Massive lindane overdose with toxicokinetics analysis.

BACKGROUND: Lindane is a possible carcinogen with known teratogenicity and immunologic and neurotoxic properties. Despite reports of seizures, coma, and death associated with its use as well as banning of its environmental use by the Environmental Protection Agency (EPA), the US Food and Drug Administration (FDA) still allows treatment with lindane as a second-line scabicide and pediculicide. We present a case of a massive suicidal ingestion of lindane in which the patient survived the ingestion, though he did expire shortly thereafter from an unrelated cause pre-discharge. METHODS: Pharmacokinetic analysis of serum lindane concentrations was performed with Phoenix® WinNONLIN®. The estimated distribution half-life for lindane was 10.3 h, and the terminal half-life was 162.9 h, much longer than the previously reported terminal half-life of 25-36 h. Because of this long half-life, repeated lindane exposures may lead to accumulation of lindane in the tissues. RESULT: After overdose, toxicity may be delayed and full recovery may be prolonged.

CD4+ immune response as a potential biomarker of patient reported inflammatory bowel disease (IBD) activity.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBDs) which are characterized by dysfunctional regulation of the immune system. A number of immune modifying drugs are used to treat CD and UC. Therapy is adjusted largely on the bases of subjective reports of disease activity and non-specific laboratory tests. Identification of a single or combination of immune markers of disease activity could be useful to select and monitor therapeutic responses. However, to date no reliable quantitative associations between IBD activity and laboratory measures of immune function have been identified. This study was designed to evaluate the usefulness of a commercially available laboratory measure of CD4(+) immune function, the Cylex® ImmuKnow®, as a surrogate marker of IBD activity. METHODS: Adult IBD patients with either CD (N=55, 27 males, mean, SD age=38.5, 11.5 years) or UC (N=45, 24 males, mean, SD age=41.7, 15.4 years) were enrolled. Patients both in clinical remission and with active disease provided responses to structured, validated questionnaires (CDAI and HBI for CD patients and SCCAI for UC patients) used to monitor IBD activity. Whole blood and plasma samples were collected to quantify various markers of disease status including routine cell counts and differentials (CBCs), CRP, and albumin (Alb), as well as CD4(+) immune response (Cylex® ImmuKnow®, N=98). Results were compared between all IBD patients as well as between CD and UC subgroups. RESULTS: There was a good correlation between the results of CDAI and HBI scores (r=0.811, p<0.01, Spearman-Rho) but HBI scores correlated slightly better (r=0.575, p<0.001) than the CDAI's (r=0.449, p=0.001) with CD patients' reported perception of their general condition. CDAI and HBI scores categorized 12/55 versus 36/55 of CD patients respectively as having active disease. SCCAI scores indicated that 25/45 of UC patients had active disease. Cylex® results (in ng/mL of ATP) were increased in 74/98 IBD subjects (≥525 ng/mL) but were influenced by the use of systemic corticosteroids (SCS) and infliximab. There were weak but statistically significant Spearman-Rho correlations between Alb concentrations and both CDAI (r=0.413, p=0.002) and HBI (r=0.325, p=0.017) scores as well as between CRP values and HBI scores (r=0.331, p=0.016). Correlations between CRP and both CDAI and SCCAI scores and between Alb and SCCAI scores were not significant and there were no significant positive associations between any of the three clinical scores and Cylex® results. CONCLUSIONS: CD4(+) immune responses were significantly elevated in IBD patients whether or not they were in clinical remission but were influenced by treatment. There were some significant correlations between the clinical scores and CRP or Alb but not with the CD4(+) results. Both other clinical scoring systems, other measures of immune function, and CD4(+) immune response changes over time should be examined to see if this or other laboratory measures of immune response are predictive of actual disease activity or symptoms in CD or UC patients.

Measurement of acetaminophen-protein adducts in children and adolescents with acetaminophen overdoses. .

Acetaminophen-protein adducts are biomarkers of acetaminophen toxicity present in the centrilobular region of the liver of laboratory animals following the administration of toxic doses of acetaminophen. These biomarkers are highly specific for acetaminophen-induced hepatic injury and correlate with hepatic transaminase elevation. The objective of this prospective, multicenter study was to evaluate the clinical application of the measurement of acetaminophen-protein adducts in pediatric acetaminophen overdose patients. Serum samples were obtained from 51 children and adolescents with acetaminophen overdose at the time of routine blood sampling for clinical monitoring. Six subjects developed "severe" hepatotoxicity (transaminase elevation > 1,000 IU/L), and 6 subjects had transaminase elevation of 100 to 1,000 IU/L. Acetaminophen-protein adducts were detected in the serum of only 1 study subject, a patient with marked transaminase elevation (> 6,000 IU/L) and high risk for the development of hepatotoxicity according to the Rumack nomogram. While this study provides further support for the occurrence of covalent binding of acetaminophen to hepatic protein in humans following acetaminophen overdose, the detection of acetaminophen-protein adducts in serum with the current methodology requires significant biochemical evidence of hepatocellular injury.

Technical report: precautions regarding the use of aerosolized antibiotics. Committee on Infectious Diseases and Committee on Drugs.

In 1998, the Food and Drug Administration (FDA) approved the licensure of tobramycin solution for inhalation (TOBI). Although a number of additional antibiotics, including other aminoglycosides, beta-lactams, antibiotics in the polymyxin class, and vancomycin, have been administered as aerosols for many years, none are approved by the FDA for administration by inhalation. TOBI was approved by the FDA for the maintenance therapy of patients 6 years or older with cystic fibrosis (CF) who have between 25% and 75% of predicted forced expiratory volume in 1 second (FEV(1)), are colonized with Pseudomonas aeruginosa, and are able to comply with the prescribed medical regimen. TOBI was not approved for the therapy of acute pulmonary exacerbations in patients with CF nor was it approved for use in patients without CF. Currently, no other antibiotics are approved for administration by inhalation to patients with or without CF. The purpose of this statement is to briefly summarize the data that supported approval for licensure of TOBI and to provide recommendations for its safe use. The pharmacokinetics of inhaled aminoglycosides and problems associated with aerosolized antibiotic treatment, including environmental contamination, selection of resistant microbes, and airway exposure to excipients in intravenous formulations, will be discussed.

Pharmacokinetics of etodolac in patients with stable juvenile rheumatoid arthritis.

This was a single-center, open-label, single-dose pharmacokinetic study of etodolac in pediatric and adolescent patients with stable juvenile rheumatoid arthritis (JRA). Eleven male and female patients with JRA (8.1 to 14.8 years of age, weighing 26.4 to 59.5 kg) received a single oral dose of etodolac (200, 300, or 400 mg based on body weight). Clinical laboratory measurements, measurement of vital signs, and physical examinations were performed to monitor safety. Concentrations of etodolac were determined in plasma using high-performance liquid chromatography with ultraviolet detection with a limit of quantitation of 0.2 mg/L and were analyzed using a noncompartmental pharmacokinetic method. Pharmacokinetic parameters observed were consistent in magnitude and degree of variability with data from healthy adult subjects receiving a single 400- or 600-mg dose of etodolac. Although the mean fraction of unbound drug in patients with JRA was higher than in healthy adults, the oral clearance was independent of age. No serious adverse events occurred during this study. Etodolac yielded consistent pharmacokinetic values among stratified dose subgroups. Single doses of all etodolac treatments were well tolerated in both pediatric and adolescent patients.

Patient recruitment: US perspective.

There are many ethical, legal, economic, scientific, and practical problems associated with conducting drug trials in children. The single most difficult is subject identification and enrollment (ie, recruitment). This article reviews various aspects of the recruitment process and proposes potential solutions to recruitment problems.

Ten guiding principles for teaching children and adolescents about medicines. US Pharmacopeia.

In 1996, an open conference sponsored by the US Pharmacopeia (USP) and attended by more than 100 health care professionals established the need and rationale for teaching children and adolescents about medicines. After the conference, a public, iterative, consensus-development process including participation by 35 health-professional organizations was undertaken. This process resulted in a USP position statement, "Ten Guiding Principles for Teaching Children and Adolescents About Medicines," which supports the right of children and adolescents to receive developmentally appropriate information and direct communications about medicines that are consistent with their health status, capabilities, and culture. The position statement is intended to stimulate activities that will help children become active participants in the process of appropriate use of medicines and prepare them for the day they begin to use medicines independently.

Therapeutic drug monitoring in special populations.

Therapeutic drug monitoring (TDM) is commonly used to maintain "therapeutic" drug concentrations. Even in compliant patients, with "average" drug kinetics, TDM is useful to identify the causes of unwanted or unexpected responses, prevent unnecessary diagnostic testing, improve clinical outcomes, and even save lives. TDM has greatest promise in certain special populations who are: (a) prone to under- or overrespond to usual dosing regimens, (b) least able to tolerate, recognize, or communicate drug effects, or who are (c) intentionally or accidentally misdosed. TDM is especially useful in patients at the extremes of age, in adolescents, and in patients who are either taking multiple drugs or expressing unusual pharmacokinetics as a result of physiological, environmental, or genetic causes. Less-well-appreciated uses of TDM include prevention of dangerous underdosing of patients, investigation of adverse drug reactions, and identification of serious medication errors, even for a number of drugs that are not traditionally monitored. TDM can be useful for some drugs in any patient and for most drugs in some special populations.

Occlusion and levodopa-carbidopa treatment for childhood amblyopia.

PURPOSE: The purpose of the current study was to compare the effects of levodopa-carbidopa with and without part-time occlusion on visual function in older amblyopic children. METHODS: Thirteen older amblyopic children were randomly assigned to receive or not receive part-time occlusion (3 h/day) combined with 7 weeks of oral dosing with levodopa-carbidopa (1.02 mg/0.25 mg/kg body weight three times daily). Visual acuity, contrast sensitivity, and fusion were measured at baseline; 1, 3, 5, and 7 weeks during the treatment regimen; and 4 weeks after termination of all treatment. At these same times health status was assessed with standard laboratory blood tests, physical examination, and subjective questionnaire. RESULTS: From baseline to the follow-up test trial, both groups improved in visual acuity in the amblyopic eyes (occlusion group 20/116 to 20/76, P < .001; no occlusion group 20/90 to 20/73, P < .01) and dominant eyes (occlusion group 20/18 to 20/15, P > .05; no occlusion group 20/20 to 20/16, P < .01). The occlusion group exhibited a significant decrease in the difference in acuity between the dominant and amblyopic eyes of 1.3 lines (P < .02), whereas the no occlusion group revealed no significant effect. A comparison between groups revealed a significantly greater improvement in visual acuity in the amblyopic eye in the occlusion group compared with the no occlusion group (P = .01). In contrast, there was no significant difference between groups in terms of the change in visual acuity in the dominant eye (P = .15). Mean log contrast sensitivity in the amblyopic eye significantly improved in the occlusion group and did not significantly change in the no occlusion group. Fusion changed similarly in both groups. The improvements in visual function were maintained 4 weeks after the termination of all treatment. Adverse side effects were minimal in both groups. CONCLUSION: The combination of levodopa-carbidopa and occlusion improves visual function more than levodopa-carbidopa alone in older amblyopic children.

Levodopa-carbidopa and childhood retinal disease.

PURPOSE: Our purpose was to determine the influence of levodopa-carbidopa on visual function in children with retinal disease. METHOD: Two studies were undertaken, a single-dose study and a longitudinal dosing study. A double-masked, placebo controlled single-dose study was undertaken of levodopa-carbidopa (2.08 mg/kg of body weight levodopa with 25% carbidopa) on monocular visual acuity in 14 children with retinal disease. Subjects received two capsules approximately 2.5 hours apart, and monocular visual acuity was measured 2 hours after each capsule ingestion. The second study was a double-masked, placebo-controlled 12-week longitudinal dosing (0.62 mg/kg of body weight) crossover study in which subjects received levodopa-carbidopa for 6 weeks and placebo for 6 weeks. RESULTS: The single-dose study revealed a small but statistically significant improvement in monocular visual acuity after levodopa-carbidopa ingestion. The longitudinal study revealed a small but statistically significant improvement in binocular visual acuity after levodopa ingestion. In both studies placebo had no significant effect on visual acuity. Six subjects participated in both studies and demonstrated a significant correlation (r = 0.76, p < 0.05) between change in visual acuity in the single-dose study and the longitudinal dosing study. CONCLUSION: The results are consistent with the hypothesis that dopamine influences the receptive field characteristics of retinal cells. The results also suggest that there may be low retinal dopamine levels in some types of retinal disease, which may be amenable to treatment.

Population pharmacokinetics of felbamate in children.

Information about the pharmacokinetics of felbamate in children is limited. Even though it is claimed that monitoring of felbamate concentrations is unnecessary, many neurologists have requested therapeutic drug monitoring (TDM) for various reasons. This study used the NONMEM program to describe the pharmacokinetics and the influence of other anticonvulsants on the pharmacokinetics of felbamate. Felbamate, carbamazepine (CBZ), phenytoin (PHY), valproate (VPA), and barbiturate serum levels were obtained by our TDM service as requested by the clinician. The clearance and volume of distribution of felbamate were 41.1 ml/h/kg and 908 ml/kg, respectively. CBZ and PHY increased the clearance 49 and 40% while VPA decreased it 21%. Barbiturate had no significant effect. Clearance also decreased with age.

Serum lidocaine concentrations after subcutaneous administration in patients undergoing cardiac catheterization in a pediatric institution.

OBJECTIVE: We wished to determine serum lidocaine concentrations after subcutaneous injection during cardiac catheterization. METHOD: Serum lidocaine concentrations were measured in 50 patients during catheterization. RESULTS: Serum concentration was linearly related to dose per kilogram of body weight. Lidocaine concentrations were therapeutic in 38% of patients. CONCLUSION: Lidocaine dose must be considered when the drug is used for local anesthesia in children.

Clonazepam disposition in pediatric patients.

Plasma clonazepam (CZP) and its metabolite [7-aminoclonazepam (7ACZP) and 7-acetamidoclonazepam (7AACZP)] concentrations were measured during a single dosing interval in 10 pediatric epilepsy patients (2-18 years, 11-102 kg) who had been receiving CZP therapeutically from 2 weeks to 4 years. These concentrations were used to determine CZP and metabolite pharmacokinetics. With controlled dosing and postdose sample collection times, large variations were observed in calculated CZP nitroreduction rates [clearance (CL/F) ranged from 7 to 64 ml/h/kg] as well as 7ACZP acetylation rates (CL/F from 10 to 85 ml/h/kg). No 7AACZP (i.e., < 5 ng/ml) was detected by the methods used. Acetylation rates are known to be under genetic control. Further studies are needed to determine whether nitroreduction rates are also under genetic control and whether differences in either of these metabolic rates can explain intraindividual differences in clinical responses observed in CZP-treated patients.

Levodopa/carbidopa treatment for amblyopia in older children.

The purpose of the present study is to determine how long visual function improves during levodopa/carbidopa with part-time occlusion treatment in older amblyopic children. A 7-week open clinical trial of levodopa (0.55 mg/kg, three times daily) with 25% carbidopa combined with part-time occlusion (3 hours/day), was undertaken in 15 older (mean age, 8.87 years) amblyopic children. Visual acuity, fusion, and stereo acuity were measured at baseline, at weeks 1, 3, 5, and 7 during treatment, and 6 weeks following the end of all treatment. Health status was assessed by physical examination, questionnaire, and standard laboratory tests (CHEM 20, complete blood cell count [CBC], and differential). The results revealed that visual acuity in the amblyopic eye improved for 5 weeks, from 20/170 at baseline to 20/107, then stabilized for the last 2 weeks. Visual acuity also improved in the dominant eye by 0.6 lines, from 20/19 to 20/16. At the 6-week follow up, visual acuity in the amblyopic eye remained at 20/107 (paired t = 4.78, df = 14, P < .001), a 37% improvement. Thirty-three percent of the subjects demonstrated improved fusion from baseline to the 7-week trial that was maintained at follow up (chi 2 = 3.97, P < .05). Stereo acuity did not significantly change. Physical exam (blood pressure, body temperature, respiration, heart rate) and standard laboratory tests remained normal and side effects were minimal.(ABSTRACT TRUNCATED AT 250 WORDS)

Anticonvulsant tolerance to clonazepam in amygdala kindled rats: clonazepam concentrations and benzodiazepine receptor binding.

The relationship between anticonvulsant tolerance to clonazepam and benzodiazepine receptor changes was studied in amygdala kindled rats. Fully kindled rats were given 1 mg/kg clonazepam (clonazepam treated) or vehicle (kindled control) orally three times per day for 4 weeks. During chronic treatment, amygdala stimulation was given twice per week, 30 min after a single protective dose of clonazepam (0.5 mg/kg, i.p.) was injected to both groups of rats. As measured by seizure stage, clonazepam treated rats showed a greater degree of tolerance than kindled control rats; contingent tolerance to the anticonvulsant effects of clonazepam developed in kindled control rats, while clonazepam treated rats shows contingent plus pharmacologic tolerance. There were no significant differences between clonazepam treated and kindled control rats in "peak" plasma clonazepam concentrations 40 min after clonazepam injections. Benzodiazepine receptor assays showed no significant difference in maximal binding capacity (Bmax), dissociation constant (Kd) or gamma-aminobutyric acid (100 microM) enhancement of benzodiazepine receptor binding between clonazepam treated and kindled control rats. These data suggest that pharmacologic tolerance to anticonvulsant action of clonazepam is not related to either plasma clonazepam concentrations or benzodiazepine receptor changes.

Phenytoin age-dose-concentration relationship in children.

A list (n = 423) of phenytoin steady-state concentrations from children taking phenytoin alone or in combination with other drugs (n = 308) was obtained from our therapeutic drug monitoring database (1984-1990). Only 43% of concentrations were within the commonly accepted "therapeutic" or "reference" range (10-20 mg/L). Age-dose-concentration relationships showed that while occasional concentrations were above 20 mg/L, many patients receiving commonly recommended pediatric phenytoin doses (4-8 mg/kg/day) achieved concentrations below the reference range, especially children under 3 years of age. Michaelis-Menten pharmacokinetic parameters, maximal elimination rate (Vmax) and Michaelis constant (Km), were evaluated for patients with at least two steady-state concentrations measured for two or more different daily doses. Comedication with other drugs had no effect on either Vmax or Km for phenytoin. Vmax appeared to decrease significantly with age, but there was no age relationship for Km.

Role of therapeutic drug monitoring (TDM) in pediatric anti-convulsant drug dosing.

The role of therapeutic drug monitoring (TDM) in patient care has grown rapidly since its introduction three decades ago. The role of a TDM service in establishing proper pediatric anti-epileptic drug (AED) use is described. A number of studies are reviewed which identified proper pediatric dosage regimens for phenobarbital, carbamazepine, valproic acid, phenytoin and clonazepam. Finally, the potential role of TDM in the use of new AEDs is mentioned. These studies are given as examples of how professionals knowledgeable in clinical epilepsy management, clinical pharmacology and pharmacokinetics, can use TDM to design individualized dosage regimens, as well as assess compliance, toxicity and drug interactions.