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Trials in special populations
CURRENT THERAPEUTIC RESEARCH® VOL. 58, NO. 12, DECEMBER 1997
Trials in S p e c i a l P o p u l a t i o n s Editorial Comment The Special Populations section of this issue contains four open-label, uncontrolled studies conducted in four clinically important patient populations. Kasckow et al report the effects of divalproex sodium in the treatment of agitated elderly patients with dementia; Fainstein et al describe the short-term effects of melatonin in elderly patients with sleep disturbance with or without dementia; Abrams used bowel sterilization and selective recolonization in the treatment of six adults with a number of inflammatory bowel diseases; and Buzzi et al, in a multicenter trial, used fluvastatin in the treatment of adults with hypercholesterolemia. Kasckow et al found behavioral improvements in 5 of 10 patients with a wide range of divalproex sodium dosages (500 to 2250 mg/d) and peak blood levels (46 to 83 p~/mL) in the treatment of behavioral agitation in elderly patients with dementia--an important growing special population. These results are important if replicated in larger, longer-term, double-masked, placebocontrolled studies; however, comments on the use ofvalproate concentrations are needed. The therapeutic range for anticonvulsant efficacy or toxicity may be useful for behavioral effects. The authors refer to peak VPA blood levels when they mean maximal morning predose level during the trial rather than levels measured at any given interval post dose. This nomenclature may be confusing to clinicians accustomed to ~peak and trough" drug concentrations. Peak valproate concentrations occur when the rate of absorption eq, ml.~the rate of elimination; the time at which this occurs is not predicted by absorption studies conducted in younger or otherwise different patient populations where product performance (gastric transit, dissolution, or absorption), drug clearance, and central nervous system penetration protein binding can all differ. Future studies should be designed to investigate both the pharmacokinetic and pharmacodynamic predictors of response beth therapeutic and toxic (especially hepatic) effects. Various liquid and solid dosage forms also should be studied because not all elderly patients will take divalproex sodium willingly. Dosing intervals should also be controlled because there may be large differences in morning predose levels on every 8 hour versus three times a day dosing. Despite these minor points, the authors suggest that these pilot results could have major therapeutic implications for this important ~special population." Fainstein et al studied the efficacy of melatonin in the treatment of patients representing a number of important, expanding "special populations"---elderly patients with sleep disturbances alone, sleep disturbances and depression, and sleep disturbances and dementia. The relatively short-term, open-label, uncontrolled design without posttreatment followup observations for signs of rebound significantly limits the strength of the conclusions that can be attained. However, the clinical impact of the results would be greater if the observations were confirmed in larger, longer, adequately controlled trials. A decrease in the use of benzodiazepines 979
0011-393x/97/$3.50
EDITORIAL COMMENT
alone, without any change in sleep quantity or quality, could have major health benefits and cost savings because benzodiazepine use can be associated with significant direct and indirect health care costs, falls, drug interactions, and cognitive changes in m a n y elderly patients. Melatonin has been shown to have important actions in the treatment of sleep disturbances in patients without vision and the prevention of symptoms of "jet lag." Readers should note, however, that quality control data are required for the use of melatonin products in Argentina. Fewer such controls exist in many countries, including the United States, where melatenin is sold as a "nutritional" product and, therefore, is exempt from most federal drug administration controls applied to drugs. Without such controls there is less guarantee of the safety, efficacy, or even the content, quantity, or purity of melatonin products. This important health oversight should be corrected. Abrams presented the results of bowel sterilization and selective recolonization in only six patients with a variety of i~flammatery bowel diseases. Although this study represents a relatively small number of patients, these difl~cult-to-treat patients consume significant medical resources. Therapy is unusual and complicated and requires long-term hospitalization. These potentially promising results are at best unconfirmed, preliminary, and incomplete. Long-term controlled trials are needed to determine whether the short-term improvement is a result of the treatment used or the well-known variable course ofinflammatery bowel diseases, how long clinical improvement will be maintained, and what effect the therapy will have on long-term complications such as malignancy. Nevertheless, many patients with inflammatory bowel disease suffer significant short- and long-term disability. Serious therapeutic approaches, no matter how unorthodox, are worthy of intense consideration and review. Little has been published on this approach, and previous uncontrolled trials have not reported the results of long-term follow-up. Readers who are famih'ar with these diseases, as well as potential therapies, are urged to review these results carefully and provide comments and criticisms. The final paper in this section, by Buzzi et al, reported the results of a large multicenter, open-label, uncontrolled clinical trial of fluvastatin in the treatment of hypercholesterolemia. These results are similar to those of previous trials from other countries. There appears to be little doubt that this agent produces a significant decrease in serum lipid levels with an acceptable incidence of adverse effects. What is not clear is the relative place of fluvastatin in terms of cost, efficacy, or toxicity versus other agents used in similar or dissimilar patient populations, as well as what the ideal dose offluvastatin should be in individual patients within these populations. All four studies in this section were conducted in diverse but clinically important special populations. Readers are encouraged to submit the results of other studies that investigate these and other important special populations. Philip D. Walson, M.D. Former Editor-in-Chief 980
Trials in S p e c i a l P o p u l a t i o n s Editorial Comment The Special Populations section of this issue contains four open-label, uncontrolled studies conducted in four clinically important patient populations. Kasckow et al report the effects of divalproex sodium in the treatment of agitated elderly patients with dementia; Fainstein et al describe the short-term effects of melatonin in elderly patients with sleep disturbance with or without dementia; Abrams used bowel sterilization and selective recolonization in the treatment of six adults with a number of inflammatory bowel diseases; and Buzzi et al, in a multicenter trial, used fluvastatin in the treatment of adults with hypercholesterolemia. Kasckow et al found behavioral improvements in 5 of 10 patients with a wide range of divalproex sodium dosages (500 to 2250 mg/d) and peak blood levels (46 to 83 p~/mL) in the treatment of behavioral agitation in elderly patients with dementia--an important growing special population. These results are important if replicated in larger, longer-term, double-masked, placebocontrolled studies; however, comments on the use ofvalproate concentrations are needed. The therapeutic range for anticonvulsant efficacy or toxicity may be useful for behavioral effects. The authors refer to peak VPA blood levels when they mean maximal morning predose level during the trial rather than levels measured at any given interval post dose. This nomenclature may be confusing to clinicians accustomed to ~peak and trough" drug concentrations. Peak valproate concentrations occur when the rate of absorption eq, ml.~the rate of elimination; the time at which this occurs is not predicted by absorption studies conducted in younger or otherwise different patient populations where product performance (gastric transit, dissolution, or absorption), drug clearance, and central nervous system penetration protein binding can all differ. Future studies should be designed to investigate both the pharmacokinetic and pharmacodynamic predictors of response beth therapeutic and toxic (especially hepatic) effects. Various liquid and solid dosage forms also should be studied because not all elderly patients will take divalproex sodium willingly. Dosing intervals should also be controlled because there may be large differences in morning predose levels on every 8 hour versus three times a day dosing. Despite these minor points, the authors suggest that these pilot results could have major therapeutic implications for this important ~special population." Fainstein et al studied the efficacy of melatonin in the treatment of patients representing a number of important, expanding "special populations"---elderly patients with sleep disturbances alone, sleep disturbances and depression, and sleep disturbances and dementia. The relatively short-term, open-label, uncontrolled design without posttreatment followup observations for signs of rebound significantly limits the strength of the conclusions that can be attained. However, the clinical impact of the results would be greater if the observations were confirmed in larger, longer, adequately controlled trials. A decrease in the use of benzodiazepines 979
0011-393x/97/$3.50
EDITORIAL COMMENT
alone, without any change in sleep quantity or quality, could have major health benefits and cost savings because benzodiazepine use can be associated with significant direct and indirect health care costs, falls, drug interactions, and cognitive changes in m a n y elderly patients. Melatonin has been shown to have important actions in the treatment of sleep disturbances in patients without vision and the prevention of symptoms of "jet lag." Readers should note, however, that quality control data are required for the use of melatonin products in Argentina. Fewer such controls exist in many countries, including the United States, where melatenin is sold as a "nutritional" product and, therefore, is exempt from most federal drug administration controls applied to drugs. Without such controls there is less guarantee of the safety, efficacy, or even the content, quantity, or purity of melatonin products. This important health oversight should be corrected. Abrams presented the results of bowel sterilization and selective recolonization in only six patients with a variety of i~flammatery bowel diseases. Although this study represents a relatively small number of patients, these difl~cult-to-treat patients consume significant medical resources. Therapy is unusual and complicated and requires long-term hospitalization. These potentially promising results are at best unconfirmed, preliminary, and incomplete. Long-term controlled trials are needed to determine whether the short-term improvement is a result of the treatment used or the well-known variable course ofinflammatery bowel diseases, how long clinical improvement will be maintained, and what effect the therapy will have on long-term complications such as malignancy. Nevertheless, many patients with inflammatory bowel disease suffer significant short- and long-term disability. Serious therapeutic approaches, no matter how unorthodox, are worthy of intense consideration and review. Little has been published on this approach, and previous uncontrolled trials have not reported the results of long-term follow-up. Readers who are famih'ar with these diseases, as well as potential therapies, are urged to review these results carefully and provide comments and criticisms. The final paper in this section, by Buzzi et al, reported the results of a large multicenter, open-label, uncontrolled clinical trial of fluvastatin in the treatment of hypercholesterolemia. These results are similar to those of previous trials from other countries. There appears to be little doubt that this agent produces a significant decrease in serum lipid levels with an acceptable incidence of adverse effects. What is not clear is the relative place of fluvastatin in terms of cost, efficacy, or toxicity versus other agents used in similar or dissimilar patient populations, as well as what the ideal dose offluvastatin should be in individual patients within these populations. All four studies in this section were conducted in diverse but clinically important special populations. Readers are encouraged to submit the results of other studies that investigate these and other important special populations. Philip D. Walson, M.D. Former Editor-in-Chief 980