- Email: [email protected]
Death of LD50
62
News & Comment
double-blind, randomized, placebocontrolled parallel group study in three European centres, intravenous infusion of a single dose of SB240563 (10 mg kg−1) to male patients with mild asthma significantly reduced (>75%) the number of eosinophils in venous blood and sputum, which was maintained throughout the study period (16 weeks and 30 days, respectively). Contrary to expectation, SB240563 had no effect on the maximum late-phase response following allergen or airways responsiveness to histamine. The latter finding is particularly worrying because pulmonary eosinophilia and airways responsiveness are believed, by some investigators, to be causally related phenomena. So, how can these data be explained? The heretical interpretation is that eosinophils are not implicated in the pathogenesis of asthma. However, credence in this controversial proposal requires the elimination of all other possibilities and independent verification. For example, tissue eosinophil number was
TRENDS in Pharmacological Sciences Vol.22 No.2 February 2001
not enumerated by Leckie et al.1 Moreover, even if there is a dearth of tissue eosinophils in anti-IL-5-treated patients this does not imply the absence of degranulation products, such as major basic protein – although it is difficult to envisage how cytotoxic proteins could remain in tissue after a prolonged period of eosinopaenia unless another cytokine, such as granulocyte–macrophage colonystimulating factor, enhances the longevity of tissue eosinophils. It is possible that The heretical interpretation is that eosinophils are not implicated in the pathogenesis of asthma. resolution of airways inflammation is a protracted process in patients treated with an anti-IL-5 blocking antibody. Equally, the severity or phenotype of the disease might determine the efficacy of this treatment. There might also be redundancy or marked cooperativity in the processes that effect asthmatic inflammation such that
elimination of a single pro-inflammatory cell might have little impact on the disease. These possibilities notwithstanding, the future does not seem bright for the eosinophil. Indeed, intravenous administration of a different IL-5 blocking monoclonal antibody SCH55700 to patients with severe persistent asthma, provided negligible improvement in lung function despite the production of a very long-lasting (180 days) eosinopaenia2. If these data are confirmed through more extensive and thorough investigations, the inflammatory basis of asthma will require fundamental re-evaluation. 1 Leckie, M.J. et al. (2000) Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356, 2144–2148 2 Kips, J. et al. (2000) Results of a Phase I trial with SCH55700, a humanized anti-IL-5 antibody, in severe persistent asthma. Am. J. Respir. Crit. Care Med. 161, A505
Mark Giembycz [email protected]
In Brief
Death of LD50 The controversial LD50 Draize test, which determines the dose of a drug required to kill 50% of animals tested and is an indicator of acute oral toxicity, has recently been abolished by The Organisation for Economic Co-operation and Development (OECD). Known as OECD Test Guideline 401 and criticized for being unnecessary, inhumane and lacking in scientific merit, the LD50 test is to be phased out over the next 12 months. Laboratories and regulatory authorities are expected to adopt one of a number of alternative tests, as recommended by the OECD (http://www.oecd.org). DC
Despite the streamlining of lead compound discovery over recent years, average development times for new drugs remain unaltered. Worried about this ‘development bottleneck’, the European Federation for Pharmaceutical Sciences (EUFEPS) is lobbying for funds from the Sixth Framework Programme of the European Community, which is due to run from 2003 to 2007. EUFEPS is requesting that 300 M Euros ($280M) be set aside for an initiative
called ‘New Safe Medicines Faster’. If accepted, the funding would be used to increase coordination between academia, the pharmaceutical industry and the health and regulatory authorities, with the aim of speeding up the drug development process. Last year, 120 scientists gathered in Brussels to develop proposals for research topics, methodologies, techniques and other means of promoting the drug development process. These are described in a report, which can be downloaded from www.eufeps.org. The European Commission is currently working with the material and EUFEPS has made a major effort to encourage all European pharmacology departments, as well as every other related organization, to campaign on behalf of the initiative. AS
Crosstalk
priorities. Further details of the programme will be available later in the year. RC
Kappa opioid receptor patented The sequence of the cloned mammalian kappa opioid receptor, a receptor that might play a key role in the development of non-addictive analgesic agents, has been patented by the US-based Adolor Corporation. The exclusive worldwide licence gives Adolor sole access to develop further pharmaceuticals tools aimed at this receptor, as well as related opioid receptor technologies. Adolor’s lead compounds, currently in Phase II/III clinical trials for the alleviation of visceral pain in pancreatitis or postoperative ileus, target peripheral opioid receptors without causing the addictive side-effects of classical opioid narcotics. DC
The Royal Society plans to spend £1 million on a new initiative to promote a dialogue between science and society. The programme, headed by Sir Paul Nurse, Director General of the Imperial Cancer Research Fund, will aim to develop channels of communication between scientists and the rest of society, allowing a greater degree of public involvement in setting research
http://tips.trends.com 0165-6147/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.
This month’s In Brief articles were written by David Cutler ([email protected]), Rebecca Craven (rebecca.craven@ clinical-neurology.oxford.ac.uk) and Adam Smith ([email protected])
News & Comment
double-blind, randomized, placebocontrolled parallel group study in three European centres, intravenous infusion of a single dose of SB240563 (10 mg kg−1) to male patients with mild asthma significantly reduced (>75%) the number of eosinophils in venous blood and sputum, which was maintained throughout the study period (16 weeks and 30 days, respectively). Contrary to expectation, SB240563 had no effect on the maximum late-phase response following allergen or airways responsiveness to histamine. The latter finding is particularly worrying because pulmonary eosinophilia and airways responsiveness are believed, by some investigators, to be causally related phenomena. So, how can these data be explained? The heretical interpretation is that eosinophils are not implicated in the pathogenesis of asthma. However, credence in this controversial proposal requires the elimination of all other possibilities and independent verification. For example, tissue eosinophil number was
TRENDS in Pharmacological Sciences Vol.22 No.2 February 2001
not enumerated by Leckie et al.1 Moreover, even if there is a dearth of tissue eosinophils in anti-IL-5-treated patients this does not imply the absence of degranulation products, such as major basic protein – although it is difficult to envisage how cytotoxic proteins could remain in tissue after a prolonged period of eosinopaenia unless another cytokine, such as granulocyte–macrophage colonystimulating factor, enhances the longevity of tissue eosinophils. It is possible that The heretical interpretation is that eosinophils are not implicated in the pathogenesis of asthma. resolution of airways inflammation is a protracted process in patients treated with an anti-IL-5 blocking antibody. Equally, the severity or phenotype of the disease might determine the efficacy of this treatment. There might also be redundancy or marked cooperativity in the processes that effect asthmatic inflammation such that
elimination of a single pro-inflammatory cell might have little impact on the disease. These possibilities notwithstanding, the future does not seem bright for the eosinophil. Indeed, intravenous administration of a different IL-5 blocking monoclonal antibody SCH55700 to patients with severe persistent asthma, provided negligible improvement in lung function despite the production of a very long-lasting (180 days) eosinopaenia2. If these data are confirmed through more extensive and thorough investigations, the inflammatory basis of asthma will require fundamental re-evaluation. 1 Leckie, M.J. et al. (2000) Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356, 2144–2148 2 Kips, J. et al. (2000) Results of a Phase I trial with SCH55700, a humanized anti-IL-5 antibody, in severe persistent asthma. Am. J. Respir. Crit. Care Med. 161, A505
Mark Giembycz [email protected]
In Brief
Death of LD50 The controversial LD50 Draize test, which determines the dose of a drug required to kill 50% of animals tested and is an indicator of acute oral toxicity, has recently been abolished by The Organisation for Economic Co-operation and Development (OECD). Known as OECD Test Guideline 401 and criticized for being unnecessary, inhumane and lacking in scientific merit, the LD50 test is to be phased out over the next 12 months. Laboratories and regulatory authorities are expected to adopt one of a number of alternative tests, as recommended by the OECD (http://www.oecd.org). DC
Despite the streamlining of lead compound discovery over recent years, average development times for new drugs remain unaltered. Worried about this ‘development bottleneck’, the European Federation for Pharmaceutical Sciences (EUFEPS) is lobbying for funds from the Sixth Framework Programme of the European Community, which is due to run from 2003 to 2007. EUFEPS is requesting that 300 M Euros ($280M) be set aside for an initiative
called ‘New Safe Medicines Faster’. If accepted, the funding would be used to increase coordination between academia, the pharmaceutical industry and the health and regulatory authorities, with the aim of speeding up the drug development process. Last year, 120 scientists gathered in Brussels to develop proposals for research topics, methodologies, techniques and other means of promoting the drug development process. These are described in a report, which can be downloaded from www.eufeps.org. The European Commission is currently working with the material and EUFEPS has made a major effort to encourage all European pharmacology departments, as well as every other related organization, to campaign on behalf of the initiative. AS
Crosstalk
priorities. Further details of the programme will be available later in the year. RC
Kappa opioid receptor patented The sequence of the cloned mammalian kappa opioid receptor, a receptor that might play a key role in the development of non-addictive analgesic agents, has been patented by the US-based Adolor Corporation. The exclusive worldwide licence gives Adolor sole access to develop further pharmaceuticals tools aimed at this receptor, as well as related opioid receptor technologies. Adolor’s lead compounds, currently in Phase II/III clinical trials for the alleviation of visceral pain in pancreatitis or postoperative ileus, target peripheral opioid receptors without causing the addictive side-effects of classical opioid narcotics. DC
The Royal Society plans to spend £1 million on a new initiative to promote a dialogue between science and society. The programme, headed by Sir Paul Nurse, Director General of the Imperial Cancer Research Fund, will aim to develop channels of communication between scientists and the rest of society, allowing a greater degree of public involvement in setting research
http://tips.trends.com 0165-6147/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.
This month’s In Brief articles were written by David Cutler ([email protected]), Rebecca Craven (rebecca.craven@ clinical-neurology.oxford.ac.uk) and Adam Smith ([email protected])