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In order to determine the association between dementia and low body weight in outpatients, Body Mass Index (BMI) was evaluated prospectively in 346 frail elderly outpatients presenting for comprehensive geriatric assessment. Patients were categorized into four groups (cognitively intact, dementia of the Alzheimer's type (DAT), other dementia, and patients with depressive symptoms). Patients were assessed for severity of dementia by the Clinical Dementia Rating scale. Differences between groups for various clinical parameters were evaluated using an analysis of variance and Duncan's Multiple Range Test. Patients with dementia, regardless of etiologic type or severity, and patients with depressive symptoms had BMI's greater than or equal to 10% lower than the cognitively intact patients. BMI was positively correlated with Instrumental Activities of Daily Living (IADL) but not Activities of Daily Living (ADL) or Mini-Mental State Exam (MMSE) score. Low BMI was not associated with increased physical illness. In fact, in the subset of patients with DAT, lower BMI correlated with significantly lesser amounts of comorbid physical illness. Finally, compared to cognitively intact outpatients, patients with DAT appeared to be physically healthier despite their having a lower BMI. These results suggest an association between dementia and low BMI. On the other hand, the presence of comorbid physical illness, a common focus of evaluation in these patients, was not more common in those patients with lower BMI's.

Kinetics and sedative and psychomotor effects of diphenhydramine were investigated in elderly Caucasian women (greater than 64 yr. old). In a double-blind trial, each of 12 healthy subjects received on one of three occasions 50 mg/70 kg IV or oral diphenhydramine HCl or oral placebo. Plasma levels of diphenhydramine were measured in six subjects and tests of sedation and psychomotor performance were performed hourly for 8 hr in all subjects. Kinetic analysis showed that the volume of distribution (295 +/- 50 [SEM] l/70 kg), clearance (42 +/- 5 l/70 kg/hr), and plasma t1/2 (4.9 +/- 0.7 hr) were of the same order as in young adults. As in young adults, there was minimal psychomotor impairment after oral and after intravenous diphenhydramine. In contrast to young adults, however, elderly women did not report significant sedation after diphenhydramine. These results suggest that diphenhydramine may not be an effective sedative/hypnotic in elderly women.

A randomized crossover trial of the effect of oral activated charcoal on the kinetics of intravenous theophylline was carried out in six normal male subjects. After intravenous aminophylline (6 mg/kg), subjects received water or water with activated charcoal (140 gm) in divided doses over 12 hr. Serum theophylline concentrations were measured from 0 to 24 hr after the aminophylline infusion. Treatment with activated charcoal decreased the serum t 1/2 from 6.4 +/- 1.2 to 3.3 +/- 0.4 (SEM) hr and the serum AUC from 78 +/- 14 to 42 +/- 4 mg . hr/l. Percent decrease in AUC after treatment with charcoal correlated positively with the endogenous theophylline serum t 1/2 (r = 0.94). These results suggest that oral activated charcoal (1) enhanced the total body clearance of theophylline and (2) may be efficacious in the treatment of theophylline poisoning, especially in patients with prolonged serum t 1/2s of theophylline.

The localization and mechanism of thymidine and deoxyuridine transport in the central nervous system were studied in vivo and in vitro. Previous studies have shown that thymidine enters brain from blood in part via the CSF. In vitro, isolated adult bovine cerebral microvessels, which readily concentrated and phosphorylated deoxyglucose, were unable to concentrate thymidine and deoxyuridine. In vivo, [3H]thymidine (0.2 microM) and [3H]deoxyuridine (0.4 microM) were not extracted more readily than [14C]sucrose in a single pass through the cerebral circulation of rats. In vivo, [3H]thymidine retention in CSF and brain after entry from blood was increased when the efflux of [3H]thymidine from CSF and the phosphorylation of [3H]thymidine in brain were depressed by the intraventricular injection of unlabeled thymidine. These studies and previous work suggest that the transfer of thymidine (and deoxyuridine) through the blood-brain barrier in either direction must be extremely low. The present studies are consistent with the postulate that thymidine is transported by an active transport system in the choroid plexus that transfers thymidine from blood into the CSF; from the CSF, the thymidine enters brain cells and is phosphorylated.

The treatment of theophylline intoxication is reviewed. Efforts should be made to decrease the absorption of theophylline from the gastrointestinal tract by the oral administration of activated charcoal and sorbitol; stomach emptying procedures are recommended only in limited circumstances. Patients should receive intensive supportive care and appropriate treatment for complications of intoxication, including metabolic and cardiovascular abnormalities and seizures. Despite these treatments, morbidity (including residual neurological deficits) and mortality may occur. Therefore, efforts to actively remove theophylline from the body before complications occur should be considered in an attempt to reduce morbidity and mortality. The oral administration of multiple doses of activated charcoal (which increases theophylline clearance) is recommended for nearly all patients with theophylline intoxication. Although controversial, hemoperfusion--an efficient but invasive active removal procedure--is recommended in severely intoxicated patients who satisfy specific indications; the prophylactic administration of phenobarbital to prevent seizures should also be considered in these patients. Although these recommendations are rationally based on the extant evidence, controlled clinical trials in patients with theophylline intoxication are needed to prove their utility.

A decrease in dietary protein is known to depress renal plasma flow and creatinine clearance. Using a randomized crossover design, we investigated the pharmacokinetics of allopurinol and its principal metabolite, oxypurinol, after oral administration of 600 mg of allopurinol in six normal subjects receiving a high-protein (268 g per day) or low-protein (19 g per day) diet. For allopurinol, the area under the curve of plasma concentration versus time increased by a factor of 1.45 (P less than 0.02), the renal clearance decreased by 28 per cent (P less than 0.02), and the ratio of the clearance of allopurinol to that of creatinine (fractional excretion) was unchanged between the low-protein and high-protein diets. For oxypurinol, the area under the curve increased nearly three-fold (P less than 0.02), the renal clearance decreased by 64 per cent (P less than 0.02), the fractional excretion decreased by 49 per cent (P less than 0.02), and the plasma oxypurinol half-life increased nearly threefold from 17.3 +/- 1.5 (mean +/- S.E.M.) to 49.9 +/- 2.9 hours (P less than 0.02) during the low-protein diet, as compared with the high-protein diet. We conclude that with the low-protein diet, the absorption, metabolism, and excretion of allopurinol were minimally altered but the total-body clearance of oxypurinol was greatly reduced because of a large increase in the net renal tubular reabsorption of oxypurinol.

Excerpt An overdose with phenylbutazone causes a syndrome that may include seizures, coma, and metabolic acidosis (1). Serious tissue damage such as hepatic necrosis, renal failure, cardiovascular ...

The renal clearance of oxipurinol, the major metabolite of allopurinol, was studied in six healthy subjects during normal and restricted (low protein and low calorie) diets. A 600 mg oral dose of allopurinol was administered after 7 days of a normal diet (100 mg protein/day) and again after 2 and 4 weeks of a restricted diet (19 gm protein/day). The renal clearance of oxipurinol was reduced from 19.6 ±1.5 ml/ min during the normal diet to 10.9 ± 0.8 and 12.0 ± 0.9 ml/min (both P < 0.001) during the restricted diet at 2 and 4 weeks, respectively. These changes in oxipurinol renal clearance paralleled changes in uric acid renal clearance. Furthermore, the plasma oxipurinol half-life was increased from 27.0 ±1.7 hours during the normal diet to 51.1 ± 4.3 and 45.7 ± 3.7 hours (both P < 0.001) during the restricted diet at 2 and 4 weeks, respectively. We conclude that dietary protein and calorie restriction cause a sustained reduction in the elimination of oxipurinol. Clinical Pharmacology and Therapeutics (1987) 41, 616–621; doi:10.1038/clpt.1987.84

We investigated the effect of multiple oral doses of activated charcoal on the pharmacokinetics of intravenously administered phenobarbital in a randomized crossover trial. Six healthy men volunteered to take 200 mg of phenobarbital sodium per 70 kg of body weight intravenously on two separate occasions. On one occasion, each subject received oral activated charcoal (180 g) in divided doses over three days after the infusion of phenobarbital. Serum levels of phenobarbital were measured in all subjects up to 96 hours after the infusion, and urinary excretion of phenobarbital was measured in two subjects 24 to 96 hours after the infusion. A pharmacokinetic analysis showed that the charcoal decreased the serum half-life of phenobarbital form 110 +/- 8 to 45 +/- 6 hours (S.E.M.) (P less than 0.01), increased the total body clearance of phenobarbital from 4.4 +/- 0.2 to 12.0 +/- 1.6 ml per kilogram per hour (P less than 0.01), and increased the nonrenal clearance from 52 to 80 per cent of the total body clearance. We conclude that oral administration of activated charcoal enhances the nonrenal clearance of phenobarbital.

Patients with phenobarbital overdose who are treated only with supportive care may remain comatose for several days because of the long elimination half-life of phenobarbital. We treated two patients with phenobarbital overdoses with the nasogastric administration of multiple doses of activated charcoal. This safe therapy markedly shortened both the elimination half-life of phenobarbital and the duration of coma in these patients. If all such patients respond similarly, we believe that the nasogastric administration of multiple doses of activated charcoal is the method of choice to accelerate the elimination of phenobarbital from the body.

To the Editor.— Previous studies have shown that the administration of multiple oral doses of activated charcoal will decrease the elimination half-life of phenobarbital. 1,2 An uncontrolled trial in patients with phenobarbital overdose treated with this regimen suggested that coma time and duration of mechanical ventilation were decreased consistent with the decrease in phenobarbital halflife. 3 However, the obvious thesis that decreasing the half-life of phenobarbital by administering multiple doses of activated charcoal would result in a decrease in coma time and duration of mechanical ventilation in patients with phenobarbital overdose requires final proof. Pond et al 4 have tested this thesis. In a small randomized controlled trial, they have confirmed that repeated doses of activated charcoal, compared with single doses, decrease the serum half-life of phenobarbital in patients with phenobarbital overdose. But, it is surprising that the duration of mechanical ventilation was not different in the two groups. However