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Assessment of the variability of blood flow and metabolism measured via pet, in healthy volunteers
Abstracts
126
REDUCTION IN CEREBRAL GLUCOSE METABOLISM CAUSED BY QUINOLONE ADMINISTRATION IN HEALTHY VOLUNTEERS Jeffrey A. Green, Pharm.D., FCP, Edward M. Bednarczyk, Pharm.D., Floro Miraldi, M.D., SC. D., Stephanie F. Gardner, Pharm.D., A. Dennis Nelson, Ph.D., Gregory P. Leisure, B.S., Depts. of Medicine & Radiology, University Hospitals of Cleveland/Case Western Reserve Univ. Cleveland. In 1983 the FDA requested PET data to explore the CNS adverse effect profile of the fluorinated quinolones. PET was pursued after conventional assessments of neurologic function yielded no useful information. To this Absolute, end, 6 quinolones were studied in 90 healthy volunteers. quantitative information on cerebral blood flow (CBF) and glucose metabolism (GM) was acquired at baseline and following 2-7 days of quinolone administration in a placebo-controlled, randomized and doubleblind fashion. All individual quinolones, except one, showed a trend for a diminution in GM. Nalidixic acid showed the greatest change in GM. Analysis of a pooled “generic” quinolone effect (N=62) demonstrated a reduction in GM (mg/min/lOOg) from 6.2 f 1.5 to 5.8 f 1.5 vs 5.5 f 1.4 to 5.8 f 1.6 in the placebo group (N= 28); (p < ,031. There was no consistent effect seen in CBF. Since there was no correlation between the reduction seen in GM and any reported side effects, coupled with the general limitations of healthy volunteer data, the implications of a quinolone-induced decrease in GM is unknown at this time.
ASSESSMENT METABOLISM VOLUNTEERS
OF THE VARIABILITY MEASURED VIA
OF BLOOD FLOW AND PET, IN HEALTHY
Edward M. Bednarczyk, Pharm.D., Floro Miraldi, M.D.,Sc.D., A.Dennis Nelson, Ph.D., Gregory P. Leisure B.S., Lee Adler M.D., Marc S. Berridge Ph.D., Jeffrey A. Green Pharm.D.. Case Western Reserve University, Depts. of Med., Radiol., Univ. Hospitals of Cleveland, Cleveland, OH. Positron emission tomography (PET) holds great promise as an in-vivo assessor of physiologic parameters such as blood flow, metabolism and receptor affinity. Application of this tool to the realm of pharmacologic development is now underway. Inherent to the design of any study is the variability of the measured parameter, both inter and intra-subject. Over 90 healthy volunteers have been studied at our institution as participants in trials of various agents, Subjects underwent PET scans of blood principally the fluorinated quinolones. flow (4 separate measurements) using H$sO, glucose metabolism (2 measurements)
via
18FDG,
oxygen
metabolism
(2 measurements)
via
150
labelled oxygen and blood volume using C150. Measurements of these physiologic functions in subjects not receiving active drug therapy will be discussed. Both inter and intra-subject variability significantly impact on the design of These parameters must be studies evaluating an interventional process. adequately described and controlled for before studies are undertaken.
126
REDUCTION IN CEREBRAL GLUCOSE METABOLISM CAUSED BY QUINOLONE ADMINISTRATION IN HEALTHY VOLUNTEERS Jeffrey A. Green, Pharm.D., FCP, Edward M. Bednarczyk, Pharm.D., Floro Miraldi, M.D., SC. D., Stephanie F. Gardner, Pharm.D., A. Dennis Nelson, Ph.D., Gregory P. Leisure, B.S., Depts. of Medicine & Radiology, University Hospitals of Cleveland/Case Western Reserve Univ. Cleveland. In 1983 the FDA requested PET data to explore the CNS adverse effect profile of the fluorinated quinolones. PET was pursued after conventional assessments of neurologic function yielded no useful information. To this Absolute, end, 6 quinolones were studied in 90 healthy volunteers. quantitative information on cerebral blood flow (CBF) and glucose metabolism (GM) was acquired at baseline and following 2-7 days of quinolone administration in a placebo-controlled, randomized and doubleblind fashion. All individual quinolones, except one, showed a trend for a diminution in GM. Nalidixic acid showed the greatest change in GM. Analysis of a pooled “generic” quinolone effect (N=62) demonstrated a reduction in GM (mg/min/lOOg) from 6.2 f 1.5 to 5.8 f 1.5 vs 5.5 f 1.4 to 5.8 f 1.6 in the placebo group (N= 28); (p < ,031. There was no consistent effect seen in CBF. Since there was no correlation between the reduction seen in GM and any reported side effects, coupled with the general limitations of healthy volunteer data, the implications of a quinolone-induced decrease in GM is unknown at this time.
ASSESSMENT METABOLISM VOLUNTEERS
OF THE VARIABILITY MEASURED VIA
OF BLOOD FLOW AND PET, IN HEALTHY
Edward M. Bednarczyk, Pharm.D., Floro Miraldi, M.D.,Sc.D., A.Dennis Nelson, Ph.D., Gregory P. Leisure B.S., Lee Adler M.D., Marc S. Berridge Ph.D., Jeffrey A. Green Pharm.D.. Case Western Reserve University, Depts. of Med., Radiol., Univ. Hospitals of Cleveland, Cleveland, OH. Positron emission tomography (PET) holds great promise as an in-vivo assessor of physiologic parameters such as blood flow, metabolism and receptor affinity. Application of this tool to the realm of pharmacologic development is now underway. Inherent to the design of any study is the variability of the measured parameter, both inter and intra-subject. Over 90 healthy volunteers have been studied at our institution as participants in trials of various agents, Subjects underwent PET scans of blood principally the fluorinated quinolones. flow (4 separate measurements) using H$sO, glucose metabolism (2 measurements)
via
18FDG,
oxygen
metabolism
(2 measurements)
via
150
labelled oxygen and blood volume using C150. Measurements of these physiologic functions in subjects not receiving active drug therapy will be discussed. Both inter and intra-subject variability significantly impact on the design of These parameters must be studies evaluating an interventional process. adequately described and controlled for before studies are undertaken.