ARTHRITIS & RHEUMATISM
Vol. 50, No. 8, August 2004, pp 2391–2399
DOI 10.1002/art.20424
© 2004, American College of Rheumatology
REVIEW
The Discovery and Development of Antiinflammatory Drugs
Kay Brune and Burkhard Hinz
From willow bark to morphine: traditional therapy
Inflammation was one of the earliest recognized
and defined disease entities. Celsus characterized in-
flammation by the 4 cardinal signs, namely, pain (dolor),
redness (rubor), warmth (calor), and swelling (tumor);
Galenius (others say Virchow) added “loss of function”
(functio laesa). These signs are still valid. Attempts to
modify these symptoms by drug therapy are at least as
old as the cardinal signs themselves.
Dioscourides, a Greek physician of the Roman
army, prescribed extracts of willow bark for joint pain,
an approach that was later propagated by Hildegard von
Bingen in continental Europe and, of course, by the
Reverend Stone in his famous letter to the Royal Society
of Medicine in London (1,2). The physicians of those
times recognized that local inflammation often accom-
panies “general inflammation” manifested by fever and
malaise. The reason for this association was only re-
cently uncovered, namely, the release of the pyrogenic
cytokines, such as tumor necrosis factor ␣ (TNF␣) and
interleukin-1, that are produced by inflamed tissue and
mediate generalized symptoms. Fever, along with mal-
aise, was regarded by the Hippocratic School as a
cardinal sign of an imbalance in the body fluids, resulting
in disease (3). Based on this Hippocratic concept, pur-
gation, sweating, and bloodletting were employed to
alleviate inflammation and other diseases on the as-
sumption that these procedures could change the com-
position of the body fluids. Such practices were contin-
ued until the 19th century and were used to cure all
types of diseases, including mental disorders (4). Not
surprisingly, these measures yielded limited success.
A more rational approach to treating inflamma-
Kay Brune, MD, Burkhard Hinz, PhD: Friedrich-Alexander
University, Erlangen, Germany.
Address correspondence and reprint requests to Kay Brune,
MD, Department of Experimental and Clinical Pharmacology and
Toxicology, Friedrich-Alexander University, Fahrstrasse 17, D-91054
Erlangen, Germany. E-mail: brune@pharmakologie.uni-erlangen.de.
Submitted for publication December 18, 2003; accepted in
revised form April 29, 2004.
2391
tion became possible after the invention of the ther-
mometer (5). As soon as fever could be measured, it lent
itself to therapeutic trials. The bark of the cinchona tree
(containing quinine) was one of the earliest drugs dis-
covered to be effective against fever. In the 18th century,
malaria was a prominent disease in many parts of
Europe. Since cinchona bark turned out to be effective,
why shouldn’t European barks be tested? The results are
well known. First, willow bark was confirmed to be
effective, and then the natural ester of salicylic acid
(salicin) was isolated as the willow’s active ingredient
(1,2). Later, salicylic acid itself was isolated. Eventually,
Kolbe described the complete synthesis of pure salicylic
acid. To provide sufficient amounts, the first “scale up”
of a synthetic process was invented, and the first drug
factory was built (Salicylic Acid Works, founded by von
Heyden in Dresden in 1874) (see ref. 6).
Earlier (in 1806), a young pharmacist in Einbeck,
Germany had made another major discovery. W. Ser-
türner, an admirer of the French Revolution and the
scientific discoveries that followed it, had used his large
pharmacy (apothecary) to extract the active ingredient
of opium, the sap of the poppy. Sertürner had checked
his extracts for sedative activity in his pack of dogs and
was able to isolate a pure substance that he named
morphine, after the god of sleep (7). The importance of
this discovery is hard to appreciate even now. Until the
discovery of morphine, a drug effect was always the
consequence of the combined ingredients of a plant or
animal product and the suggestive effect of the “healer”
(physician, apothecary, witch doctor). With morphine,
for the first time, a pure (crystalline) substance mediated
the effect. Since the substance could be reliably dosed,
the physician was now less important. Caventou and
Pelletier in Paris adapted this method and isolated
several alkaloids, among them quinine (8). This mole-
cule was the target for many new chemical syntheses.
While Sertürner, Caventou and Pelletier, and others
isolated the active ingredients from different plants
(among them strychnine, veratrine, and others), Ma-
gendie in Paris introduced the first pharmacopeia based
2392
Figure 1. Synthesis of phenazone (antipyrine).
exclusively on administration of purified substances.
Moreover, he used experiments in animals and humans
to properly ascertain both the dose and the effect of the
drugs (9).
Pure chemicals
The next step forward was taken by continental
European pharmacists and chemists who tried to com-
pensate for an impaired supply of Oriental and South
American drugs (morphine, quinine, and others) by
chemical synthesis. These alkaloids were soon shown by
Dumas and Pelletier to include nitrogen-containing ring
systems. Emil Fischer, then in Munich, found a reagent,
phenylhydrazine, for the synthesis of nitrogen-
containing ring systems. His scholar, Ludwig Knorr,
tried to synthesize quinine and produced phenazone by
esterifying phenylhydrazine with acetoacetic acid. Some
of these synthetic compounds proved to be active against
fever. One was phenazone (antipyrine), which was syn-
thesized in Erlangen in 1882 (2) (see Figure 1). The
patent for this compound enabled the starting of a small
dye factory (Meister, Lucius und Bruening) in a suburb
BRUNE AND HINZ
of Frankfurt called Hoechst. This was the start of the
pharmaceutical company Hoechst (10). Another chem-
ist, as we will show below, esterified salicylic acid with
acetate and discovered aspirin. This synthesis was done
in another dye factory, Bayer, on the shores of the Rhine
river.
Two hundred years ago, many Huguenots had
left France following the Edict of Nantes and had
brought their skills as silk weavers and silk dyers to a
more hospitable environment, the Protestant areas
around Basel, Frankfurt, and Cologne. This emigration
proved useful later, when the German and Swiss silk
industry transformed itself into the dye industry and
later the drug industry. The new science of chemistry
added to this transformation by providing both new
synthetic dyes and new synthetic drugs. With the discov-
ery that salicylic acid was active against fever (by Buss in
Switzerland) and rheumatoid arthritis (by Stricker in
Berlin), and with the synthesis of phenazone, an active
antipyretic and analgesic drug (2), two dye factories,
Bayer and Hoechst, began developing into leading phar-
maceutical companies.
HISTORY OF ANTIINFLAMMATORY DRUGS
The development of a chemical–pharmaceutical
industry was aided by another accidental discovery. In
the famous Medical Clinic in Strasbourg, two young
physicians, Cahn and Hepp, were asked by the famous
clinician Kussmaul to eradicate intestinal worms with
naphthalene. They were amazed that the worms survived
(in one patient) but the fever resolved (10). An analysis
of this unusual result revealed that the pharmacy had
incorrectly provided acetanilide rather than naphthalene
for treatment. This led to the discovery of the pharma-
cologic activity of acetanilide, which was marketed soon
by another small dye factory close to Frankfurt (Kalle)
under the name Antifebrin. Bayer further investigated
acetanilide and found that a derivative (a byproduct of
aniline dye production), namely, “acetophenitidine,” was
equally effective. They marketed it under the brand name
Phenacetin. These discoveries constituted, as phrased by
Tainter (11), “. . . the beginning of the famous German
drug industry and ushered in Germany’s forty-year domi-
nance of the synthetic drug and chemical field.”
Thus, by the end of the 19th century, 3 prototype
substances were already available for the treatment of
pain, fever, and inflammation. One was a synthetically
prepared natural substance (salicylic acid). The other
two were pure chemical entities found by serendipity.
All were made available as drugs by a growing chemical
industry. This industry took advantage of the science of
chemistry to fulfill the need for pure and readily avail-
able therapeutic substances (i.e., drugs). Almost all of
the drug industry was founded along the Rhine, where
chemistry was developed, water was available, and skill-
ful dye workers could be recruited. The continental
blockade (during 1806–1815), which interfered with the
supply of chocolate powder, quinine, morphine, and
latex from overseas, stimulated chemical research and
the production of synthetic alternatives to natural prod-
ucts from coal tar. It should be added that these early
drugs were produced by chemists and taken directly to
the clinic. Pharmacology and toxicology played no sig-
nificant role in this early phase.
The phase of improvement: pharmacology comes into
play
As soon as salicylic acid, phenazone, and phen-
acetin were widely used, physicians and patients came to
recognize the disadvantages of these analgesic antipyret-
ics. Each was of relatively low potency, and patients
needed to take them in several-gram quantities daily (by
spoon). Ingesting up to 10 spoonfuls of sodium salicylate
was extremely unpleasant and unpalatable. Taking sev-
2393
eral grams of phenacetin led to potentially dangerous
methemoglobinemia, while phenazone, taken in gram
quantities, often caused allergic reactions. Conse-
quently, the expanding drug industry, especially Bayer in
Wuppertal and Hoechst in Frankfurt, put their chemists
to work to produce improved derivatives.
Felix Hoffmann, a young chemist at Bayer, was
highly motivated to improve the palatability of salicylic
acid, since his father had rheumatoid arthritis and found
taking several grams of salicylic acid or sodium salicylate
increasingly unbearable (2,5). On a suggestion of A. von
Eichengrün, who was at that time in charge of (syn-
thetic) chemistry at Bayer, Hoffmann researched the
literature thoroughly and learned that C. F. von Ger-
hardt in Strasbourg had produced acetylsalicylic acid a
couple of years earlier. Hoffmann reproduced this syn-
thesis and gave the acetylated product to his father, who
preferred it (5). In everyday practice, acetylsalicylic acid
proved difficult to handle because it was extremely
sensitive to humidity and disintegrated quickly if water
was present. Since the substance was previously known,
Bayer could only obtain a patent on the water-free
production process. The company also secured the trade
name Aspirin (derived from acetyl and one source of
salicylic acid, the plant Spirea ulmaria). It is of note that,
as a consequence of the end of World War I and the
Treaty of Versailles in 1919, Bayer lost the exclusive
rights to the name “Aspirin.”
The favorable judgment of Felix Hoffmann’s
father wasn’t sufficient for marketing. Therefore, Hein-
rich Dreser, the first pharmacologist at Bayer, tried to
demonstrate the reduced toxicity of aspirin to the stom-
ach mucosa compared with salicylic acid. At that time,
gastroscopy was impossible. Instead, Dreser used a
goldfish model, believing that the “mucosa” of the fins
was an analog of human intestinal mucosa. Dipping the
tail fins of (living) goldfish into solutions of either
salicylic acid or aspirin, he observed that higher concen-
trations of aspirin than of salicylic acid were necessary to
“cloudy” the clear fins (Figure 2). He concluded that this
was proof of less toxicity and, therefore, of better
gastrointestinal tolerability of aspirin (12). This dogma
still prevails today, despite the fact that Heinrich Dreser
himself recognized his error. Dreser had measured
“acidity” rather than a “gastrotoxic effect,” and salicylic
acid is more acidic than aspirin (13).
To further improve the tolerability of phenacetin,
Bayer, working together with the chemist Joseph von
Mering, investigated a metabolite of phenacetin called
acetaminophen (paracetamol). It appeared that, proba-
bly due to impurities, acetaminophen also caused met-
2394
Figure 2. Discovery of aspirin. The goldfish fins are from the original publication by Heinrich
Dreser.
hemoglobinemia and, in addition, was dangerous when
administered in excessive doses. Thus, phenacetin re-
mained on the market in Germany. In contrast, Sterling
in the UK found that acetaminophen did not induce
methemoglobinemia and marketed the product world-
wide under the name Panadol (now the property of
GlaxoSmithKline) (5).
Hoechst finally followed a suggestion of Filehne,
the pharmacologist who discovered the antipyretic ac-
tion of phenazone, and introduced more amino groups
into the structure of phenazone. The resulting com-
pounds amidopyrin, melubrin, and dipyrone proved to
be somewhat more active, and dipyrone was useful as an
injectable. Hoffmann-La Roche, however, did not follow
this path, but instead substituted an isopropyl group for
the amino group of 4-amino-diethyl antipyrine. The
resulting drug, propyphenazone, is still in use. Propy-
phenazone has been shown to have little specific toxicity
(i.e., it lacks bone marrow toxicity [14] and kidney
toxicity), and it remains an enigma why this drug is not
used much more intensively worldwide.
Finally, several companies combined the two
active ingredients (e.g., by producing salts of aspirin or
salicylic acid with amidopyrin or esters linking paraceta-
mol and salicylic acid [benorylate]). All attempts to
BRUNE AND HINZ
increase antiinflammatory/antipyretic/analgesic activity
as well as tolerability by this strategy were unsuccessful.
Moreover, the 3 basic ingredients were mixed with each
other and supplemented, for example, with caffeine to
produce APC powders (aspirin, paracetamol, caffeine,
vitamins, minerals, and other partly obscure ingredi-
ents). Without doubt, this diversity of “drugs” pleased
the consumer, but was of no major medical benefit. It
may instead have led to abuse and kidney toxicity (15).
New compounds on the basis of pharmacologic
(screening) models
An important new development occurred after
World War II. Once again, an unplanned event paved
the way. Hoping to reduce bone marrow damage attrib-
uted to aminophenazone, Geigy in Basel attempted to
produce an injectable preparation. From among several
candidates (synthesized by H. Stenzl) that formed water-
soluble salts of aminophenazone, the acidic 3,5-dioxo-
1,2-diphenyl-4-n-butylpyrazolidine (later named phenyl-
butazone) was selected (Figure 3). The initial
formulation was called Irgapyrine. This salt turned out
to be extremely active, particularly in rheumatic (inflam-
matory) pain. Two clinicians appear to have been of
HISTORY OF ANTIINFLAMMATORY DRUGS 2395

Figure 3. Discovery of the antiinflammatory action of phenylbutazone. Gerhard Wilhelmi estab-

lished the ultraviolet-elicited erythema in the depilated skin of guinea pigs. By means of this assay,
phenylbutazone was determined to have a pronounced antiinflammatory action.

remarkable importance in this discovery: Otto Gsell of
St. Gallen (Switzerland) and Ludwig Heilmeyer of
Freiburg (Germany). They observed a dramatic antiin-
flammatory effect never seen before with salicylates or
phenazones (16). Axelrod and Brodie evaluated the
plasma concentrations of phenylbutazone and
phenazones in patients for Geigy. They learned that
phenylbutazone was present in much higher concentra-
tions, and for much longer periods of time, than amino-
phenazone. This corresponded to the intensity and
duration of the antiinflammatory effects of the salt. The
conclusion was that the “salt-forming” partner of amino-
phenazone was the dominant active ingredient.
To understand these clinical observations, a phar-
macologist at Geigy, Gerhard Wilhelmi, developed
novel models of inflammation (17). Phenylbutazone
turned out to be particularly active in reducing the
erythema elicited in the depilated skin of guinea pigs
following irradiation with ultraviolet (UV) light (18).
This was the first model of inflammation used to define
the activity of what we now call nonsteroidal antiinflam-
matory drugs (NSAIDs). By applying this model, several
phenylbutazone analogs and the phenylbutazone metab-
olite, oxyphenbutazone, as well as the fenamates, an-
other chemical class of antiinflammatory agents, were
discovered to be of particular value in inflammation and
inflammation-related pain. These discoveries gave Geigy
a major boost. They led to the successful merger with
Ciba and, much later, with Sandoz (all in Basel, Switzer-
land) to form the present Novartis.
Across the Atlantic, Charles Winter, initially at
Merck, Sharp, and Dohme and later at Parke-Davis,
tried to develop his own model of inflammatory pain. He
eventually developed the cotton string granuloma test
and used it to identify indomethacin (synthesized by
T. Y. Shen) as a potent antiinflammatory drug. Indo-
methacin was also particularly active in the carrageenan-
induced rat paw model of inflammation. This assay
turned out to be especially useful for measuring antiin-
flammatory activity (19) (Figure 4). A similar model had
been used earlier by Randall and Selitto for detecting
the analgesic activity of new compounds (20). Through
the use of these models, 3 different chemical classes of
drugs were discovered. First, Merck, Sharp, and Dohme
identified indole antiinflammatory agents. Among 350
indole compounds screened in animals, the most suc-
cessful were indomethacin (marketed in 1964) and
sulindac. Indomethacin is still regarded as the gold
standard for a compound that combines both anti-
inflammatory and analgesic activity (16).
2396
Figure 4. Carrageenan-induced rat paw edema as a model of inflammatory pain. Charles
Winter found indomethacin (synthesized by T. Y. Shen) to be particularly active in this assay.
In contrast, the company Boots found success
with a variety of propionic acid derivatives. Ibuprofen
(marketed in 1969) and flurbiprofen (marketed in 1977)
are still widely used, and ibuprofen is currently regarded
as the gold standard for an over-the-counter analgesic
(21). Parke-Davis embarked on the investigation of
fenamic acid derivatives. Flufenamic acid was the first,
followed by others (16). This group of agents has been
widely abandoned due to central nervous system (CNS)
toxicity at higher doses. The former pioneering compa-
nies in Europe concentrated on acetic acid derivatives.
Geigy was most successful with diclofenac (first mar-
keted in 1974 in Japan), and Rhône-Poulenc, together
with Bayer, contributed to the development of propionic
acids with ketoprofen (marketed in 1973). Many other
propionic acids were patented and marketed. Most of
them (e.g., indoprofen, pirprofen, benoxaprofen, and
many others) did not offer advantages or were taken off
the market because of serious side effects.
Finally, Lombardino at Pfizer revitalized the con-
cept of ketoenolic acids (phenylbutazone, oxyphenbuta-
zone). The advantage of these compounds is that all
pharmacokinetic parameters can be defined by minor
changes in the molecular structure (22). Pfizer’s piroxi-
BRUNE AND HINZ
cam (23) was soon followed by tenoxicam at
Hoffmann-La Roche, and recently, this group of agents
was augmented by meloxicam. There were no major
differences in efficacy or limiting side effects of these
diverse compounds. They simply differed in their po-
tency and pharmacokinetic parameters, including me-
tabolism and drug interactions.
All of these antiinflammatory drugs were identi-
fied using animal models before the mode of action of
“aspirin-like” drugs—as these substances were formerly
named—was determined. It would be more than 70
years after the synthesis of aspirin before John Vane’s
group could demonstrate that these compounds were
inhibitors of prostaglandin synthesis (24).
One of the questions that arises is, Why were
many of the old compounds found by serendipity (such
as phenazone, propyphenazone, dipyrone, phenacetin,
paracetamol) nonacidic chemicals that only weakly in-
hibited cyclooxygenases (COX) (see below), while all of
the compounds developed after the almost-unexpected
discovery of phenylbutazones in animal models were
acidic (25)? We are convinced that these models are
primarily models of inflammation and not of pain.
Consequently, drugs that work by blocking COX in the
HISTORY OF ANTIINFLAMMATORY DRUGS
inflamed tissue completely, as well as by reducing COX
activity in the CNS, were found to be superior to those
that only partially reduced the activity of COX through-
out the body. We were able to show, by different
methods, that all acidic compounds (comprising pKa
values between 4 and 5, 99% protein binding, and
amphiphilic structures) concentrate not only in body
compartments such as the bloodstream, liver, spleen,
and bone marrow (due to high protein binding and an
open endothelial layer of the vasculature), but also in
body compartments with acidic extracellular pH values,
such as the kidney (collecting ducts), stomach wall, and,
most importantly, inflamed tissue (26). This skewed
distribution causes almost complete inhibition of pros-
taglandin synthesis in these locations, which results in
superior antiinflammatory activity but also leads to
relatively high kidney and stomach toxicity (26).
Distributional selectivity may have reduced some
of the side effects (including liver toxicity and CNS
toxicity) and increased the antiinflammatory effects
compared with, for example, phenazone. However, non-
acidic compounds such as phenazone or paracetamol
lack distributional selectivity. Indeed, paracetamol and
phenazone, compounds with almost neutral pKa values
and scarce binding to plasma proteins, are distributed
homogeneously and quickly throughout the body due to
their ability to easily penetrate barriers, such as the
blood–brain barrier. Consequently, they should be used
only to curb mild pain with low doses. Although the
nonacidic compounds may also be poorer COX inhibi-
tors than the acidic ones, high doses eventually lead to
complete inhibition of both COX-1 and COX-2 through-
out the body. These high doses are also dangerous, as is
well known to any physician who has ever treated a case
of paracetamol overdose.
This difference may be less important today, since
strong antiinflammatory effects in rheumatoid arthritis
are now provided by biologics such as anti-TNF antibod-
ies or methotrexate. Therefore, the antiinflammatory
effects seen with indomethacin or phenylbutazone are
less important. This may also explain why, for long
periods of time, nonacidic compounds such as the
indoxyl-like analogs of indomethacin (e.g., indoxole) or
nonacidic compounds like proquazone (CP22, 655),
despite their very effective inhibition of COX, were
neither highly antiinflammatory nor clinically effective.
They caused serious side effects, including skin (UV
toxicity) and liver damage, when used in antiinflamma-
tory doses.
The discovery of the existence of two cyclooxy-
genases (COX-1 and COX-2) (27) has changed the
2397
pharmacologic landscape. It provides for a new dimen-
sion of selectivity, not limited to differences of tissue
distribution, but now based on enzyme selectivity.
Antiinflammatory drugs in the age of molecular
pharmacology
Analgesics, including morphine and salicylates,
were among the first reported drugs used by humans.
They are still the most widely administered drugs world-
wide. The search for new and better analgesics now
employs molecular and genomic approaches. This devel-
opment already started in the late 1940s, when E.
Kendall (in the US) and T. Reichstein (in Switzerland)
discovered cortisone, and P. Hench (at the Mayo Clinic,
in Rochester, MN) used cortisone to treat a patient with
rheumatic disease who was unable to get out of bed
without assistance. The patient recovered miraculously
and went—as the story goes—to downtown Rochester to
go shopping. In 1950, these scientists (Figure 5) received
the Nobel Prize. In the same year, Raoul Dufy, a French
painter with rheumatoid arthritis, was treated with cor-
tisone at age 73. For years, he had hardly been able to
hold the brush. He had to fix it to his hand with tape. His
paintings were accordingly colorful, but clumsy (Figure
5). After treatment with aspirin plus cortisone, he be-
lieved that he might be able to continue painting for at
least 10 more years. Regrettably, he died soon after of
gastrointestinal bleeding, which may reasonably have
been related to the concomitant administration of aspi-
rin and cortisone.
Since that time, the pharmaceutical industry has
been searching for new ways to separate the effective-
ness of steroids plus NSAIDs from their gastrointestinal
toxicity. The discovery of prostaglandins as well as the
inhibition of prostaglandin production by aspirin-like
drugs gave rise to the investigation of the effects of
steroids on prostaglandin production. Many researchers,
including ourselves, observed that steroids could reduce
prostaglandin production but could not block it com-
pletely (28). Most of us accepted this as fact. It was
Philip Needleman (at that time in St. Louis, MO) who
eventually proposed that there must be 2 enzymes, one
whose expression could be blocked by steroids and
another whose expression was constitutive. In 1990, the
group led by Needleman provided proof of the existence
of 2 different enzymes (29,30). At the same time, the
group led by Harvey Herschman (in Los Angeles, CA)
isolated and characterized an inducible COX isoform
(31). For the first time in the history of pharmacology, 2
targets of selective drugs were identified before the roles
2398 BRUNE AND HINZ

Figure 5. Discovery of cortisone. In the late 1940s, E. Kendall and T. Reichstein discovered cortisone, which was
first administered by P. Hench to a patient with rheumatoid arthritis. Raoul Dufy, a French painter with
rheumatoid arthritis, came to the US for cortisone treatment in 1950. Pleased by the effect of the drug, he painted
“La Cortisone” in 1951 and continued to paint until his death in 1953 from an acute gastric hemorrhage.

of those targets, the enzymes COX-1 and COX-2, were
fully defined. John Vane and Philip Needleman rea-
soned that inhibition of COX-2, the enzyme whose
expression is under the control of cortisone, would be
sufficient for antiinflammatory and analgesic effects but
would be free of gastrointestinal and kidney toxicity—a
contention that would prove to be only partly correct.
It was soon clear that it might indeed be advan-
tageous to have drugs that only interfered with COX-2,
because this enzyme was not involved in the production
of gastrointestinally protective prostaglandins. All drug
companies searched their shelves for compounds that
might exert this selectivity. Diclofenac and meloxicam
were two drugs that showed some selectivity toward
COX-2 (32), probably contributing to the worldwide
success of diclofenac as well as to the successful launch
of meloxicam. Both of these compounds, however, still
interfere with COX-1 activity at therapeutic doses.
This situation changed with the discovery of
highly selective sulfonamides, celecoxib and valdecoxib,
and the methylsulfones, rofecoxib and etoricoxib. In
truth, these compounds are not the result of pharmaco-
logic or chemical revolutions. Instead, they are close
relatives of old compounds like phenazone (see Figure
1). They extend the paracetamol/phenazone group of
nonacidic compounds that were always relatively devoid
of gastrointestinal toxicity but lacked prominent antiin-
flammatory effects, possibly because they distribute ho-
mogeneously throughout the whole organism and do not
accumulate in inflamed tissue, compared with, for exam-
ple, phenylbutazone or indomethacin (26). These new
analgesics are not free of side effects, since inhibition of
COX-2 affects kidney function, blood pressure, and
possibly other parameters of physiology (for review, see
ref. 33). Moreover, these compounds remain in the body
for prolonged periods of time, distribute equally
throughout all body compartments, and are occasionally
associated with skin and liver toxicity.
HISTORY OF ANTIINFLAMMATORY DRUGS
The scene is still changing. Lumiracoxib, soon to
be on the market, is a chemical and pharmacologic
relative of diclofenac. It distributes in the same manner
as the other acids and combines COX-2 selectivity with
tissue distributional selectivity (34). The clinical result of
this compound will determine whether it is a meaningful
extension of the acidic compounds, which began with
salicylic acid and led to the arylpropionic, arylacetic, and
ketoenolic acids.
After 120 years of the development of
antipyretic/antiinflammatory analgesics, we have made
progress. Serendipity, as well as targeted research, has
provided clinicians with many useful drugs which differ
in their pharmacologic and clinical aspects. Knowing a
little of the history of their discovery and development
may provide a perspective to better understand their
effects and side effects. Humble acknowledgment of the
role of serendipity may change our attitude toward
research and marketing claims. However, serendipity is
not all, as phrased by E. Kaestner, a German poet:
Irrtümer sind ganz gut,
Jedoch nur hier und da.
Nicht jeder, der nach Indien fährt,
entdeckt AMERIKA.
Errors are fine,
but only some time(s).
Not everyone heading for India
discovers AMERICA.
ACKNOWLEDGMENTS
Helpful discussions with many scientists, in particular
I. Otterness, A. Sallmann, T. Y. Shen, and G. Wilhelmi, are
gratefully acknowledged.
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