This news item was created by students Kimberly Williams, Jennifer Elliott, Bonnie Taylor, Megan German, CJ Roebke and Nathan Means as part of their Chemistry 210 Semester Project in WS99 under the guidance of Prof. Rainer Glaser.

Glaser's "Chemistry is in the News"
To Accompany Wade Organic Chemistry 4/e.
Chapter 24. Amino Acids, Peptides and Proteins.



NEW TECHNIQUE COULD INCREASE TREATMENT TIME FOR VICTIMS OF STROKES SQUIRTING DRUG DIRECTLY INTO BRAIN CAN REVERSE EFFECTS, DOCTORS SAY
St. Louis Post Dispatch, Febuary 5, 1999.


Editorial Comments

In 1996, strokes killed 159,942 people, becoming the third leading cause of death behind heart disease and all cancers. These startling statistics are the driving forces behind research into improved therapies for stroke victims. One specific product of this research is the development of a new clot-dissolving enzyme called prourokinase, also known as Abbokinase, prourokinase, or r-ProUK. Naturally occurring clot-dissolving enzymes are always present in the body, but enzymes that target specific types of clots are used therapeutically.

There are two types of strokes, ischemic and hemorrhagic. Prourokinase is being used to treat ischemic attacks, which are the result of a blood clot that decreases oxygen flow to the brain. Neurological damage caused by this type of stroke can be slowed or reversed by breaking up the clot and allowing blood to flow freely.

Clots are formed in blood vessels by the binding of plasminogen to fibrin and fibrinogen, a clotting protein, thereby incorporating plasminogen into the clot. Prourokinase, a type of protein kinase, transforms plasminogen into plasmin by cleaving the arginine-valine bond in plasminogen. Plasmin then digests the fibrin, and the result is a soluble product to which neither plasmin or plasminogen can bind. To read more about the activity of prourokinase, visit Abbott Labs, where initial development and research of prourokinase occurred.

Though prourokinase has distinct advantages over currently used drug therapies, such as heparin and tissue plasminogen activator (TPA) [structure], there are also side effects associated with its use. These possible effects include bleeding, allergic reactions, fever, nausea, chills, cyanosis, and others. Also, the long-term effects on the health of the stroke victim are not known, as there have been no long-term clinical studies on prourokinase.

Pertinent Text References:
Chapter 24. Amino Acids, Peptides, and Proteins

Questions

Question 1: What is the advantage of prourokinase over currently used drugs such as heparin and tissue plasminogen activator (TPA)?


A. Prourokinase can be useful up to six hours following the stroke because it is injected directly into the brain. Previously used drugs were only successful up to three hours after the stroke because they require intravenous injection. If administered after three hours, they could also be detrimental to the patient's health.


Question 2: Why is prourokinase only effective for ischemic attacks and not hemorrhagic strokes?


A. Ischemic attacks are caused by blood clots blocking blood flow to the brain. However, hemorrhagic strokes result in uncontrolled bleeding, and therefore, clot-dissolving drugs, such as prourokinase, are not effective.


Question 3: Prourokinase is a globular protein because it folds into a roughly spherical structure. Some globular proteins act as enzymes to catalyze reactions. How does the blood's aqueous environment affect the folding of the enzyme?


A. The hydrophobic side chains fold toward the inside and the hydrophilic side chains remain exposed to water on the outside of the enzyme.


Question 4: How does prourokinase actually dissolve the clot?


A. Prourokinase cleaves the asparagine-valine bond in plasminogen to plasmin. The plasmin then digests the fibrin. Plasmin and plasminogen can no longer bond to the fibrous proteins, so the clot cannot reform.


Question 5: Does this research into new stroke treatments appear credible?


A. The study, ProAct II, was conducted by Abbott Labs and backed by the American Heart Association. It was a phase III, randomized, controlled study, and therefore, we believe it appears credible.


Question 6: Read the "Important Drug Warning". If you are a stroke patient, would you want this drug used although the long-term effects are unknown?


A. Answers may vary.