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ALMITRINE AND PERIPHERAL NEUROPATHY
571 intoxication suggested a biological half-life of about 3 months.4,5 The difference between these reports and our finding that serum levels of heptachlor epoxide and oxychlordane did not decrease over time cannot be wholly explained by continued exposure to the contaminated dairy products-although exposure to background contaminant levels probably contributed to the maintenance serum pesticide residue levels. Our data suggest that following transiently higher-than-background subacute exposure to contaminated dairy products, heptachlor epoxide and oxychlordane body burdens reached a new, higher steady-state level. Centers for Disease Control, Atlanta, Georgia 30333, USA
PAUL A. STEHR-GREEN VIRLYN W. BURSE
Arkansas Department of Health, Little Rock, Arkansas
JAMES C. WOHLLEB
1. Food and Drug Administration. Heptachlor and heptachlor epoxide in milk: revision of regulatory level. Fed Reg 1982; 47: 47466. 2. Stehr-Green PA, Wohlleb JC, Royce W, Head SL. An evaluation of serum pesticide residue levels and liver function in persons exposed to dairy products contaminated with heptachlor. JAMA 1988, 259: 374-77. 3. Tashiro S, Matsumara F. Metabolism of trans-nonachlor and related chlordane components in rat and man. Arch Environ Contam Toxicol 1978; 7: 113-27. 4. Aldrich AD, Holmes JH. Acute chlordane intoxication in a child. Arch Environ Health 1969; 19: 129-32. 5. Curley A, Garrettson LK. Acute chlordane poisoning. Arch Environ Health 1969; 18: 211-15.
ALMITRINE AND PERIPHERAL NEUROPATHY
SIR,-Dr Wouters and colleagues (Aug 6, p 336) report on the problems of peripheral neuropathy associated with the chemoreceptor-stimulant almitrine bismesylate. I have also found a high frequency of neuropathy in patients who received a smaller Serum concentrations of heptachlor metabolites and related residues in 6 individuals with high initial serum levels.
Survey [NHANES 11]). The exposed group had significantly higher serum levels of primary heptachlor metabolites and related residues (ie, heptachlor epoxide, oxychlordane, and transnonachlor) than did either of the comparison groups. We found no evidence of related acute/subacute neurological or hepatic effects in any of the exposed persons, regardless of serum concentrations of pesticide residues. 12 individuals in the exposed group had initial serum levels above the 95th percentile from the NHANES II sample. We monitored their serum pesticide levels to estimate the serum half-lives of these lipophilic compounds in man. We tried to collect non-fasting blood 0, 4, 11, and 19 months after the last reported exposure to the contaminated dairy products. The results for the 6 people followed up throughout that period (figure) indicate serum concentrations that remained constant or even increased slightly over time. The exception was a 44-year-old man who began with the highest heptachlor epoxide and oxychlordane concentrations but in whom concentrations levelled off, after initial steep falls. For these 6 individuals there was some evidence of seasonal variation, higher levels being observed in the summer and autumn, which may be related to the increased use of pesticides at that time. These fluctuations were slight, however, and could simply be artifacts caused by analytical or within-person variability. We observed similar temporal and seasonal associations in the other 6 participants for whom time series data were incomplete. We could not derive serum half-lives from the data for these 12 people. Chlorinated hydrocarbon pesticides tend to accumulate in adipose tissue and other tissues that are high in neutral fat, but rates of metabolism and excretion of individual compounds vary considerably.’ There are no previous reports of estimated serum half-life for these compounds in man with which we can compare our results. For trans-nonachlor, however, we can draw inferences from in vitro evidence that the human liver is (relatively) incapable of metabolising trans-nonachlor.3 Thus, even slightly increased exposure (eg, by consuming contaminated dairy products for 8 months) could lead to body burdens that are persistently higher than those seen in populations with only background exposure. In contrast, measurements of serum levels of chlordane (closely related structurally to heptachlor) in two children with acute chlordane
dose of almitrine. 25 patients who were hypoxaemic because of chronic bronchitis and emphysema (mean PaOz 7,58 kPa, SD 0°7) entered a double-blind study and received placebo (n = 13) or almitrine 50 mg (n = 12) twice daily for one year. All patients who took placebo completed the study. 2 patients who received almitrine were withdrawn at five and nine months because of severe peripheral neuropathy; of the remaining 10,3 had neuropathy by the end of the study. No cause for the neuropathy was apparent and only 1 patient, a 66-year-old man, showed a rapid symptomatic improvement after cessation of therapy. Aimitrine is effective in increasing PaOz in patients with hypoxaemic chronic bronchitis and emphysema,’ but caution is necessary, especially in those patients with clinical or sub-clinical
neuropathy. Chest Unit, City Hospital, Edinburgh EH10 5SB
MARTIN B. ALLEN
C, Howard P, Ansquer JC. Almitrine bismesylate: a long-term placebo controlled double blind study in COAD: Vectarion international multicentre study group. Bull Eur Physio Pathol Resp 1987; 23 (suppl 11): 169S.
1. Voisin
NEW METHOD SPECIFIC FOR ACETYLCHOLINESTERASE IN CEREBROSPINAL FLUID: APPLICATION TO ALZHEIMER’S DISEASE
SIR,-Several workers have investigated the possibility that the activity of acetylcholinesterase (AChE; EC 3.1.1.7) in cerebrospinal fluid (CSF) might reflect the loss of forebrain cholinergic neurons in Alzheimer’s disease (AD).1-3 Daviesz showed no change in AChE activity, whereas Soininen et aP reported that in the lumbar CSF of patients with a clinical diagnosis of AD AChE was lower than that in controls. The first reports on the AChE levels of CSF in patients in whom AD was diagnosed histologically came from Appleyard et al4 who found AChE was reduced by 62% in ventricular CSF, and from Arendt et als who showed a 55% lower AChE level in the lumbar CSF. There have since been over 20 reports on CSF AChE levels in AD, roughly equally claiming no change or a decrease in AChE.6,7 Many factors might contribute to these discrepancies, such as the accuracy of the diagnosis (clinical or histological), the procedure
PAUL A. STEHR-GREEN VIRLYN W. BURSE
Arkansas Department of Health, Little Rock, Arkansas
JAMES C. WOHLLEB
1. Food and Drug Administration. Heptachlor and heptachlor epoxide in milk: revision of regulatory level. Fed Reg 1982; 47: 47466. 2. Stehr-Green PA, Wohlleb JC, Royce W, Head SL. An evaluation of serum pesticide residue levels and liver function in persons exposed to dairy products contaminated with heptachlor. JAMA 1988, 259: 374-77. 3. Tashiro S, Matsumara F. Metabolism of trans-nonachlor and related chlordane components in rat and man. Arch Environ Contam Toxicol 1978; 7: 113-27. 4. Aldrich AD, Holmes JH. Acute chlordane intoxication in a child. Arch Environ Health 1969; 19: 129-32. 5. Curley A, Garrettson LK. Acute chlordane poisoning. Arch Environ Health 1969; 18: 211-15.
ALMITRINE AND PERIPHERAL NEUROPATHY
SIR,-Dr Wouters and colleagues (Aug 6, p 336) report on the problems of peripheral neuropathy associated with the chemoreceptor-stimulant almitrine bismesylate. I have also found a high frequency of neuropathy in patients who received a smaller Serum concentrations of heptachlor metabolites and related residues in 6 individuals with high initial serum levels.
Survey [NHANES 11]). The exposed group had significantly higher serum levels of primary heptachlor metabolites and related residues (ie, heptachlor epoxide, oxychlordane, and transnonachlor) than did either of the comparison groups. We found no evidence of related acute/subacute neurological or hepatic effects in any of the exposed persons, regardless of serum concentrations of pesticide residues. 12 individuals in the exposed group had initial serum levels above the 95th percentile from the NHANES II sample. We monitored their serum pesticide levels to estimate the serum half-lives of these lipophilic compounds in man. We tried to collect non-fasting blood 0, 4, 11, and 19 months after the last reported exposure to the contaminated dairy products. The results for the 6 people followed up throughout that period (figure) indicate serum concentrations that remained constant or even increased slightly over time. The exception was a 44-year-old man who began with the highest heptachlor epoxide and oxychlordane concentrations but in whom concentrations levelled off, after initial steep falls. For these 6 individuals there was some evidence of seasonal variation, higher levels being observed in the summer and autumn, which may be related to the increased use of pesticides at that time. These fluctuations were slight, however, and could simply be artifacts caused by analytical or within-person variability. We observed similar temporal and seasonal associations in the other 6 participants for whom time series data were incomplete. We could not derive serum half-lives from the data for these 12 people. Chlorinated hydrocarbon pesticides tend to accumulate in adipose tissue and other tissues that are high in neutral fat, but rates of metabolism and excretion of individual compounds vary considerably.’ There are no previous reports of estimated serum half-life for these compounds in man with which we can compare our results. For trans-nonachlor, however, we can draw inferences from in vitro evidence that the human liver is (relatively) incapable of metabolising trans-nonachlor.3 Thus, even slightly increased exposure (eg, by consuming contaminated dairy products for 8 months) could lead to body burdens that are persistently higher than those seen in populations with only background exposure. In contrast, measurements of serum levels of chlordane (closely related structurally to heptachlor) in two children with acute chlordane
dose of almitrine. 25 patients who were hypoxaemic because of chronic bronchitis and emphysema (mean PaOz 7,58 kPa, SD 0°7) entered a double-blind study and received placebo (n = 13) or almitrine 50 mg (n = 12) twice daily for one year. All patients who took placebo completed the study. 2 patients who received almitrine were withdrawn at five and nine months because of severe peripheral neuropathy; of the remaining 10,3 had neuropathy by the end of the study. No cause for the neuropathy was apparent and only 1 patient, a 66-year-old man, showed a rapid symptomatic improvement after cessation of therapy. Aimitrine is effective in increasing PaOz in patients with hypoxaemic chronic bronchitis and emphysema,’ but caution is necessary, especially in those patients with clinical or sub-clinical
neuropathy. Chest Unit, City Hospital, Edinburgh EH10 5SB
MARTIN B. ALLEN
C, Howard P, Ansquer JC. Almitrine bismesylate: a long-term placebo controlled double blind study in COAD: Vectarion international multicentre study group. Bull Eur Physio Pathol Resp 1987; 23 (suppl 11): 169S.
1. Voisin
NEW METHOD SPECIFIC FOR ACETYLCHOLINESTERASE IN CEREBROSPINAL FLUID: APPLICATION TO ALZHEIMER’S DISEASE
SIR,-Several workers have investigated the possibility that the activity of acetylcholinesterase (AChE; EC 3.1.1.7) in cerebrospinal fluid (CSF) might reflect the loss of forebrain cholinergic neurons in Alzheimer’s disease (AD).1-3 Daviesz showed no change in AChE activity, whereas Soininen et aP reported that in the lumbar CSF of patients with a clinical diagnosis of AD AChE was lower than that in controls. The first reports on the AChE levels of CSF in patients in whom AD was diagnosed histologically came from Appleyard et al4 who found AChE was reduced by 62% in ventricular CSF, and from Arendt et als who showed a 55% lower AChE level in the lumbar CSF. There have since been over 20 reports on CSF AChE levels in AD, roughly equally claiming no change or a decrease in AChE.6,7 Many factors might contribute to these discrepancies, such as the accuracy of the diagnosis (clinical or histological), the procedure