Institutes of Health. Similar units eventually are expected to be made available commercially. The original device, meanwhile, will soon be moved to Carnegie-Mellon, where it will become part of NIH's National NMR Facility for Biomedical Studies and will be available to all qualified researchers. D
sprains, osteoarthritis, and the like. Dolobid received approval from the | U.K. Committee on the Safety of Medicines last year and from com Profit margin, % parable regulatory bodies in Belgium 8 and Denmark. Registration is immi nent in France, Sweden, and else Martin Marietta ^ ^ ^ where. It still awaits clearance by the U.S. Food & Drug Administration. 6 Dolobid's active ingredient is 2,4X difluorophenyl salicylic acid, in which / ^ / ' the difluorophenyl moiety is para to / Airco φ * ' BOC Airco takeover A salicylic acid's carboxyl group. Elim ination of aspirin's acetyl radical and becomes more clouded the presence of 2,4-difluorophenyl combine to give Dolobid its superior Events last week put Airco's fight to pharmacological activity. Simple as avoid being taken over by BOC In 2 this substitution may seem, the new ternational into even more confusion. chemical is the result of about 20 Martin Marietta officially entered the years of research effort that Merck game with a bid of $50 per share for I I I executives conservatively estimate the outstanding stock of Airco. The o 1973 74 75 76 77 cost their company some $15 million. offer was quickly accepted by Airco's Nor will commercial production be a 13-member board of directors by a Note: Profit margin is net income as a percentage of net sales. I simple procedure. In all, 12 discrete 10-to-3 vote. The three votes against chemical steps are involved in the the proposal were cast by BOC's manufacturing process. representatives on the board. 2,4-Difluorophenyl salicylic acid, or Before the vote, BOC notified sition of Airco. Other conditions in Airco that, as majority shareholder clude that no other company make a diflunisal as it is commonly referred with a 54% holding in Airco, it had bid higher than $50 per share and to, is rapidly and completely absorbed changed the bylaws so that a unani that the business not change sub in the body reaching peak plasma mous vote of the board was needed to stantially by the time the deal is levels within two hours after ingestion approve a merger proposal. BOC then closed. One other condition puts the of a single dose. In studies involving deal seriously in doubt. That is the long-term treatment of chronic pain called the merger vote invalid. Also last week, James M. Smith, resolution of the pending lawsuit over associated with osteoarthritis, be chief of the New Jersey Bureau of the legality of BOC's tender offer and tween 250 and 375 mg of diflunisal, Securities, issued a cease and desist the resolution of the ownership of the administered twice daily, have the order that prohibited BOC from ac disputed 1.8 million Airco shares. D equivalent pain-relief effect of up to 900 mg of aspirin taken four times quiring any more Airco stock as well daily. Like aspirin, diflunisal is be as preventing BOC from voting any lieved to work by inhibiting produc stock acquired after Jan. 4. This tion of prostaglandins. would include more than 2.6 million Merck develops potent shares. However, the order was au aspirin substitute An important aspect of diflunisal tomatically stayed, Smith tells is that, unlike aspirin, it has no ap C&EN, when BOC appealed the There are few households today that parent effect on blood platelet order. The stay will remain in effect don't keep a bottle of aspirin handy. aggregation or other hematological until after hearings on the matter by Since it was first synthesized by Dr. parameters. Equally important, it the Bureau of Securities. In effect, Felix Hofmann in 1889, acetylsali- does not bring about gastric or intes this means that, as far as New Jersey cylic acid has ranked among the most tinal bleeding. Moreover, Dolobid is concerned, things are back to the common medications. Last week, does not produce tinnitus, the sen way they were before the order was Merck Sharp & Dohme Ltd., the U.K. sation of noise that continued use of issued. BOC can acquire more subsidiary of Merck & Co., head aspirin frequently induces. D stock—although it has said that it will quartered in Rahway, N.J., launched not—and BOC can vote the shares an aspirin substitute that, the com that it already owns. pany claims, is more potent and has DOE panel asks solar However, according to a federal a longer-lasting analgesic effect. At court in Wilmington, Del., BOC can the same time, it does not cause the energy R&D changes not vote the 1.8 million shares that it degree of adverse side effects associ picked up in its January tender offer ated with aspirin's use. Some significant changes in emphasis (C&EN, Jan. 30, page 6). The court is Tradenamed Dolobid, the active and in allocation of resources for se expected to rule later this month on ingredient will be made in a $30 mil lected technologies should be made in whether BOC can keep these 1.8 lion plant that Thomas Morson Co., the Department of Energy's solar million shares or whether they will a Merck associate company, is energy R&D program, according to a have to be returned to their former building at Ponders End near Lon study of the program by the depart owners. don. When it starts up early next ment's Solar Working Group. As long as these shares remain in year, the plant will be capable of The group notes that the public has doubt, or if they are awarded to BOC, producing sufficient material to make high expectations for successful it will be impossible for Airco to more than 400 million tablets annu commercialization of solar technolo muster a majority vote of its stock ally. In addition to supplying the gies. But at the same time the public holders to approve a merger with British market, Merck will export underestimates costs for solar energy Martin Marietta. Majority approval Dolobid to countries where it has development and the time needed to is one of the conditions that Martin been cleared for use for the relief of achieve desired and expected results. Marietta set for its proposed acqui- pain caused by dental surgery, These pressures, it says, lead to dis-
Profitability has risen for Airco, suitors since 1973
April 10, 1978 C&EN
7
tortions and imbalances in the program, sometimes legislated. It finds in particular a strong, often irresistible push toward pilot and demonstration projects even when the technology isn't ready. The Solar Working Group, chaired by Resources for the Future president Charles J. Hitch, is the successor of the General Advisory Committee of the Energy Research & Development Administration following that agency's absorption into DOE last October. The committee had been asked à year earlier by ERDA to examine whether the agency's solar energy program was justified by the promise of the various technologies. To carry out the study, the working group contracted with SRI International to assemble data and make a thorough, impartial analysis. The group reviewed SRI's approach, commented on findings as they emerged, and generally guided the analysis. Its evaluative judgments then were based on that analysis and other related information, with the just-released study the result. Specifically, the working group thinks that increased emphasis is warranted for some biomass technologies, thin-film photovoltaics, and basic research. Decreased emphasis, it says, should be given ocean thermal energy conversion, single-crystal silicon and concentrator photovoltaics, and solar thermal electric demonstrations (other than one currently under way). Heating/cooling of buildings and the wind programs are balanced and justified, the group finds, except that demonstrations of cooling should be deferred. The study, "Solar Energy Research & Development: Program Balance," DOE/IR-0004, February 1978, will be available soon from the National Technical Information Service, Springfield, Va. 22161. D
Computer study yields new anticancer agents Physical organic chemistry, a computer, and pharmacology all have come together to produce several new anticancer drugs that can cure welladvanced tumors in mice more effectively than can drugs now used to treat human cancers. Using computer modeling to predict the chemical and biological properties of hypothetical drugs before they are synthesized, a team of pharmacologists and biochemists at the University of California, San Francisco, has been able to design several molecules that bind more tightly to DNA than do existing anticancer drugs. The effect, at least 8
C&EN April 10, 1978
in mice, is to kill many more cancer cells with one dose. The drugs have not been tested in humans yet. So far they have been synthesized in only milligram amounts; and studies, even in animals, of their toxicology and side effects still need to be done. Dr. Martin A. Apple described his work with Dr. Hiroaki Yanagisawa and Dr. J. V. Formica at an American Cancer Society science writers' seminar in Houston last week. The team set out to construct a molecule that would bind to the DNA of a cancer cell more tightly than existing anticancer drugs do. Such drugs, some of which bind to the DNA for about one second, block cell replication and cause the cell to die. The scientists studied the binding sites of three naturally occurring antibiotics that bind to DNA: echionmycin, adriamycin, and actinomycin. Next step was to make computer simulations of molecules with similar binding sites and predict how active they would be. This was done with the aid of the National Institutes of Health's national computer network of data on chemical-biological interactions called PROPHET. Based on the PROPHET studies, they focused on two classes of compounds, anthracyclines and phenoxazinones, and synthesized likely candidates from each class. The most active of the new compounds in animal tests is a compound of the phenoxazinone class which Apple calls azetomicin. This compound binds to DNA for 1500 to 1700 seconds. Tests of this compound on mice with ROS osteogenic sarcomas as large as 10 to 15% of the animal's body weight routinely cured the cancer with a single dose, Apple says. To do this several million cancer cells must be killed without killing the mouse in the process. No drug that is known to be active in human cancer is that effective in this animal model. In another animal system, mice with P388 leukemia, cures can be made routinely with as few as three doses of azetomicin. This test is particularly encouraging, Apple points out, since this leukemia's responsiveness to drugs correlates well with human tumor responsiveness. Although the animal tests are very promising, Apple and others caution that applicability to human cancer treatment depends both on killing cancer cells and on not harming the rest of the patient. Many other anticancer compounds that work by binding to DNA also attack other rapidly dividing cell systems, such as the bone marrow. This can limit or even prohibit the compound's use as a human drug. D
EPA/FDA to audit pesticide safety data About 70 commercial laboratories that have performed animal safety tests on farm, home, and industrial pesticides over the years will be getting surprise visits from Food & Drug Administration test auditors this year. The visits are part of a joint program announced by the Environmental Protection Agency and FDA last week. Previous investigations by the two agencies, they say, have raised serious questions about the accuracy of animal tests used to support government approval for pesticides and other regulated chemicals. For example, EPA for some time has been concerned about animal test studies performed by Industrial Bio-Test (IBT), one of the biggest independent toxicology labs. EPA has in its files 620 different studies, some of which have proved faulty, conducted by IBT in support of 123 pesticide registrations and 160 applications for pesticide tolerances, the amount of a chemical that is legally permitted to remain in food crops (C&EN, Aug. 22, 1977, page 15). Under the agreement, EPA will provide FDA with a list of the toxicological test reports it wants audited. The agency says selection criteria will include the volume of work done for pesticide manufacturing companies—with labs that have done a lot of animal and safety health tests more likely to be audited than those that have done only a few—and the importance of the study. Thus, the first round of auditing will focus on studies involving long-term hazards such as cancer and reproductive effects. With the list in hand, FDA, which has been conducting animal test audits for some time, will make on-site visits to the labs. FDA audit reports are to contain complete descriptions of errors, deficiencies or questionable practices noted during the audits, documented with copies of the original lab records pertinent to each case. To ensure that raw data are available to FDA for auditing purposes, EPA says it will notify the sponsor of the audited study by telephone on the working day preceding the scheduled visit. For its part, FDA says it will maintain the confidentiality of all the data it receives. At this point, EPA says it has no clear idea of how many pesticide test reports will be audited. It points out that if problems are uncovered with tests of one pesticide during a visit to a lab, other test results will have to be audited at the same laboratory. D
