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This article is an historical investigation of the term non-steroidal anti-inflammatory drugs and its acronym NSAIDs. Drug names and categories tend to be taken at face value in everyday practice, as natural categories existing in their own right. The main argument of this article is that the term NSAID is a reminder that drug names and categories are complex cultural and social products that have been created by specific people, for specific purposes, through specific historical processes, and that this is relevant for their use today. The article locates the first appearances of the phrase non-steroidal at the entry to the 1960s, when the iatrogenic tragedies that followed from the introduction of corticosteroids had become apparent, and where a clear separation between these drugs and emerging anti-inflammatory alternatives was needed. The article then shows how both the phrase and the acronym appeared for the first time out of specific textual contexts in publications by Michael W. Whitehouse, before they were taken up by a wider community and transformed into concepts independent on the context of their first appearances.
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Origins and impact of the term ‘NSAID’
Jonas Kure Buer
Department of Social Anthropology, University of Oslo
Postboks 1091 Blindern
0317 Oslo, Norway
Abstract This article is an historical investigation of the
term non-steroidal anti-inflammatory drugs and its acronym
NSAIDs. Drug names and categories tend to be taken at face
value in everyday practice, as natural categories existing in
their own right. The main argument of this article is that the
term NSAID is a reminder that drug names and categories
are in fact complex cultural and social products that have
been created by specific people, for specific purposes,
through specific historical processes, and that this is
relevant for their use today. The article locates the first
appearances of the phrase non-steroidal at the entry to the
1960s, when the iatrogenic tragedies that followed from the
introduction of corticosteroids had become apparent, and
where a clear separation between these drugs and emerging
anti-inflammatory alternatives was needed. The article then
shows how both the phrase and the acronym appeared for
the first time out of specific textual contexts in publications
by Michael W. Whitehouse, before they were taken up by a
wider community and transformed into concepts
independent on the context of their first appearances.
NSAID; history; drug names; drug categories;
Origins and impact of the term 'NSAID’.
In 2012, I did ethnographic fieldwork in a rheumatology
ward. The purpose was to study processes of interaction of
health care workers and patients. The term NSAID was in
frequent use in a way that attracted my interest: It referred
to a number of drugs, but the name NSAID did not seem to
add much meaning. Even when written out in full as non-
steroidal anti-inflammatory drugs the term did not say much
about the drugs it comprised, other than their being anti-
inflammatory, like so many other anti-rheumatic drugs.
However, in addition, the term NSAID curiously identified
what the drugs it referred to were not: they were not
steroids. Why was it necessary, and even pertinent, to
communicate that Diclofenac, for instance, was not
Prednisolone? In 2012, Prednisolone and other steroids had
for several decades been used at low-dose against rheumatic
diseases (Case, 2001:130), and to me as a newcomer to the
field, steroids seemed to be a standard, conventional part of
the rheumatologists’ tool kit. Defining a different group of
drugs as not steroids did not immediately make sense.
Looking into the matter, I soon realized that the term
NSAID, like a lot of other terms in medicine, was not easy
to examine historically. NSAIDs do “…have anti-
inflammatory, analgesic, and antipyretic properties”
(Klippel et al., 2010:205); what they don’t have is a
recorded history. Yet, in the case of NSAIDs, the two first
letters of the NSAID acronym turned out to function as a
time capsule, making it possible to set the directions for
inquiries of the past where the term originated. It turned my
attention to the introduction to medicine of the thing that
NSAIDs are not namely anti-inflammatory steroids.
The introduction of corticosteroids
In 1941 Hans Selye had given the first scientific description
of corticosteroids (Selye, 1941a, Selye 1941b).
Then in
1949 a corticosteroid treatment was presented for the first
time in medicine. It was arguably a cure for rheumatic
arthritis (Case, 2001:130), and the first anti-rheumatic drug
with disease modifying
properties (Whitehouse, 2011:2). As
The Editors thank Professor Ludmila Filaretova, St Petersburg for her
knowledge on the original scientific discovery of corticosteroids.
More than two decades should pass before the term disease-modifying
The final publication is available at Springer via
the news leaked from the conference room to the press,
steroids came to be presented as “a genuine miracle cure”,
and already the following year the individuals behind its
discovery received the Nobel Prize (Le Fanu, 2011:33). A
long feature article in the June 1951 issue of Popular
Science (Pfeiffer, 1951) provides a salient example of the
enthusiasm that the discovery of steroids spurred:
The hormones [ACTH and cortisone] represent
an entirely new approach in the art of healing.
Penicillin, streptomycin, the sulfa drugs, and
most other medicines you’ve been reading about
are poisons intended specifically to attack
invading germs. (…) But ACTH and cortisone are
not germ-killers. They are natural products,
gland hormones. They influence the body’s built-
in chemical factories that go into action
whenever extra supplies of tissue are required.
Using rheumatoid arthritis as example, journalist John E.
Pfeiffer elaborated on the miraculous effects of steroids:
The hormone can reshape (…) a deformed joint
into a smoothly work ing fulcrum. Pain
disappears, and the accumulated debris dissolves.
Furthermore, destruction of supporting tissue is
stopped in its tracks for months and fresh cells
may come in to repair the damage.
While Pfeiffer was aware that there were side-effects to the
drug, he seemed to interpret those as just other marvels of
the miracle:
No modern drugs have so many bizarre and
baffling effects, wanted and unwanted. How do
ACTH and cortisone produce excess hair growth
and a moon-shaped face? Why do they increase
the multiplication rate of tuberculosis germs -
and at the same time prevent the disease from
s p r e a d i n g i n t h e e a r l y s t a g e s ?
He perceived the ability to induce euphoria in patients as
“perhaps the most intriguing effect of all”:
Cortisone and ACTH are potent ‘pep’
preparations. Patients experience a marked
mental lift after the first doses. They sleep only
four or five hours a night, and don’t seem to mind
In the meantime, physicians and patients learned that the
side-effects of treatment with these steroids - “…the moon
face, the perforated and bleeding ulcers, the bruising and
crushed vertebrae…”(Le Fanu, 2011:34) - were all but
marvels. The year Pfeiffer published his article in Popular
Science, the first monograph on steroids’ adverse effects
(Derbes and Weiss 1951) was also published (Whitehouse
2011:2). Gradually rheumatologists realized that the
miracles came at too high a price. Popularity waned and by
anti-rheumatic drug (DMARD) was coined.
the early 1960s, steroid treatment was “shunned altogether
by the rheumatology community” (Case, 2001:130). An
anti-steroid zeitgeist arose, and although steroid treatment
was reborn in the 1980s as a low-dose regimen, its use
remained controversial (Case, 2001:130).
Following, on this background it seems reasonable to
formulate the hypothesis that the concept of NSAIDs had
been coined not only after the emergence of steroid therapy
in 1949, but also after the fall from prestige of steroids in
rheumatology around 1960, and before the revival of
steroids as a low-dose treatment in the 1980s. PubMed
searches for the term (on May 5 2014) point to the early 60s
as the origin of the term “non-steroid”: The earliest mention
of "non-steroid anti-inflammatory" that I was thus able to
pinpoint was in the article "A biochemical distinction
between non-steroid anti-inflammatory and analgesic drugs"
(Whitehouse, 1963).
A necessary separation
I identified the author of this 1963 article as Professor
Michael W Whitehouse of Griffith University, Brisbane
As I asked Professor Whitehouse to share any
information he might have on the forging and popularizing
of the terms non-steroid anti-inflammatory and NSAIDs,
Whitehouse described a situation where the steroids and
their analogues had been overused and mis-prescribed.
Their euphoric properties had induced addiction in patients,
and severe side effects had transformed the hopeful
sufferers into “steroid-wrecks” i.e. “patients with ulcers,
fragile skin, osteoporosis, impaired immune responses and
damaging cartilage repair.”
In the late 1950s and early 1960s, a different family of drugs
developed from phenylbutazone (indomethacin and
flufenamic acid among others being introduced in the
1960s), while pharmaceutical companies were competing to
introduce ‘super steroids’, failing to disclose the full side-
The record of iatrogenic tragedies that steroids had
accumulated, and the problems of deciding whether any
new drug was or wasn’t related to the known steroids, and
thus determining the risks related to it, called for moves that
could clarify the situation. In the early 1960s, no known
mechanism or other known characteristic could distinguish
from steroids the drugs that were soon to be known as
Whitehouse was in the middle of research that provided him
with the right point of view to produce a conceptual tool
able to make just such a distinction. Having earned his D
Phil from the University of Oxford in 1955, he had
relocated to the Department of Physiological Chemistry at
the University of Pennsylvania in Philadelphia. There he
had become acquainted with Howard Holzer and Jay Lash,
after department chairman Sam Gurin had suggested he go
and see them in the Anatomy department, one floor below,
to discuss alternatives to histological staining as ways to
Personal communication May 2014.
For details on this, see “Anti-inflammatory glucocorticoid drugs:
reflections after 60 years” (Whitehouse 2011).
The final publication is available at Springer via
characterize embryonic cartilage and distinguish it from
embryonic muscle:
‘Borrowing’ their tissue culture system for
initiating cartilage development from embryonic
chicken somites, it was easy to confirm that [anti-
inflammatory] steroids poisoned this process.
From pragmatic solution to independent concept
Upon his return to Oxford in 1959, Whitehouse analyzed the
data from the experiments he had conducted in Philadelphia,
and in 1960 he presented the first results at the first
International Congress of Endocrinology, Copenhagen. It is
in the proceedings to that congress, in a short paper entitled
“Effect of hydrocortisone and some of their synthetic
analogues upon the biogenesis of cartilage in vitro”
(Whitehouse and Lash, 1960), that Whitehouse used the
phrase non-steroid anti-inflammatory for what was probably
the first time:
We have studied the effects of a number of
glucocorticoids and also of some non-steroid
anti-inflammatory agents upon the biogenesis of
cartilage in tissue culture.
The following year, the final version of that paper was
published as an article in Nature: Effect of cortisone and
related compounds on the biogenesis of cartilage”
(Whitehouse and Lash, 1961). In the article, results with
different substances were grouped together under three
separate headings: Results with Cortisone and
Hydrocortisone”, “Results with Some Synthetic
Glucocorticoids”, and “Results with some Non-Steroid
Anti-inflammatory Agents”. Further the term non-steroid
appeared twice in the text, in the introduction and in the
conclusion, in the following sentences:
For comparison we also observed the effects of
some non-steroid inflammatory agents upon this
system in vitro.
This desirable end is found otherwise with certain
non-steroid drugs, for example phenylbutazone.
It is interesting to note that the use of non-steroid in these
examples can be read as merely resulting from the logic of
the text. The phrase appears within the pattern X, and non-
X (where steroids are X and where “for example
phenylbutazone”, which is not a steroid, is referred to as
non-X). This separation categorized, within the context of
the article, all substances that had been tested. Nothing in
the text indicates that this was more than a pragmatic
solution, or that a new concept was about to be introduced
to medicine.
But by 1963, however, it is clear that the phrase that
appeared in the 1960 and 1961 publications had been
established as an independent concept. In the article A
Biochemical Distinction Between Non-Steroid Anti-
inflammatory and Analgesic Drugs” (Whitehouse, 1963),
the term non-steroid figures for the first time in a heading,
but more importantly, the non-X (the non-steroid) appeared
in a linguistic context where there was no mention of the X
(the steroid). Conversely and rather unusually, the
distinction that was drawn was now between non-X and Y,
i.e. between “Non-Steroid Anti-Inflammatory Drugs” and
“Analgesic Drugs.” That the phrase non-steroid anti-
inflammatory drugs had been taken up as a concept by a
wider research community was evident when in September
1964 an “International symposium on non-steroidal anti-
inflammatory drugs” was organized in Milan, resulting in
the publication of a book (Garattini and Dukes, 1965) with
the term in its title.
Acronym and concept-acronym
Still, during the 1960s, the drugs were referred to as non-
steroidal anti-inflammatory drugs, not as NSAIDs, as they
often are today. Ten years seem to have passed before the
concept-phrase was challenged in use by its acronym. In
1973, Paulus and Whitehouse published an article titled
"Nonsteroid anti-inflammatory agents" (Paulus and
Whitehouse, 1973), and at the bottom of the first page, the
authors use the acronym, for the first time, in the following
Demonstration of the anti-rheumatic properties
of these new drugs (…) establishes to some
degree the validity of the rat edema assays for
selecting moderately effective nonsteroidal "anti-
inflammatory" drugs (NSAIDs).
The acronym was introduced, it seems, in compliance with
norms of using acronyms sparingly and fully explained
when first used. The ambition of the authors, clearly, was
not to introduce a new term, but to communicate their
research results to their readers.
As with the term non-steroid in 1960, it therefore seems as
though the appearance of the acronym NSAID was
somehow brought forward by the internal logics of research
publishing. In a similar way to how the phrase non-steroid
anti-inflammatory had become concept in its own right, the
acronym NSAID was soon established as an independent
concept with no need of explanation. By the late 1970s, the
acronym even figured in the titles of scientific journal
articles: “Possible causes of treatment failure with the
NSAID” (Gylding-Sabroe, 1978), and “Relation between
ulcerogenic activity of various NSAID and their potency as
inhibitors of prostaglandin synthesis in vivo” (Strub and
Muller, 1979), being the two earliest examples of this in
Subsequently, the acronym-concept gained popularity and
widespread use: A PubMed search (on June 3 2014) on the
term NSAID, resulted in 191.349 hits. A Google search that
same day resulted in 4.420.000 hits in 0,11 seconds. Today,
the term NSAID is so widely used that it seems difficult to
conceptualize any discourse on drug treatments in
rheumatology without it. In Whitehouse’s own words:
Though clumsy, the acronym NSAIDs seemed to
The final publication is available at Springer via
have served us well; for example, reassuring
physicians that their use will not produce pseudo-
steroid wrecks, though their patients may still
suffer stomach (but not skin) ulcers and in
extreme cases intestinal perforation.
It is perhaps not insignificant that the popularization of the
acronym NSAID as an independent concept, which played
down the message of caution against steroids, coincided
with a rising awareness of the dangers associated with
NSAIDs themselves.
The term NSAID seems to have been born from a perceived
need to distinguish new anti-inflammatory drugs from
steroids, and from the determination of a young researcher,
Michael Whitehouse, to separate his biochemical studies on
salicylates and other acidic anti-inflammatories “from the
odium associated with the anti-inflammatory steroids.” It
seems that it was the perceived need to separate these drugs
from the steroids, and the absence of a clear logic for
internal identification of the emerging group of anti-
inflammatory drugs, was what led Whitehouse to use the
term “non-steroidal anti-inflammatory”. Doing so, he forged
a category that reflected his research findings, and which
defined this emerging field of research at an early point. At
the same time, the term that he introduced answered to
needs outside of laboratory research - i.e. in clinical practice
and public discourse. The concept non-steroid anti-
inflammatory proved useful in the 60s as a tool for handling
the complexities of inflammopharmacology, by signaling
what it was not. Later the NSAIDs were to be associated
with their own series of severe iatrogenic effects, while the
term as such remained robust. What was introduced as a
warning has become a thing - and it continues to be useful,
we must assume, though perhaps for totally different
reasons. For me, it has been useful as an entry point into the
rather impenetrable but immensely interesting history of
development of cultural categories in pharmacology.
In the excavations I have relayed above, we may well have
identified the time when the term was coined, the context of
the coining, and even the originator’s reasons for coining it.
We may have appreciated some of the uses the term have
served, and serves today. But we can only speculate on the
total impact that the rather serendipitous introduction of this
term has had on rheumatology, on pharmacology in general,
on drug development, research finance, marketing; on
clinical communication, patient safety, and so on - over the
50 years since its coining. A perceived need to minimize
harm to the patient, deflecting attention away from the
steroids as prime therapy, seems to have been a driving
force behind this striking development. On a more detailed
level, this has required that the term be perceived, again and
again, as answering to a number of needs of a multitude of
social actors, actors who have found it opportune to
perpetuate the use of its term, until the point where its use
ceased to be a choice, became reflex, and the term was
established as an entity in its own right.
The concept seems to have been naturalized in the sense that
NSAIDs and “non-steroidal anti-inflammatory drugs”
appear almost as an a priori category, as though the
category existed before the individual drugs that the
category comprises appeared, even before the discovery of
the steroids. This is perhaps the most interesting insight we
can draw from this investigation. In medical literature and
everyday language and practices, drug categories such as
NSAIDs are often taken at face value, as phenomena
existing in their own right. The term NSAIDs remind us that
these categories are not a priori given; they have been
created by specific people, for specific purposes, through
specific historical processes. They could be different, and
they needn’t be at all, but being - as complex cultural,
social, historical creations - and being exactly what they are,
they have worked not only in our world, but also on it, and
continue to do so.
Jonas Kure Buer
PhD fellow
Department of social anthropology
University of Oslo
Acknowledgments: I am heavily indebted to Professor
Michael Whitehouse and Professor KD Rainsford for
encouraging an historical commentary on this topic, and for
providing informational fixed points that allowed me to
make the step from speculations to facts. Thanks to
Professor Whitehouse for sharing his memories and insights
about the origin of the term, and for proofreading my
analysis. Thanks also to Professor KD Rainsford for
checking for other early appearances in rheumatological
literature from the period, including several of Derek
Willoughby's papers and more (Gourley, 1964, Rechenberg
and Kunz, 1962, Dixon et al., 1963, Smith and Smith,
1966). Thanks to Professor KD Rainsford’s verifications, it
seems even safer to identify Michael Whitehouse as the
originator of the term “non-steroidal anti-inflammatory”
drugs, as well as of the NSAID acronym. Any
misinterpretations or other mistakes are entirely mine. I will
be thankful to anyone who points this out for me. I also
want to underscore that the identification of Michael
Whitehouse as originator of the terms is based on my
investigations as well as KD Rainsford’s verifications, and
that Michael Whitehouse has not made any claims on his
own behalf; he has merely contributed with a personal
account that does not contradict, but supports, the
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cortisone and ACTH. Blackwells Scientific
Publications, Oxford
DIXON, A., MARTIN, J., SMITH, B. & WOOD, M. 1963.
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sponsored by the Empire Rheumatism Council,
with the support of the Nicholas Research
Institute Ltd, London, Churchill.
GARATTINI, S. & DUKES, M. N. G. 1965. International
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The final publication is available at Springer via
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Even though many genetic risk loci for human diseases have been identified and comprehensively cataloged, strategies to guide clinical research by integrating the extensive results of genetic studies and biological resources are still limited. Moreover, integrative analyses that provide novel insights into disease biology are expected to be especially useful for drug discovery. Herein, we use text mining of genetic studies on colorectal cancer (CRC) and assign biological annotations to identified risk genes in order to discover novel drug targets and potential drugs for repurposing. Risk genes for CRC were obtained from PubMed text mining, and for each gene, six functional and bioinformatic annotations were analyzed. The annotations include missense mutations, expression quantitative trait loci (eQTL), molecular pathway analyses, protein-protein interactions (PPIs), genetic overlap with knockout mouse phenotypes, and primary immunodeficiency. We then prioritized biological risk candidate genes according to a scoring system for the six functional annotations. Each functional annotation was assigned one point, and those genes with a score ≥2 were designated "biological CRC risk genes". Using this method, we revealed 82 biological CRC risk genes, which mapped to 128 genes in an expanded PPI network. Further utilizing DrugBank and the Therapeutic Target Database (TTD), we found 21 genes in our list that are targeted by 166 candidate drugs. Based on data from, we found our list contains four known target genes with six drugs approved for CRC treatment, as well as three known target genes with nine drugs under preclinical investigation for CRC. Additionally, 12 genes are targeted by 32 drugs approved for other indications, which can possibly be repurposed for CRC treatment. Finally, our analysis from Connectivity Map (CMap) showed that 18 of the 41 drugs under clinical and preclinical investigation have high potential to be useful for CRC.
Auf einen Blick Im Pharmakologie-Unterricht, in den Lehrbüchern und dementsprechend auch in der medizinischen deutschsprachigen Literatur und den im Internet abrufbaren Informationen hat sich eine Vielzahl von pharmakologischen Begriffen etabliert, die in der Kommunikation unter Ärzten und in der Kommunikation mit Patienten gewohnheitsmäßig verwendet werden, ohne dass sie in Hinsicht auf ihre wissenschaftliche Aktualität reflektiert werden. Jeder Arzt wird sich schon einmal gedacht haben, dass der eine oder andere Begriff etwas ungenau ist, aber im täglichen Sprachgebrauch hat sich dennoch nichts geändert. Bei der Entwicklung der Arzneistoffliste für den Nationalen Kompetenzbasierten Lernzielkatalog Medizin und den neuen Gegenstandskatalog Medizin des Instituts für Medizinische und Pharmazeutische Prüfungsfragen wurden nun erstmals mechanistische und chemische Begriffe für Arzneistoffgruppen implementiert. Damit ist ein erster Schritt zu einer zeitgemäßen, präzisen Arzneistoffgruppen-Nomenklatur erfolgt, die in zukünftigen Auflagen des Arzneiverordnungs-Reports ebenfalls Eingang finden soll. Mit diesem Artikel soll ein Beitrag dazu geleistet werden, dass es zu keinen Kommunikationsproblemen zwischen jungen Ärzten und bereits langjährig tätigen Ärzten kommt, die die neue Arzneistoffgruppen-Nomenklatur im Studium noch nicht kennengelernt haben. Langfristig wird die neue Arzneistoffgruppen-Nomenklatur auch die Arzt-Patient-Kommunikation präzisieren und erleichtern.
Radical cascade cyclization of β,γ‐unsaturated hydrazones/oximes has recently emerged as an efficient and powerful protocol for the construction of diverse and valuable functionalized pyrazolines and isoxazolines. In this review, three catalytic ways of radical cascade cyclization of β,γ‐unsaturated hydrazones/oximes are summarized and classified, which are transition‐metal‐ catalyzed systems, transition‐metal‐free systems, or photo‐/electrocatalytic systems, respectively. Through these methods, various functional groups are installed on the pyrazoline and isoxazoline skeletons to enrich the small organic molecules library.
Background Nonalcoholic Steatohepatitis (NASH) results from the accumulation of fatty acids in the liver. The elevated production of pro-inflammatory factors is the reason for the hyper inflammation in NASH. The α-L-Guluronic acid (G2013), a new member of NSAID family, is a plant-originated agent with immunomodulatory properties. The current study investigated the effects of G2013 on inflammatory factors in PBMCs of NASH patients. Methods PBMCs of 14 NASH patients and 14 healthy controls were isolated and cultured. The patient’s cells were treated with low (5 µg/mL) and moderate (25 µg/mL) doses of G2013 alongside the diclofenac optimum dose (3 µg/mL). The expression and secretion levels of variables were assessed by real-time PCR and ELISA, respectively. Results Findings indicated that the expression levels of TLR4 and NF-κB, as well as the secretion levels of TNF-α and IL-6 cytokines, were significantly elevated in NASH patients compared to healthy individuals. The expression levels of TLR4 and NF-κB were strikingly downregulated in treated cells of patients in both low and moderate doses of G2013. A considerable reduction was obtained in the secretion level of IL-6 using both low and moderate doses of G2013 and in the secretion level of TNF-α using the moderate dose of G2013. Conclusion The results indicated that G2013 could meaningfully decrease the expression and secretion levels of evaluated factors (TLR4, NF-κB, TNF-α, and IL-6) in PMBCs of NASH cases. Since there is no effective treatment for NASH patients, we hope that G2013 would be a promising immunomodulatory agent in reducing inflammation and improvement of patients.
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This study aimed at evaluating the nephroprotective role of different doses of the methanol extract of Laportea aestruans leaves on indomethacin-induced nephrotoxicity in adult male Wistar rats. Forty rats were divided into five groups of eight rats and pretreated orally for three days with methanol extract of Laportea aestruans before administration of indomethacin. Rats in group one; normal control received 0.5 ml normal saline (0.9 % v /v). Rats in group two received 20 mg/kg body weight indomethacin alone. Rats in group three, four and five received 200, 400 and 800 mg/kg body weight of methanol extract of Laportea aestruans. At the expiration of the experiment, rats were sacrificed, blood and the kidney were collected for renal functions tests. The results showed that administration of indomethacin alone caused a significant (p ˂ 0.05) increase in the concentrations of creatinine, urea, uric acid, cholesterol and total protein and the activity of glucose-6-phosphatase and renal 5'-nucleotidase in the piroxicam alone treated group. However, pretreatment methanol extract of Laportea aestruans showed a dose-dependent decrease in the concentrations and the activities of all the kidney markers assayed for. The results show that methanol extract of Laportea aestruans possesses nephroprotective potential against indomethacin-induced renal damage.
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Rheumatoid arthritis is the paradigmatic immune-mediated inflammatory arthropathy and may be of comparatively recent, New World origin. Apart from the symptom-relieving nonsteroidal anti-inflammatory drugs, whose natural congeners have been in use since antiquity for musculoskeletal pain and inflammation, only a dozen drugs or drug classes--the disease-modifying antirheumatic drugs--are currently in common use in rheumatoid arthritis. Development of these drugs has been a notable achievement of the 20th century. Some were developed serendipitously (glucocorticoids, antimalarials), some were the product of faulty reasoning (gold, D-penicillamine), and others were applied for plausible reasons but whose mechanism remains unproven (sulfasalazine, methotrexate, minocycline). A minority were originally applied on the basis of actions that remain germane to the pathophysiology of rheumatoid arthritis as currently understood (azathioprine, cyclosporine, leflunomide, infliximab, etanercept). Among the latter are the more recently introduced and effective agents. The practical use of these drugs is determined by efficacy-toxicity considerations, which have also driven the recent development of the cyclooxygenase-2-selective nonsteroidal anti-inflammatory drugs.
A new edition of the Primer on the Rheumatic Diseases appears as a supplement to this issue of JAMA. The title of the monograph has been modified slightly over the years, but each edition after the first has been prepared by a committee of the American Rheumatism Association. Assuming full risk of the charge that I lack all sense of humility, as well as accepting the castigation as a name-dropper, I believe it appropriate to mention a number of physicians, personal friends closely identified with rheumatism and arthritis for more than four decades, who contributed to the composition of one or more editions of the Primer. My working interest in the Primer began as a contributor to the third edition, which appeared in 1949. Later, as editor of JAMA I accepted for publication the fifth and sixth editions, which appeared in 1959 and 1964. Now it is my privilege to
This review considers the problem of the serious concomitant side effects of powerful anti-inflammatory drugs modelled upon the principal human glucocorticoid hormone, cortisol. The very nature of the original bio-assays to validate their cortisol-like hormonal and anti-inflammatory activities ensured that pleiotropic toxins were selected for clinical studies. Other complicating factors have been (1) considerable reliance on bio-assays conducted in laboratory animals that primarily secrete corticosterone, not cortisol, as their principal anti-inflammatory adrenal hormone; (2) some differences in the binding of xenobiotic cortisol analogues (vis á vis cortisol) to transport proteins, detoxifying enzymes and even some intra-cellular receptors; (3) the "rogue" properties of these hormonal xenobiotics, acting independently of--but still able to suppress--hormonal mechanisms regulating endogenous cortisol; and (4) problems of intrinsic/acquired "steroid resistance", diminishing their clinical efficacy, but not necessarily all their toxicities. The rather gloomy conclusion is that devising new drugs to reproduce the effect of multi-potent hormones may be a recipe for disaster, in contexts other than simply remedying an endocrine deficiency. Promising new developments include "designed" combination therapies that allow some reduction in total steroid doses (and hopefully their side effects); sharpening strategies to limit the actual duration of steroid administration; and resurgent interest in searching for more selective analogues (both steroidal and non-steroid) with less harmful side effects. Some oversights and neglected areas of research are also considered. Overall, it now seems timely to engage in some drastic rethinking about (retaining?) these "licensed toxins" as fundamental therapies for chronic inflammation.
A series of non-steroidal anti-inflammatory drugs (NSAID) and a few other agents were evaluated for their ability to: 1) reduce the acute toxicity of intravenously injected arachidonic acid (AA) in mice; 2) prevent castor oil-induced diarrhoea in mice; 3) enhance the formation of gastric mucosal erosions by a water stress in rats. A correlation between the activity in the three tests has been found for most NSAID studied, and the results point to inhibition of cyclooxygenase as a common mechanism of action.
The clinical efficacy of non-steroidal anti-inflammatory drugs (NSAID) is often disappointing in spite of their well-known antiphlogistic actions. The reasons for this failure are probably due to irregular intake by patients on long-term treatment with such agents. These considerations inevitably point to the necessity of concomitant determination of the plasma levels of all NSAID tested, and the need to perform clinical trials in an appropriate setting in which such determinations can be conveniently carried out.
Nonsteroidal antiinflammatory agents (NSAID) are reviewed. Aspirin, indomethacin, and salicylate have all been shown to interfere or prevent the synthesis of prostaglandins (PGs), a main tissue inflammatory substance. However, an exception to the correlation of PG-synthetase inhibition with antiinflammatory activity has been noted with certain arylacetic acids. Studies on the role of lysosomes in the inflammation are criticized in this review, mainly because of improper understanding of the role of lysosomes in a physiological system. Since lysosomes are not a specific body, but an activator, attempts to isolate lysosomes to study functions are doomed to failure; i.e., a lysosome has no definition without the rest of its self-regulating system. NSAIDs work in 2 main ways; either via antiaggregation or antiinflammation. This may result in drug interactions between various types of NSAIDs. For example, simultaneous administration of aspirin with indomethacine did not produce an additive effect; rather they produced no effect in the rat paw edema test dissimilar to the action of either drug separately. However, hydrocortisone combined with another NSAID enhanced its antiinflammatory effects. Albumin binding theories of NSAID mechanism of action state that drugs are active only when albumin-bound because it has displaced tryptophane, or urate, or some other normally bound substance. The only way to discover an efficient antiinflammatory agent is to obviate the need for it by discovering the actual mechanism of inflammation, for when specific anti-etiologic therapy is developed, the need for treatment with NSAIDs is irrelevant.
After a 20-year hiatus, drug development for rheumatoid arthritis resumed in the early 1980s with cyclosporine, continuing in the 1990s with minocycline, leflunomide, and the tumor necrosis factor-alpha antagonists, infliximab and etanercept. Unlike the older disease-modifying antirheumatic drugs (apart from the cytotoxics), the newer drugs were designed with strict reference to proven pathophysiology in rheumatoid arthritis and, apart from minocycline, the intended action of these agents is highly likely the explanation for the observed efficacy. The evidence for the evolution of more rational drug development in rheumatoid arthritis has not altered the fact that efficacy versus toxicity still remains the major determinant in the practical use of these agents, as well as in the use of other, experimental agents briefly discussed. Action, efficacy, and toxicity also determine the rational chronologic use of these drugs alone and, in particular, in combination.