Acute tolerance to methylphenidate in the treatment of attention deficit hyperactivity disorder in children.

OBJECTIVES: To evaluate the efficacy of several drug delivery patterns of methylphenidate and to determine whether acute tolerance develops to this widely used stimulant medication in the treatment of children with attention deficit hyperactivity disorder. METHODS: Double-blind trials were conducted in a laboratory school setting in which multiple measures of efficacy were obtained frequently in the morning and afternoon across the school day. In study I, relative efficacy was determined for three dosing patterns of methylphenidate: a standard twice-daily profile, a flat profile, and an ascending profile. In study II, tolerance was assessed by comparison of three-times-a-day regimens in which the time of the middle dose varied. RESULTS: In study I, the efficacy of the ascending treatment increased across the day, and in the afternoon it was equal to the efficacy of the twice-daily treatment, indicating that an initial bolus was not required for efficacy. The efficacy of the flat treatment declined across the day, and in the afternoon it was significantly less than in the twice-daily treatment, suggesting that tolerance may be developing. In study II, acute improvements in efficacy were reduced to the second of two closely spaced but not to two widely spaced bolus doses, suggesting that shortly after exposure to high concentrations, efficacy is reduced to given concentrations of methylphenidate. In a concentration-effect model, a tolerance term was needed to account for counterclockwise hysteresis. CONCLUSIONS: Acute tolerance to methylphenidate appears to exist. This should be considered in the design of an optimal dosing regimen for the treatment of children with attention deficit hyperactivity disorder.

Multiple-dose pharmacokinetics and pharmacodynamics of OROS and immediate-release amitriptyline hydrochloride formulations.

The pharmacokinetics and pharmacodynamics of amitriptyline hydrochloride after oral administration of an OROS osmotic system, which provides controlled drug delivery, and an immediate-release (IR) tablet, were evaluated in 24 healthy volunteers after repeated administration for 14 days. Each morning, subjects received either 75 mg of the OROS (amitriptyline HCl) controlled-release formulation or the 75 mg IR amitriptyline tablet for 14 days on two separate occasions with a washout period of 21 days according to a randomly assigned sequence. Serial blood samples were collected for a period of 58 hours after the day 14 dose, then these samples were analyzed by the gas chromatography method for amitriptyline and nortriptyline. Subjective ratings of dry mouth and drowsiness were collected at specific times throughout each treatment period. Administration of the OROS formulation resulted in much more consistent plasma concentrations of the drug and metabolite compared with the IR formulation at steady state. The mean maximum concentration (Cmax) of amitriptyline was significantly lower after administration of OROS than the IR formulation. Mean values for area under the concentration--time curve (AUC0-24) for the OROS and IR formulations were 1,265 and 1,393 ng. hr/mL, respectively. The drug-to-metabolite ratio was found to be similar for both treatments, suggesting that there was no difference in metabolism between treatments. Incidence and severity of the anticholinergic effects were similar for the two treatments. A clockwise hysteresis between baseline-corrected drowsiness and drug concentration suggests development of tolerance of the anticholinergic effects after both treatments. Using a hypothetical anatagonist metabolite model to explain tolerance development, the shape of the hysteresis curves of the two treatments could be explained by differences in dosing frequency.

Reliability and validity of the SKAMP rating scale in a laboratory school setting.

In children with attention deficit hyperactivity disorder (ADHD), the effects of methylphenidate were investigated in a pharmacodynamic comparison of placebo and the standard b.i.d. administration of methylphenidate. In each of these conditions, teachers completed ratings in classroom settings at times chosen to coincide with expected "peaks" and "troughs" of serum concentrations in the b.i.d. condition. Analyses of variance (ANOVAs) revealed the expected differences between the two conditions in the laboratory classroom setting using standard rating scales (Conners and the IOWA Conners) and a new rating scale (the SKAMP), which specifically measures the classroom manifestation of ADHD. The psychometric properties of the SKAMP were evaluated by calculating test-retest reliability and by calculating correlations with the standard rating scales to establish concurrent validity.

In vitro and in vivo evaluation of a once-daily controlled-release pseudoephedrine product.

The functionality of a once-daily, osmotic dosage form--gastrointestinal therapeutic system (pseudoephedrine HCl) or GITS (PeHCl)--was studied in vitro and in vivo. The in vitro release profiles were close to identical from pH 1 to 7.5 and between USP apparatus 2 and 7, independent of paddle speeds from 50 to 200 rpm; GITS also released drug at the normal rate in aqueous media after incubation in bile salts or fatty media. Both strengths of GITS (PeHCl)--240 and 120 mg--were then compared with a commercially available pseudoephedrine solution given every 6 hours and a timed-release 12-hour pseudoephedrine capsule given every 12 hours in a randomized 4-way crossover study in 24 healthy men. All four formulations were equivalent in total drug absorbed. Both GITS treatments had AUCinf values equivalent to those of PeHCl solution and capsules, and Cmax values equivalent to PeHCl capsules. Cmax for GITS and capsule treatments were each significantly lower than for solution, but the differences were small (14-17%). A one-to-one correlation was shown between rate of absorption and in vitro release profiles for the GITS products, indicating that drug release from GITS controls absorption. Insensitivity to conditions of in vivo release accounts for the close in vitro/in vivo correlation of release rates. In a second randomized crossover trial (12 men), the effect of a high-fat breakfast on GITS performance was evaluated. Mean pseudoephedrine concentrations in plasma were close to identical with or without the breakfast, and the treatments were bioequivalent.(ABSTRACT TRUNCATED AT 250 WORDS)

Object representations and symptomatology: preliminary findings in young adult psychiatric inpatients.

This study was designed to contribute to the empirical clarification of the object representation construct by assessing the relationships (a) among the levels of cognitive representation of four distinct and relevant individuals; and (b) among those cognitive object representations and dimensions of symptomatology. Subjects were 30 long-term inpatients of a private psychiatric hospital in Connecticut. Cognitive-developmental level of object representation was assessed according to the system described by Blatt, Brenneis, Schimek, and Glick (1976) and symptom dimensions via the SCL-90. Object representations all were interrelated significantly and tended to be related to depressive, but not other, symptomatology. Results could not be accounted for by variation in subjects' verbal production. Findings are discussed in terms of expected developmental increases in object-representation consistency; the potential influence of psychotherapy on object representations; the relative salience of different objects; unknown test-retest reliability of the instrument; and methodological and sampling issues. It is recommended that future empirical research investigate more systematically the nature of developmental level of object representation.

Bacteriophage N4-coded 5'----3' exonuclease. Purification and characterization.

Bacteriophage N4 DNA replication requires the activity of a phage-induced exonuclease. We show here that the activity is phage coded. We have purified this enzyme to apparent homogeneity. It has a denatured molecular weight of 45,000 and exists in solution as a dimer. Duplex DNA is the preferred substrate which it degrades in a 5'----3' direction to 5' mononucleotides by a distributive mechanism. The enzyme does not act at a nick or a gap; indeed, it requires an end for activity. A possible role for this exonuclease in N4 replication is discussed.

Early replication and expression of oocyte-type 5S RNA genes in a Xenopus somatic cell line carrying a translocation.

In Xenopus somatic cells, the somatic-type 5S RNA genes replicate early in S phase, bind the transcription factor TFIIIA, and are expressed; in contrast, the late replicating oocyte-type genes do not bind TFIIIA and are transcriptionally inactive. These facts support a model in which the order of replication of the somatic-type versus the oocyte-type 5S genes causes their differential expression in somatic cells due to sequestration of TFIIIA by the early-replicating somatic genes. Here we provide further evidence for the model by showing that in one Xenopus cell line in which some oocyte-type 5S genes are translocated, some oocyte-type 5S genes replicate early and are expressed.

Differential order of replication of Xenopus laevis 5S RNA genes.

In Xenopus laevis there are two multigene families of 5S RNA genes: the oocyte-type 5S RNA genes which are expressed only in oocytes and the somatic-type 5S RNA genes which are expressed throughout development. The Xenopus 5S RNA replication-expression model of Gottesfeld and Bloomer (Cell 28:781-791, 1982) and Wormington et al. (Cold Spring Harbor Symp. Quant. Biol. 47:879-884, 1983) predicts that the somatic-type 5S RNA genes replicate earlier in the cell cycle than do the oocyte-type genes. Hence, the somatic-type 5S RNA genes have a competitive advantage in binding the transcription factor TFIIIA in somatic cells and are thereby expressed to the exclusion of the oocyte-type genes. To test the replication-expression model, we determined the order of replication of the oocyte- and somatic-type 5S RNA genes. Xenopus cells were labeled with bromodeoxyuridine, stained for DNA content, and then sorted into fractions of S phase by using a fluorescence-activated cell sorter. The newly replicated DNA containing bromodeoxyuridine was separated from the lighter, unreplicated DNA by equilibrium centrifugation and was hybridized with DNA probes specific for the oocyte- and somatic-type 5S RNA genes. In this way we found that the somatic-type 5S RNA genes replicate early in S phase, whereas the oocyte-type 5S RNA genes replicate late in S phase, demonstrating a key aspect of the replication-expression model.

Host and phage-coded functions required for coliphage N4 DNA replication.

Escherichia coli strains containing mutations in various deoxyribonucleic acid synthesis cistrons have been tested for their ability to support bacteriophage N4 growth and, specifically, N4 DNA synthesis. N4 DNA synthesis is independent of the activity of the products of the E. coli dnaA, dnaB, dnaC, dnaE, dnaG, and rep genes. In contrast, N4 DNA replication requires the products of the dnaF, (ribonucleotide reductase) and lig (DNA ligase) genes of E. coli. N4 DNA replication, specifically processing of short DNA fragments requires the 5'-3' exonuclease activity of the polA gene product. However, its DNA polymerizing activity is not required. In addition, the sensitivity of N4 DNA synthesis to inhibitors or temperature-sensitive mutants of E. coli DNA gyrase suggests that this activity is required for N4 DNA synthesis. To date, we have found five N4 gene products required for N4 DNA replication: dbp (a single-stranded DNA binding protein), dnp (a DNA polymerase), dns (unknown function), vRNAp (the N4 virion-associated, DNA-dependent RNA polymerase) and exo (a 5'-3' exonuclease).