Drug Evaluation

Drugs 30: 514-538 (1985)

0012-6667/85/00 12-0514/$12.50/0
© ADiS Press Limited
All rights reserved.

Suprofen
A Review of Its Pharmacodynamic and Pharmacokinetic
Properties, and Analgesic Efficacy

P.A. Todd and R.C. Heel

ADIS Drug Information Services, Auckland

Various sections of the manuscript reviewed by: H. Berry, Department of Rheumatology

and Rehabilitation, King's College Hospital, London, England; S.A. Cooper, Stephen A.
Cooper Associates Inc., Short Hills, New Jersey, USA; N. Fellmann, Rheumaklinik mit
Physikalisch-Balneologischen Institut, Rheuma-Volksheilstatte, Leukerbad, Switzerland:
F.D. Hart, Harley Street, London, England; A. Hedges, Department of Clinical Phar-
macology, St. Bartholomew's Hospital, London, England; W.J. Honig, Nijmegen, The
Netherlands.

Contents

Summary .............. ............ ............................. ....... .......... ............. ......... ........... ....... .............. ....... 515
I. Pharmacodynamic Properties ................ ................... ............... .... ................ ......................... 517
1.1 Analgesic Activity .................................... ........ .............. ... ................ .............................. 517
1.2 Anti-Inflammatory Activity ........................... .......................... .......... ......... ................... 518
1.3 Antipyretic Activity ......................................................................... ...............................519
1.4 Gastrointestinal Effects ................................................... .................. .............................. 520
1.5 Effect on Prostaglandins ............... ........................... ............ ....................................... .... 520
1.6 Effects on the Endometrium ................. .... ........ .............................. .... ........................... 521
1.7 Cardiovascular Effects ............................................................................. ....................... 521
1.7.1 Haematological Effects ................. .... ............................... ...................................... 521
1.7.2 Haemodynamic Effects ....... ............ ....................................................................... 522
1.8 Other Effects .................................................................... .. ............................... ....... ..... ... 522
2. Pharmacokinetic Properties .... ...... ............. ... .. .. ... ................. ........... .. ..... ....... ..... .... .. ............ 522
2.1 Absorption .............................................................. ......... ............................................. ... 522
2.2 Distribution ..................................................................................................................... 523
2.3 Elimination .................................................................. ................... ................................. 523
3. Therapeutic Trials .......... ......... ..... .............................. ......... .......... .. ...................................... 523
3.1 Studies in Acute Pain .......... .................. ......................................................................... 524
3.1.1 Comparisons with Placebo ........... .. ................. ..................................................... .524
3.1 .2 Comparisons with Diflunisal .................. .............. .. .................................... .......... 524
3.1.3 Comparisons with Aspirin and Aspirin/Codeine Combinations ....................... 528
3.1.4 Comparisons with Codeine, Dextropropoxyphene, Dipyrone, Oxycodone,
Pentazocine and Combinations ...................................................................................... 528
3.1.5 Comparisons with Paracetamol, and in Combination with Paracetamol ......... 530
3.1.6 Comparisons with Other Non-Steroidal Anti-Inflammatory Drugs .................. 530
Suprofen: A Review 515

3.2 Studies in Chronic Pain ................................................................................................. 530

3.2.1 Open Study ............................................................................................................. 531
3.2.2 Comparisons with Aspirin .................................................................................... 531
3.2.3 Comparisons with Dextropropoxyphene .............................................................. 531
3.2.4 Comparisons with Dic1ofenac, Ibuprofen, Indomethacin and Naproxen ......... 531
3.3 Studies in Dysmenorrhoea ............................................................................................. 532
3.4 Studies in Fever .............................................................................................................. 533
4. Side Effects ............................................................................................................................. 533
5. Effect on Laboratory Values ................................................................................................. 534
6. Drug Interactions ................................................................................................................... 534
7. Overdosage ............................................................................................................................. 535
8. Dosage and Administration .................................................................................................. 535
9. The Place of Suprofen in Therapy ....................................................................................... 535

Summary Synopsis: Suprofen (sutoprofen)' is a non-steroidal anti-inflammatory analgesic. closely

related structurally to drugs such as ibuprofen. ketoprofen and naproxen. In patients with
acute pain. single oral doses ofsuprofen are at least as effective as: usual therapeutic doses
of aspirin; codeine alone or combined with aspirin; dextropropoxyphene alone or in var-
ious combinations; oxycodone combined with aspirin; dipyrone; pentazocine; paracetamol
(acetaminophen); diflunisal; ibuprofen; indomethacin; or mefenamic acid. In chronic pain
due to osteoarthritis. suprofen is as effective as usual dosages of aspirin or dextropropoxy-
phene during long term therapy. and as effective as diclofenac. ibuprofen. indomethacin
and naproxen during short term treatment. As with other non-steroidal anti-inflammatory
drugs. gastrointestinal complaints are the most frequently reported side effects. although
discontinuation due to gastrointestinal effects may be necessary less frequently with su-
pro/en than with aspirin. dextropropoxyphene or combinations of the two.
Supro/en appears to be a useful alternative to mild analgesics. analgesic combinations
or the older more established non-steroidal anti-inflammatory drugs in the treatment of
patients with acute or chronic pain. However. further definition of its efficacy and toler-
ability is required. especially in comparison with newer non-steroidal anti-inflammatory
analgesics.

Pharmacodynamic Properties: In vitro studies show that suprofen, in common with

aspirin and other non-steroidal anti-inflammatory drugs, is a potent inhibitor of pros-
taglandin synthesis. In standard animal models of analgesic activity, oral suprofen is
similar in potency to ketoprofen, ibuprofen, diflunisal and sulindac, more potent than
aspirin, paracetamol (acetaminophen) and codeine, and less potent than parenteral mor-
phine. In a rat adjuvant arthritis flexion test, the analgesic activity of suprofen lasted
about 4 hours with a rapid onset (0.5 hours). Suprofen is devoid of activity in animal
tests specifically designed to detect narcotic-type analgesic activity. Suprofen is more
potent as an analgesic than as an anti-inflammatory agent, and is generally equipotent
to ibuprofen, indomethacin, ketoprofen and naproxen in animal models of acute and
chronic inflammation. It is also similar in potency to these agents in reducing pyrogen-
induced fever in animals. Because suprofen is more potent as an analgesic than as an
anti-inflammatory agent, it has been developed as an analgesic and few anti-inflammatory
studies have been conducted in man.
In a guinea-pig model of dysmenorrhoea, suprofen was more potent than aspirin,
ibuprofen, indomethacin and naproxen in inhibiting arachidonic acid-induced uterine
contractions.

I 'Supranol' (Cilag); 'Suprocil' (Cilag); 'Suprol' (Cilag. Ortho, McNeil).

Suprofen: A Review 516

The ulcerogenic activity of suprofen in animals is less than that of aspirin, ketoprofen
and indomethacin when ulcerogenic dosages are related to dosages that effectively pro-
vide analgesia. In man, suprofen 800mg daily produces less faecal blood loss than aspirin
2600mg daily, although comparisons with other non-steroidal anti-inflammatory drugs
have not been performed. As with other non-steroidal anti-inflammatory drugs, suprofen
is a potent reversible inhibitor of platelet aggregation. Unlike aspirin, this inhibition is
short lived.

Pharmacokinetic Properties: Suprofen is almost completely absorbed after oral admin-

istration and shows linear pharmacokinetics from dose-proportional bioavailability data,
which fit a 2-compartment model. Following the oral administration of suprofen 200mg,
maximum plasma concentrations are usually reached in about 1 hour, but this may vary
between 0.25 and 2 hours in individual subjects. The peak plasma concentration after
this dose ranges from 14.3 to 25.3 mgJL in healthy subjects. No accumulation occurs
after repeated doses of suprofen 400mg every 6 hours. In common with other non-ster-
oidal anti-inflammatory drugs, suprofen is extensively (99.4%) bound to human plasma
proteins. There is minimal transfer of drug from maternal plasma to breast milk (about
0.D1 5 to 0.03% of the usual adult dose). The elimination half-life of suprofen is short (1
to 3 hours). In man, 90% of the drug is excreted in urine following single-dose admin-
istration, and the principal urinary metabolite is a glucuronide conjugate. The influence
of renal or hepatic insufficiency on the elimination of suprofen has not been studied.

Therapeutic Trials: Suprofen has been evaluated in many single-dose and a few short
term studies in patients with acute pain due to headache, oral surgery, a variety of other
surgical procedures, musculoskeletal disorders and primary dysmenorrhoea. Most of these
studies were of a similar design and made reasonable attempts to overcome the inherent
difficulties in evaluating analgesic drugs. In single-dose studies in patients with acute
pain, suprofen 100 to 400mg usually proved more effective than aspirin 650mg. Suprofen
200 and 400mg proved as effective or superior to aspirin 650mg + codeine 60mg, aspirin
325mg + oxycodone 4.88mg, paracetamol 650mg, codeine 60mg, dipyrone 500mg, pen-
tazocine 30mg, dextropropoxyphene hydrochloride 65mg, dextropropoxyphene napsylate
100mg + paracetamol 650mg, and dextropropoxyphene hydrochloride 65mg + aspirin
389mg + caffeine 32.4mg. The analgesic efficacy of suprofen was enhanced by the ad-
dition of paracetamol or codeine. Thus, a single dose of suprofen 100mg + paracetamol
650mg was clearly superior to suprofen 400mg or paracetamol 650mg alone. Single doses
of suprofen 200 and 400mg provided equivalent analgesia to diflunisal 750mg. Diflunisal
tended to show a longer duration of action but onset of analgesia tended to be faster
with suprofen. Compared with other non-steroidal anti-inflammatory analgesics, single
doses of suprofen 100 and 200mg were more effective than mefenamic acid 250mg, while
suprofen 300mg daily was equivalent to indomethacin 75mg daily in patients with low
back pain, and suprofen 800 and 1600mg daily was equivalent to ibuprofen 1600mg daily
in primary dysmenorrhoea.
In patients with chronic pain due to osteoarthritis, suprofen 800 to 900mg daily proved
at least as effective and was equally well tolerated as aspirin 2600 to 4000mg daily,
dextropropoxyphene hydrochloride 260mg daily, ibuprofen 1600mg daily, indomethacin
150mg daily and naproxen 750mg daily. Suprofen 600mg daily was a more effective
analgesic, with a faster onset, than diclofenac 150mg daily, and it was better tolerated.
Suprofen has not been compared with other newer non-steroidal anti-inflammatory
analgesics, such as piroxicam, in patients with either acute or chronic pain.
Studies in adult and paediatric patients with fever also indicate that suprofen is an
effective antipyretic agent. It appears at least as effective as standard agents, e.g. para-
cetamol, mefenamic acid, metamizol and aspirin.

Side Effects: Suprofen has been well tolerated in most patients to date. However,
further data are required to determine clearly its side effect profile in patients receiving
Suprofen: A Review 517

long term therapy, particularly when compared with other frequently used analgesics,
The most frequent side effects are mild gastrointestinal complaints, followed by mild
central nervous system effects and rash, In a summary oflong term comparative studies,
suprofen had a lower overall patient withdrawal rate because of side effects (17.7%) com-
pared with aspirin, dextropropoxyphene and aspirin + dextropropoxyphene (23.9%). The
respective withdrawal rates because of gastrointestinal problems were 10.9% and 17.2%.

Dosage: The recommended dosage of suprofen is 200mg 3 or 4 times daily for the
treatment of mild or moderate pain. Suprofen is contraindicated in patients with active
gastrointestinal ulceration or allergy to salicylates or other non-steroidal anti-inflam-
matory drugs. Caution or careful monitoring is required during administration in patients
with impaired renal function, fluid retention, heart failure, hypertension, past history of
gastrointestinal disease or coagulation disorders, and in patients receiving concomitant
anticoagulant therapy.

1. Pharmacodynamic Properties probably explained by different strains of test an-

Suprofen (sutoprofen) is a non-steroidal, non-
narcotic analgesic with anti-inflammatory and an-
tipyretic activity. It is a propionic acid (phenylal-
kanoic acid) derivative (fig. I), and during research
was selected from a series of thienyl substituted
benzene acetic acid derivatives as having the best
separation of analgesic activity from gastrointes-
tinal toxicity. In vitro and animal studies show that
suprofen, in common with aspirin-like anti-inflam-
matory analgesics, is a tissue-selective inhibitor of
prostaglandin (PG) synthesis.
l.l Analgesic Activity
Suprofen was consistently more potent than as-
pirin, phenylbutazone and tolmetin, and generally
comparable with ketoprofen, in the various animal
models of analgesic efficacy shown in table I. Su-
profen was usually similar in potency to indo-
methacin in analgesic efficacy but was less potent
than indomethacin in the arachidonic acid-in-
duced writhing test (Capetola et ai., 1980) and in
inhibiting adjuvant-induced arthritis in rats (Aw-
outers et ai., 1975a; Wong and Gardocki, 1983).
The considerable potency differences between
studies in the acetic acid-induced writhing tests in
mice (Fujimura et ai., 1982; Singh et ai., 1983) and
the adjuvant-induced arthritis tests in rats (Awou-
ters et ai., 1975a; Wong and Gardocki, 1983) are
imals and other differences in experimental pro-
tocols.
In a rat adjuvant arthritis flexion test (Capetola
et aI., 1980), the analgesic activity of suprofen was
evident at 0.5 hours, reached a peak at 2 hours,
and was still statistically significant at 4 hours. U s-
ing the same model and comparing drug potencies
at peak effect (Capetola et aI., 1980), suprofen was
equipotent to zomepirac, diflunisal, sulindac and
ibuprofen, but was more potent than paracetamol
[acetaminophen] (50 times) and codeine (5 times),
and less potent than proquazone (1.56 times) and
parenteral morphine (20 times). In the Randall-
Selitto paw pressure test in rats (Capetola et aI.,
1980), oral suprofen was equipotent (weight-for-
weight) to parenteral morphine, and 7, 142 and 238
times more potent than oral indomethacin, phen-
ylbutazone and aspirin, respectively. Pain thresh-
old in both normal and inflamed paws was raised
by morphine (Capetola et aI., 1980) and dextro-
propoxyphene (propoxyphene) [McGuire et ai.,
1978], whereas the other drugs raised the pain
threshold in the inflamed paw alone. These find-
ings together with the lack of analgesic effect of
suprofen in the 'hot plate' and 'tail flick' tests in
mice, and when administered intracerebroventri-
cularly in adjuvant-induced arthritis in rats, and
the inability of naloxone to block suprofen's an-
algesic activity, indicate that it is a peripherally act-
ing analgesic (Capetola et aI., 1980, 1981, 1983a,b).
Suprofen: A Review 518

arthritic flexion test (Capetola et ai., 1980): oral su-

profen 10 mg/kg caused a statistically significant
CH 3 COOH CH 3 COOH
' \CH. / " CH /
reduction in the number of vocalisations on flex-
ion of the oedematous paw while there was no

¢ Q
change in paw volume.
Comparison of oral ED so values in an adjuvant-
induced arthritis model of inflammation in rats
CO showed that suprofen (24.8 mg/kg) was less potent

6
CO than zomepirac (0.54 mg/kg), indomethacin (0.56

d
mg/kg), flufenamic acid (5.48 mgjkg), naproxen
(14.5 mg/kg) and phenylbutazone (15.3 mgjkg), and
more potent than fenoprofen (31.3 mg/kg), tol-
metin (56.7 mg/kg), ibuprofen (136 mg/kg) and as-
Ketoprofen
pirin (452 mg/kg) [Wong and Gardocki, 1983; see
Suprofen
also table I).
Oral suprofen was approximately equivalent to
indomethacin and ketoprofen in reducing rat paw
oedema induced by carrageenan, dextran, formalin
and serotonin (5-hydroxytryptamine) [Fujimura et
CH 3 COOH
CH 3 COOH
,,/ ai., 1981) and by nystatin (Fujimura et ai., 1982),
,,/ CH but less potent than these drugs against mustard-

¢y2 induced paw oedema (Fujimura et ai., 1982). How-

ever, suprofen tended to be more potent than in-
domethacin, ketoprofen or ibuprofen in reducing
ultraviolet-induced erythema in guinea-pigs (Fuji-
mura et ai., 1981). Fujimura et ai. (1981) also
o showed that the anti-inflammatory activity of su-
CH I profen is unaffected by adrenalectomy, indicating
/""-CH
CH 3 3
CH 3 non-steroidal activity. Oral suprofen 5 to 40 mg/
kg produced dose-dependent inhibition of granu-
loma tissue formation induced by the cotton pellet
Ibuprofen Naproxen method in rats (Niemegeers et ai., 1975d), and its
potency was greater than that of ibuprofen, similar
to ketoprofen, and less than that of indomethacin
Fig. 1. Structural formulae of suprofen and other commonly used (Fujimura et ai., 1982). Fujimura et ai. (1982) con-
phenylalkanoic acid derivatives. cluded from their data that suprofen has a greater
effect on the primary rather than the secondary
1.2 Anti-Inflammatory Activity stages of inflammation.
Suprofen 5% cream was as effective as triam-
Suprofen appears more potent as an analgesic cinolone acetonide 0.1 % in the prevention of paw
than as an anti-inflammatory agent in animal oedema induced by carrageenan. Suprofen 5%
models (for review see Tolman et ai., 1984) [table cream also inhibited the erythematous effect of ar-
I), and the drug has therefore been developed pri- achidonic acid applied to the guinea-pig ear. This
marily as an analgesic in man. effect was enhanced by the addition of triamci-
The analgesic and anti-inflammatory activities nolone 0.1 % (Capetola et ai., 1981). In a placebo-
of suprofen can be separated in the rat adjuvant controlled study in 8 human volunteers (Eagistein
Suprofen: A Review 519

Table I. Analgesic. anti-inflammatory and antipyretic activity of suprofen compared with some other non-steroidal anti-inflammatory
analgesics in animal models

Test (reference) Oral EDso (mg/kg)

suprofen indomethacin ketoprofen tolmetin aspirin phenylbutazone

Analgesic activity
Acetic acid-induced writhing in rats (1) 0.074 1.1 0.45 2.2 15.2 22.4
Acetic acid-induced writhing in mice (2) 53.7 100.0 67.6
Acetic acid-induced writhing in mice (3) 4.9 5.0 5.5
Modified" Haffner's method in mice (3) 5.6 5.9 5.7
Arachidonic acid-induced writhing in mice (4) 0.072 0.014 15.0 2B.3
Phenylquinone-induced writhing in mice (2) 4.22 56.2 77.1
Sodium urate-induced arthritis in dogs (5) 0.64 2.47 >40.0 5.B1

Anti';nflammatory activity
Nystatin-induced oedema in rats (6) 2.7 6.2 3B 34
Ultraviolet-induced erythema in guinea-pigs (7) 0.19 1.83 0.93 B.20 4.79
Ultraviolet-induced erythema in guinea-pigs (B)b 0.3B O.BO 1.20 75.0 15.0
Adjuvant-induced arthritis in rats (9) 1.4B 0.31 18.0 440 1B.2
Adjuvant-induced arthritis in rats (10) 24.B 0.56 2.03 56.7 452 15.3

Antipyretic activity
Yeast-induced pyresis in rats (11) 10.0 5.7 38 113 76
Yeast-induced pyresis in rats (12) 6.6 2.8 76.2 16.4

a In combination with morphine 2.0 mg/kg subcutaneously.

b Drugs administered intraperitoneally.
Reference key: 1 Niemegeers et al. (1975e); 2 Singh at al. (1983); 3 Fujimura et al. (1982); 4 Capetola at al. (1980); 5 Niemegeers
and Janssen (1975); 6 Niemegeers et al. (1975a); 7 Awouters et al. (1975b); 8 Tsurumi and Fujimura (1983); 9 Awouters et al.
(1975a); 10 Wong and Gardocki (1983); 11 Niemegeers at al. (1975b); 12 Vericat Cadesas et al. (1979).

et al., 1979), a combination of suprofen 5% and
triamcinolone 0.1 % cream applied after ultraviolet-
B irradiation prevented subsequent erythema. This
effect, lasting from 6 to 30 hours, was maximal
when application of the cream was immediately
after irradiation (5 minutes). The combination
treatment was more effective than either agent
alone, and suprofen was more effective than the
steroid alone.
In a parallel, double-blind study in 207 patients
with acute upper respiratory tract infection (Fuji-
mori et aI., 1983), suprofen 300 mgJday was more
effective (p < 0.05) than aspirin 1500 mgJday in
reducing the severity of sore throat, cough and
pharyngeal redness after 3 days' treatment. Three
patients receiving suprofen reported side effects
compared with 7 on aspirin. Preliminary results
from an ongoing parallel study (Stark et al., 1984)
indicate that topical 0.5% suprofen tends to be more
effective than placebo in preventing cystoid mac-
ular oedema following cataract surgery and lens
implantation. All patients received standard treat-
ment with neomycin and dexamethasone, and su-
profen or placebo applied 4 times daily for 10 weeks
started immediately before surgery. For the 16 pa-
tients so far completing treatment, 20% receiving
suprofen developed cystoid macular oedema com-
pared with 50% of those receiving placebo.
1.3 Antipyretic Activity
For the reference non-steroidal anti-inflamma-
tory analgesics shown in table I, only indometha-
cin showed superior antipyretic activity to supro-
Suprofen: A Review
fen. At the fully effective antipyretic dose each of
the reference agents produced transient hypother-
mia or in the case of indomethacin, protracted hy-
pothermia, whereas suprofen did not produce hy-
pothermia even at 4 times the fully effective
antipyretic dose of 160 mgJkg (Niemegeers et aI.,
1975b). Suprofen was more effective than ibupro-
fen but less effective than ketoprofen and indo-
methacin (weight-for-weight) in reducing fever in-
duced by lipopolysaccharide in rabbits or induced
by yeast in rats (Fujimura et aI., 1982).
1.4 Gastrointestinal Effects
Suprofen has been compared with a large num-
ber of other non-steroidal anti-inflammatory drugs
for the prevention of endotoxin-induced diarrhoea
in mice (Tsurumi and Fujimura, 1983) and castor
oil-induced diarrhoea in rats (Awouters et aI., 1978).
Suprofen was more potent than indomethacin, ke-
toprofen, tolmetin, aspirin and phenylbutazone, and
in both tests the ED50 values for the prevention of
induced diarrhoea were closely related to the anti-
inflammatory activity of the drugs. The authors
therefore proposed that these tests could be used
along with other standard tests for screening anti-
inflammatory drugs.
The ulcerogenic activity of suprofen in rats has
been investigated by several authors. Fujimura et
ai. (1981) showed that under normal physiological
conditions the ulcerogenic dosage (UD50) of su-
profen (13 mgJkg) after repeated oral administra-
tion exceeded that of ketoprofen (2.2 mgJkg) and
indomethacin (1.5 mgJkg). Niemegeers et ai. (l975c)
found the following UD 50 values for single-dose oral
administration under normal physiological condi-
tions: aspirin (1190 mgJkg); suprofen (200 mgJkg);
ketoprofen (46.0 mgJkg); and indomethacin (9.30
mgJkg). When these UD 50 values are related to the
analgesic ED 50 values for these agents (Capetola et
aI., 1981) [see table I], then the therapeutic index
(UD 50/ED 50) for suprofen (2703) exceeded that of
indomethacin (78), ketoprofen (103) and aspirin
(8.5). However, in cold stress-sensitised rats
(Rainsford, 1977), suprofen was considered as hav-
ing 'high' ulcerogenic activity, together with aspi-
520
rin, ketoprofen and indomethacin, when compared
with other non-steroidal anti-inflammatory agents.
Rainsford (1978) also showed that suprofen inhib-
ited (p < 0.05) gastrointestinal mucus glycoprotein
production in rats as measured by 35S incorpora-
tion in vivo. Other agents, e.g. diflunisal, naproxen
and sulindac, caused no inhibition.
The 5lCr-tagged erythrocyte method has been
used to determine the effect of therapeutic doses
of suprofen on faecal blood loss in man. In a 1-
week double-blind crossover study (Arnold and
Berger, 1983), aspirin 650mg 4 times daily caused
more faecal blood loss than suprofen 200mg 4 times
daily in 20 male volunteers (4.2 vs 1.8 ml/day,
p < 0.01). In a 10-day double-blind parallel study
in 30 male volunteers (Cohen and Smith, 1984),
mean daily faecal blood loss on a combination of
suprofen 200mg plus codeine 60mg 4 times daily
was about half that with aspirin 325mg plus co-
deine 60mg 4 times daily (6.46 vs 3.58ml).
The gastrointestinal toxicity of suprofen has not
been compared with that of the newer non-steroi-
dal anti-inflammatory drugs, such as piroxicam, or
the 'prodrugs' fenbufen and sulindac.
1.5 Effect on Prostaglandins
Suprofen is a potent inhibitor of prostaglandin
biosynthesis, a mechanism by which many of its
pharmacological effects are exerted (Capetola et aI.,
1981). It is a reversible inhibitor of cyclo-oxygen-
ase, which catalyses the formation of cyclic endo-
peroxides (and eventually prostaglandins) from ar-
achidonic acid (Ferreira et aI., 1974; Vane, 1974).
Suprofen inhibits in vitro prostaglandin biosyn-
thesis from bovine seminal vesicles (Capetola et
aI., 1980): ED 50 values for suprofen, indomethacin,
naproxen, ibuprofen and phenylbutazone were 1.82,
3.16,14.42,45.20 and 169.00 ILmol/L, respectively.
Basal PGE 2 production from rabbit renomedullary
interstitial cells in tissue culture is also inhibited
by suprofen (Zusman and Keiser, 1977): ED50 val-
ues for naproxen, ibuprofen, suprofen, indometh-
acin and aspirin were 0.04, 0.14, 1.5, 2.7 and 58
ILmol/L, respectively. Suprofen inhibits the in vitro
production of PGI 2 (prostacyclin) in rat aorta (Imai
Suprofen: A Review
et aI., 1982) and the in vivo production of prosta-
glandins in mouse small intestine (Borowska et aI.,
1981). Suprofen also inhibits arachidonic acid-in-
duced malondialdehyde production from guinea-
pig and cat platelets in vitro (Nevelsteen et aI., 1984;
Van Nueten et ai., 1976), arachidonic acid hydro-
peroxide-induced contractions of guinea-pig ileum
and rat fundic strips in vitro (Van Daele et aI., 1975;
Van Nueten et aI., 1976), the peristaltic reflex of
isolated guinea-pig ileum (Fontaine et aI., 1977),
arachidonic acid-induced bronchoconstriction in
guinea-pigs in vivo (Rosenthale et aI., 1981), arach-
idonic acid-induced writhing in mice in vivo (see
section 1.1), and the lethal effect of arachidonic
acid in rabbits (Fujimura et aI., 1981; Imai et aI.,
1982).
When suprofen and indomethacin were com-
pared in most of the aforementioned tests, they
were in a similar potency range. However, supro-
fen SO mg/L caused a SS% inhibition of arachi-
donic acid conversion into PGE2 in rabbit heart or
kidney in vitro while indomethacin 0.1 to 0.3 mg!
L caused 100% inhibition (Capetola et aI., 1980).
These data, together with results showing that su-
profen does not affect renal blood flow in dogs
(section 1.7.2), suggest the tissue selective nature
of prostaglandin inhibition by suprofen.
Topical suprofen O.S% inhibited (p < O.OS) the
release ofPGE 2, PGF2", PGI 2 and thromboxane B2
from inflamed rabbit cornea, and appeared more
effective than topical prednisolone 1% (Tong et aI.,
1984). Suprofen inhibited prostaglandin produc-
tion by inflamed human gingival tissue in vitro only
at concentrations greater than 10 mmolfL, which
is much higher than for other tissues, indicating
that suprofen is not selective for this tissue (Elattar
and Lin, 1983).
Suprofen inhibited the mouse stretching re-
sponse (Dubinsky and Schupsky, 1984) and guinea-
pig uterine contractions (section 1.6) induced by
arachidonic acid. This was taken as evidence of in-
hibition of prostaglandin biosynthesis via the cy-
do-oxygenase pathway. However, at higher doses
suprofen still blocks the stretching response and
uterine contractions induced by endogenously ap-
plied PGE 2 and PGF2", respectively. This suggests
521
that suprofen may directly antagonise prostaglan-
din activity.
1.6 Effects on the Endometrium
There is evidence to suggest that prostaglandins
playa role in the aetiology of primary dysmenor-
rhoea (Tolman et aI., 1985). The role of kinins in
dysmenorrhoea is unknown, but bradykinin in-
duces uterine contractions and can potentiate the
pain-producing action of prostaglandins (Capetola
et aI., 1981).
An in vivo guinea-pig model has been developed
in which the effects of drugs on uterine contrac-
tions induced by prostaglandins, arachidonic acid
and bradykinin can be studied (Carraher et aI.,
1981; Hahn et aI., 1982). Oral pretreatment with
prostaglandin synthetase inhibitors blocked the
uterine response to arachidonic acid. The relative
order of potency was suprofen (1) > indomethacin
(0.6S) > naproxen (0.S2) > ibuprofen (0.43) > as-
pirin (0.31), and the maximal response to suprofen
was greater (p < O.OS) than to each of the other
agents. PGF2" and bradykinin-induced contrac-
tions were also inhibited by suprofen. These data
suggest that suprofen may be of use in the treat-
ment of primary dysmenorrhoea.
1.7 Cardiovascular Effects
1. 7.1 Haematoiogicai Effects
Like most other non-steroidal anti-inflamma-
tory analgesics, suprofen is an inhibitor of induced
platelet aggregation in vitro and ex vivo in diverse
animal species (De Clerck et aI., 1975a,b, 1976; Imai
et aI., 1982) and in man (De Clerck et aI., 1975a).
Suprofen dosing inhibits aggregation induced by
arachidonic acid, collagen, thrombin and adrena-
line (epinephrine). Only the secondary phase of
ADP-induced aggregation is affected by suprofen.
In general, suprofen is more potent than other non-
steroidal anti-inflammatory analgesics (e.g. indo-
methacin, ketoprofen, ibuprofen). Oral single doses
of suprofen as low as 0.31 mg!kg prolonged (p <
O.OS) tail bleeding time in rats whereas whole blood
clotting time was unaffected by doses up to 10 mg!
Suprofen: A Review
kg (De Clerck et al., 1975b). In vivo in man supro-
fen has been shown to have a mild inhibitory effect
on haemostasis which is not of clinical signifi-
cance. Return to normal occurs by 24 hours fol-
lowing administration (unpublished data on file,
Ortho).
1.7.2 Haemodynamic Effects
Intravenous administration of suprofen 5 mg/
kg had no effect on blood pressure, cardiac output
or ECG in anaesthetised dogs (Capetola et al.,
1981). Higher intravenous doses of suprofen 50 to
100 mg/kg (Fujimura et al., 1983) had no effect on
heart rate or ECG in anaesthetised dogs and rab-
bits, although blood pressure and cardiac output
were increased. Intravenous suprofen administra-
tion up to 10 mg/kg had no effect on renal blood
flow in the anaesthetised dog whereas phenylbu-
tazone 2 mg/kg caused a significant reduction (p <
0.05) [Capetola et al., 1980]. PGE 2 is capable of
dilating renal vasculature, and some inhibitors of
prostaglandin biosynthesis (e.g. phenylbutazone)
can therefore reduce renal blood flow. Acute doses
of suprofen 25 to 100 mg/kg caused a transient in-
crease in renal blood flow in anaesthetised dogs but
there was no effect on sodium, potassium or chlo-
ride excretion (Fujimura et al., 1983).
In man, the repeated intramuscular or intra-
venous administration of suprofen 200mg 3 times
daily to healthy volunteers has no significant effect
on heart rate or blood pressure (Michos et al.,
1985a,b).
1.8 Other Effects
Suprofen inhibits secretion of lysosomal en-
zymes from guinea-pig neutrophils and phagocy-
tosis by these cells in vitro (Smith, 1978). Keto-
profen was more active than suprofen, and sulindac
was inactive. Lysosomal enzymes can mediate tis-
sue injury, and their inhibition by suprofen may
represent one mechanism, besides prostaglandin
inhibition, by which the drug alleviates inflam-
mation. Yokoya et al. (1984b) has shown that su-
profen inhibits Type I (homologous passive cuta-
neous anaphylaxis in rats; histamine release from
522
rat peritoneal mast cells; histamine and slow re-
acting substance of anaphylaxis release from guinea-
pig lung tissue), Type II (Forssman cutaneous vas-
culitis in guinea-pigs) and Type III (Arthus reac-
tion in guinea-pigs) allergic reactions. However, su-
profen did not inhibit Type IV allergic reaction
(delayed cutaneous hypersensitivity in guinea-pigs)
or IgM or IgG antibody production in mice and
rats.
2. Pharmacokinetic Properties
The pharmacokinetics of suprofen have been
studied in animals and healthy subjects following
single and repeated doses. The influence of disease
on pharmacokinetics has not been studied in pa-
tients. High-performance liquid chromatography
(HPLC) has been used to determine plasma supro-
fen concentrations (Alton and Patrick, 1978; Lagu
et al., 1982; MUller et al., 1982).
2.1 Absorption
Following the parenteral and systemic admin-
istration of single and repeated therapeutic doses,
the pharmacokinetics of suprofen are linear, with
maximal plasma concentration and area under the
plasma concentration time curve (AUC) being re-
lated to dosage (Abrams et a1., 1983b; Zulliger and
Fassolt, 1983, 1985). In healthy subjects the max-
imum plasma concentration is usually reached
about 1 hour after oral administration but can vary
between 0.25 and 2 hours in different subjects
(Abrams et al., 1983a; Chaikin et al., 1983; Mori
et al., 1985; Weintraub, 1978; Zulliger and Fassolt,
1983). Compared with oral administration, the
maximum plasma concentration is reached more
rapidly after intramuscular administration: about
20 to 30 minutes after 50 to 200mg (Michos et al.,
1985b; Zulliger and Fassolt, 1983). However, total
absorption is not significantly different after either
route (corrected AUC 454.86 intramuscular vs
436.07 mg/L' h oral for 50mg).
The absolute bioavailability of suprofen 200mg
taken as a capsule in healthy subjects is 92.2%
compared with intravenous administration, indi-
Suprofen: A Review
cating no significant first-pass effect (Zulliger and
Fassolt, 1985). The maximum plasma concentra-
tion following oral and intramuscular administra-
tion of single and repeated doses of suprofen 200mg
varies between mean values of 14.3 and 25.33 mg/
L (Abrams et al., 1983a,b; Michos and Zulliger,
1985; Weintraub, 1978; Zulliger and Fassolt, 1983,
1985). On the basis of maximum and minimum
plasma concentrations and AUC values, no accu-
mulation occurs in healthy subjects after 6 to 7 days'
treatment with oral suprofen 400mg every 6 hours
(Abrams et al., 1983b), intramuscular suprofen
200mg 3 times daily (Michos et al., 1985b), or in-
travenous suprofen 200mg twice daily as a bolus
or infusion (Zulliger et al., 1985).
Following administration of a single dose of su-
profen 200mg as an oral solution or as 1 or 2 cap-
sules (Weintraub, 1978), AUC values are similar-
indicating equivalent physiological availability.
Food and, to a lesser extent, milk cause a decrease
in the maximum plasma concentration of suprofen
and a slight decrease in AVC (Chaikin et al., 1982).
This is consistent with data reported for other non-
steroidal anti-inflammatory drugs. When suprofen
200 and 400mg is administered to elderly subjects,
there is no trend to change the maximum plasma
concentration or to prolong the elimination half-
life. These results suggest that age does not alter
the disposition of suprofen to any marked extent
(unpublished data on file, Ortho).
2.2 Distribution
At times up to 24 hours after the oral or intra-
venous administration of 3H-suprofen in mice and
rats, the only organs to show concentrations sim-
ilar to or greater than corresponding plasma sam-
ples are those involved with absorption, metabo-
lism and excretion (gastrointestinal tract, liver and
kidney) [Mori et al., 1984a,b; Yokoya et al., 1984a].
Mori et al. (1983a) showed that, following oral
administration of 3H-suprofen in rats, the drug
crossed the placenta to a moderate extent. Also, in
rats with carrageenan-induced oedema, the level of
radioactivity in the inflamed paw reached about
twice that of the non-inflamed paw.
523
Few data are available on the distribution of su-
profen and its metabolites in man. The apparent
volume of distribution after oral administration in
healthy subjects is 11.9L (Zulliger and Fassolt,
1983). 3H-Suprofen is extensively bound in vitro to
human plasma protein (99.4%), principally to al-
bumin (94.5%), independently of the drug concen-
tration over the range 2.6 to 130 mg/L (Chaikin et
al., 1980, 1983). There is minimal binding to hu-
man milk protein (10.4%). Based on simple passive
diffusion, little transfer of suprofen from plasma to
milk would be expected in vivo. This was con-
firmed in 6 nursing women administered a single
oral dose of suprofen 200mg in whom the milkl
plasma AUC ratio was 1.4% (Chaikin et al., 1983).
Minimal suprofen ingestion (approximately 0.Q15
to 0.03% of the usual daily adult dose) would there-
fore be expected in a nursing infant whose mother
is receiving suprofen.
2.3 Elimination
Few data are published on the metabolism and
excretion of suprofen in man. In healthy subjects
the elimination half-life is about 1 to 3 hours after
single intravenous doses of 50 to 200mg, and
plasma clearance is 5.72 to 7.62 L/h depending on
dose and administration route (Zulliger and Fas-
solt, 1983, 1985). After a single dose of tritiated
suprofen 200mg in man, about 90% of radioactiv-
ity is recovered in urine and 7% in faeces (Capetola
et al., 1981). The major urinary metabolite is an
acyl glucuronide of suprofen; other minor metab-
olites are formed by hydroxylation (Mori et al.,
1985). Suprofen undergoes enterohepatic circula-
tion and excretion into bile in rats (Mori et al.,
1983b; Yokoya et al., 1984a), but it is not known
if this occurs in man. The effects of renal or hepatic
insufficiency on the metabolism and excretion of
suprofen are not reported in the literature.
3. Therapeutic Trials
Methods employed in the clinical evaluation of
analgesics, and problems encountered in these
studies because of the complex nature and subjec-
Suprofen: A Review
tive variables of pain and pain relief, have been
reviewed by Dundee (1980) and Littlejohns and
Vere (1981).
The choice of a pain model requires careful con-
sideration in any clinical evaluation of analgesics.
The most sensitive assays of analgesic efficacy are
single-dose studies in patients with acute pain, but
multiple-dose studies in patients with acute or
chronic pain provide information on the general
clinical acceptability and safety of the analgesic.
Some painful conditions (e.g. oral surgical pain, and
episiotomy or meniscectomy pain) are particularly
suitable models for analgesic efficacy studies, as the
source of pain is understood, the duration of pain
is fairly predictable, and a relatively homogeneous
population of otherwise healthy subjects may be
selected. Instances in which acute pain is likely to
be more variable, but which represent important
uses of analgesics, include headache, postsurgical
pain, musculoskeletal pain and pain during dys-
menorrhoea.
As there are substantial differences between
acute and chronic pain, extrapolation of the results
obtained from analgesic efficacy studies in patients
with acute pain, in order to gain some indication
of analgesic effectiveness in patients with chronic
pain, is often unreliable. Psychological factors may
considerably modify pain perception in patients
experiencing chronic pain, and reaction to the pain
may dominate the actual pain stimulus in some of
these patients.
Suprofen is primarily indicated as an analgesic
and has been studied in patients with acute pain
(section 3.1), chronic pain (section 3.2) and dys-
menorrhoea (section 3.3). Suprofen shows anti-in-
flammatory activity in animals but, because it is
more potent as an analgesic, it has been developed
as such and has been little studied in patients
with inflammatory conditions (section 1.2). Su-
profen is an effective antipyretic agent in man
(see section 3.4).
3.1 Studies in Acute Pain
Suprofen has been compared with placebo (sec-
tion 3.1.1) and a number of analgesics, analgesic
524
combinations and non-steroidal anti-inflammatory
drugs (tables II and III) in parallel double-blind
studies in patients with acute pain. Most studies
included a placebo control and used standard eval-
uation scales from which SPID (summed pain in-
tensity difference) and TOTPAR (total pain relief)
scores could be calculated. Single-dose studies were
usually conducted within a clinic or hospital en-
vironment and used trained observers to try and
minimise the effects of variability on assessments
of pain perception. Multiple-dose studies were
either of short duration or were only reported as
abstracts. More published data are therefore re-
quired to determine the suitability of suprofen for
longer term treatment.
3.1.1 Comparisons with Placebo
A single dose of suprofen 200mg has been com-
pared with placebo in a double-blind parallel study
in 77 patients with pain following tooth extraction
(Ishibashi et ai., 1982). Suprofen was superior
(p < 0.0 I) to placebo for analgesic efficacy and
overall clinical evaluation score. No side effects
were reported with suprofen.
The majority of comparative studies reported in
the remainder of this section on acute pain (section
3.1) were placebo controlled. Single doses of su-
profen 100, 200 and 400mg were therefore com-
pared with placebo in these studies. In general, all
doses were superior to placebo, both statistically
and clinically. A dose-related response was usu-
ally apparent, but not always (see Honig, 1983
and Mok et ai., 1978) [table II and subsequent
sections].
3.1.2 Comparisons with Dijlunisf}l
Single doses of diflunisal 750mg and suprofen
200 or 400mg were approximately equipotent in
relieving pain following meniscectomy (Honig,
1983). There was a tendency for suprofen 200mg
to show better SPID and TOTPAR scores, as well
as a faster onset of action, compared with the other
treatments. Diflunisal tended to have a longer du-
ration of action than suprofen. The incidence of
side effects with either drug was not different to
that seen with placebo.
Table II. Summary of randomised double-blind parallel studies comparing suprofen (S) with other analgesics in patients with acute pain (J)

Reference Population Dosage (mg) Study design Results Comments

'..."
"0
0

and no. of and dosage

<>'
?
patients' schedule b SPIDc TOTPARc overall side ;J;>
effects d effects ;;tl
'"<:
Comparisons with di"unisal (OIF) ,,"
~
Honig (1983) Meniscectomy S200 (32) Single oral dose S200;;' DIF = S;;' DIF S = DIF S = DIF DIF;;' S for
pain S400 (32) with 8h S400 duration of
DIF750 (32) observation analgesia

Comparisons with aspirin (ASA)

Cooper et al. Oral surgical S200 (44) Single oral dose S > ASA S > ASA S > ASA S = ASA S > ASA for time
(1983) pain S400 (45) with Sh to remedication
ASAS50 (43) observation

Markus and Oral surgical S200 (4S) Every Sh orally as S = ASAe S';; ASA
Gough (1980) pain ASA700 (47) required for S
days

Mok et al. Undefined S100 (23) Single oral dose S;;' ASA S;;' ASA S = ASA
(1978) moderate pain S200 (27) with Sh (drowsiness)
ASAS50 (23) observation

Silberman Musculoskeletal S200 (24) Four times daily S > ASA S> ASA S;;' ASA S';; ASA S> ASA for
(1983) pain ASAS50 (25) orally for 3 days sleep and activity
impairment

Comparisons with aspirin and aspirin/codeine (ASA + C) combinations

Mehlisch Oral surgical S200 (35) Single oral dose S400 > ASA S400> ASA S400> ASA S = ASA and S400 > ASA and
(1985) pain S400 (34) with Sh and and and ASA + C ASA + C for time
[see also ASAS50 (37) observation ASA + C ASA + C; ASA + C to remedication
Frakes et al. ASAS50 + CSO (33) S200> ASA
(1984)]

Sunshine et Oral surgical S200 (33) Single oral dose S = ASA and S = ASA and S = ASA and S = ASA + C S ;;. ASA and
al. (1983) pain S400 (27) with 4h ASA + C ASA + C ASA + C .;; ASA ASA + C for
ASAS50 (30) observation onset of analgesia
ASAS50 + CSO (32)

Vargha von Neurological S200 (40) Single oral dose S400> S200 = S400> S200 = S400;;' S200 = S = ASA.;;
Szeged and pain S400 (39) with Sh ASA + C;;. ASA+C;;' ASA + C;;. ASA + C
Michos (1983) ASAS50 (37) observation ASA ASA ASA
ASAS50 + CSO (40)
V>
Continued on next page IV
V>
Table II. Contd. Vl
c:
"0
Reference Population Dosage (mg) Study design Results Comments aiii'
and no. of and dosage ?
patients a schedule b SPIDC TOTPAW overall side ~
effects" effects
...<:
~

;;;.
Comparison with aspirin and aspirin/oxycodone (ASA + 0) combinations ~
Mehlisch et al. Postsurgical S200 } S ;. ASA and S ;. ASA and S ;. ASA and S = ASA and S;' ASA and
(1984) pain S400 ASA + 0 ASA + 0 ASA + 0 ASA + 0 ASA + 0 for time
(orthopaedic ASA650 (206)'Single oral dose to remedication.
and general) ASA325 + with 6h Abstract
04.889 observation

Olson et al.
(1984)
Postpartum pain S100
S200
1
Comparison with codeine (C), and in combination with codeine (S + C)
Single oral dose
with 4h
S+C ;. Sand C S+C;' Sand C Abstract

C30 observation
S100 + C30 (392)'
S200 + C30
S200 + C60

Comparison with codeine (C) and dextropropoxyphene (0)

Wagenberg et Oral surgical S200 } Single oral dose S ;. C and D S ;. C and D S .;; C and D Abstract
al. (1983) pain C60 (212)'with 6h
D65h observation

Comparison with OAC.I dextropropoxyphene/paracetamol (0 + P) and aspirin/codeine (ASA + C) combinations

Mehlisch and Postsurgical S200 } Single oral dose S > all other S > all other S ;. all other S ". all other Abstract
Eglsaer (1983) pain DACI with 6h treatments treatments treatments treatments
(orthopaedic D100' + P650 (153)'observation
and general) ASA650 + C60

Comparison with dipyrone (DIP)

Lorenzi et al. Postsurgical S200 (29) Single oral dose S ;. DIP S;' DIP S = DIP
(1985) pain DIP500 (28) with 6h
(orthopaedic) observation ,,,
v-
0'
 [Jl
Comparison with pentazocine (PEN) t:
'0
Bodner and Postsurgical S200 (29) Single S " PEN S " PEN S " PEN S = PEN a
Michos (1985) pain (general
[see also surgery)
PEN30 (29) intramuscular
dose with 6h
'"
?
»
Bodner 1985] observation" ;:0
<>
<:
(ii'
Comparison with paracetamo/ (P), and in combination with paracetamo/ (S + P) ~
Fassolt and Postsurgical S200 (32) Single oral dose S+P > S200; S+P " S400 " S+P " all other S = all other All treatments "
Stocker (1983) pain (general S400 (28) with 6h S+P" S400 = P ;. S200 treatments treatments S200 for time to
surgery) P650 (29) observation P " S200 remedication
S100 + P650 (29)

a Number of patients evaluated for efficacy in each group.

b All studies included a placebo control group, except Markus and Gough (1980).
c Summed pain intensity difference (SPID) and total pain relief scores (TOTPAR).
d Overall (global) effects as assessed by patient and investigators.
e Mean pain relief 1h after each dose.
f Total number of patients, including placebo.
g Oxycodone hydrochloride 4.5mg plus oxycodone terephthalate 0.38mg.
h Dextropropoxyphene hydrochloride.
Dextropropoxyphene napsylate.
DAC = dextropropoxyphene hydrochloride 65mg + aspirin 389mg + caffeine 32.4mg.
k Single-blind.

Symbols in al/ 'results' columns: > = statistically significant difference in favour of first drug; " = tendency for first drug to be superior or statistical analysis not performed;
v.
'" = tendency for first drug to produce fewer and/or less severe side effects. tv
-..J
Suprofen: A Review
3 a single-dose study in patients with pain following
~ 2
'wc
.l!l
.S
c
'iii
0..
o noted a similar degree of analgesic efficacy with
2 4 6 single doses of suprofen 100 and 200mg, and Sun-
Time (hours)
Fig. 2. Mean pain intensity scores (0 =no pain, 3 = severe pain)
in 196 patients with neurological pain following a single dose of
suprofen 200mg (0) and 400mg (6), aspirin 650mg (e), aspirin
650mg plus codeine 60mg (A), and placebo (0) [after Vargha
von Szeged and Michos, 1983).
3.1.3 Comparisons with Aspirin and
Aspirin/Codeine Combinations
The analgesic efficacy of suprofen was generally
superior to that of aspirin, in both single- and mul-
tiple-dose studies. Similarly, single doses of supro-
fen 400mg were usually superior to a combination
of aspirin 650mg plus codeine 60mg, while supro-
fen 200mg showed similar analgesic efficacy to the
aspirin combination (table II).
Suprofen 200mg and aspirin 700mg provided a
similar degree of pain relief in patients with oral
surgical pain (Markus and Gough, 1980). How-
ever, the patient groups in this study were not
shown to be comparable for the degree of surgical
trauma; and self-assessment of pain, while meant
to be made I hour after each dose, was earlier on
suprofen than on aspirin (p < 0.001). In another
study in patients with pain following oral surgery,
Sunshine et al. (1983) demonstrated a similar de-
gree of analgesic efficacy following single-dose
administration of suprofen 200 and 400mg, aspirin
650mg and a combination of aspirin 650mg plus
codeine 60mg. Based on pain relief scores, Cooper
528
et a1. (1983) showed the duration of action of su-
profen 400mg to be longer than that on 200mg in
periodontal surgery.
In patients with neurological pain (Vargha von
Szeged and Michos, 1983), a single dose of supro-
fen 400mg was superior to 200mg, which in turn
was approximately equivalent to aspirin 650mg
combined with codeine 60mg and superior to as-
pirin 650mg (fig. 2).
A dose-related analgesic response to suprofen
was not always apparent. Thus, Mok et a1. (1978)
shine et a1. (1983) with suprofen 200 and 400mg.
Generally, suprofen did not cause more side ef-
fects than placebo, but central nervous system
(eNS) and gastrointestinal symptoms were more
frequent or more severe on aspirin and aspirin/
codeine combinations.
3.1.4 Comparisons with Codeine.
Dextropropoxyphene. Dipyrone. Oxycodone.
Pentazocine and Combinations
Most of the studies reported in this section were
reported as abstracts only, and lacked details of ex-
perimental protocol and results. Wagenberg et a1.
(1983) reported that a single dose of suprofen
200mg was 'substantially more effective' and pro-
duced fewer centrally mediated side effects than
either dextropropoxyphene hydrOChloride 65mg or
codeine 60mg in patients with pain following per-
iodontal surgery. A single dose of suprofen also gave
statistically superior analgesia compared with 2
dextropropoxyphene combinations in patients with
pain after general and orthopaedic surgery, and side
effects were less severe and of shorter duration with
suprofen (Mehlisch and Eglsaer, 1983). Mehlisch et
a1. (1984) noted that single doses of suprofen 200
and 400mg were 'consistently more effective' than
a combination of aspirin 325mg and oxycodone (see
table II) in patients with postsurgical pain. Olson
et a1. (1984) noted that the addition of codeine 30
or 60mg to single doses of suprofen 100 and 200mg
appeared to increase the analgesic effect of supro-
fen in patients with postpartum pain. Bodner and
Table III. 8ummary of randomised double-blind parallel studies comparing suprofen (8) with other non-steroidal anti-inflammatory drugs in patients with acute pain Vl
s::
Reference Population Dosage (mg) and 8tudy design and Results
...
'0
0
Comments
0-
no. of patients· dosage schedule b Po
analgesic overall side :>
effect effect" effects
...'"
~.
Comparison with ibuprofen (lSU) ~
Heffron et al. Primary 8200 } Four times daily as 8400 ~ 8200 = 8400 ~ 8200 = 8 = IBU Abstract
(1984) dysmenorrhoea 8400 (457)d needed for up to 5 IBU IBU
IBU400 days

Comparison with indomethacin (1M)

8chichikawa et al. Low back pain 8100 (81) Three times dailye 8 = 1M 8.;; 1M
(1983) IM25 (86)

Comparison with indoprofen (lP)

Honig and Michos Meniscectomy pain 8200 intravenous (44) 8ingle dose with 6h 8 < IP 8 = IP 8 = IP Abstract
(1984) IP200 intravenous (43) observation

Comparison with mefenamic acid (M)

Pujalte et al. Musculoskeletal pain 8100 (40) 8ingle dose with 4h 8>M 8>M 8=M 8 ~ M for time to
(1984) 8200 (40) observation remedication
M250 (40)

Comparison with oxyphenbutazone (OX)

8urace et al. Pain (mainly back and 8200 (30) Three times daily for 8 = OX 8 ~ OX 8 = OX
(1982) post-traumatic) OX100 (29) up to 7 days

a Number of patients evaluated for efficacy in each group.

b 8tudies by Heffron et al. (1984) and Honig and Michos (1984) included placebo control group.
c Overall (global) effect as assessed by patients and physicians.
d Total number of patients in all groups, including placebo group for Heffron et al. (1984).
e Duration not stated.
Symbols in a/l 'results' columns: > = statistically significant difference in favour of first drug; ~ = tendency for first drug to be superior or statistical analysis not performed;
< statistically significandifference in favour of second drug; .;; = tendency for first drug to produce fewer and/or less severe side effects. VI
N
\Q
Suprofen: A Review
Michos (1985) showed that a single intramuscular
dose of suprofen 200mg is an effective analgesic
(determined from SPID and TOTPAR scores)
compared with placebo in patients with moderate
to severe pain following general surgery. A parallel
group of patients receiving intramuscular penta-
zocine 30mg, a dose which might be considered
therapeutically low, did not show results which were
significantly different from placebo. Lorenzi et al.
(1985) showed that a single oral dose of suprofen
200mg was marginally more effective than dipy-
rone 500mg in patients with acute pain following
orthopaedic surgery.
3.1.5 Comparisons with Paracetamol. and in
Combination with Paracetamol
In a single-dose study in patients with post-
surgical pain, the analgesic efficacy of suprofen
400mg was similar to paracetamol (acetamino-
phen) 650mg, which tended to be better than su-
profen 200mg (fig. 3). However, the most effective
treatment was a combination of suprofen 100mg
and paracetamol 650mg; the difference between this
60
.~
If)
c:
.~ 40
c:
'iii
0.
c:
'"
Q)
::2 20
o 2 4 6
Time (hours)
Fig. 3. Mean pain intensity scores on visual analogue scale
(0 = no pain. 100 = unbearable pain) in patients with postsurg-
ical pain fOllowing a single dose of suprofen 200mg (0) and
400mg (L'», paracetamol 650mg (e), suprofen 100mg plus par-
acetamol 650mg (A), and placebo (0) [after Fassolt and Stocker.
1983].
530
combination and suprofen was statistically signif-
icant. Results from animal experiments also show
an additive analgesic effect when suprofen and par-
aceta mol are combined (section 6), which may im-
ply that this is a particularly suitable analgesic
combination.
3.1.6 Comparisons with Other Non-Steroidal
Anti-Inflammatory Drugs
The analgesic response to single doses of supro-
fen 100 and 200mg was approximately equivalent
in patients with undefined musculoskeletal pain,
and both doses were superior (p < 0.05) to a single
dose of mefenamic acid 250mg as evaluated by
SPID and TOT PAR scores. Schichikawa et al.
(1983) found a similar global response to treatment
with suprofen 100mg and indomethacin 25mg, each
given 3 times daily, in 167 patients with low back
pain. Side effects were reported by fewer patients
with suprofen (7.6%) than with indomethacin
(18.2%). In another repeated-dose study (Surace et
aI., 1982) in 59 patients with pain of diverse ae-
tiology (low back pain, sciatica, and post-traumatic
and postoperative pain), the reduction in pain
compared with baseline after 7 days' treatment with
suprofen 200mg and oxyphenbutazone lOOmg, each
given 3 times daily, was similar. Global assess-
ments by the patients and physicians favoured su-
profen. The number of side effects reported was
similar on both treatments. This study was not pla-
cebo controlled.
Comparison of single intravenous doses of su-
profen 200mg and indoprofen 400mg in 87 pa-
tients with postmeniscectomy pain showed no
overall intergroup differences determined from the
investigators' global evaluation of effectiveness, al-
though SPID and TOTPAR scores significantly fa-
voured indoprofen (Honig and Michos, 1984; un-
published data on file, Ortho).
3.2 Studies in Chronic Pain
There has been one open multiple-dose study of
suprofen in patients with chronic pain, which was
performed in a relatively small number of elderly
patients studied for a short period (section 3.2.1).
Suprofen: A Review
In parallel double-blind multiple-dose studies, the
analgesic efficacy of suprofen was similar to that
with standard dosages of aspirin, dextropropoxy-
phene, ibuprofen, indomethacin and naproxen, but
superior to that of diclofenac (table IV). These
studies were either of short duration of performed
in few patients or only reported as abstracts. More
published data are therefore required to determine
the role of suprofen in the treatment of chronic
pain, especially with respect to long term efficacy
and tolerability.
3.2.1 Open Study
The effects of suprofen 200mg every 4 hours as
required (mean dosage 1050 mg/day) were exam-
ined in an open 4-week study in 19 patients of mean
age 75.9 years with chronic pain, generally from
osteoarthritis or rheumatoid arthritis (Denis and
De Beer, 1983). All patients were receiving con-
comitant treatment for other disorders (e.g. dia-
betes, hypertension, bronchitis). No patients were
withdrawn because of side effects, and all but 1
patient reported good tolerability. After 4 weeks
94% of patients had a moderate to very good re-
duction in pain severity, and 72% assessed their
treatment with suprofen as better than their pre-
vious treatment.
3.2.2 Comparisons with Aspirin
Suprofen 200mg 4 times daily has been com-
pared with aspirin 650 to 1000mg 4 times daily in
several published (Bowers et ai., 1984; Willkens,
1983; table IV) and unpublished (data on file, Or-
tho) double-blind parallel studies of 12 to 24 weeks'
duration in patients suffering from chronic pain due
to musculoskeletal disorders, osteoarthritis and
rheumatoid arthritis. Relief of pain and inflam-
mation, improvement in activity impairment, and
global assessment scores were comparable with both
drugs, as were the type and incidence of side ef-
fects. The clinical relevance of the study by Will-
kens (1983) was limited by the small number of
patients completing the trial (8 in each group) and
by the permitted use of supplementary analgesics
(dextropropoxyphene or codeine), the consump-
tion of which was not reported. These authors re-
531
ported an increase (p < 0.05) in mean diastolic
blood pressure for the group on suprofen (see sec-
tion 4).
3.2.3 Comparisons with Dextropropoxyphene
Suprofen 200mg and dextropropoxyphene 65mg
each given 4 times daily for 24 weeks produced
similar analgesic responses and global assessment
scores in a double-blind parallel study in 114 pa-
tients with chronic pain from osteoarthritis (Salz-
man and Brobyn, 1983) [table IV]. More patients
were withdrawn because of side effects, primarily
gastrointestinal complaints, on dextropropoxy-
phene (34%) than on suprofen (24%).
3.2.4 Comparisons with Diclofenac. Ibuprofen.
Indomethacin and Naproxen
Suprofen has been compared with diclofenac,
ibuprofen, indomethacin and naproxen in short
term (1 to 2 weeks) double-blind parallel studies
in patients with osteoarthritic pain (table IV).
Suprofen 200mg and diclofenac 50mg each given
3 times daily for 7 days were compared in 60 hos-
pitalised women with acute exacerbation of os-
teoarthritic pain (Porzio, 1985). Suprofen proved
clinically more effective and better tolerated than
diclofenac. Not only was the degree of analgesia
significantly greater with suprofen but it also had
a faster onset of action. Global evaluation of effi-
cacy by both patient and physician indicated a sig-
nificantly better response with suprofen: 'very good
or good' responses were recorded in all 30 suprofen
patients compared with only 3 receiving diclo-
fenac. Gastrointestinal side effects were reported
by 15 patients receiving diclofenac compared with
4 of those receiving suprofen.
Suprofen 400mg and ibuprofen 400mg each
given 4 times daily produced similar improvement
of pain at rest, pain on motion, joint tenderness
and joint mobility, and similar overall evaluations
of efficacy and tolerability as assessed by both pa-
tients and investigators. There was a tendency for
a more rapid analgesic effect with suprofen, and
the improvement in pain on motion after 1 week
compared with baseline was better (p ~ 0.05) with
suprofen than with ibuprofen (Schuermans, 1983).
Suprofen: A Review 532

Table IV. Summary of randomised parallel double-blind studies comparing suprofen (S) with other analgesics in patients with
osteoarthritis

References Dosage (mg) and no. of patients· Duration Results

(weeks)
analgesic overall side
effect effectb effectsC

Comparisons with aspirin (ASA)

Bowers et al. (1984) S200 qid 24 S = ASA S = ASA S = ASA
ASA800 qid } (180)

Willkens (1983) S200 qid (8) 12 S = ASA S = ASA S = ASA

ASA650 qid (8)

Comparison with dextropropoxyphene (D)

Salzman and Brobyn S200 qid (48) 24 S=D S=D S:O;;D
(1983) D65 qid (51)

Comparison with die/ofenae (O/C)

Porzio (1985) S200 bid (30) S;;' DIC S;;' DIC S:O;; DIC
DIC50 tid (30)

Comparison with ibuprofen (lBU)

Sehuermans (1983) S200 qid (21) 2 S = IBU S = IBU S = IBU
IBU400 qid (21)

Comparison with indomethacin (lNO)

Hauzeur{1984,1985) S300 tid suppositories S = IND S = IND S = IND
IND50 tid suppositories } (60)

Comparison with naproxen (N)

Fellmann et al. (1983) S400 bid (39) 2 S=N S;;'N S=N
N375 bid (40)

a Number of patients evaluated for efficacy in each group.

b ;;. = tendency for first drug to be superior.
c :0;; = tendency for first drug to produce fewer side effects.
Abbreviations: bid = twice daily; tid = 3 times daily; qid = 4 times daily.

In hospitalised patients with osteoarthritis, su-
profen 300mg and indomethacin 50mg each ad-
ministered as suppositories 3 times daily proved
equipotent for the relief of pain and similar for tol-
erability. Local tolerability was considered good in
80% and 72% of patients on suprofen and indo-
methacin, respectively, when assessed by both the
investigator and the patients (Hauzeur, 1984, 1985).
Suprofen 400mg twice daily relieved osteoar-
thritic pain as effectively as naproxen 375mg twice
daily. Fair to very good global responses as as-
sessed by the investigators were seen in 72% of pa-
tients receiving suprofen and in 60% of those on
naproxen (Fellmann et aI., 1983).
3.3 Studies in Dysmenorrhoea
Suprofen has been studied in over 900 women
who suffer from primary dysmenorrhoea. For the
most part, studies were double-blind, parallel or
crossover, comparisons of suprofen with placebo,
dextropropoxyphene plus paracetamol, or ibupro-
fen (Cooke et aI., 1984, 1985; Heffron et aI., 1984;
unpublished data on file, Ortho). One open-label
Suprofen: A Review
study (Deere et aI., 1984) was conducted in which
suprofen up to 800 mg/day was taken for 2 con-
secutive cycles. Over 80% of the women in this
study experienced complete or moderate relief of
menstrual symptoms during both cycles. Both the
women and their physicians indicated a good or
excellent response to suprofen in over 80% of the
cycles treated. In the double-blind comparative
studies, suprofen 200 to 400mg was shown to be
statistically superior and clinically more acceptable
than either the dextropropoxyphene combination
or placebo. Suprofen 400mg was consistently bet-
ter, though not statistically, than both suprofen
200mg and ibuprofen 400mg (Heffron et aI., 1984).
3.4 Studies in Fever
In a dose-finding study (Weipp1, 1985), paedia-
tric patients with fever from respiratory tract in-
fection were given a single dose of suprofen 1 to
10 mg/kg as a syrup. The optimal dose proved to
be 5 mg/kg. This caused a peak reduction of rectal
temperature of about l.soC after 3 hours, and the
patients were maintained subfebrile for at least 4.5
hours. Higher doses did not produce any addi-
tional effect, and hypothermia was not seen.
The antipyretic effect of suprofen administered
as capsules, syrup, drops and suppositories has been
examined in a number of open studies and com-
parative trials against placebo and other standard
antipyretic agents (Rizzo et aI., 1983; Weippl, 1984;
unpublished data on file, Ortho). These studies have
involved several hundreds of adult and paediatric
patients suffering from fever of diverse aetiologies
(e.g. cancer, otitis media, respiratory tract infec-
tion). In most patients, effective fever control was
achieved within 60 to 90 minutes, and they re-
mained subfebrile with repeated doses. Suprofen
showed a fast onset of antipyretic activity and was
as effective as usual therapeutic doses of aspirin,
paracetamol, mefenamic acid and metamizoi.
4. Side Effects
Suprofen is well tolerated following single and
repeated oral doses in patients with acute or chronic
533
pain. Suprofen 200mg 3 times daily for 7 days ad-
ministered systemically (intramuscularly and in-
travenously as a bolus or slow infusion) is also well
tolerated both locally and systemically in healthy
volunteers (Michos et aI., 1985a,b; Zulliger et aI.,
1985). The most frequently occurring side effects
are mild gastrointestinal disturbances (e.g. nausea,
diarrhoea, constipation, gastralgia, heartburn, in-
digestion), mild CNS disturbances (e.g. headache,
drowsiness, dizziness, somnolence) and skin rash
(Denis and De Beer, 1983; Salzman and Brobyn,
1983; Schuermans, 1983; Silberman, 1983; Will-
kens, 1983). The incidence and nature of side ef-
fects in single-dose studies with suprofen is gen-
erally similar to that found with reference analge-
sics, and often with placebo. The clinical relevance
of such 'side effects' must therefore be interpreted
with caution as their relationshipo drug adminis-
tration is often uncertain.
Suprofen produces less gastrointestinal bleeding
than equipotent doses of aspirin in healthy vol-
unteers (section 1.4). However, the incidence of
gastrointestinal bleeding during suprofen admin-
istration relative to that of more established pro-
pionic acid derivatives (e.g. ibuprofen and na-
proxen) and newer agents (piroxicam) or prodrugs
(fenbufen and sulindac) has not been determined.
During long term administration of suprofen, gas-
trointestinal complaints remain the most fre-
quently reported side effects (Salzman and Brobyn,
1983; Willkens, 1983), and peptic ulceration has
been reported occasionally (Yeadon et aI., 1983).
In a 24-week study in patients with osteoarthritis,
nausea and epigastric distress occurred in 3.7% and
7.4% of patients, respectively, receiving suprofen
200mg 4 times daily compared with 20% and 26.7%
of patients, respectively, receiving dextropropoxy-
phene 65mg 4 times daily.
Other reactions infrequently associated with su-
profen include single case reports of acute hae-
molytic anaemia (Tosato et aI., 1985), and severe
contact dermatitis following application of a topi-
cal suprofen cream (Dooms-Goossens et aI., 1979).
The latter patient was found to be cross-sensitive
to ibuprofen, ketoprofen and naproxen. A very
marked blood pressure elevation has been noted in
Suprofen: A Review 534

Table V. Frequency of withdrawals due to side effects in 1053 administration of suprofen. In addition, occasional
patients with osteoarthritis and musculoskeletal disorders re- elevations of serum bilirubin, alkaline phospha-
ceiving suprofen 200 to 400mg or reference drugs· 4 times daily tase, lactate dehydrogenase, AST (SGOT) and ALT
in studies longer than 3 months (after Yeadon et aI., 1983)
(SGPT) have been observed but without clinical
Side effect Patients withdrawing because of symptoms or signs of liver disease. The uricosuric
side effects (%) activity of suprofen causes a decrease in serum uric
suprofen reference drugs
acid concentrations (Yeadon et aI., 1983). Statis-
(n = 605) (n = 44,8) tically significant reductions in haematocrit and
haemoglobin, which are not clinically significant,
Body as a whole 1.7 1.6 have been noted during treatment with suprofen
CardiovascularIrespiratory 1.7 1.3 (Bowers et aI., 1984; Denis and De Beer, 1983).
Central nervous system 4.0 5.6 In a pharmacokinetic study in 45 healthy vol-
Cutaneous 3.6 1.6 unteers comparing diclofenac 25mg, suprofen
Gastrointestinal 10.9 17.2 200mg and placebo administered intramuscularly
Genitourinary 0.8 0.4 3 times daily for 7 days, diclofenac treatment had
Musculoskeletal 0.2 0.2 to be suspended after 4 days because of extreme
Special senses 0.8 2.9 increases in creatine phosphokinase. Creatine
phosphokinase also increased with suprofen, but
Overall withdrawal b 17.7 23.9 not to unacceptable levels. These enzyme eleva-
tions are probably attributable to tissue trauma
a Aspirin 650 to 1000mg, dextropropoxyphene 65mg and a from injection of the drugs since administration of
combination of dextropropoxyphene 65mg + aspirin 227mg the suprofen vehicle as placebo did not cause the
+ phenacetin 162mg + caffeine 32.4mg.
b Some patients withdrawn because of more than 1 side ef-
enzyme elevation (Michos and Zulliger, 1985; Mi-
fect. chos et aI., 1985b; Zulliger, 1984).

6. Drug Interactions

3 patients receiving suprofen (Willkens, 1983) but
the authors did not discuss relationship to treat-
ment, underlying disease or possible drug interac-
tion.
In a summary of withdrawals due to side effects
during long term double-blind trials (Yeadon et aI.,
1983), the overall withdrawal rate was lower on su-
profen (17.7%) than with reference drugs (23.9%)
[table V]. The withdrawal rate was similar with su-
profen 200 and 400mg 4 times daily, and increased
with age. Gastrointestinal complaints were the most
frequent cause for withdrawal from suprofen
(10.9%), but occurred at a lower rate than with the
reference analgesics (17.2%).
5. Effect on Laboratory Values
Mild, clinically insignificant, leucopenia was re-
ported in 8 of 605 patients receiving long term
At therapeutic concentrations suprofen does not
displace warfarin and phenytoin from human al-
bumin in vitro (Chaikin et aI., 1980). De Clerck et
al. (1975b) found that the anticoagulant effect of
warfarin is only potentiated after repeated admin-
istration of very high doses of suprofen in rats (5
x 30 mg/kg). A crossover study conducted by
Abrams et al. (1983a) in 24 healthy subjects given
a single dose of suprofen 200mg alone and com-
bined with liquid antacid (aluminium hydroxide
1.32g plus magnesium hydroxide 1.17g) showed that
the antacid did not significantly alter the bioavail-
ability of suprofen. Studies of the potential inter-
action of suprofen with other drugs after repeated
administration in man have not been published.
The analgesic effects of suprofen and paraceta-
mol potentiate each other when administered to-
gether in the rat adjuvant arthritic flexion test (Ca-
petola et aI., 1980). The analgesic effects of suprofen
Suprofen: A Review
and paracetamol also appear to be additive in man,
and this combination may therefore provide a use-
ful analgesic combination. Codeine also adds to the
analgesic effect of suprofen (sections 3.1.4 and
3.1.5).
7. Overdosage
There are few data on overdosage with- supro-
fen. In a case report of a young woman who in-
gested suprofen 4g, the drug plasma concentration
was 662 mg/L about 6 hours later (i.e. about 40
times the highest peak concentration with a single
200mg dose in healthy subjects). The patient re-
mained fully conscious, and the authors concluded
that suprofen is relatively non-toxic in overdosage
(Freestone and Critchley, 1984).
8. Dosage and Administration
Suprofen is indicated in mild to moderate pain,
such as musculoskeletal pain, episiotomy pain,
postoperative pain following general surgery or
dental procedures, headache, and pain associated
with osteoarthritis, rheumatoid arthritis and dys-
menorrhoea. The usual recommended dosage of
suprofen is 200mg 3 or 4 times daily. Suprofen
400mg twice daily may provide an adequate dos-
age regimen (Fellmann et aI., 1983). In acute pain,
single doses of suprofen 400mg may provide a bet-
ter analgesic response than lower doses.
As with other non-steroidal anti-inflammatory
drugs, suprofen should be avoided in patients with
active gastrointestinal ulcer or allergy to salicylates
or other non-steroidal anti-inflammatory drugs.
Suprofen should be used with caution in patients
with impaired renal function, fluid retention, heart
failure and hypertension, and those with a history
of gastrointestinal ulceration. Close monitoring is
required in patients with coagulation disorders and
in patients receiving concomitant anticoagulants.
9: The Place of Suprofen in Therapy
Suprofen is an effective orally active analgesic
for acute pain states of moderate intensity, includ-
535
ing dysmenorrhoea. Single doses of suprofen pro-
vide equivalent or superior analgesia to therapeutic
doses of other analgesics (e.g. aspirin, codeine, de x-
tropropoxyphene, paracetamol, and their combi-
nations). Suprofen is rapidly absorbed and there-
fore has a fast onset of action, but because of its
short elimination half-life repeated doses may be
required more frequently than with some other
drugs, such as diflunisal. In chronic pain due to
osteoarthritis or musculoskeletal disorders, supro-
fen appears as effective and as safe as aspirin, dex-
tropropoxyphene, ibuprofen, indomethacin and
naproxen. Its gastrointestinal tolerability may be
superior to the former 2 drugs. In both acute and
chronic pain, suprofen has not been compared with
many other newer non-steroidal anti-inflammatory
analgesics, such as piroxicam. In conclusion, su-
profen appears to offer a suitable alternative to the
older, more established simple analgesics and non-
steroidal anti-inflammatory analgesics in the treat-
ment of acute and chronic pain of moderate inten-
sity.
References
Abrams. L.S.: Marriott. T.B. and Van Horn. A.: The effect of
Maalox on the bioavailability of suprofen. (Abstract No. 69.)
Clinical Research 31: 626A (1983a).
Abrams. L.S.: Marriott. T.B.: Chaikin. P.: Czerniecki. B.: Danna.
R.P. and Friedmann. N.: Dose proportionality and multiple-
dose pharmacokinetics of suprofen. (Abstract.) Clinical Re-
search 31: 626A (1983b).
Alton. K.B. and Patrick, J.E.: High-performance liquid chro-
matographic assay for suprofen, a potent new analgesic, in
plasma. Journal of Pharmaceutical Sciences 67: 985-987 (1978).
Arnold. J.D. and Berger. A.E.: Comparison of fecal blood loss
after use of aspirin and suprofen. Pharmacology 27 (Supp!. I):
14-22 (1983).
Awouters. F.: Niemegeers. CJ.E.: Lenaerts. F.M. and Janssen.
P.AJ.: Delay of castor oil diarrhoea in rats: a new way to eval-
uate inhibitors of prostaglandin biosynthesis. Journal of Phar-
macy and Pharmacology 30: 41-45 (1978).
Awouters, F.: Niemegeers. CJ.E.: Lenaerts. F.M. and Janssen,
P.AJ.: The effects ofsuprofen in rats with Mycobacterium bu-
tyricum-induced arthritis. Arzneimittel-Forschung 25: 1526-
1537 (1975a).
Awouters. F.: Niemegeers, CJ.E.: Lenaerts, P.M.H. and Janssen.
P.AJ.: Suprofen. a potent antagonist of ultraviolet-erythema
in guinea-pigs. Arzncimillel-Forschung 25: 1509-1511 (1975b).
Bodner. E.: Single-dose comparison of intramuscular suprofen,
pcntazocine. and placebo in patients with moderate-to-severe
post-operative pain. Royal Society of Medicine International
Congress and Symposium Series 90: 69-77 (1985).
Bodner. E. and Michos, N.: Clinically controlled comparative study
ofsuprofen. pentazocine. and placebo. Arzneimittel-Forschung
35: 755-759 (1985).
Suprofen: A Review
Borowska, A.; Mackowiak, J. and Wisniewski, K.: Prostaglan-
dins/PGs/ and peristalsis. Prostaglandins and Medicine 6: 13-
16 (1981).
Bowers, D.E.; Honig, S.; Miller, J.L. and Gardner, M.C: A long
term double-blind evaluation of suprofen and aspirin in os-
teoarthritis. Poster presented at the 4th World Congress on
Pain. Seattle (1984).
Capetola, RJ.; Argentieri, D.; Weintraub, H.S.; Chasin, M.; Doyle,
P. et al.: Suprofen; in Goldberg (Ed.) Pharmacological and Bio-
chemical Properties of Drug Substances Vol. 3, pp. 347-368
(American Pharmaceutical Association Academy of Pharma-
ceutical Sciences, Washington DC 1981).
Capetola, R.J.; McGuire, J.L. and Rosenthale, M.E.: Introduction
to the pharmacology of suprofen. Pharmacology 27 (Suppl. I):
1-13 (1983a).
Capetola, RJ.; Rosenthale, M.E.; Dubinsky, B. and McGuire, J.L.:
Peripheral antialgesics: A review. Journal of Clinical Phar-
macology 23: 545-556 (1983b).
Capetola, R.J.; Shriver, D.A. and Rosenthale, M.E.: Activity of
a new non-narcotic analgesic, suprofen, on pathologic-induced
pain in the rat. (Abstract No. 630.) Pharmacologist 20: 270
(1978).
Capetola, RJ.; Shriver, D.A. and Rosenthale, M.E.: Suprofen, a
new peripheral analgesic. Journal of Pharmacology and Ex-
perimental Therapeutics 214: 16-23 (1980).
Carraher, R.P.; Hahn, D.W. and McGuire, J.L.: Pharmacological
selectivity of suprofen, a new analgesic prostaglandin synthe-
tase inhibitor. (Abstract No. 259.) Federation Proceedings 40:
280 (1981).
Chaikin, P.; Abrams, L.; McKenna, M. and Weintraub, H.: Su-
profen protein binding studies in l'itro. (Abstract No. 69.)
Academy of Pharmaceutical Sciences (of the American Phar-
maceutical Association), San Antonio, Texas, Nov 9-13 (1980).
Chaikin, P.; Marriott, T.B.; Simon, D. and Weintraub, H.S.:
Comparative bioavailability of suprofen after coadministra-
tion with food or milk. (Abstract No. 88.) Academy of Phar-
maceutical Sciences (of the American Pharmaceutical Asso-
ciation), San Diego, California, Nov 14-18 (1982).
Chaikin, P.; Chasin, M.; Kennedy, B. and Silverman, B.: Supro-
fen concentrations in human breast milk. Journal of Clinical
Pharmacology 23: 385-390 (1983).
Cohen, A. and Smith, K.E.: Double-blind evaluation of safety and
gastrointestinal blood loss following oral administration of su-
profen plus codeine, aspirin plus codeine and placebo. (Ab-
stract.) Journal of Clinical Pharmacology 14: 400-401 (1984).
Cooke, CW.; Ellsworth, H.S. and Wentz, A.C: Double-blind
comparison of suprofen 200mg, suprofen 400mg, and placebo
in the treatment of primary dysmenorrhoea. Royal Society of
Medicine International Congress and Symposium Series 90: l-
ID (1985).
Cooke, CW.; Ellsworth, H.S.; Wentz, A.C and Czerniecki, B.:
Efficacy and safety of two dosage regimens of suprofen in the
treatment of primary dysmenorrhea. Poster presented at the
4th World Conference on Pain, Seattle (1984).
Cooper, S.A.; Wagenberg, B.; Eskow, R. and Zissu, J.: Double-
blind evaluation of suprofen and aspirin in the treatment of
periodontal pain. Pharmacology 27 (Suppl. I): 23-30 (1983).
De Clerck, F; Goossens, J. and Reneman, R.: Effects of anti-
inflammatory, anticoagulant and vasoactive compounds on tail
bleeding time, whole blood coagulation time and platelet re-
tention by glass beads in rats. Thrombosis Research 8: 179-
193 (1976).
De Clerck, F; Vermylen, J. and Reneman, R.: Effects ofsuprofen,
an inhibitor of prostaglandin biosynthesis, on platelet func-
tion. plasma coagulation and fibrinolysis I. In l'itro experi-
ments. Archives Internationales de Pharmacodynamie et de
Therapie 216: 263-279 (1975a).
De Clerck, F.; Vermylen, J. and Reneman, R.: Effects ofsuprofen,
an inhibitor of prostaglandin biosynthesis, on platelet func-
536
tion, plasma coagulation and fibrinolysis II. In l'il'O experi-
ments. Archives Internationales de Pharmacodynamie et de
Therapie 217: 68-79 (1975b).
Deere, J.L.: Howlett. RJ.; Jennings. CL.; Kochell, R.L.; Newton,
Z. and Purdon, T.F: Suprofen in the treatment of primary
dysmenorrhoea: Results of an open study. Advances in Ther-
apy I: 363-369 (1984).
Denis, F.R. and De Beer. J.M.M.: Clinical evaluation of suprofen
in the treatment of elderly patients with pain of diverse etiol-
ogy. Pharmacology 27 (Suppl. I): 81-86 (1983).
Desjardins. P.J.; Wagenberg, B.; Eskow, R.; Reynolds, D.; Gal-
legos. O. and Kruger, G.: Analgesic efficacy of suprofen in two
dental pain models. (Abstract No. A-25.) Clinical Pharmacol-
ogy and Therapeutics 29: 240 (1981).
Dooms-Goossens. A.; Dooms. M.; Van Lint. L. and Degreef, H.:
Skin sensitizing properties of arylalcanoic acids and their an-
alogues. Contact Dermatitis 5: 324-328 (1979).
Dubinsky, B. and Schupsky, J.J.: Mechanism ofaction of supro-
fen. a new peripheral analgesic. as demonstrated by its effects
on several nociceptive mediators. Prostaglandins 28: 241-252
(1984).
Dundee. J.W.: Clinical evaluation of mild analgesics. British
Journal of Clinical Pharmacology ID (Suppl.): 329S-334S (1980).
Eaglstein. W.H.; Ginsberg. L.D. and Mertz. P.M.: Ultraviolet ir-
radiation-induced inflammation: Effects of steroid and non-
steroid anti-inflammatory agents. Archives of Dermatology 115:
1421-1423 (1979).
Elattar. T.M.A. and Lin, H.S.: Effect of nonsteroidal anti-inflam-
matory agents on prostaglandins biosyntheses by human gin-
gival tissue. (Abstract No. 270.) Journal of Dental Research
62: 679 (1983).
FassoIt, A. and Stocker. H.: Behandlung des postoperativen
Wundschmerzes mit Suprofen. Arzneimittel-Forschung 33:
1327-1330 (1983).
Fellmann. N.; Stocker. H. and Reuteler, H.: Double-blind study
of suprofen vs naproxen in the treatment of osteoarthritic pain.
European Journal of Rheumatology and Inflammation 6: 216-
221 (1983).
Ferreira. S.H.; Moncada, S. and Vane. J.R.: Prostaglandins and
signs and symptoms of inflammation; in Robinson and Vane
(Eds.) Prostaglandin Synthetase Inhibitors, pp. 175-187 (Raven
Press, New York 1974).
Frakes, 1..; Mehlisch. D.R. and Van Horn. A.W.: A double-blind
evaluation of suprofen 200mg and 400mg. aspirin 650mg both
alone and with codeine 60mg. and placebo in post-surgical
dental pain. Poster presented at the 4th World Conference on
Pain, Seattle (1984).
Fontaine, J.; Van Nueter, J.M. and Reuse. J.1.: Effects of pros-
taglandins on the peristaltic reflex of the guinea pig ileum. Ar-
chives Internationales de Pharmacodynamie et de Therapie 226:
341-343 (1977).
Freestone, S. and Critchley. J.AJ.H.: Self poisoning with suto-
profen. British Medical Journal 289: 470 (1984).
Fujimori. I.; Kono, M.; Sekita. T.; Takeda, Y.; Ogihara. K. et al.:
A double-blind clinical evaluation of suprofen on acute upper
respiratory infection comparing with aspirin. Journal of the
Japanese Association for Infectious Diseases 57: 62-81 (1983).
Fujimura. H.; Nakayama. T.; Hiramatsu, Y.; Tamura. Y. and
Maekawa. K.: General pharmacological studies of (± )-2-[p-(2-
thenoyl)phenyl] propionic acid (suprofen). Pharmacometrics
26: 415-440 (1983).
Fujimura, H.; Tsurumi. K.; Hasegawa, J.; Yanagihara, M.; Hir-
amatsu, Y. and Maekawa, K.: Anti-inflammatory, analgesic and
antipyretic activities of a-(p-thenoylphenyl) propionic acid. Folia
Pharmacologica Japonica 79: 123-136 (1982).
Fujimura. H.; Tsurumi, K.; Nakayama. T.; Kokuba. S.; Hira-
matsu, Y. and Tamura. Y.: Effect of a-(p-thenoylphenyl)-pro-
pionic acid (TN-762) on acute inflammatory reactions and
prostaglandin biosynthesis. Folia Pharmacologica Japonica 77:
Suprofen: A Review
321-336 (1981).
Hahn. D.W.; Carraher. R. and McGuire. J.L.: Effects ofsuprofen
and other prostaglandin synthetase inhibitors in a new animal
model for myometrial hyperactivity. Prostaglandins 23: 1-16
(1982).
Hauzeur. J.P.: Comparison of effectiveness and tolerability ofsu-
profen 300mg suppositories with indomethacin 50mg suppos-
itories in osteoarthritis pain. Poster presented at the 4th World
Congress on Pain. Seattle (\984).
Hauzeur. J.P.: Double-blind comparison of suprofen supposito-
ries and indomethacin suppositories in patients with pain due
to osteoarthritis. Royal Society of Medicine International Con-
gress and Symposium Series 90: 61-68 (1985).
Heffron. W.; Gordon. S.; May. J.; Mehlisch. D.; Gravelee. Let
al.: A double-blind evaluation of two dosage regimens of su-
pr;pfen and ibuprofen in primary dysmenorrhea. Poster pre-
sented at the 4th World Conference on Pain. Seattle (\984).
Honig. W.J.: Clinical comparison of the analgesic efficacy of su-
profen. diflunisal and placebo in the treatment of pain after
meniscectomy. Pharmacology 27 (Suppl. I): 74-80 (1983).
Honig. W.J. and Michos. N.: Comparison of suprofen and in-
doprofen after intravenous injection in pain following men-
iscectomy. Poster presented at the 4th World Conference on
Pain. Seattle (1984).
Imai. H.: Muramatsu. Y.; Niu. K.; Nozaki. M. and Fujimura. H.:
Inhibitory effect of TN-762 (suprofen) on the platelet aggre-
gation. Folia Pharmacologica Japonica 80: 61-68 (\982).
Ishibashi. K.; Asada. K.: Hashimoto. F.; Nakagawa. Y.; Doi. Y.:
Ohtsubo. K. and Tanaka. T.: A double-blind study of a new
non-steroidal anti-inflammatory analgesic agent. suprofen. after
tooth extraction. Oral Therapeutics and Pharmacology I: 53-
64 (1982).
Lagu. A.L: Young. R.: McGonigle. E. and Lane. P.A.: High-per-
formance liquid chromatographic determination of suprofen
in drug substance and capsules. Journal of Pharmaceutical Sci-
ences 71: 85-88 (1982).
Littlejohns. D.W. and Vere. D.W.: The clinical assessment of an-
algesic drugs. British Journal of Clinical Pharmacology II: 319-
332 (1981).
Lorenzi. G.L; Bertini. G.; Peveraro. A.: Rosso. V. and Rossi. E.:
A single-dose. double-blind evaluation of suprofen and dipy-
rone in post-operative pain. Royal Society of Medicine Inter-
national Congress and Symposium Series 90: 31-40 (1985).
Markus. A.F. and Gough. D.: A clinical trial of suprofen and
aspirin in post-operative dental pain. International Journal of
Oral Surgery 9: 477-479 (\980).
McGuire. J.E.; Niemegeers. C.J.E.; Shriver. D.A. and Awouters.
F.: Antinociceptive properties of suprofen. a new analgesic agent.
(Abstract No. 2915.) Federation Proceedings 37: 769 (1978).
Mehlisch. D.R.: Double-blind evaluation of analgesic efficacy and
safety of suprofen. aspirin. aspirin plus codeine. and placebo
in patients with post-operative dental pain. Royal Society of
Medicine International Congress and Symposium Series 90:
41-50 (1985).
Mehlisch. D.R. and Eglsaer. M.: A double-blind evaluation of
analgesic efficacy and safety of suprofen 200mg compared to
Darvon Compound-65. Darvocet-N 100. aspirin 650mg and
codeine 60mg. and placebo in patients with postoperative pain.
(Abstract No. 362.) Presented at the II World Conference on
Clinical Pharmacology and Therapeutics, Washington DC, July
3 I-August 5 (\ 983).
Mehlisch. D.R.; Friedman. N. and Van Horn. A.W.: A double-
blind evaluation of suprofen. aspirin and an oxycodone com-
bination analgesic in post-operative pain. Poster presented at
the 4th World Conference on Pain. Seattle (\984).
Michos. N. and Zulliger. H.: Local and systemic tolerance of su-
profen. diclofenac and placebo. and plasma levels of suprofen
given intramuscularly in normal subjects for 7 days. Royal So-
ciety of Medicine International Congress and Symposium Se-
537
ries 90: 11-22 (1985).
Michos. N.; Zulliger. H.W. and Fenzl. CE.: Local and systemic
tolerability of suprofen. Arzneimittel-Forschung 35: 745-748
(1985a).
Michos. N.; Zulliger. H.W. and Fenz\' E.: Pharmacokinetics and
tolerability of suprofen. Arzneimittel-Forschung 35: 738-745
(1985b).
Mok. M.S.: Steen. S.N. and Lippmann. M.: Suprofen in the relief
of pain. IRCS Medical Science; Clinical Medicine; Clinical
Pharmacology and Therapeutics 6: 5 II (1978).
Mori. Y.; Kuroda. N.; Sakai. Y.: Yokoya. F.; Toyoshi. K. and
Baba. S.: Species differences in the metabolism of suprofen in
laboratory animals and man. Drug Metabolism and Disposi-
tion 13: 239-245 (1985).
Mori. Y.: Yokoya. F.: Sakai. Y.: Toyoshi. K.: Furuta. T. and Baba.
S.: Absorption and excretion of suprofen in both sexes of rats.
guinea-pigs. and rabbits. Radioisotopes 32: 416-418 (\ 983a).
Mori. Y.: Yokoya. F.: Sakai. Y.: Toyoshi. K. and Baba. S.: Ab-
sorption. distribution. and excretion of suprofen in mice of
both sexes. Chemical and Pharmaceutical Bulletin 32: 1106-
1112 (1984a).
Mori. Y.: Yokoya. F.: Sakai. Y.: Toyoshi, K. and Baba. S.: Dis-
tribution of suprofen in rats of both sexes. Radioisotopes 33:
284-290 (1984b).
Mori. Y.; Yokoya. F.: Toyoshi. K.; Baba. S. and Sakai. Y.: Ab-
sorption and excretion of suprofen in rats. Drug Metabolism
and Disposition II: 387-391 (\983b).
Muller. H.: Zulliger, H.W.: Dorig, BA and Egli, R.A.: Quanti-
tative determination of suprofen in human plasma and urine
by fully automated high-performance liquid chromatography.
Arzneimittel-Forschung 32: 257-260 (1982).
Nevelsteen. A.; De Clerck. F.: Loots, W. and De Gryse. A.: Res-
toration of post-thrombotic peripheral collateral circulation in
the cat by ketanserin. a selective 5-HT ,-receptor antagonist.
Archives Internationales de Pharmacodynamie et de Therapie
270: 268-279 (\ 984).
Niemegecrs. C.J.E. and Janssen, P.AJ.: Suprofen. a potent an-
tagonist of sodium urate crystal-induced arthritis in dogs. Arz-
neimittel-Forschung 25: 1512-1515 (1975).
Niemegeers. C.J.E.: Awouters. F.; Lenaerts, F.M. and Janssen.
P.AJ.: The activity ofsuprofen on nystatin-induced paw oed-
ema in rats. Arznemittel-Forschung 25: 1516-1519 (\975a).
Niemegecrs. C.J.E.: Lenaerts. F.M. and Janssen. P.AJ.: The an-
tipyretic effect of suprofen in rats with yeast-induced fever.
Arzneimittel-Forschung 25: 1519-1524 (1975b).
Niemegeers. C.J.E.; Lenaerts. F.M.; Awouters. F. and Janssen.
P.AJ.: Gastrointestinal effects and acute toxicity of suprofen.
Arzneimittel-Forschung 25: 1537-1542 (\975c).
Niemegeers. C.J.E.: Van Bruggen. W.: Awouters. F. and Janssen.
PAJ.: The effects of suprofen in rats with implanted cotton
pellets. Arzneimittel-Forschung 25: 1524-1526 (1975d).
Niemegeers. C.J.E.: Van Bruggen. J.A.A. and Janssen. P.AJ.: Su-
profen. a potent antagonist of acetic acid-induced writhing in
rats. Arzneimittel-Forschung 25: 1505-1509 (1975e).
Olson. N.: Sunshine. A.: Roure. C: Colon. A.: Laska. E. et al.:
Analgesic efficacy of suprofen. codeine and placebo. Poster
presented at the 4th World Conference on Pain. Seattle (\ 984).
Porzio. F.: A double-blind evaluation of suprofen and diclofenac
in acute exacerbations of osteoarthritic pain. Royal Society of
Medicine International Congress and Symposium Series 90:
51-60 (1985).
Pujaite. J.: Valdez. E. and de la Paz, R.: Clinical comparison of
the analgesic efficacy of suprofen and mefenamic acid in the
treatment of musculoskeletal pain. Current Therapeutic Re-
search 36: 245-252 (1984).
Rainsford. K.D.: The comparative gastric ulcerogenic activities
of non-steroid anti-inflammatory drugs. Agents and Actions 7:
573-577 (1977).
Rainsford. K.D.: The effects of aspirin and other non-steroid anti-
Suprofen: A Review
inflammatory/analgesic drugs on gastro-intestinal mucus gly-
coprotein biosynthesis in rim relationship to ulcerogenic ac-
tions. Biochemical Pharmacology 27: 877-885 (1978).
Rizzo. S.C: Sarchi, C: Pacchiarini, L. and Ricevuti, G.: Studio
comparativo sull'attivita antipyretica del suprofen. Bollettino
Chimico Farmaceutico 122: 28S-36S (1983).
Rosenthale, M.E.: McGuire, J.L. and Capetola, R.J.: Pharmacol-
ogical properties of a new peripheral analgesic, suprofen. Eu-
ropean Journal of Rheumatology 4: 469-480 (1981).
Salzman. R.T. and Brobyn, R.D.: Long-term comparison of su-
profen and propoxyphene in patients with osteoarthritis. Phar-
macology 27 (Supp!. I): 55-64 (1983).
Schuermans, Y.: Comparison of suprofen and ibuprofen in the
treatment of pain secondary to osteoarthritis. Pharmacology
27 (Supp!. I): 41-47 (1983).
Schichikawa. K.: Orihara, M.: Kimura, M.: Komatsubara, Y.:
Maeda, A. et a!.: The clinical evaluation of suprofen on low
back pain - multi-center double-blind study in comparison with
indomethacin. Japanese Pharmacology and Therapeutics II:
225-242 (1983).
Silberman. H.M.: Multiple-dose comparison of suprofen, aspirin
and placebo in the treatment of musculoskeletal pain. Phar-
macology 27 (Supp!. I): 65-73 (1983).
Singh. P.P.; Junnarkar, A.Y.: Rao, C.S.: Varma, R.K. and Shri-
dhar. D.R.: Acetic acid and phenylquinone writhing test: a crit-
ical study in mice. Methods and Findings in Experimental and
Clinical Pharmacology 5: 601-606 (1983).
Smith, R.J.: Nonsteroid anti-inflammatory agents: Regulators of
the phagocytic secretion of lysosomal enzymes from guinea-
pig ncutrophils. Journal of Pharmacology and Experimental
Therapeutics 207: 618-629 (1978).
Stark, W.J.: Maumeree, A.E.: Fagadau, W.: Datiles, M.M.: Baker,
c.c. et a!.: Cystoid macular edema in pseudophakia. Survey
of Ophthalmology 28 (Supp!.): 442-451 (1984).
Sunshine, A.: Marrero, I.: Olson, N.Z.: Laska, E.M. and Mc-
Cormick, N.: Oral analgesic efficacy of suprofen compared to
aspirin, aspirin plus codeine, and placebo in patients with post-
operative dental pain. Pharmacology 27 (Supp!. I): 31-40 (1983).
SuSace, A.: Previtera, A.M.: Sarchi, C. and Pietrogrande, V.:
Sull'impiego di un nuovo antiflogistico in ortopedia. Ortope-
dia e Traumatologia Oggi 2: 407-411 (1982).
Tolman, E.L.: McGuire, J.L. and Rosenthale, M.E.: Pharmacol-
ogy of nonsteroidal anti-inflammatory drugs and their use in
dvsmenorrhea: in Dawood et a!. (Eds) Premenstrual Syndrome
a~d Dysmenorrhea, pp. 159-175 (Urban and Schwarzenberg,
Baltimore 1985).
Tolman. E.L.: Rosenthale, M.E.: Capctola, R.J. and McGuire, J.L.:
Suprofen: The pharmacology and clinical efficacy of a new non-
narcotic peripheral analgesic. Clinics in Rheumatic Diseases
10: 353-368 (1984).
Tong, E.Y.: Leibowitz, H.M. and Kupferman, A.: Suppression of
prostaglandin release from the inflamed cornea. (Abstract No.
3916.) Federation Proceedings 43: 954 (1984).
Tosato, F.: Fossaluzza, V. et a!.: Acute haemolytic anaemia in-
duced by suprofen. (Abstract.) British Medical Journal 290:
1042 (1985).
Tsurumi, K. and Fujimura, H.: Effect of anti-inflammatory drugs
on endotoxin-induced diarrhea in mice. Japanese Journal of
Pharmacology 33: 165-173 (1983).
Van Daele, P.G.H.: Boey, J.M.; Sipido, V.K.; De Bruyn, M.F.L.
and Janssen, P.A.J.: Synthesis of ,,-methyl-4-(2-thienylcar-
bonyl) bcnzeneacetic acid, suprofen, and derivatives. Arzneim-
ittcl-Forschung 25: 1495-150 I (1975).
Van Nueten, J.M.: Hoebeke, J.: De Clerck, F.; Awouters, F. and
Janssen. P.A.J.: Inhibition by suprofen and other non-narcotic
analgesic drugs of the effects of prostaglandin precursors on
538
isolated tissues and platelets. Archives Internationales de Phar-
macodynamic et de Therapie 220: 297-310 (1976).
Vane, J.R.: Mode of action of aspirin and similar compounds; in
Robinson and Vane (Eds) Prostaglandin Synthetase Inhibitors,
pp. 155-163 (Raven Press, New York 1974).
Vargha von Szeged, A. and Michos, N.: Erfahrungen mit Supro-
fen bei akuten und chronische Schmerzen in der neurolo-
gischen Praxis. Arzneimittel-Forschung 33: 1334-1338 (1983).
Vericat Cadesas, F.; Igual, A. and Giralt, J.: Estudio eomparativo
de la actividad de LC-R 505 frente a otros antiinflamatorios.
Archivos de Farmacologia y Toxicologia 5: 259-261 (1979).
Wagenberg, B.; Eskow, R.; Zissu, J. and Cooper, S.A.: Relative
analgesic efficacy of suprofen 200mg, d-propoxyphene 65mg,
codeine 60mg, and placebo. (AbstraclNo. C36.) Clinical Phar-
macology and Therapeutics 33: 199 (1983).
Weintraub. H.S.: Human acute pharmacokinetics and compara-
tive bioavailability of suprofen from various dosage forms.
(Abstract.) Clinical Research 26: 595A (1978).
Weipp!. G.: Effect of suprofen on fever and pains in young chil-
dren with infection of the upper respiratory tract and otitis
media. (Abstract No.9!.) Pain (Supp!. 2): S63 (1984).
Weipp\. G.: Treatment of fever in children: clinical comparison
of seven different doses ofsuprofen. Royal Society of Medicine
International Congress and Symposium Series 90: 23-30 (1985).
Willkens, R.F.: Long-term clinical evaluation of suprofen and as-
pirin in patients with osteoarthritis. Pharmacology 27 (Supp!.
I): 48-54 (1983).
Wong, S. and Gardocki, J.F.: Anti-inflammatory and antiarthritic
evaluation of acetaminophen and its potentiation oftolmetin.
Journal of Pharmacology and Experimental Therapeutics 226:
625-632 (1983).
Yeadon. A.; Gardner, M.e.; Milak, D.M. and Smith, K.E.: Su-
profen: an overview of long-term safety. Pharmacology 27
(Supp!. I): 87-94 (1983).
Yokoya, F.; Mori. Y.; Toyoshi, K.: Sakai, Y.; Baba, S. and Horie,
M.: Disposition of suprofen in rats following intravenous in-
jcction. Radioisotopes 33: 137-141 (1984a).
Yokoya. F.; Nakayama, T.: Sakamoto, K.; Ohhira, K.; Ohshika,
Y. et al.: Effect of (± )-2-[p-(2-thenoyl)phenyl] propionic acid
(suprofen) on experimental allergic reactions. Japanese Journal
of Pharmacology 34: 23-31 (I 984b).
Zulliger. H.: Comparison of local and systemic tolerability of su-
profen I.M. 200 mg/ml versus diclofenac I.M. 25 mg/ml and
placebo I.M. I ml: Determination of 'steady state' plasmaki-
netics of suprofen in 15 volunteers each. Poster presented at
the 4th World Congress on Pain, Seattle (1984).
Zulliger, H. W. and Fassolt, A.: Suprofen kinetics in healthy male
volunteers after intramuscular injection of increasing dosages.
Arzneimittel-Forschung 33: 1322-1326 (1983).
Zulliger, H.W. and Fassolt, A.: Pharmacokinetics and bioavail-
ability of suprofen injection solution after intravenous appli-
cation versus capsules on six healthy male volunteers. Arz-
neimittel-Forschung 35: 976-980 (1985).
Zulliger, H.W.; Michos, N. and Fenzl, E.: Local and systemic tol-
erability of suprofen, Arznemittel-Forschung 35: 748-755 (1985).
Zusman, R.M. and Keiser, H.R.: Prostaglandin biosynthesis by
rabbit renomedullary interstitial cells in tissue culture: Stim-
ulation by angiotensin II, bradykinin and arginine vasopressin.
Journal of Clinical Investigation 60: 215-223 (1977).
Authors' address: P.A. Todd, ADIS Drug Information Services,
Private Bag, Mairangi Bay, Auckland 10 (New Zealand).