Some information may come from a completely different direction. Several research groups find that small molecules such as aspirin derivatives and short peptides can prevent aggregation of he moglobin. Aspirin derivatives modify hemoglobin covalently, by acylation. Adding peptides, on the other hand, does not involve covalent modification. In stead, certain peptides apparently mimic the contact sites along which hemoglobin S molecules aggregate. Two research groups, one at the Uni versity of California, San Francisco, and the other at Massachusetts Institute of Technology in Cambridge, have surveyed a variety of peptides. For example, the California scientists, Dr. Shigeo Kubota and Dr. Jen J. Tsi Yang, find that several hexapeptides and two pentapeptides in terfere witfc aggregation of hemoglobin S. The hexapeptides contain either the amino acids that are found in the first part of the hemoglobin S β chain (in cluding the valine that substitutes for the normal glutamic acid) or residues 79 to 84 of that chain (a region in the intact pro tein that is thought to bind to the adjacent hemoglobin molecule in aggregates). The pentapeptides studied bear no resem blance to hemoglobin structure, but sur prisingly are effective in preventing aggregation. Those two pentapeptides are enkephalins, recently described molecules that inhibit morphine binding in nerve cells. The MIT group, under Dr. Alexander Rich's direction, also finds that peptides bearing little or no resemblance to amino acid sequences in hemoglobin can prevent its aggregation. AU these peptides do have features in common, however, including a hydrophobic amino acid at one end. Though such findings are encouraging, they are a long way from offering new therapies. Peptides, for instance, offer potential because their toxicity is low. But other therapies being studied, such as cyanate modification of hemoglobin S, cause problems because of damaging side effects. The peptides, though free of this problem, pose another. They do not enter red blood cells where hemoglobin resides, and thus cannot be viewed as potential
therapeutic agents until a means for de livery is developed. The work with aspirin derivatives, such as acetyl-3,5-dibromosalicylic acid, is more promising from that standpoint. Such derivatives can enter red blood cells to react with the hemoglobin inside, thereby preventing sickling, according to Dr. Irving M. Klotz, leader of a group at Northwestern University. Plain aspirin acetylates hemoglobin, but too slowly to be considered for ther apy. The dibromo derivative, however, "makes a very effective acylating agent." Though the Northwestern group has un dertaken no toxicity studies yet, Klotz says that such derivatives of well-known drugs "stand a better chance of getting approval." The group also is looking at certain aldehydes.
More evidence that aspirin reduces strokes
Aspirin may prove to be an effective weapon against stroke, according to the results of a recently completed three-year study involving 10 medical institutions and 307 high-risk patients. The double-blind clinical trial indi cated that four aspirins a day significantly reduced the incidence of mild strokes— known as transient ischemic attacks (TIA's)—in 178 patients who had a his tory of previous TIA's. In 129 patients who received placebos, results were much less favorable, according to Dr. William S. Fields of the University of Texas Health Science Center in Houston. Of the 178 patients treated with aspirin, 88% either had no additional TIA epi sodes during the test period or reported a "significantly reduced number," Fields told an American Heart Association science writers forum in Newport Beach, Calif. In the placebo group, only 55% of the patients had favorable results. Although the study, coordinated by the University of Texas researchers, did not clearly indicate that a reduction in TIA's lowered the death rate or the onset of full-blown stroke, Fields says that an ongoing Canadian study confirms the U.S. results and also indicates a 50% reduction in death and disability in man. Normally about one third of patients who have had TIA's go on to have a major stroke within five years, and about three fourths of all stroke patients say they have had at least one previous TIA, Fields says. Usually TIA's make themselves known as fleeting episodes of blindness, frequently accompanied by numbness in various parts of the body. Patients in the study had TIA's resulting primarily from the dislodgement of blood clots in the carotid artery. Located on each side of the neck, the arteries are the major suppliers of blood to the brain. The clinical trials were undertaken because of an accumulation of anecdotal studies, not very carefully controlled, in dicating that aspirin might prevent heart attack and stroke. In 1954, for example, a Stacking of slx-membered disks may be physician in Glendale, Calif., reported in how hemoglobin $ aggregates an obscure medical journal that two as22
C&EN Feb. 6, 1978
One other general approach to sickle cell therapy involves removing blood from the body temporarily, treating it, and re turning it with any deleterious agents washed away. For example, covalent modification with cyanate—though damaging when done by injecting or feeding the compound—seems possible when done outside the body. The Na tional Institutes of Health is funding a project to develop a machine for sickle cell patients. It will function much like a he modialysis machine for kidney patients, according to an NIH spokesperson. The difference is that patients could be hooked up so that their blood might be chemically modified. Such treatments probably will be limited to the more seri ous afflicted persons. Jeffrey L. Fox, C&EN Washington
pirins a day seemed to lower the incidence of heart attacks in his elderly patients. Other clinicians have reported that pa tients who took aspirin regularly for headaches or to reduce the pain and in flammation of arthritis had a lower than normal rate of heart attack and stroke. Other laboratory evidence indicates that aspirin may inhibit blood clot for mation and subsequent heart attacks and stroke by inhibiting synthesis of prosta glandins, Fields says. Normally, prosta glandins contribute to the coagulation of specialized blood cells, called platelets, which in turn seem to accelerate clot for mation in ailing arteries. By acetylating the surface membrane of the platelets, aspirin deactivates the enzymes in the platelets, which also con trol the synthesis of prostaglandins. The effect, which seems to be otherwise harmless, lasts throughout the entire seven- to 10-day life span of the platelet. This means that aspirin must be taken continuously to avert the onset of adverse clot formation by the platelets. Currently, the National Heart, Lung & Blood Institute is involved in an ongoing study to clarify if aspirin will reduce heart attacks, in addition to the preliminary evidence suggesting that it may help avert strokes in high-risk individuals. Mean while, Fields warns that because of the intestinal bleeding sometimes associated with excessive use of aspirin, he would not advise taking the old standby drug as a hedge against strokes in the future. D
New clue to hardening of the arteries Isolation of a protein that seems to trigger the proliferation of specialized cells be lieved to underlie the onset of hardening of the arteries has been reported by Dr. Russell Ross and his colleagues at the University of Washington's school of medicine in Seattle. Described as a "low-molecular-weight, heat-stable, basic glycoprotein," the
Ro$$: flbromusculoslastlc lésions
substance is still unpurified, Ross told an American Heart Association science writers forum in Newport Beach, Calif. It is released from blood platelets, cells that are found in whole blood serum and that have long been associated with normal blood clotting processes. In cell culture, the glycoprotein stimulates the growth of arterial smooth muscle cells as well as the endothelial cells that line the inner arterial walls, Ross explains. Recent work shows that the protein is released specifically from blood platelets during the process of serum formation in laboratory animals. Based on test tube work as well as ongoing work with primate models of atherosclerosis, Ross hypothesizes that the glycoprotein acts on endothelial cells that have been exposed to the platelets following some physical or chemical injury. The cells then form increased amounts of structural proteins such as collagen, which then accumulate deposits of cholesterol from the bloodstream. In this way, the arterial walls thicken and become clogged with hardened cholesterol deposits, ultimately resulting in heart attack or stroke, Ross suggests. The theory is built on several converging lines of evidence, Ross says. For example, he and his colleagues find that they can damage the inner arterial walls in the primates with an intra-arterial catheter, which scrapes off the overlying cells. Once exposed, the arteries develop "fibromusculoelastic lesions," believed to be the precursors for atherosclerosis. Other University of Washington experiments show that if baboons with the arterial lesions are placed on a high-cholesterol diet, their arteries take on atherosclerotic characteristics essentially identical to what is found in man. Without high dietary cholesterol, the arterial lesions will regress and disappear, but as long as they are exposed to high cholesterol levels, the lesions become progressively worse, Ross says. Additional support for Ross' theory of atherosclerosis is work also carried out at the University of Washington that shows that baboons with a disease associated with hardening of the arteries, as well as other baboons with abnormally high levels of serum cholesterol, lack up to 10% of the endothelial cells in their arterial walls. "As long as endothelium is missing in
sufficient quantities in the arterial tree, platelet survival may be decreased below normal levels. When the endothelium has regenerated sufficiently, platelet survivals will return to normal," Ross explains. Ross also says that when the laboratory animals were given the drug dipyrimadol, platelets did not adhere to the exposed cells in the damaged arteries and release the glycoprotein. In addition, the atherosclerotic lesions did not occur. If the platelet-produced glycoprotein ultimately is proved to be the cause of atherosclerosis in human beings, platelet-blocking drugs such as dipyrimadol may help avert or control the disease in high-risk individuals, Ross proposes. D
Hypertension-causing gene identified The portion of the gene that is at least partially responsible for high blood pressure that develops in rats fed on high salt diets has been identified by Dr. John Rapp and his colleagues at the Medical College of Ohio in Toledo. The gene locus—designated Hyp-1, for hypertension—codes specifically for an enzyme that guides the synthesis of 18hydroxy-deoxycorticosteroid, a hormone similar to steroids known to induce hypertension in human beings, Rapp told an American Heart Association forum for science writers in Newport Beach, Calif. The gene locus was identified in rats, known as the S-strain, which the late Dr. Lewis K. Dahl of Brookhaven National Laboratory found developed abnormally high blood pressures (200 to 240 mm Hg) when fed a high-salt diet for eight weeks. In another strain of rats (R-strain), blood pressures remained low (120 to 140 mm Hg) on the same high-salt diet. It is now known from classical genetic techniques that S and R rats have identifiable differences at approximately two to four genetic loci which influence blood pressure, Rapp explains. When the two strains were bred together, the Ohio group determined that about 16% of the blood pressure differences between the S and R rats could be ascribed to the Hyp-1 locus. Current work under way at the Medical College of Ohio is aimed at identifying the genetic loci responsible for the other 84%. Preliminary evidence suggests that some of the other gene loci may code for four proteins produced by the pituitary gland and which also may play a role in hypertension. Knowing which genes are responsible for high blood pressure could lead to better methods of diagnosis and control for that disease, Rapp suggests. Evidence that there is a strong genetic component in hypertension comes from studies with identical and nonidentical twins which indicate that the blood pressures of the identical twins remain closely related in the same environment, whereas the blood pressures of nonidentical twins may differ widely under the same conditions. D
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Feb. β, 1978 CAEN 23
