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Inhaled antibiotics effective for cystic fibrosis
SCIENCE AND MEDICINE
Should familial hypercholesterolaemia be treated with statins?
O
ne year’s treatment with lovastatin reduces LDL-cholesterol values in adolescent boys with heterozygous familial hypercholesterolaemia, with no apparent side-effects, report researchers from the USA and Finland. In boys with severe disease, they say, the potential benefits of lowering LDLcholesterol with statins seem to outweigh the theoretical risks. However, other experts disagree. Evan Stein of the Metabolic and Atherosclerosis Research Center (Cincinnati, OH, USA) and coworkers gave 110 boys with familial hypercholesterolaemia placebo or daily lovastatin starting at 10 mg, with forced titration to 20 mg at 8 weeks and 40 mg at 16 weeks. Lovastatin treatment at these doses reduced LDL-cholesterol values by 17%, 24%, and 27%, respectively; at 48 weeks, LDL-cholesterol concentrations remained 25% lower in the treated boys compared with boys given placebo. No differences in growth, hormonal, or nutritional status were seen between the groups but the authors warn that the study was underpowered for detection of significant differences in safety parameters (JAMA 1999; 281: 137–44). Patients with familial hypercholesterolaemia face life-long treatment, notes Basil Rifkind of the US National Heart, Lung, and Blood Institute (Bethesda, MD, USA). That the drug seems safe in a 1-year study is reassuring, he says, but “it’s not long enough to give you the degree of security that you would prefer”. Kilmer McCully (Providence Veteran’s Administration Hospital, RI, USA) adds that a dietary approach—increased consumption of vegetables, fruits, whole grains, fish, and meat, and “drastic” reduction of refined carbohydrates, processed foods, and added fat—“is more sensible for adolescents than treatment with lovastatin, which inhibits the cholesterol synthesis needed for growth of cells and tissues”. Long-term use of statin drugs in adolescents carries “the spectre of possible carcinogenesis, muscle and liver damage, and heart failure”, he warns.
Marilynn Larkin
THE LANCET • Vol 353 • January 16, 1998
b-carotene supplements linked to cancer he results of a new study may explain why high-dose bcarotene supplements unexpectedly increased lung-cancer rates in two cancer prevention trials. When ferrets were given b-carotene doses equivalent to those used in the clinical trials, changes in b-carotene metabolism were induced that may promote rather than inhibit tumorigenesis.
T
Epidemiological data indicate that people with diets rich in b-carotene have lower cancer rates, particularly lung-cancer rates, than people with b-carotene-poor diets. But in the a-tocopherol, b-carotene cancer prevention trial (ATBC) and the b-carotene and retinol efficacy trial (CARET), both of which included smokers, there were more new cancers and deaths in the treatment arms than in the placebo arms. To explain these findings, Xiang-
Dong Wang of Tufts University School of Medicine (Boston, MA, USA) and co-workers looked at the effect of b-carotene supplementation and smoke on the lungs of ferrets— animals that metabolise b-carotene in much the same way as people. After 6 months of supplementation, all the animals given b-carotene had squamous metaplasia in their lungs, a precancerous change. The changes were more pronounced in animals given b-carotene and exposed to cigarette smoke, but were also present in those given b-carotene alone (J Natl Cancer Inst 1999; 91: 60–66). In addition, whereas b-carotene is normally converted to retinoic acid, an inhibitor of cell division, in ferrets given high-dose b-carotene, the nutrient’s metabolism was altered so that b-carotene and retinoic acid concentrations were lower than normal. These changes down-regulated expression of the tumour suppressor retinoic-acid-receptor-b, loss of expression of which has been linked to non-small-cell lung cancers. Expression of the tumour promoters c-jun and c-fos was also increased. The amount of b-carotene obtained from the diet would not cause such changes, Wang hastens to add. “bcarotene from the diet is 100% safe.” Michael McCarthy
Inhaled antibiotics effective for cystic fibrosis n two randomised trials, patients with cystic fibrosis who took three 4-week courses of inhaled tobramycin at 4-week intervals had significantly improved lung function and a reduced risk of admission to hospital compared with those given placebo. Lead author Bonnie Ramsey (University of Washington, Seattle, WA, USA) explains that the results are “an important proof of concept” and predicts that inhaled antibiotics will soon be used for cystic fibrosis and other respiratory diseases. Pseudomonas aeruginosa often colonises the airways of patients with cystic fibrosis and contributes to the relentless decline of lung function in these patients, 90% of whom die from lung disease. Exacerbations of P aeruginosa infection are usually treated with a 7–21 day course of intravenous antipseudomonal antibiotics but this does not halt lungfunction decline. Long-term therapy might help preserve lung function,
I
but intravenous antipseudomonals are costly, have serious side-effects, and may select for resistant bacteria. 520 patients with cystic fibrosis received three cycles of 300 mg inhaled tobramycin or a “tastematched” placebo for 4 weeks followed by no drug for 4 weeks. Intermittent dosing was used in the hope that it would reduce costs, reduce the likelihood of creating bacterial resistance, and increase compliance. The forced expiratory volume at 1 second (FEV1) of patients given tobramycin was increased by 10% at week 20 compared with week 0. In control patients, FEV1 declined by 2%. Patients given tobramycin were 26% less likely to be admitted to hospital than those given placebo, and there were no detectable ototoxic or nephrotoxic effects, or accumulation of the drug in serum in the study (N Engl J Med 1999; 340: 23–30). Michael McCarthy
215
Should familial hypercholesterolaemia be treated with statins?
O
ne year’s treatment with lovastatin reduces LDL-cholesterol values in adolescent boys with heterozygous familial hypercholesterolaemia, with no apparent side-effects, report researchers from the USA and Finland. In boys with severe disease, they say, the potential benefits of lowering LDLcholesterol with statins seem to outweigh the theoretical risks. However, other experts disagree. Evan Stein of the Metabolic and Atherosclerosis Research Center (Cincinnati, OH, USA) and coworkers gave 110 boys with familial hypercholesterolaemia placebo or daily lovastatin starting at 10 mg, with forced titration to 20 mg at 8 weeks and 40 mg at 16 weeks. Lovastatin treatment at these doses reduced LDL-cholesterol values by 17%, 24%, and 27%, respectively; at 48 weeks, LDL-cholesterol concentrations remained 25% lower in the treated boys compared with boys given placebo. No differences in growth, hormonal, or nutritional status were seen between the groups but the authors warn that the study was underpowered for detection of significant differences in safety parameters (JAMA 1999; 281: 137–44). Patients with familial hypercholesterolaemia face life-long treatment, notes Basil Rifkind of the US National Heart, Lung, and Blood Institute (Bethesda, MD, USA). That the drug seems safe in a 1-year study is reassuring, he says, but “it’s not long enough to give you the degree of security that you would prefer”. Kilmer McCully (Providence Veteran’s Administration Hospital, RI, USA) adds that a dietary approach—increased consumption of vegetables, fruits, whole grains, fish, and meat, and “drastic” reduction of refined carbohydrates, processed foods, and added fat—“is more sensible for adolescents than treatment with lovastatin, which inhibits the cholesterol synthesis needed for growth of cells and tissues”. Long-term use of statin drugs in adolescents carries “the spectre of possible carcinogenesis, muscle and liver damage, and heart failure”, he warns.
Marilynn Larkin
THE LANCET • Vol 353 • January 16, 1998
b-carotene supplements linked to cancer he results of a new study may explain why high-dose bcarotene supplements unexpectedly increased lung-cancer rates in two cancer prevention trials. When ferrets were given b-carotene doses equivalent to those used in the clinical trials, changes in b-carotene metabolism were induced that may promote rather than inhibit tumorigenesis.
T
Epidemiological data indicate that people with diets rich in b-carotene have lower cancer rates, particularly lung-cancer rates, than people with b-carotene-poor diets. But in the a-tocopherol, b-carotene cancer prevention trial (ATBC) and the b-carotene and retinol efficacy trial (CARET), both of which included smokers, there were more new cancers and deaths in the treatment arms than in the placebo arms. To explain these findings, Xiang-
Dong Wang of Tufts University School of Medicine (Boston, MA, USA) and co-workers looked at the effect of b-carotene supplementation and smoke on the lungs of ferrets— animals that metabolise b-carotene in much the same way as people. After 6 months of supplementation, all the animals given b-carotene had squamous metaplasia in their lungs, a precancerous change. The changes were more pronounced in animals given b-carotene and exposed to cigarette smoke, but were also present in those given b-carotene alone (J Natl Cancer Inst 1999; 91: 60–66). In addition, whereas b-carotene is normally converted to retinoic acid, an inhibitor of cell division, in ferrets given high-dose b-carotene, the nutrient’s metabolism was altered so that b-carotene and retinoic acid concentrations were lower than normal. These changes down-regulated expression of the tumour suppressor retinoic-acid-receptor-b, loss of expression of which has been linked to non-small-cell lung cancers. Expression of the tumour promoters c-jun and c-fos was also increased. The amount of b-carotene obtained from the diet would not cause such changes, Wang hastens to add. “bcarotene from the diet is 100% safe.” Michael McCarthy
Inhaled antibiotics effective for cystic fibrosis n two randomised trials, patients with cystic fibrosis who took three 4-week courses of inhaled tobramycin at 4-week intervals had significantly improved lung function and a reduced risk of admission to hospital compared with those given placebo. Lead author Bonnie Ramsey (University of Washington, Seattle, WA, USA) explains that the results are “an important proof of concept” and predicts that inhaled antibiotics will soon be used for cystic fibrosis and other respiratory diseases. Pseudomonas aeruginosa often colonises the airways of patients with cystic fibrosis and contributes to the relentless decline of lung function in these patients, 90% of whom die from lung disease. Exacerbations of P aeruginosa infection are usually treated with a 7–21 day course of intravenous antipseudomonal antibiotics but this does not halt lungfunction decline. Long-term therapy might help preserve lung function,
I
but intravenous antipseudomonals are costly, have serious side-effects, and may select for resistant bacteria. 520 patients with cystic fibrosis received three cycles of 300 mg inhaled tobramycin or a “tastematched” placebo for 4 weeks followed by no drug for 4 weeks. Intermittent dosing was used in the hope that it would reduce costs, reduce the likelihood of creating bacterial resistance, and increase compliance. The forced expiratory volume at 1 second (FEV1) of patients given tobramycin was increased by 10% at week 20 compared with week 0. In control patients, FEV1 declined by 2%. Patients given tobramycin were 26% less likely to be admitted to hospital than those given placebo, and there were no detectable ototoxic or nephrotoxic effects, or accumulation of the drug in serum in the study (N Engl J Med 1999; 340: 23–30). Michael McCarthy
215