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Warning issued about switching from mibefradil to other antihypertensives
SCIENCE AND MEDICINE
“Personalised” drug therapy could be near smaller and smaller pieces”, resulting in an “orphan drug syndrome”. Also, “the diagnostic tests may not be accurate. What if you treat someone based on a faulty test?” Physicians do not test for variants now because of liability concerns, he noted. And,
Science Photo Library
more than US$100 billion yearly in increased hospital admissions, lost productivity, and premature deaths. Pharmacogenomics may change all this by exploiting normal genetic polymorphisms that influence how individuals absorb and metabolise drugs. Theoretically, testing for these variants should allow physicians to write prescriptions based on a patient’s genetic predisposition to tolerate specific medicines, thus avoiding drugs that are likely to be ineffective or harmful. For example, Judes Poirier (McGill Centre for Studies in Aging, Montreal, Canada) has discovered that patients with Alzheimer’s disease who have certain APOE-⑀4 variants do not respond to tacrine therapy. And Richard Weinshilboum (Mayo Foundation, Rochester, MN, USA) has shown that patients US Genome Institute targets SNPs with cancer who have variants A US federal initiative to identify single of the thiopurine methylnucleotide polymorphisms (SNPs or “snips”) transferase gene experience and place them in the public domain for use “profound myelosuppression” by medical researchers is being if treated with standard doses spearheaded by the US National Human of thiopurine drugs. Genome Research Institute (NHGRI). But William Haseltine According to NHGRI chief Francis Collins, (Human Genomic Sciences, the 3-year, US$30-million project aims to Rockville, MD, USA) identify 100 000 SNPs and place them in a warned that testing based central database starting in October, 1998 on pharmacogenomics could (see http://www.nhgri.nih.gov/). “segregate the population into
f pharmacogenomics enthusiasts have their way, physicians will soon be doing genetic tests before prescribing drugs, said experts at Bio ’98 International (New York City, NY, USA; June 14–18). Such tests would enable safer and more effective treatment of disease, they said, by finding out in advance how patients will respond to particular drugs. Today’s drugs are designed to work “as an average dose that will make the average person less sick on average”, explained Andrew Marshall, senior editor of Nature Biotechnology. “But the average person doesn’t exist”, and so many drugs “not only make [some] patients better, but also [others] significantly worse. Underdosing, overdosing, and missed dosing, he said, account for
I
Genetically test before you try?
variations in drug response are not just related to genetic background. “Age, health, diet, other drugs—lots of different factors that have nothing to do with genes come into play.” But the strategy could be valuable in pivotal clinical trials, said Fred Ledley (Variagenics, Cambridge, MA, USA). Assessing the potential genetic influences on dosing, efficacy, or safety could speed clinical development and identify subpopulations for whom new drugs may not be appropriate. Marilynn Larkin
Warning issued about switching from mibefradil to other antihypertensives
F
our cases where patients went into cardiogenic shock within a few hours of being switched from mibefradil to other calciumchannel blockers (CCBs) will be reported in the July 8 issue of the Journal of the American Medical Association. Mibefradil’s market withdrawal on June 8 (see Lancet June 13, p 1791) prompted the early release of the article because of its public-health importance— thousands of people worldwide will be changing from mibefradil to other drugs in the next few weeks. The article reports four cases of patients who were switched from mibefradil to other CCBs because their blood pressure was not being adequately controlled by mibefradil. The patients began taking their new drug within a day of stopping mibefradil. One patient died. The other three survived after treatment in intensive care (JAMA 1998; 280: 157–58). About 200 000 people in the USA
THE LANCET • Vol 351 • June 27, 1998
alone will need to change from mibefradil to another CCB, so many more of these newly reported life-threatening drug–drug interactions could occur. Michael Mullins (Oregon Poison Center, Portland, OR, USA), an author on the new report, notes that the possibility of interactions between mibefradil and other CCBs was not included in the June 8 warning, which focused
on mibefradil’s effect on the activity of liver detoxifying enzymes. In a supplementary letter issued on June 12, Roche advises a delay of 7 days between discontinuing mibefradil and taking most other CCBs and -blockers. A 14-day delay is recommended before switching to felopidine or timolol. Hannah Wunsch
And another drug is withdrawn from the market On June 22, Wyeth-Ayerst announced the withdrawal of its analgesic Duract (bromfenac) from the market. The action was taken in response to postmarketing reports of severe hepatic failure resulting in four deaths and eight liver transplantations. Bromfenac, a non-steroidal anti-inflammatory drug, received US FDA approval in July, 1997, for short-term management of acute pain. The original labelling said that bromfenac should be used for 10 days or less. However, a few patients have taken bromfenac for longer periods of time and it is among these patients that all but one case of severe hepatic complications have occurred. In February this year, the FDA and Wyeth-Ayerst strengthened the warnings on bromfenac’s labelling, but have now concluded that, given the availability of other therapies, “it would be prudent to withdraw the drug [bromfenac] from the market” (http://www.fda.gov/cder/news/duract/qa.htm). Jane Bradbury
1937
“Personalised” drug therapy could be near smaller and smaller pieces”, resulting in an “orphan drug syndrome”. Also, “the diagnostic tests may not be accurate. What if you treat someone based on a faulty test?” Physicians do not test for variants now because of liability concerns, he noted. And,
Science Photo Library
more than US$100 billion yearly in increased hospital admissions, lost productivity, and premature deaths. Pharmacogenomics may change all this by exploiting normal genetic polymorphisms that influence how individuals absorb and metabolise drugs. Theoretically, testing for these variants should allow physicians to write prescriptions based on a patient’s genetic predisposition to tolerate specific medicines, thus avoiding drugs that are likely to be ineffective or harmful. For example, Judes Poirier (McGill Centre for Studies in Aging, Montreal, Canada) has discovered that patients with Alzheimer’s disease who have certain APOE-⑀4 variants do not respond to tacrine therapy. And Richard Weinshilboum (Mayo Foundation, Rochester, MN, USA) has shown that patients US Genome Institute targets SNPs with cancer who have variants A US federal initiative to identify single of the thiopurine methylnucleotide polymorphisms (SNPs or “snips”) transferase gene experience and place them in the public domain for use “profound myelosuppression” by medical researchers is being if treated with standard doses spearheaded by the US National Human of thiopurine drugs. Genome Research Institute (NHGRI). But William Haseltine According to NHGRI chief Francis Collins, (Human Genomic Sciences, the 3-year, US$30-million project aims to Rockville, MD, USA) identify 100 000 SNPs and place them in a warned that testing based central database starting in October, 1998 on pharmacogenomics could (see http://www.nhgri.nih.gov/). “segregate the population into
f pharmacogenomics enthusiasts have their way, physicians will soon be doing genetic tests before prescribing drugs, said experts at Bio ’98 International (New York City, NY, USA; June 14–18). Such tests would enable safer and more effective treatment of disease, they said, by finding out in advance how patients will respond to particular drugs. Today’s drugs are designed to work “as an average dose that will make the average person less sick on average”, explained Andrew Marshall, senior editor of Nature Biotechnology. “But the average person doesn’t exist”, and so many drugs “not only make [some] patients better, but also [others] significantly worse. Underdosing, overdosing, and missed dosing, he said, account for
I
Genetically test before you try?
variations in drug response are not just related to genetic background. “Age, health, diet, other drugs—lots of different factors that have nothing to do with genes come into play.” But the strategy could be valuable in pivotal clinical trials, said Fred Ledley (Variagenics, Cambridge, MA, USA). Assessing the potential genetic influences on dosing, efficacy, or safety could speed clinical development and identify subpopulations for whom new drugs may not be appropriate. Marilynn Larkin
Warning issued about switching from mibefradil to other antihypertensives
F
our cases where patients went into cardiogenic shock within a few hours of being switched from mibefradil to other calciumchannel blockers (CCBs) will be reported in the July 8 issue of the Journal of the American Medical Association. Mibefradil’s market withdrawal on June 8 (see Lancet June 13, p 1791) prompted the early release of the article because of its public-health importance— thousands of people worldwide will be changing from mibefradil to other drugs in the next few weeks. The article reports four cases of patients who were switched from mibefradil to other CCBs because their blood pressure was not being adequately controlled by mibefradil. The patients began taking their new drug within a day of stopping mibefradil. One patient died. The other three survived after treatment in intensive care (JAMA 1998; 280: 157–58). About 200 000 people in the USA
THE LANCET • Vol 351 • June 27, 1998
alone will need to change from mibefradil to another CCB, so many more of these newly reported life-threatening drug–drug interactions could occur. Michael Mullins (Oregon Poison Center, Portland, OR, USA), an author on the new report, notes that the possibility of interactions between mibefradil and other CCBs was not included in the June 8 warning, which focused
on mibefradil’s effect on the activity of liver detoxifying enzymes. In a supplementary letter issued on June 12, Roche advises a delay of 7 days between discontinuing mibefradil and taking most other CCBs and -blockers. A 14-day delay is recommended before switching to felopidine or timolol. Hannah Wunsch
And another drug is withdrawn from the market On June 22, Wyeth-Ayerst announced the withdrawal of its analgesic Duract (bromfenac) from the market. The action was taken in response to postmarketing reports of severe hepatic failure resulting in four deaths and eight liver transplantations. Bromfenac, a non-steroidal anti-inflammatory drug, received US FDA approval in July, 1997, for short-term management of acute pain. The original labelling said that bromfenac should be used for 10 days or less. However, a few patients have taken bromfenac for longer periods of time and it is among these patients that all but one case of severe hepatic complications have occurred. In February this year, the FDA and Wyeth-Ayerst strengthened the warnings on bromfenac’s labelling, but have now concluded that, given the availability of other therapies, “it would be prudent to withdraw the drug [bromfenac] from the market” (http://www.fda.gov/cder/news/duract/qa.htm). Jane Bradbury
1937