Proceedings of the Sixth International Congress of Pharmacology: Abstracts

1571 Pages·1977·345.76 MB·English

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Proceedings of the Sixth International Congress of Pharmacology
Volume 1: Receptors and Cellular Pharmacology
Volume 2: Neurotransmission
Volume 3: CNS and Behavioural Pharmacology
Volume 4: Drug Therapy
Volume 5: Clinical Pharmacology
Volume 6: Mechanisms of Toxicity and Metabolism
Sixth International Congress of Pharmacology
ABSTRACTS
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First edition 1977
Library of Congress Cataloging in Publication Data
International Congress of Pharmacology, 6th, Helsinki,
1975.
Abstracts of the Sixth International Congress of
Pharmacology.
(Proceedings of the Sixth International Congress of
Pharmacology;)
1. Pharmacology—Congresses. I. Series: International
Congress of Pharmacology, 6th, Helsinki, 1975.
Proceedings of the Sixth International Congress of
Pharmacology; [DNLM: 1. Pharmacology—Congresses
W3 IN636K 1975a / QV4 1573 1975al
RM21.I58 1975 615M 76-41261
ISBN 0-08-021308-1
Printed in Great Britain by A. Wheaton & Co,, Exeter
MONDAY MORNING
1 EXTRANEURONAL UPTAKE AND METABOLISM IN THE RAT'S SALIVARY GLAND. Pile Almgren and
Jan Jonason,Dept.of Pharmacol., Univ. of Goteborg, Fack, S-400 33 Gbteborg 33, Sweden.
The existence of an extraneuronal uptake of catecholamines in rat salivary glands was firmst demonstrated
by Anden et al. (Life Sci. 2,889,1963) and later confirmed both biochemically (Fischer et al., J. Pharmacol
exp. Ther.147, 181, 1965* Iversen et al.,J. Pharmacol.exp.Ther. 151,273,1966) and histochemically
(Hamberger et al., Acta physiol .scand.69,1,1967). The salivary gland provides a useful tool for studying ef­
fector cell mechanisms for several reasons: it is a paired organ with a dense adrenergic innervation* it can
easily be postganglionically sympathectomized which allows the study of a purely extraneuronal tissue with
respect to adrenergic nerves* the effector cell mass can be decreased (by atrophy following excretory duct
ligation) or increased (by isoproterenol treatment)* effector cell responses can be obtained (e.g. measure­
ment of salivary secretion). In the studies reported here both in vivo and in vitro techniques have been app­
lied to this tissue in order to investigate the uptake and metabolism of labelled amines.
After administration of ^H-noradrenaline (3|-j-NA) to normal salivary glands in vivo or in vitro the radio­
activity retained by the tissue consisted mainly of unchanged ^H-NA. When sympathectomized glands were
used or when protriptyline was administered to normal glands (in both cases eliminating the neuronal uptake)
the level of retained radioactivity was decreased and a shift in the metabolism was revealed. Thus, the level
of 3H-NA was severely reduced whereas the level of tritiated catabolites, mainly H-normetanephrine, was
markedly increased. The retention of catabolites, especially normetanephrine seems to reflect mainly the de­
gree of extraneuronal uptake and binding while the neuronal uptake and storage mechanisms appear to be
closely correlated to the retention of unchanged NA. In atrophied salivary glands extraneuronal mechanisms
are severely impaired. In such glands, however, almost the same amount of radioactivity is retained as in in­
tact glands when incubated with low concentrations of ^H-NA, and the major constituent of the retained
radioactivity is ^H-NA. When the neuronal uptake mechanism of the atrophied glands is impaired (by addi­
tion of protriptyline) the retention of radioactivity is drastically reduced. Thus, it appears that atlow sub-
strafe concentrations practically all amine taken up by the tissue is neuronal ly localized* first when the
neuronal uptake is impaired a significant extraneuronal uptake is revealed. At higher substrate concentrations
however, increasing amounts of extraneuronal ly retained radioactivity are seen even with an intact neuronal
uptake, probably the result of an increasing saturation of the neuronal uptake at higher substrate concentra­
tion. The uptake and retention of radioactivity in the extraneuronal tissue after incubation with 3H-NA was
not decreased after inhibition of catechol-O-methyl transferase but the unchanged amine was less efficiently
retained. When H-metaraminol was used as a substrate in an equimolar concentration about the same amounts
of radioactivity was retained and protriptyline reduced the amine retention to a greater extent in atrophied
salivary gland slices than in intact ones. Since this amine is resistent to monoamine oxidase and catechol-O-
methyl transferase these data indicate that metabolism of the amine is not a prerequisite for the extraneuronal
uptake. Obviously the amine is first taken up extraneuronal ly and then catabolized (if possible) especially
by catechol-O-methyl transferase and then retained mainly as catabolites.
As the extraneuronal amine uptake is severely impaired after glandular atrophy it is likely that this uptake
is localized to structures affected by atrophy (after excretory duct ligation), i.e.acini and to a lesser extent
ducts (Standish and Shafer, J.dent.Res.36, 866,1957).This uptake mechanism in the salivary glands is satur-
able, energy- and temperature-dependent and is not inhibited by either cocaine or tricyclic thymoleptics
like desipramine and protriptyline. The half-life of the extraneuronal ly retained radioactive material after
incubation with labelled NA is about 2.5 h.
Several drugs known to inhibit extraneuronal uptake in other tissues are also effective in the salivary
glands. Thus, normetanephrine reduces the accumulation of radioactive material in glandular slices in vitro
when an inhibitor of the neuronal uptake is also present and this effect is due to a decreased uptake rather
than to an increased efflux. Also phenoxybenzamine and corticosterone can strongly reduce the extraneuronal
accumulation of amines in rat salivary glands. On the other hand some (3-receptor antagonists like propranolol
and practolol seem to increase the extraneuronal uptake of amines in rat salivary glands in vitro and this
effect can probably be attributed to a true increase of uptake since the efflux was not significantly reduced
by the (3-receptor antagonists.
Normetanephrine and corticosterone potentiated the secretory responses to intravenously administered NA
in vivo under certain conditions. This potentiating effect of normetanephrine and corticosterone might be att­
ributed to their inhibitory effect on extraneuronal amine uptake.
(Supported by the Swedish Medical Research Council (project no. 2862).
Key words: Extraneuronal Uptake - Catecholamines - Normetanephrine - Corticosterone - Adrenergic
Receptors - Rat Salivary Glands.
MONDAY MORNING
2 EXTRANEURONAL UPTAKE AND METABOLISM OF CATECHOLAMINES IN THE PERFUSED HEART.
K.-H. Graefe, Dept. of Pharmacol., Univ. of Wurzburg, Wiirzburg, Fed. Rep. of Germany.
Lindmar and Muscholl (Naunyn-Schmiedebergs Arch. Pharmacol. 247, 469, 1964) introduced
the method of measurement of the removal of noradrenaline (NA) from the fluid perfusing
isolated hearts. "Removal" is largely independent of the metabolism that follows uptake.
With this method one can follow the time course of events in a single heart. If labelled
amine is used, the appearance of the labelled metabolites in the venous effluent can be
determined.
In a study of extraneuronal uptake and metabolism, rat hearts were perfused with 0.95 yM
3H-(+)-isoprenaline (ISO)(Bonisch et al., ibidem, 283, 191 and 283, 223, 1974). Methoxy-
isoprenaline (M-ISO) appeared in the venous effluent during the first minute of the per-
fusion and its rate of appearance increased rapidly and monophasically to reach a steady
state after 10 min (half time for approach to steady state: 1.1 min). The rate of removal
of ISO declined biphasically and finally approached a steady state (half time: 7.2 min)
at which removal equalled O-methylation. While the rate of formation of M-ISO remained
constant throughout, the accumulation of unchanged ISO in the heart increased during the
30 min of perfusion. This observation is compatible with the existence of two extraneuronal
compartments, one primarily concerned with O-methylation, the other with storage of ISO.
This view was supported also by the following findings, a) The kinetic constants for
O-methylation differed from those for removal (K : 2.9 and 21 yM, respectively; V : 1.7
and 38 nmoleS'g~l«min~l, respectively), b) Efflux of ISO from hearts initially
perfused with 0.95 yM ISO for 30 min (COMT being inhibited throughout) and then washed
out with amine-free solution originated from two extraneuronal compartments (half times:
10 and 23 min, respectively). Transport of ISO into and out of both compartments was
sensitive to corticosterone and O-methylated catecholamines. Uptake and O-methylation were
temperature-sensitive: a decrease in the temperature by 10° C increased the Km for O-methyl­
ation and for accumulation by a factor of about 6, with no change in Vmax.
The extraneuronal uptake and metabolism of ISO in the guinea-pig heart resembled that
in the rat heart, but rates of O-methylation and removal were much lower.
Hearts obtained from reserpine-pretreated cats (1 mg/kg s.c. 24 h and 0.5 mg/kg s.c.
3 h prior to experiment) were perfused with 0.3 yM 3H-(-)-NA. Normetanephrine (NMN) and
the metabolites of neuronal origin (i.e., 3,4-dihydroxyphenylglycol, 3,4-dihydroxymandelic
acid, 3-methoxy-4-hydroxyphenylglycol and 3-methoxy-4-hydroxymandelic acid) quickly appeared
in the venous effluent. The half times for the final approach to the steady-state rate of
appearance in the venous effluent were 4 min for NMN and 11 to 12 min for the "neuronal"
metabolites. The time course of the total formation of metabolites indicated that extra­
neuronal metabolism (i.e., NMN formation) equilibrated quickly, and "neuronal" metabolism
slowly. The rate of removal of NA declined multiphasically; the final approach to steady
state was very slow (half time: 150 min). When steady state was reached, the rate of removal
equalled the total formation of metabolites, NMN accounting for 35% of removal.
30 yM cocaine was added during the steady-state formation of NA metabolites. While the
"neuronal" metabolites disappeared from the venous effluent, the rate of appearance of NMN
increased to a new steady state. On addition of 30 yM hydrocortisone, on the other hand,
NMN disappeared from the venous effluent, while the "neuronal" metabolites remained
virtually unaffected. In both cases the rate of removal of NA was reduced.
Under similar conditions rat hearts exposed to 30 or loo yM cocaine exhibited con­
siderable extraneuronal formation of NMN and the various deaminated metabolites of
3H-(-)-NA (0.95 yM).
The hearts of various species have an extraneuronal, corticosteroid-sensitive uptake
mechanism which is in series with compartments able to either metabolize or store the
amine. The O-methylating compartment is in very quick equilibrium with the extracellular
amine concentration. Both storage and O~methylation are temperature-sensitive. The
compartments art characterized by different kinetic constants. There are species
differences with regard to transport capacities and to the relative importance of
extraneuronal MAO.
(Supported by the Deutsche Forschungsgemeinschaft; Tr. 96/5 and Gr. 490/1)
8
MONDAY MORNING
THE BINDING OF NORADRENALINE TO CONNECTIVE AND ELASTIC TISSUE. Garth Powis. Dept. of
Pharmacol., Univ. of Glasgow, Glasgow, Scotland.
The concept that the binding of drugs to sites within a tissue not immediately
connected with the physiological or pharmacological response might reduce the effective
drug concentration in the vicinity of the receptors was first proposed by Goldstein
(Pharmacol. Rev. J_, 102, 1949). Gillespie (Proc. Roy. Soc, B, Lond. 166. 1, 1966)
has suggested that 'silent receptors' for noradrenaline within the ground substance of
connective tissue might act to diminish the response of the effector cell. Fluorescence
histochemical studies have shown that noradrenaline, albeit at relatively high concen­
trations, will bind to collagen and elastic tissue (Avakian and Gillespie, Br. J. Pharmacol.
j>2, 168, 1968; Gillespie, Hamilton and Hosie, J. Physiol. 206. 565, 1970). Purified
collagen and elastin will bind radioactively labelled catecholamines at physiological
concentrations, and drugs which inhibit the binding will potentiate the response of the
rabbit central ear artery, a tissue rich in collagen and elastin, to noradrenaline and to
adrenergic nerve stimulation (Powis, J. Physiol. 234. 145, 1973).
Further work with a variety of vascular and non-vascular smooth muscle preparations
from different species has shown a significant correlation between the potentiation of
the response to both noradrenaline and adrenergic nerve stimulation produced by
oxytetracycline, an inhibitor of binding, and the elastin content of the tissue. There
was, however, no significant correlation between the potentiation of the response and
the collagen content of the tissue.
It might be expected that in tissues in which the neuromuscular synaptic cleft is quite
wide and in which the transmitter may diffuse relatively readily from the vicinity of the
cleft (Bevan and Su, J. Pharmacol. Exp. Ther. 190. 30, 1974) that the binding of
noradrenaline to extracellular sites would assume relatively more importance than in tissues
in which the synaptic cleft is narrow. In the present study several preparations with a
synaptic cleft ranging from around 200 A0 in the guinea pig vas deferens (Merrillees,
Burnstock and Holman, J. Cell Biol. J_£, 529, 1963) to 19,000 A0 in the rabbit pulmonary
artery ("Verity and Bevan, Bibl. Anat. Qt 60, 1966) were examined. The potentiation of the
response to nerve stimulation produced by oxytetracycline was expressed in terms of the
potentiation of the response to exogenous noradrenaline produced by oxytetracycline, to
allow for variations in the tissue content of elastin. There was a significant positive
correlation between the potentiation of the response to nerve stimulation, expressed in this
manner, and the width of the synaptic cleft.
It is concluded that the binding of noradrenaline to extracellular sites can be a factor
in diminishing the response of the effector cell, particularly in tissues which contain a
high proportion of elastin. The response to noradrenaline released at adrenergic nerve
endings is also diminished in those tissues in which there is likely to be a diffusion of
substantial amounts of the transmitter away from the vicinity of the synaptic cleft.
MONDAY MORNING
4 EXTRANEURONAL UPTAKE AND METABOLISM OF 3H-.l-NO.RADRENALINE IN RABBIT AORTA.
Jerome A. Levin. Dept. of Pharmacology and Therapeutics, Medical College of
Ohio at Toledo, Toledo, Ohio, U.S.A.
The uptake and metabolism of 3H-_l-noradrenaline (3H-NA) is being studied
in the intact rabbit aorta and in the isolated media and isolated adventitia
separated from the aorta. The isolated adventitia contains virtually all of
the adrenergic nerve terminals along with a few smooth muscle cells and
fibroblasts. The isolated media contains the smooth muscle cells and intimal
lining. Both portions contain significant amounts of collagen and elastin.
3H-NA and its five major metabolites are separated by paper chromatography
(Anal. Biochem. 5d, 42, 1973). 3H-NA (3 x 10~8M to 3 X 10"6M) is taken up by
these tissues and converted to all five of the major metabolites. In all
cases, a steady state tissue concentration of the metabolites is reached in
30 to 60 min. Thereafter, the metabolites pass out of the tissue and into
the incubation solution as fast as they are formed. The fraction of the
metabolite which passes into the incubation solution is different for the
various NA metabolites. The major metabolite formed by the media was
normetanephrine (3H-NM), whereas the adventitia formed primarily 3,4-
dihydroxy phenylethylglycol (3H-DP). Increasing the concentration of 3H-NA
from 3 x 10~8M to 3 x 10~^M increased the tissue accumulation of 3H-NA and
formation of all metabolites with no appreciable change in the proportions
of the various metabolites formed (J. Pharmacol. Exp. Therap. 190, 210,
1974) .
To study the uptake processes as isolated phenomena, it is essential to
block metabolism with inhibitors which do not directly affect the uptake
processes. Therefore, I determined the effect of at least 4 doses of several
monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT) inhibitors
on the uptake and metabolism of 3H-NA. 4-Tropolone acetamide (4-TA) or
3',4'-dihydroxy-2-methyl propiophenone (U-0521) were used to inhibit COMT.
In the media, U-0521 markedly decreased O-methylation and increased the
tissue concentration of 3H-NA. Deamination of 3H-NA was increased by lower
doses of U-0521 but decreased by the highest dose (1 mM). In the adventitia,
U-0521 slightly decreased accumulation of 3H-NA and formation of 3H-DP.
U-0521 did not decrease O-methylation in the adventitia as much as in the
media. U-0521 would be a satisfactory COMT inhibitor for studies on 3H-NA
uptake if it did not apparently decrease accumulation of )PH-NA in the
adventitia. 4-TA was less effective as a COMT inhibitor than U-0521 and
therefore would not be satisfactory for these experimentsi In the media, it
decreased formation of 3H-NM and increased 3H-NA accumulation. It also
increased formation of three of the deaminated metabolites including
vanillyl mandelic acid, which is deaminated and O-methylated. In doses up to
1 mM, 4-TA did not decrease 3H-NA O-methylation by the adventitia.
In both the adventitia and media, pargyline and pheniprazine markedly
decreased 3H-NA deamination and slightly increased ^H-NA accumulation but
did not alter O-methylation. Pargyline was a more effective inhibitor of
deamination in the media than in the adventitia. Iproniazid produced
similar effects but also increased 3H-NM formation. Harmaline decreased
deamination of 3H-NA and also markedly decreased O-methylation of 3H-NA in
adventitia and media. Harmaline did not increase 3H-NA accumulation as did
pargyline and iproniazid. Pargyline and pheniprazine appear to be the best
MAO inhibitors-tested so far.
Other inhibitors will be tested. The best MAO and COMT inhibitor will
then be tested in combination to establish that they block 3H-NA metabolism
without affecting uptake. Portions of isolated media pretreated with this
combination of inhibitors will then be used to study the kinetics of extra-
neuronal uptake of 3H-NA in rabbit aorta and the effect of drugs and other
manipulations on this process.
(Supported by USPHS Grant HL-12647 and by a grant from the American Heart
Association, Northwestern Ohio Chapter, Inc.).
10
MONDAY MORNING
EXTRANEURONAL UPTAKE AND METABOLISM IN DOG VASCULAR STRUCTURES. Walter
Osswald,Jose Garrett and Serafim.Gu imaraes. Laborat.Farmacol.,Facu1dade
Medicina, Porto, Portugal.
Two blood vessels of the dog were used: mesenterlc arteries and the sa-
phenous veinjthe former have a medio-adventitia 1 innervation,whereas in the
latter nerve terminals are distributed throughout the media (Osswa1d et al.,
Naunyn-Schmiedeberg ' s Arch . Pha rmak . 269, 1 5 , 1 971 ; Coimbra £_t al.,Blood Vess.
JJ_,128,197*0 . In an attempt to correlate data obtained by diTFerent experi­
mental approaches,the following methods were used: relaxation of the strips
in oil after contraction caused by electrical stimulation or exogenous cate-
cho1 amines(Ka1sner and Nickerson,J.Pharmacb1 .exp.Therap. 163,1,1968) ,autora-
diography of strips previously loaded with 'H-noradrena1ine or 3H-isoprena-
1 ine , perfus ion or incubation of vascular segments with labelled catecholami-
nes and determination of total radioactivity and metabo 1 ites ;modifications
of sensitivity of strips to catecho1 amines by treatment with inhibitors of
uptake and methylation.
Concerning the uptake of transmitter released by electrical stimulation,
it was found that neuronal uptake and subsequent oxidative deamination is the
main process involved in termination of action(Brandao and Guimaraes, Blood
Vess. JJ[, kS , 1 97** )• However , i n the mesenteric arteries(but not in the saphenous
vein) extraneurona1 uptake appears to be effective even in the presence of an
intact neuronal uptake;these differences are attributed to the different
patterns of innervation. For exogenous catecho1 amines,the roles played by
neuronal and extraneurona1 uptake processes depend on the concentration and
the nature of the agonists used,extraneurona1 uptake decreasing from isopre-
naline to adrenaline to noradrenaline and increasing with the concentration.
For noradrenaline and adrena1ine,which are taken up by both mechanisms,the
role played by extraneuronal uptake is profoundly affected by suppression of
the neuronal uptake.Because of this fact, isoprena1 ine is a better tool for
studying the extraneuronal uptake.
Both vascular structures studied show a high 0-methy 1 ating capacity and a
very limited capacity of storage of 0-methy1 isoprena1 ine (0M I ) . During perfu-
sion with isoprenaline,a constant rate ofO-methylation was observed,whereas
the rate of accumulation of isoprenaline approached zero.
Correlation of histologic data with sensitivity indicate that the smooth
muscle of the media is the predominant, if not the exc1usive,sIte of methyl­
ation . The COMT inhibitor U-0521 effectively blocks the formation of OMI and
results in an increased accumulation of isoprenaline in the smooth muscle.
Cortexone reduces both total radioactivity and OM I formation.
Inhibition of COMT differs from impairment of extraneuronal uptake with
regard to the changes exerted on sensitivity to and inactivation of catecho1-
am i nes . >
The results suggest that in the extraneuronal distribution of catecholami-
nes the follov/ing factors should be cons i dered : ex t racel 1 u 1 a r space , b i nd i ng to
proteins and other reactive sites and uptake into cells. After up take,storage
capacity of both the intact molecule and the metabolites as well as metabolic
capacity must be taken into account. It is felt there is a need for further
studies on these problems, attempting to correlate results observed with
different methods in order to define the topography and the kinetics of the
phenomene under study.
(Supported by Instituto de Alta Cultura, Research Project PMC-2)
11
MONDAY MORNING
5 THERAPEUTIC IMPLICATIONS OF CONTROLLED DRUG DELIVERY. Alejandro Zaffaroni. ALZA Corporation,
Palo Alto, California 94304. U.S.A.
The main thrust in the history of therapeutics has been the pursuit of chemical structures possessing particular
pharmacological activities. The chemical approach to therapeutics crystallized in the foundation of chemotherapy with
the work of Ehrlich at the turn of the century. As such, the concept of chemotherapy has focussed attention on the
relation between chemical structure and drug action, with the common but erroneous perception that drug = therapy.
This simplistic view ignores the basic fact that a drug becomes a therapeutic agent only when it is formulated and made
an integral part of a dosage form. This symposium recognizes the significance of drug delivery technology in
pharmacology and therapeutics.
Although many advances have been made in both the science and art of drug formulation, there are, however,
limitations in these dosage forms so fundamental that they have distorted the perception, definition, and quantification
of drug action, and have biased the development of new drugs. One of the fundamental limitations of virtually all
present dosage forms is that they release drug most rapidly at the outset, and at continually declining rates thereafter.
There may be certain drugs for which this peak/valley pattern of delivery is ideal, but that remains to be proved. The
peak/valley pattern of drug delivery with conventional dosage forms always necessitates a compromise between an
excess delivery of drug early in the interval between doses, and too high a dosage frequency. Conventional dosage forms
have duration of delivery at best of a few hours, with two detrimental effects on therapeutics: 1) The requirement of
high frequency of dose administration resulting in patient's failure to comply with dosage schedules and 2) The inability
to use pharmacological agents with short biological half lives, resulting in the exclusion of a large number of attractive
synthetic drugs and the majority of the mammalian hormones and humoral factors.
During the last 10 to 15 years there has been an increase in interest and effort towards improvement in drug
delivery technology with the introduction of micro-encapsulation, drug dispersions in polymer matrices, bioerodible
polymers, and other approaches leading to sustained drug release. None of these efforts, however, achieved controlled
drug release. The recognition of the major opportunity that controlled drug delivery could make to therapeutics brought
us to initiate a research program in 1968 which lead to the development of new class of drug dosage form that we have
named a therapeutic system. Therapeutic systems permit precision dosing of drugs with continuous control of drug
delivery rates and with extended operational delivery times. They are specifically designed for the unattended delivery
of drug, for either local or systemic therapy. Conventional dosage forms are defined solely in terms of their drug
content. On the other hand, a therapeutic system is meaningfully characterized by both drug delivery rate and drug
delivery duration. A therapeutic system has the aim of improving and eventually optimizing the therapeutic potential of
drugs by allowing both temporal and spatial control over the administration of drugs to the body. The principles
underlying the concept of controlled drug delivery, involve a synthesis of the principles of molecular transport in
polymeric materials, and those of pharmacokinetics and pharmacodynamics.
A therapeutic system is comprised of a minimum of three components: 1) a drug, 2) a drug delivery module, which
contains the drug reservoir, the source of energy for transferring drug from the reservoir to the body, and the
rate-controlling element that determines the rapidity with which the drug is released to the body, and 3) a platform
which assures safe and comfortable placement of the system to the selected body site. Examples of therapeutic systems
will be discussed to illustrate the power of temporal and spatial controlled drug delivery in achieving a new order of
specificity in pharmacological activity and thus a broader range of applications for established drugs and less rigid
pharmacokinetic and pharmacodynamic constraints that newly developed agents must meet to make practical,
acceptable products.
12
MONDAY MORNING
7 NOVEL METHODS OF OCULAR DRUG DELIVERY. John Urquhart. ALZA Research, Palo Alto, Californi.
94304, U.S.A.
Both the upper and lower conjunctival cul-de-sac provide space for liquid, semi-solid, and solid dosage forms foi
topical ophthalmic drug therapy. Eyedrops and ointments have been in long-standing use, but their short residence times
in the cul-de-sac necessitate frequent re-application, usually in the range of 1 to 4 times daily, and sometimes more
frequently. Two major problems attend the use of drop or ointment dosage forms: 1) variable, often poor, patient
compliance with the prescribed regimen; 2) significantly fluctuating drug effects, both desired and undesired, within
each interval between doses. The literature speaks only semi-quantitatively to the first problem, which plagues all
self-administered dosage forms to a degree that is related inversely to the interval between doses. The second problem is
inescapable with either drops or ointments because both deliver drugs to the eye with approximately first-order kinetics,
i.e. a rate which declines continuously from the moment of application. Given first-order delivery kinetics, the interval
between doses depends upon dose: the greater the dose, the longer the interval. However, a ceiling on dose is set by the
appearance of dose-dependent undesired effects, and a ceiling on interval is set by the dose-dependent time of
disappearance of desired effects. First-order delivery kinetics are, therefore, fundamentally limiting, and a dose-interval
compromise must be struck with every drug/dosage form no matter how one may retard first-order kinetics, for
example, by the addition of thickeners or binders to drops, or by the use of ointments of drug-loaded hydrophobic bases
or solid films of drug-loaded hydrophilic polymers. With any of these approaches, the rate of drug delivery to the eye
invariably cycles, within the interval between doses, first above, and later below that level which, could it be maintained,
would provide optimal therapy.
It is, of course, possible that optimal therapy with some drugs is to be realized by delivery at a fluctuating level, but
that possibility has never been conclusively demonstrated for any drug, partly because an experimental program for
doing so calls for sophisticated drug delivery technology, hitherto unavailable. In particular, ocular pharmacology has
not been a focus of such work, and so it is reasonable to proceed with the simplest hypothesis, that optimal ophthalmic
drug therapy can be achieved and sustained by maintaining constant rates of drug delivery, i.e. zero-order, rather than
first-order, delivery.
Achievement of constant, or zero-order, delivery over long periods of time has called for new technologies,
discontinuous with those that have grown up around the conventional dosage forms of tablets, capsules, solutions,
suspensions, and ointments. One of the new technologies is represented by the membrane-enclosed, discrete drug
reservoir, in which drug permeates the membrane by solution diffusion at a rate controlled by membrane properties. It is
possible to fabricate such systems as thin, poly-laminated films having dimensions, surface texture, and flexibility that
allow their safe and comfortable residence in the cul-de-sac for prolonged periods of time. Such systems for the
controlled, zero-order delivery of pilocarpine are now commercially available in the U.S. These systems deliver
pilocarpine at either 20 or 40 /ig/hour for seven days after placement in the cul-de-sac. Patients with ordinary dexterity
readily learn the technique of replacing a used system with a fresh one, and need neither special skill nor assistance to
change systems each week. Compared to pilocarpine eyedrops of conventional 1-4% strengths, one or the other of these
two delivery systems affords comparable management of intraocular hypertension with appreciably less undesired
effects such as induced myopia and miosis. The pilocarpine dosage per unit time with the membrane controlled delivery
system is about one-eighth that needed with eyedrops. Animal studies of the comparative temporal patterns of
pilocarpine distribution in ocular tissues with the zero-order delivery system versus with eyedrops show striking
differences in favor of the delivery system.
Controlled, zero-order delivery of ophthalmic drugs is also possible by osmotic means, either from single or
polydisperse reservoirs. Controlled, zero-order delivery is also possible from erodible, drug loaded, hydrophobic
polymers, whose rate of erosion and concomitant drug delivery is surface-controlled. Thus, there are three new
technologies for controlled ophthalmic drug delivery: membrane-controlled solution diffusion, membrane-controlled
osmotic pumping, and surface-controlled bio-erosion. Together they provide the means for the controlled, zero-order
delivery of virtually every drug in ophthalmic use today. It is also possible to achieve simultaneous, independent control
over the delivery of two drugs from the same system. That achievement makes it possible rationally to deliver com­
binations of drugs with widely disparate pharmacokinetic behavior.
These developments collectively represent a new class of dosage form, termed the ocular therapeutic system. Its
dosage strength is measured neither in drug quantity nor concentration, as with conventional solid, semi-solid, and liquid
dosage forms, but by the rate at which it delivers drug, and by the duration over which it maintains controlled delivery
at the specified rate. *'
These developments open new therapeutic opportunities in ophthalmology. Re-evaluation is in order of the
therapeutic potential of each agent in (and around) the ophthalmic pharmacopoiea, because, up to now, the limited
technology for ophthalmic drug delivery has imposed myopia on the perception of therapeutic potential.
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