Editor's Note: Science Scan is a roundup of recently published biotechnology-relevant research
Rheumatoid arthritis (RA) is among the most crippling forms of joint disease. It afflicts upward of 2 million Americans with joint pain and inflammation. It's a chronic condition linked to malfunction of the body's immune defenses. RA savages the proteins in the synovial fluid of joints in the skeleton, which is much like the oil or grease that lubricates moving parts in machinery. The disease can lead to severe disability and, in extreme cases, death.
One drug, Aprava, was FDA approved in 1998 as a therapeutic for RA patients. The drug is manufactured by Aventis SA, of Lyon, France. The chemical name for Arava is leflunomide, and it is in large-scale clinical trials conducted by researchers at the Veterans Affairs medical center jointly with the Washington School of Medicine in St. Louis. They have mobilized a nationwide database of RA patients on which to test the drug's effect.
Their findings to date appear in Arthritis Care & Research, dated Dec. 15, 2003. The article's title: "Leflunomide use during the first 33 months after Food & Drug Administration approval: Experience with a national cohort of 3,325 patients."
The FDA approved the use of leflunomide for RA therapy in October 1998, with high doses to rapidly trigger the drug's benefit. But the study showed that such high doses might cause adverse side effects that induce some patients to stop taking the Arava tablets. That effect risked prompting physicians to consider modifying the standard leflunomide regimen.
One of the article's first authors, a rheumatology fellow, commented: "Our data suggest that by starting on a lower dose initially, patients tolerate the drug better. The disadvantage is that it may take a bit longer for them to improve clinically. The advantage is that they may be more likely to continue the treatment."
In addition to suggesting the alternative approach, the new findings also help put to rest lingering concerns about whether leflunomide's toxicity was adequately assessed in the Phase III trials. "As far as we could tell, " the co-author went on, "there were no surprises in terms of toxicity. Sometimes it takes a lot more patients than the 3,500 we studied to pick up rare, unwanted outcomes. But I think our findings are reassuring to the larger community of patients and clinicians."
Although aware of the disadvantages of that type of study, there also were a number of potential pluses. Only a relatively small investment of money and time was required, and the VA patient population offered a chance to study portions of the general populations that typically do not enroll in clinical trials. The co-authors explained that such trials often enroll more women and younger patients from higher socioeconomic groups. That sex bias is particularly prevalent in clinical trials testing treatments for rheumatological diseases such as RA.
Enzyme Endonuclease G Confers Life & Death On Mice Denied Gene For Mitochondrial DNA
The same enzyme that ensures cells will undergo normal, programmed death also is necessary for proper formation of the embryo. Without apoptosis, cells would continue to proliferate indefinitely, leading to cancerous tumors. During cell death, a series of events leads to the eventual consumption of the cell by roving sentinels. One important step is the production and release of endonuclease G (an enzyme that cleaves the internal phosphodiesterase bonds in a DNA molecule). From the mitochondria, it's transported to the nucleus, at which point it cleaves DNA.
Cell biologists at the University of Cincinnati, and their colleagues, reported findings in the Proceedings of the National Academy of Scientists (PNAS), released online Dec. 8, 2003. The paper is titled "Endonuclease G is required for early embryogenesis and normal apoptosis in mice."
The co-authors investigated the role of that enzyme by developing strains of mice unable to produce endonuclease G. Animals missing one copy of the gene that synthesized the enzyme had cells that resisted apoptosis. Although endonuclease G has been implicated in the replication of mitochondrial DNA, mitochondrial numbers were the same in rodent and wild-type mice. Interestingly, the co-authors were unable to produce animals missing both copies of the gene; the embryos died early during development.
Iowans Put Mice To Work Digging Up New Calcium Channels Mitigating Against High Blood Pressure
At the University of Iowa in Iowa City, scientists have identified a new blood pressure-regulating switch in the cells lining coronary arteries and other tissues. Like their better-known counterparts the L-type calcium channels, these T-type channels might be useful targets for drugs that lower blood pressure. The flow of calcium ions through molecular channels on the cell surface helps control the relaxation and contraction of the smooth muscle cells lining coronary arteries. When the ions enter through L-type calcium channels, they cause contraction. A study in mice now indicates that calcium ions entering through T-type channels have the opposite effect.
A paper in Science dated Nov. 21, 2003, bears the title "Abnormal coronary function in mice deficient in a 1H T-type Ca2+ channels."
The co-authors generated a line of mice lacking the T-type channels. Further experiments suggested that the T-type channels are essential for carrying out the vessel-relaxing effects of nitric oxide. Their results suggest, the Science article concludes, "a potential target for therapeutic intervention in cardiovascular diseases."