Surviving Ebola infection depends on response

Troglitazone ban loses suppor t

A

fter a long , contentious hearing on March 26, a panel of advis er s to the US Food and Dr ug Administration (FDA) decided tha t in most instances, the benefits still outweighed the risks of the diabetes therapy troglitazone (Rezulin, Warner-Lambert). The panel did recommend that troglitazone should not be used as a first-line treatment, and said patients should be better informed of the risk of acute liver f ailure. “If I were a patient,I’d like to know if I’m being given something that might kill me”, said panelist Leonard Seeff of the National Institute for Diabetes, Digestive, and Kidney Disease (Bethesda, MD, USA). The panel’s continued endorse ment was sur prising , given what appeared to be a rising death and transplant toll. Also , the Pub lic Citizen’ s Health Research Group had petitioned last July to ha ve the drug remo ved from the US market. David Graham, FDA epidemiolo gist,said the risk of acute liver fail ure for those on troglitazone is about one in 1800 during the first 6 months of use. Since troglitazone’ s appro val in January 1997, the FDA has tallied 43 cases of acute liver failure and 28 deaths in 1·5 million patients who ha ve taken the drug. Of great concern,said Graham,is that in at least nine patients, the transition from normal to ir re versib le liver damage occur red within 4–34 days . He claimed tha t most patients ha ve only used trogli tazone for a short time, and he esti mated that failure-risk would rise with longer use. He estimated only 10 % of liver failures had been reported. “What we see isn’t reas suring”, Graham said. But W arner-Lamber t counterattacked, saying Graham’s estima tes were based on incomplete data. The company said the risk of failure had dropped from one in 36 000 in 1997 to one in 57 000 for 1998–99, and that increasing patient and physician a wareness had helped reduce injuries . The panelists struggled to recon cile the FD A’s and W arnerLambert’s opinions . In the end, they voted that the labelling should not be cahnged drastically , and to allo w combination use with insulin and sulphonylureas . Alicia Ault

THELANCET • Vol 353 • April 3,1999

Surviving Ebola infection depends on response ifferences in immune responses to Ebola virus infection may determine whether infection leads to death or recovery, say French researchers. Infection with the virus causes acute haemorrhagic fever, and about 70% of patients die. Sylvain Baize (Institut Pasteur, Lille, France) and colleagues, who analysed serial plasma samples from patients during two outbreaks of Ebola virus infection in Gabon in 1996,found that recovery was related to “orderly and well-regulated humoral and cellular responses”. By contrast, impaired humoral responses,with absent specific IgG and barely detectable IgM,predicted failure to control virus replication and a fatal outcome (Nat Med 1999; 5: 423–26). Because the circulating antigen load and clinical signs early in the disease were similar, regardless of outcome of the disease, the authors conclude that resolution of infection in survivors was “probably not related to initial viral anitgen load or, by

D

inference, infectious dose”. S u rv i vo rs developed increasing concentrations of IgG, directed mainly against the viral nucleoprotein, followed by clearance of circulating viral antigen and sustained activation of cytotoxic T cells. Patients who died generated higher concentrations of interferon-gamma (IFN-␥) in the early stages of infecton than survivors. And they showed extensive apoptosis of peripheral blood cells. In an editorial, Gary Nabel (University of Michigan, Ann Arbor, MI, USA) suggests that serum IFN-␥ concentrations could be a useful marker for predicting the outcome of Ebola virus infection. But “in the absence of effective therapy, the utility of this information is limited”. He adds, however, that “such information will help to unravel the pathophysiology of this aggressive infection and will contribute to strategies for vaccine development and treatment”. Dorothy Bonn

Retinoic acid gives new clue to skin cancer ew research shows that ultra-violet (UV) light causes a striking and prolonged reduction of vitamin-A sensitive cancer-reducing receptors, but that topical pre-treatment with retinoic acid increases the rate of recovery. In a series of trials, 70 fair skinned white people, mean age 33·9 (SD 1·3) years, with no history of skin disease were exposed to controlled periods of UV light with or without retinoic acid pre-treatment (0·1% alltrans retinoic acid). 8 h after UV irradiation, retinoicacid receptor mRNA and protein were reduced to about 35% of their respective control values and recovery took more than 48 h. After topical treatment with retinoic acid similar initial reductions in retinoic-acid receptors were seen, but there was complete recovery within 16 h. No receptor recovery was seen during a trial in which exposure was repeated every 24 h for 3 consecutive days (Nat Med 1995, 5: 418–22). Co-author John Voorhees (Uni-

N

versity of Michigan, Ann Arbor, Michigan, USA) explains that retinoid receptors loaded with retinoic acid oppose the tumour promoting and skin-ageing properties of the transcription-factor activator-protein 1, which is itself elevated by UV light. “We presume that repeatedly knocking out retinoid receptors will be a significant signal for a person to develop skin cancer”. In the accompanying News and Views, Barbara Gilcrest (Boston University School of Medicine,Boston, USA) says that with an incidence of more than a million new cases of skin cancer per year in the USA, exposure to sun should be viewed with caution. Although topical retinoic acid may prove to be a valuable antidote, and Voorhees says that he uses it on himself, he adds that “in the absence of a substantial clinical trial I think that it would be premature to recommend that people put retinoid on their skin prophylactically”. Pete Moore

1161