Expanded role of charcoal therapy in the poisoned and overdosed patient.

Activated charcoal is widely used as an adsorbent for the management of patients with drug overdoses and poisonings. Activated charcoal can be used orally to prevent drug and poison absorption in cases of overdose and poisoning. Multiple oral doses of charcoal increase the elimination of several, but not all, drugs and poisons. The effectiveness of multiple oral doses of charcoal in accelerating drug clearance is dependent primarily on the endogenous clearance of the drug or poison and its volume of distribution. Multiple doses of charcoal are used to shorten the period of supportive care in certain patients or to more rapidly remove drugs or poisons that may cause tissue damage, eg, theophylline. Charcoal is a safe, effective, and inexpensive alternative to more invasive treatments for some cases of drug overdose and poisoning.

An approach to the management of the poisoned patient.

Our systematic approach to the evaluation and treatment of the acutely poisoned patient involves establishing an accurate diagnosis and prognosis that often may be based on quantitation of the blood concentration of the toxic substance. The major feature of this approach is the proper selection of treatment(s) for the poisoned patient, ie, decontamination and supportive care and, in some cases, antidotal therapy and/or active removal of the toxic substance. Invasive, expensive methods of active removal (eg, hemodialysis or hemoperfusion) are generally recommended only if specific criteria are satisfied. Noninvasive, inexpensive methods of active removal (eg, manipulation of urinary pH or the oral administration of multiple doses of activated charcoal) may have significant utility in the treatment of poisoned patients not requiring invasive methods. This systematic approach to the poisoned patient should lead to an effective use of treatment modalities with minimal risks and optimal clinical results.

Serious adverse reactions associated with sulindac.

Sulindac is a nonsteroidal anti-inflammatory agent that has been associated with serious adverse reactions. We saw four patients with reactions associated with sulindac. Our patients, one of whom died, had high temperatures and involvement of one or more organs, including the skin, liver, CNS, lymph nodes, bone marrow, and lungs. Eight similar previously reported cases also are summarized. In view of these cases of sulindac-induced toxicity, six of which were proved unequivocally by drug rechallenge, we suggest that physicians be cautious in prescribing this agent.

A randomized controlled trial of the effects of three antihypertensive agents on blood pressure control and quality of life in older women.

We conducted a multicenter, randomized, double-blind, parallel group trial to compare the impact of titrated doses of atenolol (50 to 100 mg once a day), enalapril (5 to 20 mg once a day), and diltiazem (sustained release) (60 to 180 mg twice a day) on blood pressure and quality of life in older hypertensive women. Two hundred forty-two patients were randomized. Dose titration was completed by week 4 after randomization, and the maintenance phase was completed at week 16. Diltiazem (sustained release) demonstrated greater diastolic blood pressure lowering at both weeks 8 and 16 by an intent-to-treat analysis. At week 16, diltiazem changed diastolic blood pressure -13.7 +/- 0.7 mm Hg compared with -10.8 +/- 1.1 mm Hg for atenolol, and -10.5 +/- 0.9 mm Hg for enalapril. Diltiazem also demonstrated greater lowering of systolic blood pressure at week 3, but these differences in systolic blood pressure had decreased by week 16. More patients were classified as treatment failures during the 16 weeks of the trial for atenolol (15%) than for diltiazem (2.5%), while the treatment failure rate was intermediate with enalapril (8%). Total rates of adverse events were equivalent across the three treatment arms. There were few significant differences in the impact of the three treatments on mean scores of quality-of-life measures at week 16. There was a trend for atenolol to have somewhat worse quality-of-life scores, but none of these differences were statistically significant. In conclusion, all three treatment regimens were effective in lowering diastolic blood pressure without significant differences in rates of adverse events or deleterious effects on quality of life.

Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin.

OBJECTIVE: To determine the safety and efficacy of the long-acting analog insulin glargine compared with NPH insulin in patients with type 2 diabetes who were previously treated with insulin alone. RESEARCH DESIGN AND METHODS: A total of 518 subjects with type 2 diabetes who were receiving NPH insulin with or without regular insulin for postprandial control were randomized to receive insulin glargine (HOE 901) once daily (n = 259) or NPH insulin once or twice daily in = 259) for 28 weeks in an open-label, multicenter trial. Doses were adjusted to obtain target fasting glucose <6.7 mmol/l. At study end point, the median total daily insulin dose in both treatment groups was 0.75 IU/kg. RESULTS: The treatment groups showed similar improvements in HbA1c from baseline to end point on intent-to-treat analysis. The mean change (means +/- SD) in HbA1c from baseline to end point was similar in the insulin glargine group (-0.41 +/- 0.1%) and the NPH group (-0.59 +/- 0.1%) after patients began with an average baseline HbA1c of approximately 8.5%. The treatments were associated with similar reductions in fasting glucose levels. Overall, mild symptomatic hypoglycemia was similar in insulin glargine subjects (61.4%) and NPH insulin subjects (66.%) However, nocturnal hypoglycemia in the insulin glargine group was reduced by 25% during the treatment period after the dose-titration phase(26.5 vs. 35.5%, P = 0.0136). Subjects in the insulin glargine group experienced less weight gain than those in the NPH group (0.4 vs. 1.4 kg, P < 0.0007). CONCLUSIONS: In patients with type 2 diabetes, once-daily bedtime insulin glargine is as effective as once- or twice-daily NPH in improving and maintaining glycemic control. In addition, insulin glargine deonstrates a lower risk of nocturnal hypoglycemia and less weight gain compared with NPH insulin.

Sodium-ion storage properties of nickel sulfide hollow nanospheres/reduced graphene oxide composite powders prepared by a spray drying process and the nanoscale Kirkendall effect.

Spray-drying and the nanoscale Kirkendall diffusion process are used to prepare nickel sulfide hollow nanospheres/reduced graphene oxide (rGO) composite powders with excellent Na-ion storage properties. Metallic Ni nanopowder-decorated rGO powders, formed as intermediate products, are transformed into composite powders of nickel sulfide hollow nanospheres/rGO with mixed crystal structures of Ni3S2 and Ni9S8 phases by the sulfidation process under H2S gas. Nickel sulfide/rGO composite powders with the main crystal structure of Ni3S2 are also prepared as comparison samples by the direct sulfidation of nickel acetate-graphene oxide (GO) composite powders obtained by spray-drying. In electrochemical properties, the discharge capacities at the 150(th) cycle of the nickel sulfide/rGO composite powders prepared by sulfidation of the Ni/rGO composite and nickel acetate/GO composite powders at a current density of 0.3 A g(-1) are 449 and 363 mA h g(-1), respectively; their capacity retentions, calculated from the tenth cycle, are 100 and 87%. The nickel sulfide hollow nanospheres/rGO composite powders possess structural stability over repeated Na-ion insertion and extraction processes, and also show excellent rate performance for Na-ion storage.

The effect of dietary protein-calorie restriction on the renal elimination of cimetidine.

The renal elimination of the weak-base cimetidine was studied in five healthy male subjects during normal and restricted (low-protein, low-calorie) diets in a randomized crossover fashion. An intravenous dose of cimetidine, 7 mg/kg, was administered on day 7 of the normal (100 gm/70 kg protein/day) and the restricted (19 gm/70 kg protein/day) diets. The renal clearance of cimetidine was unchanged by the dietary restriction; however, the fractional excretion of cimetidine increased from 3.06 to 3.94 (P less than 0.05), indicating an apparent increase in net tubular secretion of cimetidine during the restricted diet. We conclude that cimetidine dosage adjustments are apparently not necessary for patients with acutely restricted nutrient intake, although other weakly acidic and basic drugs may require dosage changes.

The effect of sorbitol and activated charcoal on serum theophylline concentrations after slow-release theophylline.

The effect of the addition of sorbitol to an oral regimen of multiple doses of activated charcoal on serum theophylline concentrations was studied after the ingestion of slow-release theophylline in nine healthy male volunteers. At 6, 7, 8, 10, and 12 hours after Theo-24 (1200 mg/70 kg) ingestion, each subject received, in a randomized crossover design, either 300 ml water, 20 gm activated charcoal in water, or 20 gm activated charcoal in water plus 75 ml 70% sorbitol at 6 and 8 hours only. The serum AUCs from 6 to 30 hours after Theo-24 ingestion during the water, charcoal, and charcoal plus sorbitol phases were 305 +/- 16, 113 +/- 6, and 85 +/- 10 mg-hr/L (mean +/- SE), respectively. We conclude that the addition of sorbitol to an oral regimen of multiple doses of activated charcoal decreased the serum theophylline concentrations after therapeutic doses of slow-release theophylline to a significantly greater extent than did the activated charcoal regimen alone.

Renal clearances of oxypurinol and inulin on an isocaloric, low-protein diet.

In previous studies a low-calorie, low-protein diet caused a sustained reduction in both oxypurinol and uric acid renal clearances (CLR). With the hypothesis that the decrease in CLR was due to the low-protein and not the low-caloric content of the diet, we studied the CLR of oxypurinol, uric acid, creatinine, and inulin in normal subjects during isocaloric (2600 calories per 70 kg per day), normal-protein (150 gm per day), and low-protein (19 gm per day) diets. There were three major findings: (1) the CLR of oxypurinol declined from 26.6 +/- 1.8 ml/min on the normal-protein diet to 13.5 +/- 1.4 ml/min on the isocaloric low-protein diet (p less than 0.05); (2) the CLR of inulin and creatinine fell 14% and 20%, respectively, on the low-protein diet compared with the normal-protein diet (both p less than 0.05); and (3) there was a diurnal variation in the CLR of oxypurinol. We conclude that the decreased CLR of oxypurinol was the result of the reduced protein content of the diet and the CLR of both inulin and creatinine were decreased on the low-protein diet.

Lack of effect of oral activated charcoal on imipramine clearance.

The effect of oral activated charcoal on the pharmacokinetics of intravenous imipramine was studied in a randomized, crossover trial. Four normal men received intravenous imipramine (12.5 mg/70 kg) on two separate occasions, followed by either water or water plus high-surface-area activated charcoal (180 gm) in divided doses over 24 hours. Serum imipramine concentrations were measured from 0 to 24 hours after the imipramine infusion. There was no difference in the mean (+/- SE) t1/2 (9.0 +/- 0.8 vs. 10.9 +/- 1.6 hours), apparent volume of distribution (11.2 +/- 2.1 vs. 12.4 +/- 2.1 L/kg), or systemic clearance (992.2 +/- 138.3 vs. 930.3 +/- 101.9 ml/min/70 kg) of imipramine after dosing without and with oral activated charcoal, respectively (P greater than 0.05; paired t test). These results suggest that multiple oral doses of activated charcoal do not increase the clearance of imipramine in man.

Sustained reductions in oxipurinol renal clearance during a restricted diet.

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 less than 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 less than 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.

The determinants of response to diltiazem in hypertension.

We examined factors (blood pressure, plasma renin activity, and age) influencing the antihypertensive response in essential hypertensive patients given 240 mg/day of slow-release diltiazem in an unblinded study after a placebo run-in period. Subjects provided a range of diastolic blood pressures (90 to 115 mm Hg), of age (31 to 70 years), and of plasma renin activity (0.1 to 2.7 ng angiotensin I/ml/hr) on a 70 to 150 mEq sodium diet. Blood pressure, plasma renin activity, and plasma diltiazem concentrations were measured after the first (n = 21) and final dose (n = 19) of 120 mg diltiazem, twice daily for 4 weeks. Multiple linear stepwise regression of change in blood pressure versus age, plasma renin activity, and baseline blood pressure showed baseline blood pressure was the only predictor of response (p = 0.0002). For each increase of 10 mm Hg in baseline pressure there was a 7 mm Hg greater decrease in diastolic blood pressure. We conclude that patient age and plasma renin activity are not clinically significant predictors of antihypertensive response to diltiazem in hypertension.

Effects of size and frequency of oral doses of charcoal on theophylline clearance.

The effect of size and frequency of oral doses of activated charcoal on theophylline kinetics was studied. Six fasting, healthy men received intravenous infusions of aminophylline (6 mg/kg) over 1 hr, followed by either no activated charcoal as a control, 5 gm activated charcoal every 2 hr for 6 doses, 10 gm every 2 hr for 6 doses, 10 gm every hr for 12 doses, 20 gm every 2 hr for 6 doses, or 40 gm every 4 hr for 3 doses. Five grams every 2 hr decreased serum theophylline t 1/2 from the control of 9.1 +/- 0.7 to 5.6 +/- 0.4 (SE) hr and decreased the AUC from the control of 123 +/- 11 to 79 +/- 6 mg X hr/l. The regimen of 20 gm every 2 hr further decreased theophylline t 1/2 to 4.3 +/- 0.4 hr and decreased AUC to 62 +/- 6 mg X hr/l. When a 120-gm dose of activated charcoal was given as a regimen of 40 gm every 4 hr or as a regimen of 10 gm every hr, there were small differences in serum theophylline t 1/2 (5.4 +/- 0.3 and 4.3 +/- 0.2 hr) and in AUC (73 +/- 5 and 60 +/- 4 mg X hr/l). Repeated small doses of oral activated charcoal enhanced the total body clearance of theophylline, and larger doses induced a relatively small further increase. There was little difference between the effects of the same total dose every 4 hr vs every hour.

Model for theophylline overdose treatment with oral activated charcoal.

The effect of repeated oral doses of activated charcoal on theophylline kinetics was studied in six subjects with hepatic cirrhosis and five patients with moderate theophylline poisoning to determine whether an activated charcoal regimen would be a useful strategy in patients with theophylline poisoning who did not require hemoperfusion. Six subjects with cirrhosis were injected IV with 6 mg/kg aminophylline followed by either water or water with activated charcoal (140 gm) in divided doses over 12 hr. In these subjects, treatment with activated charcoal decreased the mean (+/- SE) serum theophylline t1/2 from 12.7 +/- 4.0 hr to 4.0 +/- 0.7 hr. Subjects with the longest control t1/2s demonstrated the greatest charcoal effect. We developed a mathematical model that predicts that treatment with repeated oral doses of activated charcoal would result in an average serum theophylline t1/2 of 7.1 hr or less even if the subject's endogenous theophylline t1/2 is very long. In a pilot study of five patients with moderate theophylline poisoning, treatment with repeated oral doses of activated charcoal was well tolerated and led to a mean (+/- SE) t1/2 that was shorter than expected (4.9 +/- 0.8 hr, range 3.1 to 7.1 hr). We conclude that repeated oral doses of activated charcoal are relatively more effective in decreasing the serum theophylline t1/2 in persons with long endogenous t1/2s and that this may be useful for certain patients with mild or moderate theophylline poisoning.

Use of hemoperfusion for treatment of theophylline intoxication.

We review our experience in the management of patients with plasma theophylline concentrations of 30 micrograms/ml or greater. Over a two-and-a-half-year period, 22 patients (Group 1) had plasma theophylline concentrations of 37 +/- 1 micrograms/ml (mean +/- SE) and experienced no severe toxicity (i.e., ventricular extrasystoles or tachycardia, seizures, cardiovascular collapse, or death). Six patients (Group 2) took overdoses of theophylline (92 +/- 12 micrograms/ml) and one died. Eight patients (Group 3) were iatrogenically intoxicated (48 +/- 6 micrograms/ml) and three died. Six patients from Groups 2 and 3 underwent hemoperfusion and did well, except for one patient, in whom seizures developed before hemoperfusion was initiated. We conclude from this experience that charcoal hemoperfusion is a useful procedure for the treatment of theophylline intoxication because of: (1) the serious morbidity and mortality of theophylline intoxication, (2) the prevention of complications with hemoperfusion, and (3) the relative safety of the procedure. We provide tentative guidelines for the initiation of hemoperfusion for the treatment of theophylline intoxication.

Prostacyclin substitution for heparin in long-term hemodialysis.

We studied prostacyclin as a substitute for heparin in 12 patients who underwent maintenance hemodialysis. All subjects underwent initial hemodialysis with prostacyclin as the sole anticoagulant; 10 of the 12 were restudied during heparin hemodialysis. Few adverse reactions occurred during prostacyclin hemodialysis in the 10 patients in whom dialysis was performed against a bicarbonate-containing dialysate; however, significant hypotension developed in two subjects when an acetate bath was used. Platelet aggregation progressively decreased during prostacyclin hemodialysis (p less than 0.02), but not during heparin hemodialysis, and returned toward control values after hemodialysis. Platelet thromboxane release decreased during both prostacyclin and heparin hemodialysis. Intradialytic percent decrements in serum urea nitrogen and creatinine were greater during prostacyclin than heparin administration (42 +/- 2.9 percent versus 36 +/- 2.6 percent [p less than 0.05] and 33 +/- 2.6 percent versus 29 +/- 2.1 percent [0.05 less than p less than 0.1], respectively). The plasma concentrations of 6-keto-prostaglandin-F1 alpha, a prostacyclin metabolite, reached peak levels by 120 minutes of hemodialysis and declined biexponentially toward predialysis concentrations during 120 minutes after hemodialysis, thereby providing an index of cumulative prostacyclin dosage. We conclude that prostacyclin is not only a safe alternative to heparin anticoagulation during hemodialysis, but that prostacyclin might also increase the efficiency of hemodialysis.

Effect of dietary protein on renal tubular clearance of drugs in humans.

Diet is one of many factors that influence the pharmacokinetics of drugs. The level of protein intake has been found to significantly influence drug metabolism and glomerular filtration, both of which play an important role in the clearance of drugs. Recently, a marked change, resulting from restricted dietary protein intake, has been reported in the handling of several drugs which are reabsorbed and/or secreted by the renal tubules. In studies of healthy volunteers on protein-restricted diets the renal clearance and fractional excretion of model compounds have been altered, falling to 30% of values obtained on normal diets in the case of the weak acids oxipurinol and uric acid; the fractional excretion of the weak base cimetidine has been increased by 30%. These studies have also found that the change in the renal clearance of both acids is sustained with prolonged dietary protein-calorie restriction, and that, for oxipurinol, the magnitude of the change is directly related to the quantity of protein in the diet, the change is related specifically to the protein content in the diet (and not the total calories), the onset of change is rapid, and on a low-protein diet the renal clearance undergoes marked diurnal variation. The mechanism for the alteration in tubular function is not clear, but may be related to renal haemodynamic changes or competition for transport associated with protein intake. Regardless of the mechanism, these results have important implications for pharmacokinetic research and clinical practice.

The use of confidence intervals to describe the precision of trough/peak ratios for diltiazem CD in the treatment of hypertension.

Once-daily diltiazem hydrochloride, CARDIZEM CD (diltiazem CD) 300 mg, was evaluated for safety, efficacy, and the relationship between peak and trough antihypertensive effects in a multicenter, placebo-controlled, parallel design trial. After a 4- to 6-week placebo baseline period, 111 patients with essential hypertension were randomized to receive placebo or diltiazem CD for a 4-week treatment period. Diltiazem CD 300 mg lowered supine diastolic and systolic blood pressure at trough significantly more than placebo (-7.5 mm Hg vs. -1.3 mm Hg, P = 0.0001 and -6.4 mm Hg vs. 0.5 mm Hg, P = 0.0051, respectively). Supine blood pressure was also measured hourly from 6 to 10 hours after the dose to assess peak effect and trough/peak ratios. Using the largest residual drug effect of -8.3 mm Hg at 6 hours as peak and the 24-hour residual drug effect of -5.9 mm Hg as trough, the trough/peak ratio was estimated to be 71%, with a lower one-sided 95% confidence limit of 50%. The precision of the trough/peak ratio is estimated by the lower confidence limit of 50%, which establishes the trough/peak ratio as statistically > or = 50%. No statistically significant differences in supine DBP were noted between the peak effect hours, indicating a plateau of the peak antihypertensive effect from 6 to 10 hours postdose. Diltiazem CD therapy was well tolerated, with no serious treatment-related adverse events reported during the trial and no patients discontinuing the trial due to a treatment-related adverse event.(ABSTRACT TRUNCATED AT 250 WORDS)

Superactivated charcoal versus cholestyramine for cholesterol lowering: a randomized cross-over trial.

To evaluate the relative abilities of superactivated charcoal (20 g twice daily) and cholestyramine (8 g twice daily) to lower plasma cholesterol concentrations acutely, six hypercholesterolemic patients were studied using a randomized cross-over design. After a 1-week dietary control period, each subject received 3 weeks of each treatment regimen on separate occasions. Superactivated charcoal and cholestyramine reduced total plasma cholesterol by 21.8 +/- 3.8% and 16.2 +/- 2.4%, respectively. Side effects were mild and similar for both treatments. At the dosage regimens studied, superactivated charcoal and cholestyramine have comparable ability to lower plasma cholesterol concentrations.

Reduced renal clearance of oxypurinol during a 400 calorie protein-free diet.

A decrease in dietary protein intake lowers the clearance of a number of substances excreted principally by the kidney including uric acid and oxypurinol, the major metabolite of allopurinol. We studied the kinetics of uric acid and oxypurinol in seven healthy volunteers on a normal protein diet (2600 calories; 100 g protein) followed by a 400 calorie, protein-free diet. A 600 mg dose of allopurinol was given orally after 6 days of the normal protein diet and again after 2 days of the 400 calorie, protein-free diet. Two major findings emerged: first, the renal clearance of oxypurinol was reduced from 21.2 +/- 1.9 ml/min during the normal protein diet to 12.3 +/- 1.2 ml/min (P less than .05) during the 400 calorie, protein-free diet, and second, there was a striking diurnal difference in oxypurinol renal clearance with a 41% decrease in the oxypurinol clearance at night (8 PM to 8 AM) versus day (8 AM to 8 PM) on the 400 calorie, protein-free diet.