Research Advances

Lengthening the Life Span -Reports on Aging The process of aging underwent detailed scrutiny in October when scientists from around the world met in Colorado Springs, CO, for the famed Beckman Conference on the Clinical Chemistry of Aging. Researcher after researcher analyzed the process, the contributing factors, and the possible "cures" to life's terminal disease. Perhaps one of the most interesting presentations was that of Dr. Paola S. Timiras of the University of California, Berkeley. Aging, Timiras said, may be one of the programmed events in a "biological master plan" governing the life cycle. If it is part of a pattern of lifetime events genetically coded in the brain, it may be possible to postpone certain events and extend the life span by manipulating the nervous and chemical signals that control growth, development, and aging. It is a fact that all living creatures, no matter how lowly or exalted, grow old and die. Modern investigators often view aging as a disease, a breakdown of the body's normal repair mechanisms. Timiras argues, however, that aging may be a normal part of some "biological master plan," locked into the organism in its genetic code. I~ the notion is correct, then aging must be viewed as just one more stage in the life cycle such as growth, reproductive maturation, and sexual cycles. Timiras feels that it should be possible to delay aging and extend the life span by delaying an earlier stage in the cycle of events. In experiments with rats, dietary manipulation and drug administration were used to reduce brain neurotransmitter serotonin. The result was an arrest of whole-body growth and a prevention of sexual maturation. Timiras speculated that the effect may have been mediated by a change in pituitary function. Later in the experiments, when the rats returned to normal diet or drugs

were withdrawn, catch-up growth occurred. But there was retardation in the senescence (aging) of reproductive activity, a delay in the onset of some aspects of age-related pathology, and in some animals a lengthening of the life span. Dr. Rachmiel Levine of the City of Hope Medical Center in Duarte, CA, said that the "normal" changes in glucose tolerance, insulin secretion, and fat metabolism so common in the elderly may be linked to the morbid states often associated with old age. As animals, including humans,

age, the circulating levels of glucose, cholesterol, and fats in the blood rise steadily. The secretion of insulin in response to a meal or the administration of the sugar glucose is delayed in older people. The tissues also appear somewhat more resistant to the action of insulation . In a younger person this situation would be deemed diabetic. Levine said that these "normal" changes of old age would be considered abnormal if they occurred in younger people. Levine questioned the rationale of designating a condition as "normal" simply because it is fairly common. Studies with rats have shown that diets that promote an extension of the life span also delay the metabolic aging changes. A common mental disorder called "presenile dementia," otherwise known as Alzheimer's disease, so often associated with older people, may actually be caused by aluminum, according to Dr. Leopold Liss of Ohio State University . According to Liss, high concentrations of aluminum have

been detected in the nuclei of brain cells located in areas of nerve fiber tangles and degeneration, a hallmark of Alzheimer's disease. Studies are now under way at Ohio's neuropathology unit to determine whether the body's pool of aluminum can be lowered. If so, Liss said, it may be possible to arrest the progression of the disease and even improve the mental function of Alzheimer patients. The condition affects mainly older people, striking those in their forties and fifties only infrequently. As a result the disease has been categorized as one of the "unavoidable consequences of aging." Far too often, Liss said, it is viewed with all the fears, guilt, and shame associated with mental disease. The fact is that Alzheimer's disease is not rare. The National Institute of Neurological and Communicative Disorders and Stroke lists Alzheimer's as the fourth most common cause of death . Studies have demonstrated that aluminum levels are elevated in those parts of the brain having the most nerve fiber degeneration. The metal appears to accumulate predominantly in the nerve cell nuclei. Patients with Alzheimer's disease have four to ten times as much aluminum in their brains as normal individuals. Aluminum also has been suggested as a possible agent in the acute onset of dementia seen in dialysis patients who are exposed to the metal in their dialysis fluid and medications. In a test regimen, tetracycline is being used to reduce the aluminum in patients. Tetracycline is known to combine with aluminum and facilitate its removal from the body. The researchers also are ruling out foods known to contain high aluminum levels. Liss warns that it is important to note that a causal relationship between aluminum and Alzheimer's disease has not yet been positively established. -WES

American Pharmacy Vol. NS19 No. 13. December 19791712

Growth RetaJrlation by Stimulants Doubted Warnings that the long-term administration of stimulants to children may slow physical development were discounted by two separate reports presented to the American Academy of Pediatrics at its recent meeting in Toronto. Researchers from Illinois and California studied the effects of amphetamine and methylphenidate (Ritalin, CIBA) in the treatment of minimal brain dysfunction (MBD) or hyperactivity in children. Neither group found significant decreases in physiological maturation or growth patterns. However, higher doses of methylphenidate (over 0.55 mg/kg/day) can significantly raise blood pressure, said Dr. Robert L. Sprague, director of the University of Illinois Institute for Child Behavior and Development, Champaign-Urbana. Therefore children on such a drug regimen should be monitored closely. Dr. Leon Oettinger Jr., a U ni versity of California at Los Angeles pediatrician, said that his group may have found out at least why the earlier warnings on slowed growth

surfaced. MBD children given methylphenidate may indeed be shorter than their peers-but they were shorter (as a group) when therapy began. Sprague and Dr. Esther Sleator compared 13 hyperactive children receiving methylphenidate with 10 nonmedicated hyperactives and with 14 normal children matched for age, weight, and height. Standing height and body weight were measured semiannually during this twoyear study. Growth rate (height and weight) was not altered in children receiving a mean dose of 0.59 mg/kg/day. In the UCLA study of physiological maturation, 26 boys received 0.31.1 mg/kg/day of methylphenidate. Bone age X rays were repeated after 10 months and after up to 49 months of treatment. A maturation index was then computed from chronological age/bone age ratios, comparing pretreatment and posttreatment rates. Oettinger found little difference between bone age and chronological age after t~o years of treatment. His team also studied growth pat-

terns in 23 boys receIvIng 0.20 mg/kg/day of amphetamine and two boys given 0.38 J?g/kg/day of methylphenidate. The drugs were given from 4 to 16 years, except for periodic withdrawals to determine the need for further treatment. UWe found no statistically significant differences between achieved heights and predicted heights," Oettinger reported. The cardiovascular effects noted by the Illinois researchers followed a double-blind crossover study of 27 hyperactive children receiving methylphenidate, a placebo, or no treatment. Heart rates and blood pressures went up, without any change in oxygen consumption, Sprague said. These responses varied among individuals but were generally dose related. When children were given less than 0.5 mg/kg/day, the mean increase in heart rate was 3.9; in systolic pressure it was 3.3 mm Hg; and in diastolic pressure it was 1.7 mm Hg. However, at higher doses the increases were 14.3, 10.7, and 7.7, respectively, suggesting the need for regular monitoring of such patients.

-Fraser Kent American Pharmacy correspondent

Alcoholism Inherited as Sex-Linked Recessive Evidence that familial alcoholism has a genetic basis has come out of a study by researchers at Washington University School of Medicine, St. Louis. Investigation of family histories of alcoholics in a psychiatric outpatient clinic revealed that the sex distribution of alcoholism in patients and their families fits the expected distribution for an Xlinked recessive genetic characteristic. Dr. Lee Spalt, Southern Illinois University, reported in the Journal of

the American Medical Association, "The family histories obtained from patient interviews demonstrated statistically significant differences for alcoholism in relatives of male and female alcoholics. Alcoholism

for mothers, paternal grandfathers, sisters, and brothers did not differ for male and female alcoholics. Significantly more maternal grandfathers of male alcoholics were suspected of having had alcoholism than were maternal grandfathers of female alcoholics." In addition, more fathers of female alcoholics than of male alcoholics were suspected of having been alcoholics. Both findings support the theory that alcoholism can be transmitted as an X-linked recessive genetic disorder. According to the theory of Xlinked recessive transmission, more fathers of affected females would have the disease than would fathers of the general female population,

American Pharmacy Vol. NS19, No. 13, December 19791713

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but there would be no difference in the incidence of alcoholism in the fathers of affected males compa~ed to the fathers of the general male population. Similarly, more mothers of both male and female alcoholics would be alcoholics than would be expected from the incidence of alcoholism among women in general. The results of Spalt's study confirm suggestions from investigators working in Chile, Iceland, and Sweden whose findings indicated a genetic distribution for alcoholism. If this work is further substantiated, alcoholism will join the list of diseases for which genetic- counseling is beneficial. 0

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Hwnan Growth Hormones Extracted By Recotnbinant DNA Technique Using the most sophisticated techniques involving recombinant DNA yet developed, two groups of scientists have succeeded independently in producing human growth hormone. One group is at the University of California at San Francisco, the other at Genentech, in south San Francisco, a commercial concern developing recombinant DNA procedures to make molecules of potential therapeutic value. Human growth hormone (HGH), used for the treatment of hypopituitary dwarfism and a number of other growth disorders, can be obtained only by extracting it from human pituitary glands obtained from cadavers. Although it has been in short supply relative to past demand, there seems to be enough for current needs, at least in the United States. About 60,000 human pituitaries are collected annually, and some 650,000 international units are produced from them in this country. Since 1963 the distribution of the ag nt has b en coordinated by the National Pituitary Agency, supported by th National Institute of Arthriti , Metabolism, and Digestive Disease . If more human growth hormone w r availabl, ucce ful therapy f r a numb r of ther di orders c uld be inve tigated, including tr ulcer , abnormal thinning of th b n in ld rly w men, failure f b n fractur thai, the manag m nt f acut liv r failure, and th timulati n f liver c II r gen m inv tigat r al feel pr fitabl to tudy f H H n nutrition and w 11

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the two research groups. The University of California scientists, Drs. John Baxter, Howard Goodman, Joseph Martial, and Robert Hallowell, have obtained only a pro-HGH molecule. This still has some non-HGH peptides attached to it, which will have to be removed before the molecule can be expected to be biologically active. By contrast, the Genentech group, including Drs. David Goeddel and Peter Seeburg, states that it has produced the HGH molecule only. "It's not attached to any other peptide," Goeddel said. Thus, say the Genentech scientists, their molecule is more potentially useful than the University of California's product. From the account of their work given at the twelfth Miles Symposium on polypeptide hormones, held in Baltimore in July, the Genentech scientists have taken significant new steps in the synthesis of biological molecules. For one thing, by obtaining the HGH molecule directly, and not as part of a large protein that must later be cleaved off to release the active molecule, they have managed to sidestep the maneuver they used in the production of insulin and somatostatin-two molecules they syn the sized by recombinant DNA procedures in the last two years. Second, the gene used by Genentech to get the HGH molecule was in part synthesized in the laboratory and in part derived from natural sources. Again, this technique is in contrast to the production of somato tatin and insulin, where the g .nes were made entirely sytheticalIy. Hence the more complex polypeptide, t 0 large to be easily ynthesized, can be efficiently produc d by thi means. The bacterium used to ynthe ize HGH i the molecular bi logist' rkhorse, E cherichia coli. Goeddel that it i po sible t make ,0 0-200,000 copies of the mole-

cule per cell. "It depends on the concentration of the bacteria," he said. "We haven't yet grown the bacteria at high concentrations." The next step is to test the synthesized HGH for biological activity. Genentech intends to have the tests done in collaboration with the Swedish pharmaceutical firm, A.B. Kabi. Kabi, one of the world's major extractors of the hormone, fund ed Genentech's program and has considerable experience with HGH . The university group also intends to test its molecule for biological activity, but concedes that its agent first must be purified and the unwanted amino acid residues removed . Goodman does not believe that these will be major obstacles. For his part, Genentech's Goeddel predicted that it would take up to three years for the synthetic agent to become available for clinical use. -Charles Marwick American Pharmacy correspo11dcllt

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