a r m a c o l o g y t e c h n i q u e s h a v e a d v a n c e d to

the p o i n t w h e r e t h e y n o w f o r m the h a r d core of the

pharmacological

profile of n e u r o l e p t i c s a n d t r a n q u i l i z e r s . S t i l l , w e l a c k m u c h i m p o r t a n t i n f o r m a t i o n i n this area. O n e of the most c h a l l e n g i n g p r o b l e m s has b e e n the search f o r w a y s to r e c o g n i z e d r u g s u s e f u l i n d e p r e s s i o n . S i n c e attempts to d e v e l o p a n i m a l m o d e l s of d e p r e s s i o n b y u s i n g d r u g s to depress the c e n t r a l n e r v o u s syst e m h a v e p r o v e d less t h a n successful, other a p p r o a c h e s h a v e b e e n t r i e d ; f o r e x a m p l e , e m p i r i c a l t e c h n i q u e s h a v e b e e n u s e d to e v a l u a t e the a b i l i t y of p o t e n t i a l antidepressant

agents to a n t a g o n i z e t e t r a b e n a z i n e

a n d re-

serpine, to potentiate a m p h e t a m i n e or cocaine, a n d to b l o c k the u p t a k e of n o r e p i n e p h r i n e , yet the l i m i t a t i o n s of s u c h t e c h n i q u e s increasingly obvious. analogous

have become

T h e y are u s e f u l f o r p r e d i c t i n g a c t i v i t y i n c l o s e l y

c o m p o u n d s w i t h i n a c h e m i c a l class k n o w n to be c l i n i c a l l y

effective, b u t t h e y are m u c h less u s e f u l i n p r e d i c t i n g s u c h a c t i v i t y i n a n e w c h e m i c a l class.

A d m i t t e d l y , the e v i d e n c e that some

antidepressants

decrease n o r e p i n e p h r i n e u p t a k e is c o n c e p t u a l l y a p p e a l i n g , b u t

whether

this c a n p r e d i c t antidepressant a c t i v i t y has yet to be d e m o n s t r a t e d . W e h a v e b e e n m o r e successful i n i d e n t i f y i n g a n d d e v e l o p i n g effective neuroleptics

(chloropromazine-like drugs)

or t r a n q u i l i z e r s

(meproba-

m a t e - l i k e , a n d c h l o r d i a z e p o x i d e - l i k e d r u g s ). O u r success has b e e n l a r g e l y the result of n e w t e c h n i q u e s i n b e h a v i o r a l p h a r m a c o l o g y .

F o r example,

i n h i b i t i o n of c o n d i t i o n e d a v o i d a n c e b e h a v i o r is g e n e r a l l y a c c e p t e d as a g o o d p r e d i c t o r of c h l o r p r o m a z i n e - or h a l o p e r i d o l - l i k e a n t i p s y c h o t i c tivity.

H o w e v e r , once a g a i n , c o m p o u n d s different f r o m the

ac-

established,

c l i n i c a l l y effective c h e m i c a l series h a v e f a i l e d to p r o d u c e the effects p r e d i c t e d o n the basis of this test.

O b v i o u s l y , w e w i l l n e e d greater u n d e r -

s t a n d i n g if w e are to i d e n t i f y n e w a n d u n r e l a t e d c h e m i c a l s w i t h i m p r o v e d therapeutic

properties.

T h e r e is a great d e a l of e n t h u s i a s m a n d i n c r e a s i n g confidence i n the v a l u e of a n t i c o n f l i c t p r o p e r t i e s of t r a n q u i l i z e r s i n a n i m a l s f o r p r e d i c t i n g anti-anxiety properties i n m a n . pressive a n d appears

reliable.

T o date, the c o r r e l a t i o n is i n d e e d i m Anti-aggressive activity, a

predominant

p r o p e r t y of m a n y n e u r o l e p t i c a n d t r a n q u i l i z i n g agents, also seems to h a v e predictive value.


168

DRUG DISCOVERY

F u r t h e r research i n p s y c h o p h a r m a c e u t i c a l s

is o b v i o u s l y i m p o r t a n t ,

b u t o u r interests s h o u l d be f o c u s e d o n the areas of greatest m e d i c a l n e e d . O n e s u c h area is s c h i z o p h r e n i a .

N o matter h o w effective today's d r u g s

are, m o r e effective ones w i l l b e r e q u i r e d . M o r e o v e r , research memory.

is n e e d e d i n n e w areas, s u c h as l e a r n i n g a n d

D r u g s to e n h a n c e the p e r f o r m a n c e of patients w i t h m e n t a l re

t a r d a t i o n , s e n i l i t y , a n d other m e n t a l deficiencies w o u l d c l e a r l y constitute


a major c o n t r i b u t i o n . m e a n i n g f u l research.

F o r t u n a t e l y , sufficient k n o w l e d g e exists to b e g i n W e c a n measure l e a r n i n g a n d m e m o r y p e r f o r m a n c e ,

a n d certain drugs do enhance such performance.

W e also h a v e e v i d e n c e

of the p o s s i b l e r o l e of m a c r o m o l e c u l e s i n l e a r n i n g - m e m o r y f u n c t i o n s . N o w w e n e e d to e l u c i d a t e f u r t h e r the r e l a t i o n s h i p b e t w e e n a n i m a l b e h a v i o r a n d i n t e l l e c t u a l f u n c t i o n s i n m a n a n d also the r e l a t i o n s h i p s of r e l e v a n t neurobiochemical and neurophysiological functions.

T h e task of i n v e s t i

g a t i n g d r u g s that m a y e n h a n c e s u c h f u n c t i o n s is f o r m i d a b l e because c l i n i c a l l y effective standards d o not exist.

T h e s e are the challenges

we

face.

Animal Models for Evaluating Anti-Inflammatory Drugs I n m a n , arthritis p r o d u c e s p a i n , s w e l l i n g , redness, t e m p e r a t u r e of joints.

and

increased

I n a n i m a l s , the same s y m p t o m s c a n be p r o d u c e d

as p a r t of a n i n f l a m m a t o r y process i n w h i c h m e m b r a n e p e r m e a b i l i t y i n creases l e a d i n g to c e l l u l a r d e s t r u c t i o n .

This inflammation, induced by

s u c h substances as p h e n y l q u i n o n e , c a r r a g e e n i n , a n d yeast, c a n b e p a r t i a l l y p r e v e n t e d b y a n t i - i n f l a m m a t o r y d r u g s , s u c h as a s p i r i n a n d p h e n y l butazone.

Screening

indomethacin

with

these tests, scientists

and mefanamic

a c i d f r o m large

were

able

groups of

to

select

compounds.

H o w e v e r , w i t h these same tests t h e y i d e n t i f i e d m a n y other c o m p o u n d s , w h i c h t h e y later h a d to d i s c a r d as false positives or p r o d u c e r s of toxic effects, p a r t i c u l a r l y u l c e r o g e n i c effects. A m o r e r e c e n t m o d e l of i n f l a m m a t i o n is the k i l l e d M y c o b a c t e r i u m a d j u v a n t a r t h r i t i s test. Besides a n a c u t e i n f l a m m a t o r y phase, it p r o d u c e s a s e c o n d a r y phase c h a r a c t e r i z e d b y i n d u c t i o n of a n i n f l a m m a t o r y lesion at sites distant f r o m the i n i t i a l l e s i o n a n d also b y the d e v e l o p m e n t b i o c h e m i c a l alterations m e a s u r e d b y changes i n b l o o d p o l y s a c c h a r i d e s a n d α-globulin.

fibrinogen,

of

muco

T h e s e distant changes m a y be m e d i a t e d

b y the k i n i n systems, s u c h as b r a d y k i n i n . T h i s n e w m o d e l is affected b y most drugs a c t i v e i n t h e h u m a n arthritis a n d p r o m i s e s better p r e d i c t i v e v a l u e t h a n ea rlier m o d e l s , w h i c h m e a s u r e d p r i m a r i l y the acute phases.

It

p e r m i t s m e a s u r i n g i n m a n a n d a n i m a l s s u c h b i o c h e m i c a l parameters

as

i n f l a m m a t i o n units r e l a t e d to the α-globulins.

S u c h measurements


may

7.

BURNS

The Biological

Knowledge

169

Gap

increase o u r u n d e r s t a n d i n g of the a r t h r i t i c process a n d g i v e better p r e d i c t a b i l i t y f o r n e w classes of c o m p o u n d s . After promising compounds

are i d e n t i f i e d i n a n i m a l s ,

formidable

p r o b l e m s of d r u g a b s o r p t i o n , b l o o d levels, u l c e r o g e n i c a c t i v i t y , a n d l i v e r t o x i c i t y m u s t b e s o l v e d . A h u g e effort has b e e n m o u n t e d b y major p h a r m a c e u t i c a l houses i n the synthesis of a n t i - i n f l a m m a t o r y c o m p o u n d s , e v a l uation b y current a n i m a l models, extended pharmacological examination,


t o x i c i t y studies, p h a r m a c o d y n a m i c studies, a n d t h e subjective i n a r t h r i t i c patients.

screening

So far, this costly effort has not b e e n v e r y p r o d u c -

t i v e ; n o d r u g has b e e n f o u n d to b e s u p e r i o r to a s p i r i n i n efficacy a n d safety f o r l o n g - t e r m use, y e t there is r o o m f o r m u c h i m p r o v e m e n t .

No

d r u g cures arthritis. N o d r u g affects t h e i m m u n o l i g i c aspects of the h u m a n disease, a n d m e a n i n g f u l a n i m a l m o d e l s are almost nonexistent.

T h e fact

that m a n y s c r e e n i n g tests are u n r e l i a b l e i n d i c a t o r s of d r u g efficacy i n m a n presents a p r o b l e m i n i n t e r p r e t a t i o n .

S c r e e n i n g results must b e c o n s i d -

e r e d c a r e f u l l y b e f o r e d e c i d i n g to b e g i n the vast effort r e q u i r e d to c o m p l e t e the d e v e l o p m e n t of a n e w d r u g .

If a p h a r m a c o l o g i s t s h o u l d d i s c o v e r a n

a c t i v e c o m p o u n d t o m o r r o w , six years o r m o r e m i g h t elapse b e f o r e i t c o u l d be i n t r o d u c e d to t h e m e d i c a l profession.

Deficient Knowledge of Drug Action and Disease Processes T h e search f o r n e w drugs w o u l d be greatly f a c i l i t a t e d i f w e k n e w more about currently used drugs. a b o u t the m e c h a n i s m

I n fact, w e k n o w s u r p r i s i n g l y little

of a c t i o n of s u c h w i d e l y u s e d d r u g s as a s p i r i n ,

b a r b i t u r a t e s , t h e p h e n o t h i a z i n e s , m o r p h i n e , a n d a n t i - i n f l a m m a t o r y agents —phenylbutazone

and indomethacin.

p h e n y l b u t a z o n e exerts its t h e r a p e u t i c

If, f o r e x a m p l e ,

we knew how

effect i n r h e u m a t o i d arthritis, w e

c o u l d d e v e l o p a m o r e r a t i o n a l screening p r o g r a m . W e also n e e d to k n o w m o r e about the disease to b e treated.

Just

h a v i n g suitable a n i m a l m o d e l s of h u m a n disease helps b y f u r n i s h i n g m o r e r e l i a b l e s c r e e n i n g tests. search,

L a c k of s u c h m o d e l s has h i n d e r e d arthritis re-

a n d the a v a i l a b i l i t y of a n i m a l m o d e l s has c o n t r i b u t e d

to o u r

l i m i t e d success i n h y p e r t e n s i o n a n d h y p e r l i p e m i a research. A n e x a m p l e of the v a l u e of u n d e r s t a n d i n g the nature of the disease is t h e c o n s i d e r a b l e progress m a d e i n gout t h e r a p y .

G o u t is c h a r a c t e r i z e d

b y a n o v e r p r o d u c t i o n of u r i c a c i d , w h i c h a c c u m u l a t e s i n the b o d y , resulti n g i n a p a i n f u l a r t h r i t i c c o n d i t i o n . D r u g s , s u c h as p r o b e n e c i d a n d sulfinp y r a z o n e , r e d u c e u r i c a c i d levels b y p r o m o t i n g its excretion i n the u r i n e . H o w e v e r , these d r u g s are less effective i n g o u t y patients w i t h i m p a i r e d r e n a l f u n c t i o n . F o r s u c h patients the d e v e l o p m e n t of a l l o p u r i n o l , w h i c h i n h i b i t s t h e synthesis of u r i c a c i d , has offered a n effective n e w t h e r a p y . A l l o p u r i n o l acts b y i n h i b i t i n g x a n t h i n e oxidase, t h e k e y e n z y m e f o r c o n -


170

DRUG DISCOVERY

v e r t i n g x a n t h i n e t h r o u g h h y p o x a n t h i n e to u r i c a c i d . T h e x a n t h i n e p r e cursors are excreted m o r e r a p i d l y t h a n u r i c a c i d , a n d thus t h e y d o not a c c u m u l a t e ( 1 ). A n o t h e r e x a m p l e is l e v o d o p a , a p r o m i s i n g d r u g f o r P a r k i n s o n ' s disease.

It was m a d e p o s s i b l e because of o u r c o n s i d e r a b l e k n o w l e d g e of

t h e m e t a b o l i s m a n d b i o l o g i c a l a c t i o n of l e v o d o p a a n d c a t e c h o l a m i n e s i n general.

P a r k i n s o n i s m patients h a v e l o w e r e d levels of d o p a m i n e i n spe-


cific areas of the b r a i n . B u t since d o p a m i n e does not penetrate i n t o the b r a i n to a n y a p p r e c i a b l e extent, it w a s necessary to a d m i n i s t e r its p r e cursor, l e v o d o p a , to correct the d e f i c i e n c y .

Subsequently, Cotzias

(2)

c o n t r i b u t e d to the successful treatment of P a r k i n s o n i s m b y s h o w i n g that large doses of l e v o d o p a w e r e most effective.

Advances in Drug Metabolism and Molecular Biology D r u g m e t a b o l i s m studies h a v e g r o w n i n c r e a s i n g l y i m p o r t a n t . A c o m m o n a p p r o a c h i n m a n y laboratories is to ask w h e t h e r a n e w d r u g is a c t i v e i n its o w n r i g h t or w h e t h e r it owes its a c t i v i t y a n d side effects to one or more metabolites.

T h i s a p p r o a c h has r e s u l t e d i n i m p r o v e d d r u g s f o r the

treatment of r h e u m a t o i d arthritis, gout, m e n t a l d e p r e s s i o n , a n d schistosomiasis.

A l s o , i n c r e a s e d k n o w l e d g e of d r u g m e t a b o l i s m has f u r n i s h e d

clues to the synthesis

of c o m p o u n d s w i t h m o r e d e s i r a b l e

absorption,

excretion, m e t a b o l i s m , a n d tissue d i s t r i b u t i o n characteristics. D r u g m e t a b o l i s m studies h a v e b e e n r e v o l u t i o n i z e d b y p h y s i c a l c h e m i c a l t e c h n i q u e s s u c h as mass s p e c t r o m e t r y a n d n u c l e a r m a g n e t i c nance.

T h e y m a k e p o s s i b l e m e t a b o l i s m studies i n a f e w w e e k s

resothat

p r e v i o u s l y w o u l d h a v e t a k e n m o n t h s or years. P h a r m a c e u t i c a l laboratories h a v e set u p extensive p r o g r a m s i n d r u g m e t a b o l i s m research, w h i c h s h o u l d establish a basis for the f u t u r e d r u g d e v e l o p m e n t . T h e past d e c a d e w i l l s u r e l y be r e m e m b e r e d f o r the n o t a b l e advances i n m o l e c u l a r b i o l o g y . M u c h i n f o r m a t i o n is n o w b e c o m i n g a v a i l a b l e : the steps i n the expression of genetic

i n f o r m a t i o n , the i n t r i c a t e details

of

t r a n s c r i p t i o n a n d t r a n s l a t i o n , a n d the m e c h a n i s m s w h e r e b y D N A directs p r o t e i n synthesis.

A l l this w i l l s u r e l y h e l p solve some of o u r c u r r e n t

problems, but we need m u c h more information. O n l y b y understanding biochemical

changes

accompanying viral

search for a n t i v i r a l d r u g s .

infection can w e rationally

O n l y b y u n d e r s t a n d i n g h o w k n o w l e d g e is

stored a n d r e c a l l e d i n the c e n t r a l n e r v o u s system a n d w h e t h e r m a c r o m o l e c u l e s are i n v o l v e d i n the m e m o r y process c a n w e s y s t e m a t i c a l l y seek d r u g s to alter l e a r n i n g a n d m e m o r y . advances

c a n be e x p e c t e d

I n the foreseeable f u t u r e , s t r i k i n g

i n t r e a t i n g those genetic

defects i n w h i c h

specific proteins are m i s s i n g or so a l t e r e d as to p r o d u c e a m e t a b o l i c l e s i o n .


7.

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The

Biological

Knowledge

171

Gap

T o a c h i e v e these advances, p h a r m a c e u t i c a l firms h a v e i n c r e a s i n g l y e m p h a s i z e d research i n m o l e c u l a r b i o l o g y . H o f f m a n n - L a R o c h e has

set

u p the R o c h e Institute of M o l e c u l a r B i o l o g y w i t h a staff of 200, i n c l u d i n g 70 at the doctorat e l e v e l (3, 4).

T h e s e scientists h a v e f r e e d o m to select

basic research p r o b l e m s b a s e d solely o n scientific m e r i t . T h e y h a v e access to a l l the firm's m o d e r n f a c i l i t i e s a n d c a n c o l l a b o r a t e if t h e y w i s h w i t h c o m p a n y scientists o n p r o b l e m s that m i g h t b e i m p o s s i b l e to solve w i t h


the l i m i t e d f a c i l i t i e s a n d staff of the u s u a l a c a d e m i c i n s t i t u t i o n .

The Need for Safety and Efficacy Criteria A n i m p o r t a n t g a p exists i n o u r k n o w l e d g e of the best means to e v a l uate the safety a n d efficacy of d r u g s .

O f t e n w e discover a c o m p o u n d

w i t h p o t e n t i a l l y v a l u a b l e t h e r a p e u t i c effects i n a n i m a l s o n l y to h a v e its use i n h u m a n disease l i m i t e d b y t o x i c i t y . O r p e r h a p s the d r u g m u s t b e a b a n d o n e d because the c l i n i c a l i n v e s t i g a t o r cannot establish its efficacy in man.

Species differ g r e a t l y : a d r u g m a y act one w a y i n the d o g , a n -

other w a y i n the rat, a n d s t i l l another w a y i n m a n .

H o w then can w e

extrapolate p h a r m a c o l o g i c a l a n d t o x i c o l o g i c a l d a t a f r o m a n i m a l to m a n ? R e c e n t studies s h o w that m e t a b o l i c différencies e x p l a i n m a n y of the v a r i ations i n species response.

Thus, using drug metabolism data w e can,

w i t h more certainty, infer d r u g action i n m a n f r o m pharmacological-toxic o l o g i c a l studies i n a n i m a l s . T o evaluate the safety of a c o m p o u n d , it m u s t be g i v e n to a n i m a l s f o r e x t e n d e d p e r i o d s — p e r i o d s as l o n g as one to t w o years i n rodents a n d , i n some instances, e v e n l o n g e r i n dogs.

R e c e n t research shows that the

m e t a b o l i s m of m a n y d r u g s is a c c e l e r a t e d m a r k e d l y after r e p e a t e d a d m i n i s t r a t i o n , a n d this m a y l e a d to less t o x i c i t y w i t h c o n t i n u e d dosage.

Such

i n f o r m a t i o n bears i m p o r t a n t l y o n the i n t e r p r e t a t i o n a n d d e s i g n of c h r o n i c t o x i c i t y tests. D e t e r m i n i n g the significance of m a l f o r m a t i o n s p r o d u c e d i n a n i m a l s w i t h h i g h doses of a n e w d r u g poses d i f f i c u l t p r o b l e m s

(5).

r e a c t i o n to the t h a l i d o m i d e disaster has fostered a n a t t e m p t

A n overto

ensure

c o m p l e t e safety b y a n i m a l e x p e r i m e n t a t i o n .

T h i s a d m i t t e d l y is a n i m -

possible goal; under certain circumstances,

even such commonly used

d r u g s as a s p i r i n cause m a l f o r m a t i o n s i n rats a n d other a n i m a l s . C l e a r l y , m o r e research is necessary to establish b e t t e r protocols for these studies and their interpretation. I n recent years p e o p l e h a v e b e c o m e c o n c e r n e d a b o u t the p o s s i b i l i t y of genetic d a m a g e c a u s e d b y d r u g s as w e l l as pesticides, f o o d i n g r e d i e n t s a n d a d d i t i v e s , i n d u s t r i a l c h e m i c a l s , a n d other substances i n the e n v i r o n m e n t (6, 7 ) .

A t present, n o one c a n p r e d i c t the risk to f u t u r e h u m a n

generations b a s e d o n c h e m i c a l m u t a g e n i c tests i n b a c t e r i a , m o l d s , f r u i t


DRUG DISCOVERY

172

flies, a n d h u m a n cells i n tissue c u l t u r e . A c o n f e r e n c e o n " E v a l u a t i o n of M u t a g e n i c E f f e c t s of C h e m i c a l s " h e l d N o v . 4 - 6 ,

1970

in Washington,

D . C , w a s s p o n s o r e d b y the D r u g R e s e a r c h B o a r d of t h e N a t i o n a l A c a d e m y of S c i e n c e s - N a t i o n a l R e s e a r c h C o u n c i l , together w i t h the E n v i r o n mental

M u t a g e n Society,

the

N a t i o n a l Institute

of

General

Medical

Sciences, F o o d a n d D r u g A d m i n i s t r a t i o n , a n d the P h a r m a c e u t i c a l M a n u facturers

Association Foundation.

T h e p a r t i c i p a n t s i n this

conference


e v a l u a t e d v a r y i n g a p p r o a c h e s to m u t a g e n i c testing a n d c o n s i d e r e d n e w areas of r e s e a r c h

(S).

P u b l i c c o n c e r n has f o c u s e d o n the p o s s i b l e c a r c i n o g e n i c effects of d r u g s a n d other c h e m i c a l s .

L o n g - t e r m c h r o n i c t o x i c i t y studies i n a v a -

r i e t y of species h a v e b e e n started i n the h o p e of m i n i m i z i n g p o t e n t i a l r i s k of c a n c e r i n m a n . H o w e v e r , the results of s u c h studies are difficult, sometimes i m p o s s i b l e , to i n t e r p r e t .

Yet their economic impact can

be

e n o r m o u s , as s h o w n b y the w i t h d r a w a l of c y c l a m a t e s w h e n b l a d d e r c a n cer w a s o b s e r v e d i n a l i m i t e d n u m b e r of rodents.

Inevitably drugs w i l l

b e affected too; a l r e a d y the safety of c e r t a i n o r a l c o n t r a c e p t i v e s has b e e n q u e s t i o n e d b e c a u s e of p o s s i b l e c a r c i n o g e n i c effects i n the breasts of dogs after e x t e n d e d use. I m m u n o l o g i c effects of d r u g s r e m a i n u n p r e d i c t a b l e b a s e d o n a n i m a l test d a t a , despite i n t e n s i v e research effort.

The pharmaceutical industry

has reason f o r c o n c e r n ; the rare o c c u r r e n c e of b l o o d d y s c r a s i a , e v e n w i t h a n e e d e d d r u g , c a n seriously l i m i t its use.

Years of w o r k o n c h l o r a m -

p h e n i c o l , f o r e x a m p l e , h a v e f a i l e d to d i s c o v e r w h y it depresses the b o n e m a r r o w i n some i n d i v i d u a l s .

N o r h a v e scientists l e a r n e d to p r e d i c t s u c h

severe s k i n reactions as e x f o l i a t i v e d e r m a t i t i s f r o m e x p e r i m e n t a l studies. F o r t u n a t e l y , progress i n p r e d i c t i n g p e n i c i l l i n s e n s i t i v i t y justifies a degree of o p t i m i s m that s i m i l a r progress c a n b e m a d e w i t h other d r u g s . N o d i s c u s s i o n of the b i o l o g i c a l k n o w l e d g e g a p w o u l d be w i t h o u t m e n t i o n i n g d r u g abuse.

complete

T h i s is one of the most c r i t i c a l p r o b l e m s

of o u r t i m e , yet o u r u n d e r s t a n d i n g of the p h a r m a c o l o g y of abuse is a l most t o t a l l y deficient.

W h y d o some i n d i v i d u a l s abuse narcotics, L S D ,

m a r i j u a n a , or a m p h e t a m i n e s ?

H o w c a n w e p r e d i c t , b a s e d o n a n i m a l tests,

the abuse p o t e n t i a l of a n e w c o m p o u n d ?

Right n o w w e can only infer

abuse p o t e n t i a l f o r c o m p o u n d s r e l a t e d c h e m i c a l l y or p h a r m a c o l o g i c a l l y to d r u g s w i t h k n o w n abuse p o t e n t i a l . W h a t is the m e c h a n i s m of tolera n c e a n d a d d i c t i o n ? P e r h a p s there is a n i m m u n o l o g i c a l basis f o r m o r p h i n e a n d h e r o i n tolerence.

P e r h a p s i n d u c t i o n of d r u g m e t a b o l i z i n g e n z y m e s i n

l i v e r m i c r o s o m e s m a y e x p l a i n tolerance to some b a r b i t u r a t e s .

M o r e re-

search is r e q u i r e d to a n s w e r these questions. A m a j o r p r o b l e m i n t h e r a p y is i n d i v i d u a l differences i n d r u g response a p p a r e n t l y c o n t r o l l e d b y genetic factors

(9).

W h a t is a safe dose f o r

one p a t i e n t m a y be either ineffective or t o x i c i n another because of faster


7.

BURNS

The Biological

Knowledge

or s l o w e r m e t a b o l i c t r a n s f o r m a t i o n .

173

Gap

Patients m a y r e c e i v e s e v e r a l d r u g s

s i m u l t a n e o u s l y w h i c h poses t h e q u e s t i o n of d r u g i n t e r a c t i o n s

(10).

A

v a r i e t y of d r u g interactions h a v e b e e n r e p o r t e d , i n c l u d i n g t h e a b i l i t y of one d r u g to s t i m u l a t e o r i n h i b i t the m e t a b o l i s m of another,

interference

w i t h r e n a l m e c h a n i s m s , d i s p l a c e m e n t of d r u g s that b i n d t o p l a s m a p r o teins, a n d i n t e r f e r e n c e

w i t h intestinal absorption.

vestigation

factors

of genetic

and drug

Almost certainly, i n -

interaction

will

help

explain


a d v e r s e reactions a n d l e a d to i m p r o v e d d r u g safety.

The Work of Government and Industry Groups I n r e c e n t years the W o r l d H e a l t h O r g a n i z a t i o n has p u b l i s h e d several reports o n t h e p r i n c i p l e s of safety e v a l u a t i o n (11)

as has t h e C o m m i t t e e

o n P r o b l e m s of D r u g S a f e t y of t h e N a t i o n a l A c a d e m y of S c i e n c e s - N a t i o n a l R e s e a r c h C o u n c i l (12).

T h e c o m m i t t e e has s t u d i e d t h e q u e s t i o n

of h o w m u c h m e t a b o l i c d a t a is u s e f u l at each stage i n t h e i n v e s t i g a t i o n of a n e w d r u g a n d s u r v e y e d t h e status a n d f u t u r e needs f o r d r u g safety research.

It has also a t t e m p t e d to f a m i l i a r i z e p h a r m a c o l o g i s t s , b i o c h e m -

ists, a n d m e d i c i n a l chemists w i t h t h e t h e o r e t i c a l a n d p r a c t i c a l aspects of d r u g m e t a b o l i s m studies.

It has h e l d s y m p o s i u m s to r e v i e w advances i n

d e v e l o p m e n t a l p h a r m a c o l o g y , i m m u n o p h a r m a c o l o g y , m e c h a n i s m of d r u g o x i d a t i o n , c h e m i c a l mutagenesis, adverse d r u g reactions r e p o r t i n g systems, a n d a n a p p l i c a t i o n of n e w e r p h y s i c a l t e c h n i q u e s

for drug

metabolism

study. T h r o u g h p r o g r a m project a n d center grants a n d t h r o u g h

contracts

w i t h p h a r m a c e u t i c a l firms, t h e P h a r m a c o l o g y - T o x i c o l o g y P r o g r a m of t h e N a t i o n a l Institute

of G e n e r a l M e d i c a l Sciences has i n v e s t i g a t e d

questions c o n c e r n e d w i t h d r u g safety.

many

T h e s e p r o g r a m a n d center grants

s p e e d t h e s t u d y of d r u g safety i n m a n b y g r o u p i n g together

first-rate

scientists i n p h a r m a c o l o g y , m e d i c i n a l c h e m i s t r y a n d t h e basic sciences. T h e P h a r m a c e u t i c a l M a n u f a c t u r e r s A s s o c i a t i o n F o u n d a t i o n has also f u r n i s h e d grants to m a n y u n i v e r s i t i e s to s t u d y m e c h a n i s m s of d r u g t o x i c i t y . Government a n d industry organizations have considered what constitutes a d e q u a t e c l i n i c a l efficacy as w e l l as s a f e t y — e s p e c i a l l y t h e d i f f i c u l t p r o b l e m of efficacy d a t a f o r a n t i c o n v u l s a n t , analgesic, a n d p s y c h o p h a r m a c o l o g i c agents. P a r t i c u l a r l y n o t e w o r t h y is t h e effort of a c o m b i n e d T a s k F o r c e of the A m e r i c a n C o l l e g e of N e u r o p s y c h o p h a r m a c o l o g y a n d t h e N a t i o n a l Institute of M e n t a l H e a l t h to e s t a b l i s h p r i n c i p l e s f o r e v a l u a t i n g psychotropic drugs.

Recently, the Pharmaceutical Manufacturers Asso-

c i a t i o n set u p panels to f o r m u l a t e efficacy g u i d e l i n e s f o r several p e u t i c classes.

thera-

T h e D r u g E f f i c a c y S t u d y of the N a t i o n a l A c a d e m y of

Sciences has p i n p o i n t e d m a n y of the p r o b l e m s i n this

field,

furthering

f u t u r e c l i n i c a l d r u g investigations.


174

DRUG DISCOVERY

Conclusion O b v i o u s l y m a n y constraints

are o p e r a t i n g against t h e d e v e l o p m e n t

of n e w d r u g s . A m o n g t h e most i m p o r t a n t is deficient b a s i c k n o w l e d g e of d r u g a c t i o n a n d of disease processes. T o h e l p r e m e d y these deficiencies, p h a r m a c e u t i c a l firms h a v e b e g u n b a s i c research i n t o cancer, v i r a l diseases, o r g a n transplants, a n d a host of d e g e n e r a t i v e c o n d i t i o n s . H o w e v e r , b a s i c research

w i l l require

ever-increasing

financial

commitments

over

long


p e r i o d s b e f o r e i m p o r t a n t n e w d r u g s w i l l b e c o m e a v a i l a b l e to t h e m e d i c a l profession. I n t r o d u c t i o n of n e w d r u g s is o f t e n d e l a y e d b y differences of o p i n i o n on w h a t constitutes

v a l i d safety a n d efficacy d a t a .

In many

c o n f u s i o n is c a u s e d b y difficulties i n i n t e r p r e t i n g a n i m a l t o x i c i t y and

inadequate

instances, findings

c r i t e r i a f o r safety a n d efficacy of a n e w d r u g i n m a n .

T o prevent unnecessarily delayed d r u g introductions, the academic com m u n i t y together w i t h t h e F o o d a n d D r u g A d m i n i s t r a t i o n a n d t h e p h a r m a c e u t i c a l i n d u s t r y s h o u l d w o r k together to establish v a l i d g u i d e l i n e s . S u c h c o o p e r a t i o n w i l l b e p a r t i c u l a r l y r e q u i r e d w h e n c u r r e n t b a s i c research y i e l d s potent n e w drugs f o r e v a l u a t i o n . Scientists

have become concerned

about the cutbacks

i n research

grant p r o g r a m s of t h e N a t i o n a l Institutes of H e a l t h a n d t h e N a t i o n a l S c i e n c e F o u n d a t i o n . E q u a l l y i m p o r t a n t is a c o n t i n u i n g generous

support

for p r e d o c t o r a l a n d p o s t d o c t o r a l t r a i n i n g p r o g r a m s , as w e l l as t r a i n i n g programs for pharmacology, medicinal chemistry, a n d related disciplines. O t h e r w i s e , advances

i n the pharmaceutical

sciences m a y b e seriously

i m p a i r e d b y t h e l a c k of a p p r o p r i a t e l y t r a i n e d researchers.

Literature Cited (1) Elion, B., Kovensky, Α., Hitchings, G. H., Metz, E., Rundles, R. W., "Metabolic Studies of Allopurinol, An Inhibitor of Xanthine Oxidase," Biochem. Pharmacol. (1966) 15, 863-880. (2) Cotzias, G.C.,Papavasiliou,P. S., Gellene, R., "Modification of Parkin sonism—Chronic Treatment with L-Dopa," New Eng. J. Med. (1969) 280 (7), 382-383. (3) Greenberg, D. S., "Molecular Biology—Drug Firm to Establish New Re search Center," Sci. (1967) 157, 408-409. (4) Hoffmann-La Roche Pioneering Innovation, The Roche Institute of Mo lecular Biology, Congressional Record (1967) 113 (129), H10558. (5) "Principles for the Testing of Drugs for Teratogenicity," WHO Tech. Rept. Ser. (1967) 364, 5-18. (6) Sanders, H. J., "Part I. Chemical Mutagens—The Road to Genetic Disas ter?," Chem. Eng. News (May 19, 1969) 47, 51-71. (7) Sanders, H. J., "Part II. Chemical Mutagens—An Expanding Roster of Suspects," Chem. Eng. News (June 2, 1969) 47, 54-68. (8) Harris, M., "Mutagenicity of Chemicals and Drugs," Sci. (1971) 171, 51-52.


7.

BURNS

The Biological

Knowledge

Gap

175


(9) "Pharmacogenetics," B. N. La Du, W. Kalow, Eds., Ann. Ν. Y. Acad. Sci. (1968) 151 (2). (10) "Symposium on Clincal Effects of Interaction Between Drugs," Proc. Roy. Soc. Med. (1965) 58 (11) Pt. 2. (11) "Principles for Pre-Clinical Testing of Drug Safety," WHO Tech. Rept. Ser. (1966) 341. (12) Report of the Committee on Problems of Drug Safety, Drug Research Board, National Academy of Sciences-National Research Council, "Application of Metabolic Data to Drug Safety Evaluation," Clin. Pharmacol. Ther. (1969) 6 (5) 607-634. RECEIVED November 5, 1970.


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