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.

Ibuprofen, acetaminophen, and placebo treatment of febrile children.

A double-blind, parallel-group, triple-dummy-designed, single-oral-dose study compared the efficacy, tolerability, safety, and dose-response of 5 mg/kg (n = 32) and 10 mg/kg (n = 28) ibuprofen suspension, 10 mg/kg acetaminophen elixir (n = 33), and placebo liquids (n = 34) in 127 children (2 to 11 years of age) with fever (101 degrees to 104 degrees F). Blood samples, oral temperatures, pulse, blood pressure, and respiration were obtained before and 1/2, 1, 2, 3, 4, 5, 6, and 8 hours after the dose was administered. The study was terminated early if oral temperature was greater than 104 degrees F or if it increased 1 degree F above baseline. All agents were well tolerated and more effective than placebo (p less than 0.05) for fever control. Ibuprofen, 10 mg/kg, was favored over 10 mg/kg acetaminophen (p less than 0.05). For temperatures greater than 102.5 degrees F, a dose-response relationship for 5 and 10 mg/kg ibuprofen was demonstrated in terms of percentage of fever reduction and in terms of the initial 2-hour rate of decrease in temperature. Antipyretic efficacy for temperatures greater than 102.5 degrees F was 10 mg/kg ibuprofen greater than 5 mg/kg greater than 10 mg/kg acetaminophen greater than placebo. All treatments were well tolerated. No significant clinical or laboratory abnormalities were noted. Ibuprofen suspension may be a safe and effective antipyretic in children.

Pharmacokinetics and pharmacodynamics of ibuprofen isomers and acetaminophen in febrile children.

The pharmacokinetics of racemic ibuprofen and its stereoisomers have been described in adults, but little has been reported for children. The pharmacodynamics of acetaminophen and ibuprofen have not been well described in either adults or children. Children (N = 39; age range, 11 months to 11 1/2 years) were randomly selected to receive a single dose of either 6 mg/kg of liquid ibuprofen or 10 to 15 mg/kg of liquid acetaminophen (mean +/- dose given, 11.6 +/- 0.7). Pharmacokinetic and pharmacodynamic analyses were performed with temperature as the effect parameter and mean acetaminophen, total ibuprofen, and ibuprofen stereoisomer concentrations over time. Time of maximum serum concentrations for ibuprofen was 54.05 minutes versus 27.0 minutes for acetaminophen, time to maximum temperature decrease was 183 minutes for ibuprofen and 133 minutes for acetaminophen. Temperature reduction for the ibuprofen dose was significantly different than that of the acetaminophen dose at later time points (240, 300, 360, 420, and 480 minutes). Further pharmacokinetic-pharmacodynamic studies with use of individual ibuprofen stereoisomers and other dosing regimens are indicated.

Phenytoin kinetics in children.

Previous studies have shown the importance of phenytoin kinetics in the management of adult patients with seizure disorders. The long half-life in adults makes single daily dosing realistic in terms of blood levels and anticonvulsant effectiveness. This report shows a wide range in both half-lives and volumes of distribution of phenytoin in 11 children (ages 6 months to 6 years) with seizure disorders. Ten of these patients have very short phenytoin half-lives (1.2 to 6.7 hours). The data strongly suggest that current recommendations for phenytoin dosage regimens in adults cannot necessarily be used in children. Blood levels must be followed closely in this age group to determine the required dosage and dose interval.

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.

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.

Coughs and colds.

Coughs and colds are seldom associated with serious diseases or complications, but they frequently cause patient discomfort, prompting many telephone calls and visits to hospitals and physicians' offices. Parents often harbor misconceptions regarding the etiology, diagnosis, and management of these conditions, leading to inappropriate treatment and home "remedies." The pitfalls associated with treating coughs and colds can be minimized when the physician takes time to educate patients and parents. Education should be anticipatory, reassuring, and unrushed. Adequate communication requires practice and thought. Good techniques include asking open-ended, nonthreatening questions and avoiding the use of jargon. Parents must be asked about their understanding of and fears concerning coughs and colds. Education must include repetition, with feedback and rewards by someone who believes in the value of education and transfers this belief to patients and parents. Effective patient education in the treatment of coughs and colds may be achieved by adopting the above common-sense techniques.

Interaction of maternal and neonatal obesity.

Maternal weight and height before pregnancy and weight gain during pregnancy were recorded for each of 109 mothers who were delivered of normal infants after gestations of 37 to 43 weeks. Infant parameters obtained included gestational age, birth weight, bilateral mid-arm circumference, and eight skin fold thickness measurements. The eight skin fold thicknesses were summed (SSFT) for each infant. Infants with SSFTs greater than 40 mm (N = 8) for the group were classified as "fatter" infants. All of the fatter infants were large for gestational age (LGA), but accounted for only one third of the LGA infants in the study. Birth weight, length, and cross-sectional mid-arm fat area were significantly increased in the fatter LGA group when compared to other LGA infants. Cross-sectional mid-arm muscle area was not significantly different for the fatter LGA infants compared to the other LGA group. Mothers were defined as obese or nonobese according to pregnant weight for height. Obese mothers had infants with significantly increased SSFTs when compared with infants of nonobese mothers. Mulitple regression analysis showed that both prepregnant weight for height and weight gain during pregnancy were associated with increased subcutaneous fat in the neonate. Weight gain during pregnancy was associated with increased neonatal fatness and length, while prepregnant weight for height was associated with neonatal fatness independent of neonatal length.

Levodopa/carbidopa for childhood amblyopia.

PURPOSE: To evaluate the efficacy and tolerance of two low doses of levodopa/carbidopa (25/6.25 mg, 50/12.5 mg) and placebo (Tums) in 20 children with amblyopia between the ages of 4 and 14 years. METHODS: A double-masked placebo-controlled randomized 8-hour study was performed during which subjects received one of two doses of levodopa/carbidopa or placebo, combined with occlusion of the dominant eye. Visual acuity was measured at baseline and at 1 and 5 hours after capsule ingestion. Tolerance was assessed by questionnaire and physical examination. RESULTS: Visual acuity significantly improved by one line, from an overall average of 20/121 to 20/96, in the amblyopic eyes of both groups that received levodopa/carbidopa. Visual acuity did not significantly change in the placebo group. Tolerance was similar among all three groups. CONCLUSION: Average dose levels of 0.95/0.24 mg/kg and 1.94/0.49 mg/kg of levodopa/carbidopa were found to be well tolerated and efficacious at temporarily improving visual acuity in amblyopic eyes of children.

Pharmacokinetics of common analgesics, anti-inflammatories and antipyretics in children.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a major component of paediatric therapeutics. This paper summarises the clinical pharmacology and pharmacokinetics of some commonly used NSAIDs as well as paracetamol (acetaminophen), which has very weak anti-inflammatory activity. Available information is reviewed in an attempt to evaluate the basis for paediatric dosing recommendations and to underline known or likely differences in drug disposition that result from diseases and changes in developmental physiology. Clinically important general considerations are stressed, including areas in which age-appropriate pharmacological information is needed but unavailable. The review is not exhaustive, as only the following selected drugs are surveyed: paracetamol, ibuprofen, indomethacin, diclofenac, naproxen and sulindac. Some compounds of interest, including salicylates (e.g. aspirin, salsalate), recently introduced drugs (e.g. ketoprofen, nimesulide) and those withdrawn (e.g. zomepirac, benoxaprofen), are not included. Non-NSAID analgesics (e.g. dextropropoxyphene, narcotics) are also not included.

Principles of drug prescribing in infants and children. A practical guide.

Paediatric prescribing is much more complicated than prescribing for adults. The specific and general aspects of paediatric patients, the limitations of commercially available dosage formulations, the vagaries of administering medicines, the general inadequacy of clinical pharmacology training, and the dearth of information about drug use in children all add to the difficulties facing the practitioner who treats infants and children. For these reasons practitioners should prescribe judiciously, select carefully the safest dosage regimen available, and educate their patients, caregivers and staff about their choices and expected positive and negative effects. Practitioners should also have available and use written, electronic, as well as human sources of expert advice. They should write all prescriptions legibly and carefully, document their therapeutic decisions and plans, and carefully monitor their patients' responses to therapy. Careful attention to the principles of clinical pharmacology can do much to improve the efficacy of paediatric prescribing and decrease its costs and risks.

Kinetics of theophylline; variability and effect of arterial pH in chronic obstructive lung disease.

The pharmacokinetic behavior of theophylline was determined in 12 patients during an acute exacerbation of their chronic obstructive pulmonary disease. A 5.6 mg/kg loading dose of aminophylilne was administered, followed three hours later by a 0.9 mg/kg/hr continuous infusion. The loading dose increased the serum theophylline level an average of only 5.77 microgram/ml. After the loading dose, only five patients had levels greater than 10 microgram/ml. Mean initial drug clearance was 0.77 L/kg/hr, half-life 9.1 hr, and apparent volume of drug distribution .887 L/kg. Wide inter- and intrapatient pharmacokinetic variability was observed. The variability of drug distribution was inversely correlated with the arterial pH. These patients with chronic obstructive pulmonary disease appeared to require more theophylline when acidemic than when alkalemic to achieve similar serum theophylline concentrations.

Effects of single large doses of phenytoin on glucose homeostasis--a preliminary report.

The effects of a loading dose of 15 mg/kg phenytoin by iv infusion on the serum levels of insulin, glucagon, and glucose were investigated in five fasting healthy male volunteers between the ages of 23 and 35 years. Serum glucose concentrations rose immediately after the infusion of phenytoin followed by a significant increase in serum insulin values (P less than 0.05). A slight elevation in mean glucagon concentrations after the infusion was not statistically significant. Further studies are indicated to determine whether phenytoin as used in the treatment of status epilepticus may aggravate the hyperglycemia associated with seizures.

Comparison of the pharmacokinetics of naproxen tablets and suspension in children.

Twenty-three children, aged 8 to 14 years, with postoperative pain, were randomly assigned to receive a fixed 250-mg dose (4.66-7.58 mg/kg) of naproxen as either a liquid suspension or tablet. After an overnight fast, the serum concentrations were measured before and at 0.5, 1, 2, 3, 4, 8, 12, 18, and 24 hours after administration of naproxen. The concentration versus time data were best fit to a one-compartment open model. The area under the concentration versus time curve, apparent volume of distribution (VDss/F), and elimination parameters (CL/F, Ke, elimination half-life) were similar in children who received suspension or tablets. Although the apparent maximum peak plasma concentration (Cmax) was greater in children who received tablets compared with those who received the suspension, Cmax/area under the curve (AUC), apparent time to maximum peak concentration (tmax), Ka, and estimated time to 10%, 50%, and 90% absorption (T10, T50, T90) were not different. The dose range was relatively narrow; hence, direct relationships between dose and elimination parameters, VDss/F, apparent tmax, Ka, T10, T50 or T90 were not observed. Neither VDss/F or CL/F were age related over the relatively narrow range of ages that were studied. Elimination of naproxen in our patients was more rapid than has previously been reported in children or adults, however. From a practical standpoint, naproxen tablets and suspension seem to be bioequivalent in fasting children ages 8 to 14 years.

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.

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.

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.

Intermittent clonazepam treatment prevents anticonvulsant tolerance in mice.

The influence of intermittent benzodiazepine treatment on anticonvulsant tolerance was studied by comparing mice treated either daily or on alternate days with clonazepam, 0.25 mg/kg, i.p., administered twice a day. Tolerance was assessed by the ability of clonazepam to prevent pentylenetetrazol (PTZ) induced clonic convulsions. In mice treated daily with clonazepam, significant tolerance was evident after 5 days of treatment but did not increase further after 10 or 20 days of treatment. However, mice treated with clonazepam only on alternate days for 10 or 20 days showed no tolerance. Our data indicate that intermittent treatment may prevent development of tolerance to the anticonvulsant action of benzodiazepines.

Antiepileptic effect of antiepilepsirine in pentylenetetrazol and amygdala kindled rats.

Antiepilepsirine (AES) is a new antiepileptic drug developed in China. Anticonvulsant effects of AES were studied in both pentylenetetrazol (PTZ, n = 20) and amygdala kindled (n = 10) rats. AES was given once per day by oral gavage for 4 weeks. On days 7, 14, 21 and 28, all rats were tested 2 h after daily AES administration: PTZ and amygdala kindled rats were given a PTZ injection (30 mg/kg, i.p.) or amygdala stimulation (400 microA, 1 s), respectively. Behavior was observed, and seizures were graded. AES (300 or 500 mg/kg) produced sustained, dose dependent, protective effects against PTZ induced seizures in PTZ kindled rats, while AES (500 mg/kg) had no effects in amygdala kindled rats.

Effect of pH on theophylline transfer across the everted rat jejunum.

The effect of pH on the cumulative transfer of theophylline across the everted rat jejunum in vitro was investigated. Intestinal integrity was assessed by light and scanning electron microscopy, while the biochemical viability of the intestine was evaluated using glucose transfer measurements. The initial (0-30 min) clearance of theophylline was directly proportional to the fraction un-ionized at pH 5.5, 7.4, 8.0, and 10.0. Plots of cumulative theophylline transfer versus time over 60 min were nonlinear, but could be subdivided into two linear segments of 30-min duration. Due to this nonlinearity, differences in theophylline transfer with pH were significant only over the first 30 min of the experiment. Intestinal tissue integrity and viability correlated with the time at which the clearance (slope) increased, while the magnitude of the increase in clearance was proportional to the degree of ionization of theophylline.