495
Capture-mark-recapture method.
surprising that the capture-mark-recapture methods have made greater inroads in medicine for many doctors have made use of it in other settings-for example, counting red blood cells by extraction, labelling, injection, and re-extraction is an accepted procedure. To count every red cell would be too costly and is not needed for accurate estimates.6 We describe elsewhere the value of this approach in heart disease’ and connective tissue disorders.8 It is
not
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15621, USA
RONALD E. LAPORTE DANIEL J. MCCARTY EUGENE S. TULL
Jikei
University, Tokyo, Japan
NAOKO TAJIMA
1 Last JM. A dictionary of epidemiology Oxford Oxford University Press, 1988 2 Eberhard LL. Appraising variability in population studies. J Wildl Manage 1978; 42: 207-38. 3. Seber GAF. The estimation of animal abundance and related parameters, 2nd ed. New York: MacMillan. 4. Sekar CC, Deming WE. On a method of estimating birth and death rates and the extent of registration. Am Stat Assoc J 1949; 44: 101-15. 5 Wolter KM. Accounting for America’s uncounted and miscounted. Science 1991; 253: 12-15 6. International Committee for Standardization in Haematology Recommended method for radioisotope red-cell survival studies Br J Haematol 1980, 45: 659-66 7. LaPorte RE, Tull ES, McCarty D. Monitoring the incidence of myocardial infarctions. applications of the capture-mark-recapture technology. Int J Epidermiol 8
(m press). McCarty DJ, Kwoh HW, LaPorte RE. The importance of incidence registries for connective tissue diseases. J Rheumatol (in press).
Chirality and drug development SIR,-Dr Kean and colleagues (Dec 21/28, p 1565) conclude that
single enantiomers should be used in all biological and clinical testing of potential new medicines. Although this may be justifiable from an academic perspective, I believe that it ignores certain realities of technological practicality and economics that are part of the drug development process. It takes 12 years and an investment of US$231 million before the average new molecular entity is available to physicians.’ If purification of enantiomers were required before all early screening tests, many fewer candidate compounds could be evaluated, and fewer innovative new medicines would reach the market. Because a compound with n chiral centres has 2n possible enantiomers, the number of tests would increase geometrically. Moreover, much of this additional effort would be wasted. Of every 4000 compounds tested in the laboratory, only 1 will satisfy rigorous safety and efficacy screening requirements and eventually reach the pharmacy shelf. Company scientists are keenly aware of the part chirality can play in the pharmacological activity of a molecule. The decision to develop either a pure enantiomer or a racemate as a drug substance is a key milestone in a lengthy, complex process. For the reasons Kean et al cite, to purify and profile each enantiomer may be desirable at some point during drug development. In many cases,2 however, it may be scientifically justifiable to pursue development of a racemate without compromising either safety or efficacy. Also,
early clinical and non-clinical testing could be done on a racemate, with profiling of pure enantiomers. Once a desired enantiomer is identified, the final stages of clinical testing can be undertaken with the drug substance intended for the marketplace. Although the technology to purify enantiomers has made tremendous strides in the past decade, it is not trivial. Furthermore, separations that can be done on drug quantities sufficient for laboratory studies cannot always survive the scale-up process to production volumes. Good science must be at the root of drug development, but inordinate delay for marginal benefits puts patients who need new medicines at a disadvantage. Rather than arguing that all testing should be done on all enantiomers, perhaps Kean et al would agree that "progression of a racemate into clinical studies concurrent with continued development activities with the individual enantiomers may be the most effective approach".2 concurrent
Pharmaceutical Manufacturers Association, DC 20005, USA
Washington
1. Di Masi JA, et al. 2. PMA Committee
development
JOHN F. BEARY III
J Health Economics 1991;
10: 107-42. Racemic Mixtures. Comments on enantiomerism process Pharmac Technol 1990; 14: 46-52. on
in
the
drug
Continuous non-invasive assessment of
pulsus paradoxus SIR,-Pulsus paradoxus is a well recognised clinical sign that is useful in assessing the severity of many cardiorespiratory diseases. It is defmed as a greater than normal (> 10 mm Hg) inspiratory decrease in systolic arterial pressure, and may indicate upper
airways obstruction, moderately severe asthma, pericardial disease, congestive heart failure, and, in some cases, hypovolaemic shock.l The degree of pulsus paradoxus reflects the severity of the underlying disorder and thus is regarded by most clinicians as an important diagnostic aid. There is increasing use of pulse oximetry to access oxygenation continuously. The presence of obvious respiratory variation in the pulse volume output of a pulse oximeter is specific for the presence of clinically significant inspiratory loading, and by extrapolation will reflect the presence of pulsus paradoxus from any cause. The pulsatile variation in light transmission that is detected by a pulse oximeter seems to have a direct relation to arterial blood pressure.2 We investigated in 13 volunteers (aged 5-50 years) respiratory variation in the plethysmograph output of a pulse oximeter as a non-invasive measure of increased respiratory effort. Each subject was asked to breathe as normally as possible through a tube closed by a valve. The valve opened to admit air when the subject produced sufficient negative pressure by inspiring. The pressure needed to open the valve was regulated by attached weights. The inspiratory pressure was measured directly within the tube via a transducer. The probe of a ’Nellcor N-200E’ pulse oximeter was taped to the second toe of the subject’s foot. The analogue output of the oximeter (which measures the pulsatile variation in light transmission over the cardiac cycle) was transformed to digital readout at 20 Hz and stored along with a digital record of mouth pressure. The power spectrum of the pulse waveform from the oximeter was then
Capture-mark-recapture method.
surprising that the capture-mark-recapture methods have made greater inroads in medicine for many doctors have made use of it in other settings-for example, counting red blood cells by extraction, labelling, injection, and re-extraction is an accepted procedure. To count every red cell would be too costly and is not needed for accurate estimates.6 We describe elsewhere the value of this approach in heart disease’ and connective tissue disorders.8 It is
not
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15621, USA
RONALD E. LAPORTE DANIEL J. MCCARTY EUGENE S. TULL
Jikei
University, Tokyo, Japan
NAOKO TAJIMA
1 Last JM. A dictionary of epidemiology Oxford Oxford University Press, 1988 2 Eberhard LL. Appraising variability in population studies. J Wildl Manage 1978; 42: 207-38. 3. Seber GAF. The estimation of animal abundance and related parameters, 2nd ed. New York: MacMillan. 4. Sekar CC, Deming WE. On a method of estimating birth and death rates and the extent of registration. Am Stat Assoc J 1949; 44: 101-15. 5 Wolter KM. Accounting for America’s uncounted and miscounted. Science 1991; 253: 12-15 6. International Committee for Standardization in Haematology Recommended method for radioisotope red-cell survival studies Br J Haematol 1980, 45: 659-66 7. LaPorte RE, Tull ES, McCarty D. Monitoring the incidence of myocardial infarctions. applications of the capture-mark-recapture technology. Int J Epidermiol 8
(m press). McCarty DJ, Kwoh HW, LaPorte RE. The importance of incidence registries for connective tissue diseases. J Rheumatol (in press).
Chirality and drug development SIR,-Dr Kean and colleagues (Dec 21/28, p 1565) conclude that
single enantiomers should be used in all biological and clinical testing of potential new medicines. Although this may be justifiable from an academic perspective, I believe that it ignores certain realities of technological practicality and economics that are part of the drug development process. It takes 12 years and an investment of US$231 million before the average new molecular entity is available to physicians.’ If purification of enantiomers were required before all early screening tests, many fewer candidate compounds could be evaluated, and fewer innovative new medicines would reach the market. Because a compound with n chiral centres has 2n possible enantiomers, the number of tests would increase geometrically. Moreover, much of this additional effort would be wasted. Of every 4000 compounds tested in the laboratory, only 1 will satisfy rigorous safety and efficacy screening requirements and eventually reach the pharmacy shelf. Company scientists are keenly aware of the part chirality can play in the pharmacological activity of a molecule. The decision to develop either a pure enantiomer or a racemate as a drug substance is a key milestone in a lengthy, complex process. For the reasons Kean et al cite, to purify and profile each enantiomer may be desirable at some point during drug development. In many cases,2 however, it may be scientifically justifiable to pursue development of a racemate without compromising either safety or efficacy. Also,
early clinical and non-clinical testing could be done on a racemate, with profiling of pure enantiomers. Once a desired enantiomer is identified, the final stages of clinical testing can be undertaken with the drug substance intended for the marketplace. Although the technology to purify enantiomers has made tremendous strides in the past decade, it is not trivial. Furthermore, separations that can be done on drug quantities sufficient for laboratory studies cannot always survive the scale-up process to production volumes. Good science must be at the root of drug development, but inordinate delay for marginal benefits puts patients who need new medicines at a disadvantage. Rather than arguing that all testing should be done on all enantiomers, perhaps Kean et al would agree that "progression of a racemate into clinical studies concurrent with continued development activities with the individual enantiomers may be the most effective approach".2 concurrent
Pharmaceutical Manufacturers Association, DC 20005, USA
Washington
1. Di Masi JA, et al. 2. PMA Committee
development
JOHN F. BEARY III
J Health Economics 1991;
10: 107-42. Racemic Mixtures. Comments on enantiomerism process Pharmac Technol 1990; 14: 46-52. on
in
the
drug
Continuous non-invasive assessment of
pulsus paradoxus SIR,-Pulsus paradoxus is a well recognised clinical sign that is useful in assessing the severity of many cardiorespiratory diseases. It is defmed as a greater than normal (> 10 mm Hg) inspiratory decrease in systolic arterial pressure, and may indicate upper
airways obstruction, moderately severe asthma, pericardial disease, congestive heart failure, and, in some cases, hypovolaemic shock.l The degree of pulsus paradoxus reflects the severity of the underlying disorder and thus is regarded by most clinicians as an important diagnostic aid. There is increasing use of pulse oximetry to access oxygenation continuously. The presence of obvious respiratory variation in the pulse volume output of a pulse oximeter is specific for the presence of clinically significant inspiratory loading, and by extrapolation will reflect the presence of pulsus paradoxus from any cause. The pulsatile variation in light transmission that is detected by a pulse oximeter seems to have a direct relation to arterial blood pressure.2 We investigated in 13 volunteers (aged 5-50 years) respiratory variation in the plethysmograph output of a pulse oximeter as a non-invasive measure of increased respiratory effort. Each subject was asked to breathe as normally as possible through a tube closed by a valve. The valve opened to admit air when the subject produced sufficient negative pressure by inspiring. The pressure needed to open the valve was regulated by attached weights. The inspiratory pressure was measured directly within the tube via a transducer. The probe of a ’Nellcor N-200E’ pulse oximeter was taped to the second toe of the subject’s foot. The analogue output of the oximeter (which measures the pulsatile variation in light transmission over the cardiac cycle) was transformed to digital readout at 20 Hz and stored along with a digital record of mouth pressure. The power spectrum of the pulse waveform from the oximeter was then
