Angioplasty procedure using nonionic contrast media

A method for treating patients in need of percutaneous transluminal coronary angioplasty which comprises administering nonionic contract media to the patient and treating the patient with a fibrinogen receptor antagonist.

BACKGROUND OF THE INVENTION 
Angioplasty procedures are commonly performed on patients having coronary 
blockages. An estimated 2 million coronary angiographic procedures are 
performed annually in the United States alone. The objective of 
angioplasty procedures is to revascularize the coronary artery where the 
blockage is located. By inflating a balloon at the point of blockage, 
blood flow is restored. 
Contrast dye is used to initially identify the presence and location of the 
blockage. It is also used during the procedure to provide an image for 
proper placement of the guide wire, catheter, and angioplasty balloon. 
There are key differences among radiographic contrast media. Ionic contrast 
media are far less expensive than nonionic contrast media. However, ionic 
contrast media are associated with several infrequent side effects of 
modest clinical significance including nausea, vomiting and allergic 
reactions. Bradycardia, abnormalities in repolarization manifest by ST 
segment and T wave alterations, depression of ventricular systolic 
function and lowering of systolic blood pressure occur commonly with ionic 
contrast media but last only seconds. 
The side effects associated with ionic contrast media are rare with 
nonionic contrast agents. However, reports of thrombotic events occurring 
during routine angiography with nonionic media suggest that nonionic media 
may be a procoagulant (Grollman et al., Cathet. Cardiovasc. Diagn. (1988) 
vol. 14 pp. 159-64 and Hwang et al., Cathet. Cardiovasc. Diagn. (1989) 
vol. 16 pp. 209-13). Studies of percutaneous coronary interventions (which 
are inherently associated with a heightened risk of intracoronary thrombus 
formation) have reported increased thrombus formation with nonionic 
contrast agent use (Doorey ey al., Clin. Cardiol. (1992) vol. 15 pp. 
117-20 and Gasperetti et al., J. Am. Coll. Cardiol. (1991) vol. 18 pp. 
443-50). Grines et al., JACC (1996) vol. 27, no. 6 pp. 1381-6 conclude 
that in patients with unstable ischemic syndromes undergoing coronary 
angioplasty, the use of ionic low osmolality contrast media reduces the 
risk of ischemic complications acutely and at 1 month after the procedure. 
Grines et al. recommend that ionic media be strongly considered when 
performing interventions in patients with unstable angina or myocardial 
infarction. 
It is known that acute or abrupt closure occurs in 2-8% of patients 
undergoing percutaneous transluminal coronary angioplasty and accounts for 
most of the short-term morbidity and mortality associated with the 
procedure. In about 75% of patients with abrupt closure, it occurs within 
minutes after percutaneous transluminal coronary angioplasty, when they 
are still in the catheterization laboratory. In the other 25%, it usually 
occurs within 24 hours after the procedure (Landau et al. New England 
Journal of Medicine vol. 330 No. 14 p. 986 (1994)). 
Glycoprotein IIb/IIIa Fibrinogen Binding Inhibitors 
Fibrinogen receptor antagonists, which inhibit the binding of fibrinogen to 
the glycoprotein IIb/IIIa (.alpha.II.beta.3) platelet receptor site, may 
be administered during and following angioplasty procedures to reduce the 
risk of ischemic events. Because the period of time following angioplasty 
procedures is associated with a higher level of coronary ischemic events, 
fibrinogen receptor antagonists are administered following angioplasty to 
inhibit fibrinogen binding to the glycoprotein IIb/IIIa platelet receptor 
site, reducing the level of ischemic events. 
Integrelin is a cyclic peptide that is based on the KGD sequence in the 
snake venom protein barbourin. It inhibits ligand binding to glycoprotein 
IIb/IIIa. Among the non-peptide compounds are Ro 44-9883 and MK-383, which 
are administered intravenously, and are also selective for glycoprotein 
IIb/IIIa. Orally active agents include SC54684, which is a prodrug (i.e., 
it requires biotransformation in vivo to its active form) with high oral 
bioavailability and RO43-8857, GR144053, and DMP728, which are themselves 
the active inhibitors. Literally thousands of other compounds have been 
synthesized in an attempt to obtain optimal potency, metabolic stability, 
receptor specificity, and favorable intravascular survival. Despite 
variations in these compounds, virtually of all of them retain the basic 
charge relations of the RGD sequence with a positive charge separated from 
a negative charge by approximately 10-20 .ANG.. All of these compounds 
inhibit fibrinogen binding to the glycoprotein IIb/IIIa platelet receptor 
site. Monoclonal antibody 7E3 also blocks the glycoprotein IIb/IIIa 
receptor. 
We have now found that angioplasty procedures conducted with nonionic 
contrast media, in combination with glycoprotein IIb/IIIa receptor 
antagonist administration, reduce the risk of ischemic complications 
(follow-up intervention associated with acute coronary ischemic syndrome, 
e.g. coronary artery bypass grafting, repeat percutaneous intervention for 
acute ischemia, insertion of a coronary endovascular stent) to a greater 
degree than procedures involving ionic contrast media with glycoprotein 
IIb/IIIa receptor antagonists, procedures involving nonionic contract 
media without glycoprotein IIb/IIIa receptor antagonists, or procedures 
involving ionic contrast media without glycoprotein IIb/IIIa receptor 
antagonists. 
SUMMARY OF THE INVENTION 
The invention is a method for diagnosing and treating a patient having 
coronary artery blockage which comprises 
a) introducing nonionic contrast dye into the coronary artery of the 
patient to image the blockage, and 
b) imaging the blockage with a nonionic contrast dye, administering a 
fibrinogen receptor antagonist to the patient, and inflating a balloon at 
the location of the coronary blockage to revascularize the artery, and 
c) administering fibrinogen receptor antagonist to the patient following 
balloon inflation. 
The fibrinogen receptor antagonist is administered to the patient during 
balloon inflation, and for a period of time of at least 24 hours 
subsequent to balloon inflation. The fibrinogen receptor antagonist may be 
orally or intravenously administered. 
When intravenously administered, the fibrinogen receptor antagonist can be, 
for example, 
Mpr-(Acetimidyl-Lys)-Gly-Asp-Trp-Phe-Cys-NH.sub.2, 
Mpr-(Acetimidyl-Lys)-Gly-Asp-Trp-Phe-Pen-NH.sub.2, 
Mpr-(Phenylimidyl-Lys)-Gly-Asp-Trp-Phe-Pen-NH.sub.2, 
Mpr-(Phenylimidyl-Lys)-Gly-Asp-Trp-Phe-Cys-NH.sub.2, 
N-Methyl-D-phenylalanyl-N-[(1S)-1-fonnyl-4-guanidinobutyl]-L-prolinamide, 
((1-(2-((4-(aminoiminomethyl)benzoyl)amino)-3-(4-hydroxyphenyl)-1-oxopropyl 
)-4-piperidinyl)oxy)-(S)-acetic acid, 
N-(2-(2-(((3-((aminoiminomethyl)amino)propyl)amino)carbonyl)-1-piperidnyl)- 
1-(cyclohexylmethyl)-2-oxoethyl)-(R,S)-glycine, and 
(2-S-(n-Butylsulfonylamino)-3[4-(piperidin-4-yl)butyloxyphenyl]propionic 
acid hydrochloride, 
When orally administered, the fibrinogen receptor antagonist can be, for 
example, 
2(S)-[(p-Toluenesulfonyl)amino]-3-[[[5,6 
,7,8-tetrahydro-4-oxo-5-[2-(piperidin-4-yl)ethyl]-4H-pyrazolo-[1,5-a][1,4] 
diazepin-2-yl]carbonyl]-amino]propionic acid, 
Methyl-N.sup.3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl 
}-acetyl]-N.sup.2 -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate acetate 
salt, 
Ethyl 
3-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoa 
te, or. 
(R)-methyl-3-[[[3-[4-(aminoiminomethyl)phenyl]-4,5-dihydro-5-isoxazolyl]ace 
tyl]amino]-N-(butoxycarbonyl)-L-alanine monoacetate. 
The invention is a method for treating patients having coronary blockage in 
an artery which comprises imaging the blockage with a nonionic contrast 
dye, administering a fibrinogen receptor antagonist to the patient, and 
inflating a balloon at the location of the coronary blockage to 
revascularize the artery. 
DETAILED DESCRIPTION OF THE INVENTION 
The method encompasses a treatment for patients having coronary blockages 
involving the use, in a manner ordinary to angioplasty procedures, of 
nonionic contrast media, in conjunction with administration, during the 
treatment, of a fibrinogen receptor antagonist. The objective of the 
treatment is to remove coronary blockages. The treatment results in lower 
incidence of ischemic events when compared with procedures using nonionic 
dye without fibrinogen receptor antagonist, ionic dye with fibrinogen 
receptor antagonist, or ionic dye without fibrinogen receptor antagonist. 
Antagonists for the glycoprotein IIb/IIIa fibrinogen receptor have been 
described in U.S. Pat. Nos. 5,470,849, 5,463,011, 5,455,243, 5,451,578, 
5,446,056, 5,441,952, 5,422,249, 5,416,099, 5,405,854, 5,397,791, 
5,393,760, 5,389,631, 5,380,713, 5,374,622, 5,358,956, 5,344,783, 
5,340,798, 5,338,7235,334,596, 5,321,034, 5,318,899 (e.g. cyclic 
heptapeptides Mpr-(Acetimidyl-Lys)-Gly-Asp-Trp-Phe-Cys-NH.sub.2, 
Mpr-(Acetimidyl-Lys)-Gly-Asp-Trp-Phe-Pen-NH.sub.2, 
Mpr-(Phenylimidyl-Lys)-Gly-Asp-Trp-Phe-Pen-NH.sub.2, and 
Mpr-(Phenylimidyl-Lys)-Gly-Asp-Trp-Phe-Cys-NH.sub.2, wherein Mpr is 
mercapto propionyl),5,312,923, 5,294,616, 5,292,756, 5,281,585 5,272,158, 
5,264,420, 5,260,307, 5,239,113 (e.g. Ethyl 
3-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoa 
te), 5,227,490, 5,206,373, 4,703,036 (e.g. 
N-Methyl-D-phenylalanyl-N-[(1S)-1-fomyl-4-guanidinobutyl]-L-prolinamide), 
EP 505 868 (e.g. 
((1-(2-((4-(aminoiminomethyl)benzoyl)amino)-3-(4-hydroxyphenyl)-1-oxopropy 
l)-4-piperidinyl)oxy)-(S)-acetic acid) WO 9311152 (e.g. 
N-(2-(2-(((3-((aminoiminomethyl)amino)propyl)amino)-carbonyl)-1-piperidnyl 
)-1-(cyclohexylmethyl)-2-oxoethyl)-(R,S)-glycine), EP 333 356, WO 9514683 
(e.g. (Methyl-N.sup.3 -[2-{3-(4-formamidinophenyl) -isoxazolin-5 (R)-yl 
}-acetyl]-N.sup.2 -(n-butyloxycarbonyl)-2,3-(S)-diaminopropionate acetate 
salt), 
(R)-methyl-3-[[[3-[4-(aminoiminomethyl)phenyl]-4,5-dihydro-5-isoxazolyl]ac 
etyl]amino]-N-(butoxycarbonyl)-L-alanine monoacetate, and WO 9422820. They 
are described as useful for inhibiting fibrinogen binding and inhibiting 
clot formation. 
Glycoprotein IIb/IIIa receptor antagonists and their pharmaceutically 
acceptable salts are useful in the present invention. The term 
"pharmaceutically acceptable salts" means non-toxic salts of the compounds 
which include, but are not limited to, acetate, benzenesulfonate, 
benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium 
edetate, camsylate, carbonate, chloride, clavulanate, citrate, 
dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, 
gluceptate, gluconate, glutamate, glycollylarsanilate, hexykesorcinate, 
hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, 
isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, 
mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, 
nitrate, oleate, oxalate, pamaote, palmitate, panthothenate, 
phosphate/diphosphate, polygalacturonate, salicylate, stearate, 
subacetate, succinate, tannate, tartrate, teoclate, tosylate, 
triethiodide, valerate. 
Pharmaceutically effective amounts of the glycoprotein IIb/IIIa receptor 
antagonists are suitable for use in the compositions and methods of the 
present invention. The term "pharmaceutically effective amount" means that 
amount of a drug or.pharmaceutical agent that will elicit the biological 
or medical response of a tissue, system or animal that is being sought by 
a researcher or clinician. 
The methods of the present invention are useful in combination with 
procedures for treating patients with other anticoagulants (e.g. heparin 
and warfarin), thrombolytic agents (e.g. streptokinase and tissue 
plasminogen activator), and platelet antiaggregation agents (e.g. aspirin 
and dipyridamole). 
In accordance with the invention, glycoprotein IIb/IIIa receptor 
antagonists can be administered to the patient in one oral composition 
such as a tablet or capsule, in several oral compositions, in one bolus 
injection, in a continuous intravenous administration, or any combination 
of oral and intravenous administration. 
Suitable oral compositions include tablets, capsules (each of which 
includes sustained release or timed release formulations), pills, powders, 
granules, elixirs, tinctures, suspensions, syrups, and emulsions, or such 
oral compositions suitably formulated with enteric coatings. Suitable 
intravenous compositions include bolus or extended infusion. Such oral and 
intravenous compositions are well known to those of ordinary skill in the 
pharmaceutical arts. 
The dosage regimen utilizing the active drug is selected in accordance with 
a variety of factors including type, species, age, weight, sex and medical 
condition of the patient; the severity of the condition to be treated; the 
route of administration; the renal and hepatic function of the patient; 
and the particular compound or salt thereof employed. An ordinarily 
skilled physician or veterinarian can readily determine and prescribe the 
effective amount of the drug required to prevent, counter, or arrest the 
progress of the condition. 
Oral dosages of active drug when used for the indicated effects, will range 
between about 0.005 mg per kg of body weight per day (mg/kg/day) to about 
50 mg/kg/day and preferably 0.005-20 mg/kg/day and most preferably 
0.005-10 mg/kg/day. Suitable oral tablets contain between 0.5 mg and 5 g, 
preferably between 0.5 mg and 2 g, most preferably between 0.5 mg and 1 g, 
e.g. 50 mg, 150 mg, 250 mg, or 500 mg. Oral administration may be in one 
or divided doses of two, three, or four times daily. The dosing objective 
is to achieve a level of drug for a period greater than 24 hours that is 
sufficient to provide at least 70% inhibition of fibrinogen binding to GP 
IIb/IIIa. 
Intravenously, the most preferred doses will range from about 0.05 to about 
50 .mu.g/kg/minute during a constant rate infusion, to achieve a plasma 
level concentration during the period of time of administration of between 
0.1 ng/ml and 1 .mu.g/ml. The dosing objective is to achieve a level of 
drug for a period greater than 24 hours that is sufficient to provide at 
least 70% inhibition of fibrinogen binding to GP IIb/IIIa. 
The active drug can be administered in admixture with suitable 
pharmaceutical diluents, excipients or carriers (collectively referred to 
herein as "carrier" materials) suitably selected with respect to the 
intended form of administration, that is, oral tablets, capsules, elixirs, 
syrups and the like, and consistent with convention pharmaceutical 
practices. 
For instance, for oral administration in the form of a tablet or capsule, 
the active drug component can be combined with an oral, nontoxic, 
pharmaceutically acceptable, inert carrier such as lactose, starch, 
sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium 
phosphate, calcium sulfate, manritol, sorbitol and the like; for oral 
administration in liquid form, the oral drug components can be combined 
with any oral, non-toxic, pharmaceutically acceptable inert carrier such 
as ethanol, glycerol, water and the like. Moreover, when desired or 
necessary, suitable binders, lubricants, distintegrating agents and 
coloring agents can also be incorporated into the mixture. Suitable 
binders include starch, gelatin, natural sugars such as glucose or 
beta-lactose, corn-sweeteners, natural and synthetic gums such as acacia, 
tragacanth or sodium alginate, carboxymethylcellulose, polyethylene 
glycol, waxes and the like. Lubricants used in these dosage forms include 
sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, 
sodium acetate, sodium chloride and the like. Disintegrators include, 
without limitation, starch methyl cellulose, agar, bentonite, xanthan gum 
and the like. 
The oral compositions may also be prepared with enteric coatings to prevent 
release of the active drug in the stomach, providing for release of the 
active drug in the intestine. Such compositions are prepared with enteric 
coatings that are insoluble in gastric juices but readily soluble on 
passage into the intestine. They are prepared by mixing the active drug 
with an excipient, and coating the mixture with a thin polymer film. 
The active drug can also be administered in the form of liposome delivery 
systems, such as small unilamellar vesicles, large unilamellar vesicles 
and multilamellar vesicles. Liposomes can be formed from a variety of 
phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. 
Active drug may also be delivered by the use of monoclonal antibodies as 
individual carriers to which the compound molecules are coupled. Active 
drug may also be coupled with soluble polymers as targetable drug 
carriers. Such polymers can include polyvinyl-pyrrolidone, pyran 
copolymer, polyhydroxy-propyl-methacrylamidephenol, 
polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxidepolylysine 
substituted with palmitoyl residues. Furthermore, active drug may be 
coupled to a class of biodegradable polymers useful in achieving 
controlled release of a drug, for example, polylactic acid, polyglycolic 
acid, copolymers of polylactic and polyglycolic acid, polyepsilon 
caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, 
polydihydropyrans, polycyanoacrylates and cross linked or ampehpathic 
block copolymers of hydrogels. 
The methods are useful in percutaneous coronary angioplasty. Because of 
unstable plaque with thrombus, percutaneous revascularization procedures 
in these patients carry with them considerable higher morbidity than 
procedures performed in patients with stable coronary disease. Patients 
receive fibrinogen receptor antagonist during the procedure, and 
optionally, additionally, heparin and aspirin. GP IIb/IIIa receptor 
antagonist is continued for a period of time greater than 24 hours. 
Patients are evaluated at 30 days for acute coronary ischemic syndrome and 
the need for follow-up intervention associated with acute coronary 
ischemic syndrome, including coronary artery bypass grafting, repeat 
percutaneous intervention for acute ischemia, and insertion of a coronary 
endovascular stent. 
Percutaneous transluminal coronary angioplasty is performed on patients 
having coronary blockage, e.g. stenosis. Typically, nasal oxygen and 
intravenous nitroglycerin are administered during the preangioplasty 
period and titrated to minimize the patient's pain and optimize the blood 
pressure. Nonionic dye is initially injected to determine whether blockage 
is present, and to locate blockage. Nonionic contrast dye is thereafter 
administered during the procedure as needed to form images of the 
blockage. A guide wire and catheter are inserted to guide the balloon to 
the blockage location. The balloon is inserted and inflated at the 
blockage site. 
During the procedure, patients receive fibrinogen receptor antagonist and 
optionally aspirin and heparin. For example, patients initially receive a 
bolus injection of fibrinogen receptor antagonist, e.g. at a level of 10 
.mu.g/kg, prior to balloon insertion. Following the initial injection, 
fibrinogen receptor antagonist is administered at a rate of, for example, 
0.15 .mu.g/kg/min.

EXAMPLE 1 
gp IIb/IIIa Antagonist Treatment (i.v.) 
Patients with acute coronary ischernic syndrome received coronary 
revascularization with angioplasty. The fibrinogen receptor antagonist 
tirofiban 
(2-S-(n-Butylsulfonylamino)-3[4-(piperidin-4-yl)butyloxyphenyl]propionic 
acid hydrochloride, described in U.S. Pat. No. 5,292,756) was given in a 
bolus injection at a dose of 10 .mu.g/kg. Following the initial injection, 
tirofiban was administered at a rate of 0.15 .mu.g/kg/min. The goal was to 
keep the activated clotting time between 300 and 350 seconds during the 
operation. Nonionic contrast dye was used to image the blockage requiring 
angioplasty. 
Patients then received intravenous infusion of tirofiban in an amount 
sufficient to achieve a plasma level concentration of between 40-60 
.mu.g/ml, for 24-36 hours following angioplasty. 
Patients were monitored and showed reduced acute coronary ischemic syndrome 
compared to patients receiving ionic contrast media. 
EXAMPLE 2 
gp IIb/IIIa Antagonist Treatment (i.v.) 
Patients with acute coronary ischemic syndromes receive coronary 
revascularization with angioplasty. Aspirin is administered in a dose of 
325 mg at least two hours before angiopolasty, and daily thereafter. 
Heparin is given intravenously in an initial bolus dose of 10,000 to 
12,000 units followed by-incremental bolus doses of up to 3000 units at 
15-minute intervals, but generally no more than 20,000 units is given 
during the procedure. Heparin is continued by constant infusion for at 
least 12 hours to maintain the activated partial-thromboplastin time at 
1.5 to 2.5 times the. control value. The fibrinogen receptor antagonist 
tirofiban 
(2-S-(n-Butylsulfonylamino)-3[4-(piperidin-4-yl)butyloxyphenyl]propionic 
acid hydrochloride, described in U.S. Pat. No. 5,292,756) was given in a 
bolus injection at a dose of 10 .mu.g/kg. Following the initial injection, 
tirofiban was administered at a rate of 0.15 .mu.g/kg/min. Nonionic 
contrast dye was used to image the blockage requiring angioplasty. Aspirin 
is required at discharge in a dose of 325 mg per day. 
Patients then received intravenous infusion of tirofiban in an amount 
sufficient to achieve a plasma level concentration of between 40-60 ng/ml, 
for 24-36 hours following angioplasty. 
Patients were monitored and showed reduced acute coronary ischemic syndrome 
compared to patients receiving ionic contrast media. 
EXAMPLE 3 
gp IIb/IIIa Antagonist Treatment (i.v. and oral) 
Patients with acute coronary ischemic syndrome receive coronary 
revascularization with angioplasty. The fibrinogen receptor antagonist 
tirofiban 
(2-S-(n-Butylsulfonylamino)-3[4-(piperidin-4-yl)butyloxyphenyl]propionic 
acid hydrochloride, described in U.S. Pat. No. 5,292,756) is given in a 
bolus injection at a dose of 10 .mu.g/kg. Following the initial injection, 
tirofiban is administered at a rate of 0.15 .mu.g/kg/min. The goal is to 
keep the activated clotting time between 300 and 350 seconds during the 
operation. Nonionic contrast dye is used to image the blockage requiring 
angioplasty. 
Patients then receive intravenous infusion of tirofiban in an amount 
sufficient to achieve a plasma level concentration of between 40-60 ng/ml, 
for 24 hours following angioplasty. 
Patients then receive an oral tablet containing 15 mg of the fibrinogen 
receptor gp IIb/IIIa antagonist 
2(S)-[(p-Toluenesulfonyl)amino]-3-[[[5,6,7,8-tetrahydro-4-oxo-5-[2-(piperi 
din-4-yl)ethyl]-4H-pyrazolo-[1,5-a][1,4]diazepin-2-yl]carbonyl]amino]propio 
nic acid, described in WO 94/18981. 
EXAMPLE 4 
Tablet Preparation 
Tablets containing 15 mg of the fibrinogen receptor gp IIb/IIIa antagonist 
2(S)-[(p-Toluenesulfonyl)amino]-3-[[[5,6,7,8-tetrahydro-4-oxo-5-[2-(piperi 
din-4-yl)ethyl]-4H-pyrazolo-[1,5-a][1,4]diazepin-2-yl]carbonyl]-amino]propi 
onic acid (compound 4-1) are prepared as illustrated below: 
______________________________________ 
Table for doses containing 15 mg of the 
gp IIb/IIIa receptor antagonist 
Ingredient mg 
______________________________________ 
4-1 15.0 
Microcrystalline cellulose 
200.0 
Modified food corn starch 
8.5 
Magnesium stearate 1.5 
______________________________________ 
Compound 4-1, cellulose, and a portion of the corn starch are mixed and 
granulated to 10% corn starch paste. The resulting granulation is sieved, 
dried and blended with the remainder of the corn starch and the magnesium 
stearate. The resulting granulation is then compressed into tablets. 
EXAMPLE 5 
Intravenous Formulations 
An intravenous dosage form of 
(2-S-(n-Butylsulfonylamino)-3[4-(piperidir-4-yl)butyloxyphenyl]propionic 
acid hydrochloride (compound 5-1) is prepared as follows: 
______________________________________ 
compound 5-1 0.5-10.0 mg 
Sodium Citrate mg 5-50 
Citric Acid mg 1-15 
Sodium Chloride mg 1-8 
Water for Injection (USP) 
L q.s. to 1 
______________________________________ 
Utilizing the above quantities, the active compound is dissolved at room 
temperature in a previously prepared solution of sodium chloride, citric 
acid, and sodium citrate in Water for Injection (USP, see page 1636 of 
United States Pharmacopeia/National Formulary for 1995, published by 
United States Pharmacopeial Convention, Inc., Rockville, Md., copyright 
1994). 
EXAMPLE 6 
Intravenous Formulations 
A pharmaceutical composition was prepared at room temperature using 
compound 5-1, a citrate buffer, and sodium chloride, to obtain a 
concentration of compound 5-1 of 0.25 mg/ml. 
800 grams of water was introduced into a standard pharmaceutical mixing 
vessel. 0.25 grams of compound 5-1 was dissolved in the water. 2.7 grams 
sodium citrate and 0.16 grams citric acid were added to obtain a finished 
citrate concentration of 10 mM. 8 grams of sodium chloride was added. 200 
grams of water was then added to achieve the desired final concentrations 
of ingredients. The resulting aqueous formulation had the following 
concentrations: 
______________________________________ 
Ingredient Amount 
______________________________________ 
compound 5-1 0.25 mg/ml 
citrate buffer mM 10 
sodium chloride 
mg/ml 8 
______________________________________ 
The finished concentrated formulation is stored in a standard USP Type I 
borosilicate glass container at 30-40 degrees C. Prior to compound 
administration, the concentrated formulation is diluted in a 4:1 ratio 
resulting in a finished concentration of 0.05 mg/ml and transferred to an 
infusion bag. 
The following table shows the percentage of ischemic events, including 
death, nonfatal myocardial infarction, revascularization, and insertion of 
a coronary endovascular stent, 2 days following PTCA. 764 patients 
received ionic contrast media during the PTCA prodedure, while 1355 
patients received nonionic contrast media. Patients in each group also 
received either placebo or tirofiban. 
TABLE 1 
______________________________________ 
Incidence of ischemic events 2 days following PTCA 
PTCA Treatment % 
______________________________________ 
Nonionic contrast media/tirofiban 
4.9 
Ionic contrast media/tirofiban 
6.3 
Ionic contrast media/placebo 
7.6 
Nonionic contrast media/placebo 
9.5 
______________________________________ 
Incidence of ischemic events is represented as a percentage of total 
patients studied. Lower percentages are associated with a lower number of 
ischemic events. 
The data clearly show a dramatic benefit to using nonionic contrast media 
for PTCA when glycoprotein IIb/IIIa receptor antagonists are administered. 
Whereas ionic contrast media, when no glycoprotein IIb/IIIa receptor 
antagonist is employed, corresponds with lower incidence of ischemic 
events (as compared with incidence of ischemic events with nonionic 
contrast media and no glycoprotein IIb/IIIa receptor antagonist), nonionic 
contrast media is preferred over ionic contrast media for PTCA procedures 
involving glycoprotein IIb/IIIa receptor antagonist administration.