Potassium repletion fails to interfere with reduction of serum lithium by sodium polystyrene sulfonate in mice.

OBJECTIVES: Previous studies have shown that oral sodium polystyrene sulfonate (SPS) lowers serum lithium concentrations after acute and chronic toxic lithium exposures. Because hypokalemia may represent a deterrent to the clinical use of SPS for lithium intoxication, this study was designed to determine whether potassium (K+) repletion interferes with the effect of SPS on serum lithium. METHODS: 168 male, CD-1 mice were given lithium chloride (LiCl) (250 mg/kg) by gavage at time 0. Half of the mice were then given SPS (5 g/kg/dose) and half an equivalent volume of water by gavage at times 20 and 40 minutes. Half of each of these subgroups was then given potassium chloride (KCl) (3 mmol/kg) intraperitoneally and half an equivalent volume of normal saline. The animals were then sacrificed at one, two, four, and eight hours after lithium administration and the sera were analyzed for lithium and K+ by atomic absorption spectrophotometry. The groups were compared with analysis of variance. RESULTS: The SPS lowered both lithium and K+ concentrations (ps < or = 0.0001). The KCl treatment was associated with transiently increased K+ concentrations (p < 0.0001) and with mildly elevated lithium concentrations when compared with the results of the animals not treated with KCl (p = 0.0016). The KCl treatment-associated increase in lithium concentration occurred both in the animals treated with water and in those treated with SPS. CONCLUSIONS: Potassium repletion did not interfere with the ability of SPS to lower serum lithium concentration in animals experimentally poisoned with lithium.

Around-the-clock, controlled-release oxycodone therapy for osteoarthritis-related pain: placebo-controlled trial and long-term evaluation.

BACKGROUND: Although opioid analgesics have well-defined efficacy and safety in treatment of chronic cancer pain, further research is needed to define their role in treatment of chronic noncancer pain. OBJECTIVE: To evaluate the effects of controlled-release oxycodone (OxyContin tablets) treatment on pain and function and its safety vs placebo and in long-term use in patients with moderate to severe osteoarthritis pain. METHODS: One hundred thirty-three patients experiencing persistent osteoarthritis-related pain for at least 1 month were randomized to double-blind treatment with placebo (n = 45) or 10 mg (n = 44) or 20 mg (n = 44) of controlled-release oxycodone every 12 hours for 14 days. One hundred six patients enrolled in an open-label, 6-month extension trial; treatment for an additional 12 months was optional. RESULTS: Use of controlled-release oxycodone, 20 mg, was superior (P<.05) to placebo in reducing pain intensity and the interference of pain with mood, sleep, and enjoyment of life. During long-term treatment, the mean dose remained stable at approximately 40 mg/d after titration, and pain intensity was stable. Fifty-eight patients completed 6 months of treatment, 41 completed 12 months, and 15 completed 18 months. Common opioid side effects were reported, several of which decreased in duration as therapy continued. CONCLUSIONS: Around-the-clock controlled-release oxycodone therapy seemed to be effective and safe for patients with chronic, moderate to severe, osteo-arthritis-related pain. Effective analgesia was accompanied by a reduction in the interference of pain with mood, sleep, and enjoyment of life. Analgesia was maintained during long-term treatment, and the daily dose remained stable after titration. Typical opioid side effects were reported during short- and long-term therapy.

Efficacy and safety of controlled-release versus immediate-release oxycodone: randomized, double-blind evaluation in patients with chronic back pain.

OBJECTIVE: To compare the efficacy and safety of controlled-release oxycodone given every 12 hours with immediate-release oxycodone given four times daily in patients with persistent back pain. DESIGN: Randomized, double-blind, active-controlled, two-period crossover trial. PATIENTS: Fifty-seven adult outpatients with stable, chronic, moderate-to-severe low back pain despite analgesic therapy were enrolled; 47 were randomized; 11 discontinued for side effects, most commonly nausea and vomiting. INTERVENTIONS: Controlled-release oxycodone tablets given every 12 hours; immediate-release oxycodone tablets given four times daily; dose titration with controlled-release or immediate-release for up to 10 days; double-blind treatment for 4-7 days each. OUTCOME MEASURES: Patients' pain scores (0 = none, 1 = slight, 2 = moderate, 3 = severe). RESULTS: Pain intensity decreased from moderate to severe at baseline to slight at the end of titration with both oxycodone formulations. The daily oxycodone dose was 40 mg or less in 68% of patients. During double-blind treatment, mean pain intensity was maintained at 1.2 (0.1 SE) with controlled-release and at 1.1 (0.1 SE) with immediate-release oxycodone. The most common adverse events were constipation, nausea, pruritus, somnolence, and dizziness. CONCLUSIONS: Controlled-release oxycodone given every 12 hours was comparable with immediate-release oxycodone given four times daily in efficacy and safety, and it provides convenient, twice-daily, around-the-clock treatment for selected patients with persistent back pain that is inadequately controlled by nonopioids or as-needed opioid therapy.

Relative potency of controlled-release oxycodone and controlled-release morphine in a postoperative pain model.

OBJECTIVE: The relative analgesic potency of single doses of oral controlled-release oxycodone and oral controlled-release morphine were compared in a randomized, double-blind trial using a postoperative pain model. METHODS: Women (n = 169) with moderate to severe pain following abdominal hysterectomy received single oral doses of controlled-release oxycodone, 20 mg or 40 mg, or controlled-release morphine, 45 mg or 90 mg. Assessments were made at 30 min, 60 min, then hourly after dosing for 12 h or until remedication. RESULTS: The most precise estimates of relative potency showed that controlled-release oxycodone was 1.8 times more potent than controlled-release morphine for total effect (95% confidence limits 1.09-2.42; lambda 0.44) and 2.2 times more potent for peak effect (95% confidence limits 0.96-4.59; lambda 0.71). Controlled-release oxycodone at doses of 20 mg or 40 mg was comparable with controlled-release morphine at doses of 45 mg or 90 mg, respectively, for total and peak analgesic effects. For the two higher doses, time to peak relief was approximately 1 h shorter with controlled-release oxycodone than with controlled-release morphine. Most patients reported onset of analgesia within 1 h with all doses. Side effects were similar with the two opioids. CONCLUSION: Oral controlled-release oxycodone was twice as potent as oral controlled-release morphine in this single-dose, relative potency assay. When converting patients from oral morphine to oral oxycodone, an initial oral oxycodone dose of one-half the oral morphine dose is recommended.

Treatment of osteoarthritis pain with controlled release oxycodone or fixed combination oxycodone plus acetaminophen added to nonsteroidal antiinflammatory drugs: a double blind, randomized, multicenter, placebo controlled trial.

OBJECTIVE: To compare the efficacy and safety of controlled release oxycodone given every 12 h around the clock with immediate release oxycodone-acetaminophen (APAP) given 4 times daily for osteoarthritis (OA) pain. METHODS: Adults (n=167) with moderate to severe OA pain despite regular use of nonsteroidal antiinflammatory drugs (NSAID) entered open label titration for 30 days with immediate release oxycodone qid; 107 qualified for randomization to double blind, parallel group treatment for 30 days with placebo, controlled release oxycodone, or immediate release oxycodone-APAP. RESULTS: Following titration with immediate release oxycodone, mean (SE) pain intensity (0, none to 3, severe) decreased from 2.44 (0.04) to 1.38 (0.05) (p=0.0001), and quality of sleep (1, very poor; 5, excellent) improved from 2.58 (0.08) to 3.57 (0.07) (p=0.0001). Mean dose was about 40 mg/day. Pain intensity and quality of sleep were significantly improved in both active groups compared with the placebo group (p< or =0.05) during the double blind trial. Pain intensity and sleep scores were comparable in both active groups during double blind treatment. Nausea (p=0.03) and dry mouth (p=0.09) were less common with controlled release oxycodone than immediate release oxycodone-APAP. CONCLUSION: Controlled release oxycodone q12h and immediate release oxycodone-APAP qid, added to NSAID, were superior to placebo for reducing OA pain and improving quality of sleep. The active treatments provided comparable pain control and sleep quality. Controlled release oxycodone was associated with a lower incidence of some side effects.

Theophylline inhibits the late asthmatic response to nighttime antigen challenge in patients with mild atopic asthma.

BACKGROUND: Inhaled antigen at night causes a more pronounced late asthmatic response (LAR) when compared with daytime challenges. Chronopharmacology with controlled-release theophylline given in the evening leads to a peak serum theophylline concentration (STC) in early morning which coincides with LAR that follows an evening challenge. OBJECTIVE: To evaluate the effect of controlled-release theophylline given with the evening meal on the immediate asthmatic response (IAR) and LAR following nighttime antigen challenge in patients with mild atopic asthma. METHODS: To qualify, subjects underwent antigen bronchoprovocation by graded nebulization until the IAR (fall in FEV1 of > or =20%) occurred; spirometry was then measured hourly for 8 hours to establish the presence of LAR (fall in FEV1 > or =15%). After 2 weeks of randomized, double-blind crossover treatment with either theophylline (target STC of 10 to 15 mg/L, (56 to 83 micromol/L)) or placebo, inhaled antigen challenge was performed at 10 PM in each subject. FEV1 values were measured immediately and then hourly for 8 hours following antigen challenge. RESULTS: Twelve subjects completed the study. During the placebo phase, the maximal fall in FEV1 during LAR was 39 +/- 3% (mean +/- SEM) compared with 31 +/- 4% fall during theophylline treatment phase (P = .01). A reduction in LAR occurred despite higher dose (P <.05) of inhaled antigen during theophylline phase, which would have been expected to result in a more pronounced LAR. Serum theophylline concentration at 8 AM on the day following antigen challenge was 9.6 +/- 1.1 mg/L (53 +/- 6 micromol/L). CONCLUSION: Nocturnal administration of controlled-release theophylline increases the tolerance to inhaled antigen and reduces severity of LAR. Because the LAR is linked to airway inflammation, these data support the possibility of antiinflammatory effects associated with theophylline use.

Use of sodium polystyrene sulfonate for reduction of plasma lithium concentrations after chronic lithium dosing in mice.

OBJECTIVES: Previous studies have shown that oral sodium polystyrene sulfonate lowers plasma lithium concentrations after acutely administered oral doses of lithium chloride. However, a significant proportion of lithium overdose cases resulting in morbidity and mortality are those in which exposure to lithium is chronic. This study was designed to determine whether multiple oral doses of sodium polystyrene sulfonate are effective in reducing plasma lithium concentrations after chronic dosing. DESIGN: Placebo-controlled animal study. INTERVENTIONS: One hundred thirty mice were given 75 mM lithium chloride in their drinking water for a period of 14 days. At the end of that period, half of the animals were given orogastric sodium polystyrene sulfonate at 5 g/kg/dose 0, 60, 120, 180, and 360 minutes after the cessation of lithium chloride; the remaining half received orogastric water at equivalent times. Subgroups of each group were sacrificed at 90, 150, 330, 480, 1440, and 2880 minutes after lithium chloride cessation and plasma analyzed for lithium content. Lithium concentrations were compared by analysis of variance and single degree of freedom contrasts. Significance was set at an alpha level of 0.05. RESULTS: Lithium concentration was lower overall in the animals treated with sodium polystyrene sulfonate (p < .0001) and specifically at 150, 330, and 480 minutes after lithium chloride cessation (p < .05). CONCLUSIONS: Repetitive oral doses of sodium polystyrene sulfonate effectively lowered plasma lithium concentrations. Further study may ultimately define a role for the use of sodium polystyrene sulfonate in the treatment of patients with chronic lithium toxicity.

Enhancement of lithium elimination by multiple-dose sodium polystyrene sulfonate.

OBJECTIVE: To determine whether multiple doses of sodium polystyrene sulfonate (SPS) enhance the elimination of IV-administered lithium (Li). METHODS: The study was a placebo-controlled, investigator-unblinded, murine trial of multiple doses of SPS on serum Li concentrations. Seventy-five male CD-1 mice were given IV pretreatment with LiCl (125 mg/ kg) followed by gavage treatments with SPS (5 g/kg/dose) 20, 40, 90, 150, and 210 minutes after LiCl (experimental group) or deionized water at equivalent times (control group). Subgroups of each treatment group were sacrificed at 1, 2, 4, and 6 hours after LiCl administration and blood was collected for Li analysis. RESULTS: Statistical analyses indicated that the SPS group had lower serum Li concentrations overall than did the control animals. This difference was apparent at the 2-, 4-, and 6-hour time points. CONCLUSION: In this murine model, repetitive doses of orogastric SPS enhanced the elimination of parenterally administered Li.

Sodium polystyrene sulfonate treatment for lithium toxicity: effects on serum potassium concentrations.

OBJECTIVE: To examine the effects of sodium polystyrene sulfonate (SPS) on serum potassium (K) concentrations in mice pretreated with parenteral lithium (Li). METHODS: A placebo-controlled murine model trial of SPS therapy following IV Li was performed. Sixty male CD-1 mice weighing 18-22 g were administered either IV LiCl (125 mg/kg) or a control solution (normal saline). Half of the mice in each of these groups were then given orogastric water 20, 40, 90, 150, and 210 minutes after LiCl or normal saline; the other half received SPS (5 g/kg/dose) at equivalent times. Subgroups of each of these four groups were sacrificed at one, two, and six hours after pretreatment and the serum was analyzed for K concentration. Serum K concentrations for the various groups were compared with analysis of variance and Newman-Keuls tests for the comparison of multiple means. RESULTS: A statistically significant reduction of serum K concentrations occurred in the animals that received SPS treatment following either IV saline or LiCl solutions. The degree of K reduction that resulted from the combination of LiCl and SPS treatment (35% reduction at six hours, compared with the placebo-treated controls) was larger than that which resulted from either IV Li with oral water (15% reduction) or IV saline with oral SPS (20% reduction). CONCLUSIONS: These findings suggest that development of hypokalemia may represent a potential limitation in the use of SPS in the treatment for Li toxicity.

Effect of delayed treatment with sodium polystyrene sulfonate on serum lithium concentrations in mice.

OBJECTIVES: To determine the efficacy of sodium polystyrene sulfonate (SPS) in lowering serum lithium (Li) concentrations. Specifically, to determine the effects of both different doses of SPS and different times to treatment with SPS on serum Li levels. METHODS: The study was a controlled, single-dose murine trial of SPS on serum Li levels. Male CD-1 mice (n = 525) were given orogastric LiCl and then divided into three main treatment groups: group SPS received a single orogastric administration of SPS in a dose of 5 gm/kg body weight at either 0, 15, 30, 45, or 90 minutes after LiCl; group half-SPS received a single orogastric administration of SPS in a dose of 2.5 gm/kg body weight at times equivalent to those of group SPS; and the control group received orogastric deionized water in a volume equivalent to that of group SPS at 0, 15, 30, 45, or 90 minutes after LiCl. Subgroups of seven to ten mice in each of the four treatment groups were sacrificed at one, two, four, and eight hours after administration of LiCl, and their blood was analyzed for Li concentration. RESULTS: 1) Single doses of SPS significantly lowered serum Li concentrations; 2) this effect was dose-related; 3) the delays in administration of SPS used in this study did not significantly reduce its ability to lower serum Li concentrations; and 4) even when administered after peak serum Li concentrations had been achieved, a single dose of SPS was effective in lowering serum Li levels. CONCLUSIONS: SPS may be efficacious in the treatment for Li toxicity under certain circumstances, even when there is delay to treatment. Additional study is warranted to further characterize the ability of SPS to alter Li kinetics.

Iron absorption from chewable vitamins with iron versus iron tablets: implications for toxicity.

The medical literature contains few, if any, reports of severe iron (Fe) poisonings from ingestion of chewable multivitamins with iron. One possible explanation for this observation is that iron from multivitamins is more poorly absorbed than iron from iron tablets. To compare iron absorption from multivitamins with iron absorption from ferrous fumarate tablets, male adult volunteers were given 6 mg of elemental Fe/kg body weight as chewable multivitamins with iron or as crushed ferrous fumarate tablets in a crossover study. Serum Fe and total iron binding capacity (TIBC) were determined prior to administration of the tablets and one, two, four, and six hours after ingestion. Statistical analyses demonstrated increased and more rapid absorption of Fe from the multivitamin preparation. These results suggest that iron is well absorbed from chewable multivitamins with iron and should theoretically have the potential for producing serious toxicity when taken in overdose. The reasons that such toxicity is not commonly seen clinically are discussed, and a plan for further investigation of this issue is proposed.

Multiple-dose sodium polystyrene sulfonate in lithium intoxication: an animal model.

Previous work in our laboratory has demonstrated that sodium polystyrene sulfonate (SPS) significantly lowered serum lithium (Li) concentrations when administered in a single oral dose after an oral dose of lithium in a mouse model. The present study was designed to determine whether: 1) repetitive doses of SPS are effective in lowering serum lithium concentrations, 2) the effect of SPS on lithium concentration is dose related and 3) SPS enhances the elimination of lithium. Mice (N = 144) were given orogastric LiCl (250 mg/kg) and then divided into 4 groups: Controls received water 0, 30, 90, 180, and 360 min. after LiCl; the Full-Dose SPS Group received SPS (5 g/kg/dose) at equivalent times; the Half-Dose SPS Group received SPS (2.5 g/kg/dose) at the same times; and the Elimination Group received water at 0 and 30 min. after LiCl and SPS at 90, 180 and 360 min. after LiCl. Subgroups of each group were sacrificed at 1, 2, 4 and 8 hr post-treatment and serum analyzed for lithium concentrations. Statistical analyses revealed that, when compared to Controls: 1) SPS significantly lowered serum lithium concentrations; 2) this effect was dose-related; 3) repetitive dosing of SPS appears to enhance the elimination of lithium.

Monitoring cyanide and thiocyanate concentrations during infusion of sodium nitroprusside in children.

Over a 19-month period, all requests for blood cyanide and/or serum thiocyanate concentrations to the Clinical Laboratory of The Children's Hospital, Boston, were reviewed in order to determine how physicians screen for nitroprusside-related toxicity. During that period, 52 patients receiving nitroprusside were monitored for cyanide and/or thiocyanate toxicity. Overall, there were 62 cyanide and 86 thiocyanate determinations. None of the thiocyanate determinations and five of the cyanide concentrations were within the toxic range as established by the reference laboratory, and no patient displayed signs or symptoms of toxicity which could not also be explained by their underlying illness. Our findings suggest that while physicians are concerned with nitroprusside toxicity in children, there exists no apparent consensus as to how to monitor for this toxicity. The results also indicate that the relationship between blood cyanide or serum thiocyanate concentrations and clinical evidence of toxicity is not straightforward and requires further delineation.

The adsorption of salicylates by a milk chocolate-charcoal mixture.

STUDY OBJECTIVE: To evaluate the adsorptive capacity of a milk chocolate-charcoal mixture to aspirin, compared with superactivated charcoal and conventional activated charcoal. DESIGN: A prospective, randomized, crossover study. SETTING: The Massachusetts Poison Control Center office in The Children's Hospital, Boston. TYPE OF PARTICIPANTS: Six healthy adult volunteers with no known allergies to aspirin or chocolate, bleeding disorders, or peptic ulcer disease. INTERVENTIONS: Each participant ingested 975 mg of crushed aspirin on separate days, followed by either water; 10 g milk chocolate-charcoal mixture; 10 g SuperChar Liquid; or 10 g Actidose Aqua activated charcoal. Total serum salicylate concentrations were determined by high-performance liquid chromatography at zero, one, two, four, eight, and 24 hours after ingestion. MEASUREMENTS AND MAIN RESULTS: Neuman-Keuls analysis was used to measure time-to-peak concentration, which was reduced by SuperChar Liquid, 67%; milk chocolate-charcoal mixture, 106%; and activated charcoal, 56%. Aspirin absorption was calculated using Neuman-Keuls analysis to measure area under the concentration-time curve. Total aspirin absorption was reduced by SuperChar, 67%; milk chocolate-charcoal mixture, 50%; and activated charcoal, 2%. There was no difference in serum salicylate concentrations between SuperChar and milk chocolate-charcoal mixture at all time intervals. Also, all serum salicylate concentrations with milk chocolate-charcoal mixture were consistently lower than with activated charcoal. CONCLUSION: Although the formulation of milk chocolate with activated charcoal reduces its adsorptive capacity compared with superactivated charcoal, it is still able to bind aspirin effectively and is superior to conventional activated charcoal. Further research may improve the binding and palatability of milk chocolate-charcoal mixture, especially for home use.

Serum magnesium concentrations after repetitive magnesium cathartic administration.

Severe hypermagnesemia has been reported by several authors after multiple doses of magnesium-containing cathartic are administered during management of a toxic ingestion. To evaluate the frequency and magnitude of serum magnesium elevations after the use of repetitive magnesium catharsis, we prospectively evaluated 102 patients who received multiple doses of magnesium citrate as a part of treatment of an overdose. Commonly ingested substances for which repetitive cathartic was administered were tricyclic antidepressants in 47%, aspirin in 17%, and phenytoin in 10%. For each case, serial electrolytes, blood urea nitrogen, creatinine, calcium and magnesium were obtained. Mean initial serum magnesium concentration was 1.8 +/- .03 mEq/L. After a mean 960 mL of magnesium citrate (9.22 g magnesium), final mean serum magnesium concentration was 2.5 +/- .05 mEq/L. Forty-seven patients (47%) developed an elevated (greater than 2.4 mEq/L) serum magnesium concentration, with 12 greater than 3.0 mEq/L. No correlation was found between total quantity of magnesium citrate administered and the increment in serum magnesium concentration. Our data indicate that serum magnesium concentrations consistently rise after repetitive magnesium citrate use. However, the magnitude of this rise appears modest. The elevation in serum magnesium concentration does not correlate with the quantity of magnesium administered. We conclude that with close monitoring, repetitive magnesium citrate can be administered without inducing severe hypermagnesemia (serum magnesium concentration greater than 5.0 mEq/L).

Office management of acute pediatric poisonings.

Over the past five years, the role of the office practitioner in diagnosis and management of acute poisoning has developed into an important first line of defense in preventing serious morbidity and mortality associated with these exposures. The prime role of the practitioner is to accurately identify and quantify a poisoning exposure, to institute appropriate initial stabilization and management, and to recognize individuals who require further treatment and transfer to hospital settings. Beyond the obvious importance of initial stabilization of severely poisoned patients, the most important step in approaching the acute overdose is to identify what was taken, how much was taken, and when it was taken. To ensure appropriate treatment, the practitioner must use all the resources possible to obtain accurate identification and quantification of these exposures. Nontoxic exposures judged by the product (see Table 5) or by the quantity ingested (see Table 4) may safely be discharged with follow-up care. With toxic exposures, all attempts must focus on terminating the exposure by gastrointestinal decontamination with oral poisonings, adequate aeration with inhalational poisonings, and copious washing with topical and/or ocular exposures. The skillful approach of the office practitioner will provide the most effective initial management of the poisoned child. Appropriate referral to an emergency department for further evaluation and treatment may then be considered.

Administration of activated charcoal or sodium polystyrene sulfonate (Kayexalate) as gastric decontamination for lithium intoxication: an animal model.

To determine whether sodium polystyrene sulfonate (SPS; Kayexalate) is effective in decreasing the absorption of lithium (Li) and to test the assumption that Li is poorly adsorbed by activated charcoal, 130 mice were administered an orogastric dose of LiCl (250 mg/kg) followed immediately by orogastric SPS (10 g/kg, SPS Group), activated charcoal (6.7 g/kg, AC Group), or water in an equivalent volume (Control Group). Subgroups of each of the 3 groups were sacrificed at 1, 2, 4 and 8 hr after treatment and serum analyzed for Li concentration. Statistical analyses revealed no overall difference between the AC Group and the Control Group. However, the SPS Group differed from both the Control and the AC Group at each time interval, with Li concentrations significantly lower in the SPS Group. These results demonstrate that: 1) SPS, in this study, effectively reduced serum Li concentrations in an in vivo model, and 2) activated charcoal did not.

Acute thyroxine ingestion in pediatric patients.

During a 1-year period, 15 cases of acute thyroxine (T4) overdose with documented serum T4 concentrations were studied. All patients were less than 5 years of age and 80% were boys. All were examined within 1 to 6 hours of ingestion and all were asymptomatic. Estimated dose ingested in 10 patients ranged from 1.5 to 8.8 mg (0.1 to 0.73 mg/kg). Three patients with initial T4 serum concentrations greater than 75 micrograms/dL manifested signs of toxicity within 12 to 48 hours (fever, tachycardia, hypertension, and/or agitation) that resolved within 24 to 60 hours. The mean elimination half-life of T4 in 7 patients with multiple serum concentrations was 2.8 +/- 0.4 days, whereas the mean elimination half-life of triiodothyronine was 6 +/- 1.7 days. It was concluded that (1) the majority of acute pediatric T4 overdoses are not severe and may be managed on an outpatient basis, (2) the absence of early clinical manifestations does not preclude delayed onset of toxicity that may be better predicted by initial T4 concentrations, and (3) the elimination half-life of T4 is shorter and the elimination half-life of tri-iodothyronine is longer than with therapeutic doses.