Effect of estrogenic perturbations on delta-aminolevulinic acid-induced porphobilinogen deaminase and protoporphyrin IX levels in rat Harderian glands, liver, and R3230AC tumors.

The Harderian gland in rodents highly expresses enzymes of the heme biosynthetic pathway that are responsible for porphyrin production. Interestingly, many of the steps in Harderian gland heme biosynthesis, including protoporphyrin production, are controlled hormonally. We hypothesized that estrogenic alterations, ovariectomy or tamoxifen administration, might also alter the response of porphobilinogen deaminase activity and/or protoporphyrin IX production to delta-aminolevulinic acid administration in the hormonally responsive R3230AC rat mammary adenocarcinoma. We also determined whether the response of the R3230AC tumor, borne on ovariectomized hosts, to delta-aminolevulinic acid-based photodynamic therapy was altered compared with tumors treated on intact hosts. Ovariectomy of female Fischer rats bearing the hormonally responsive R3230AC mammary adenocarcinoma caused a significant reduction in delta-aminolevulinic acid-induced protoporphyrin IX levels and porphobilinogen deaminase activity in tumors compared with levels in tumors from intact animals treated with delta-aminolevulinic acid. In contrast, although porphobilinogen deaminase activity in the Harderian gland from ovariectomized animals was reduced significantly compared with that in glands from intact animals, protoporphyrin IX levels were unaltered. Administration of the anti-estrogen tamoxifen to tumor-bearing rats resulted in a significant increase in porphobilinogen deaminase in both tumor and Harderian gland. Although administration of delta-aminolevulinic acid increased protoporphyrin IX levels in Harderian glands in tamoxifen-treated animals, tumor levels of protoporphyrin IX remained unaltered in the tamoxifen-treated rats. Treatment of R3230AC tumors with delta-aminolevulinic acid-based photodynamic therapy in ovariectomized rats resulted in a significantly reduced response compared with the same treatment regimen in intact animals, 4.9+/-0.39 versus 10.6+/-0.6 days to reach twice the initial tumor volume, respectively. These results indicate that the hormonal status of the host should be considered when treating hormonally sensitive tumors with delta-aminolevulinic acid-based photodynamic therapy.

2,4,6-triarylchalcogenopyrylium dyes related in structure to the antitumor agent AA1 as in vitro sensitizers for the photodynamic therapy of cancer.

Cationic chalcogenopyrylium dyes 2-4 were synthesized in six steps from 4-(dimethylamino)phenylethyne (7), have absorption maxima in methanol of 594, 631, and 672 nm, respectively, and generate singlet oxygen with quantum yields [Phi((1)O(2))] of 0.020, 0.064, and 0.037, respectively. Dyes 2-4 are hydrolytically more stable than other chalcogenopyrylium dyes evaluated previously as sensitizers for photodynamic therapy. At 10 microM final concentration, all dyes 2-4 inhibited cytochrome c oxidase during irradiation of tumor mitochondrial suspensions treated with 10 microM dye. The degree of enzyme inhibition was abated in a reduced oxygen environment and in the presence of imidazole, a singlet oxygen trap. Superoxide dismutase, at a final concentration of 30 U, did not alter the photosensitized inhibition of mitochondrial cytochrome c oxidase by dyes 2-4. These data suggest that singlet oxygen may play a major role in the photosensitized inhibition of mitochondrial cytochrome c oxidase. Irradiation of R3230AC rat mammary adenocarcinoma cells in the presence of dyes 2-4 caused a significant loss in cell viability with thiopyrylium dye 2 displaying the greatest phototoxicity. Initial acute toxicity studies in vivo demonstrate that, at 10 mg/kg, none of the three dyes displayed overt toxicity.

Self-injury in Lesch-Nyhan disease.

UNLABELLED: Parents of 40 patients with Lesch-Nyhan disease completed a questionnaire detailing developmental history, life course, management, medication, factors influencing variability and topography of self-injury. Several conclusions were reached. Characteristics: Biting was the predominant form, perhaps only because of the difficulty of preventing it. There was considerable variability in self-injury which was strongly related to stress rather than to operant influences. Even though patients could not inhibit self-injury they could predict it and request restraints. Aggression against others was as prevalent as self-injury. MANAGEMENT: Stress reduction, teeth extraction, and physical restraint were the most commonly used management techniques. Behavior modification was of limited efficacy. Benzodiazepines were the most commonly used medications for controlling self-injury. OUTCOME: The severity of self-injury did not change over years. Age of onset was a predictor of outcome. The earlier the age of onset the worse the self-injury eventually became. The discussion describes research strategies, suggests dimensions along which self-injury can be classified, and highlights behavior not commonly described in patients with Lesch-Nyhan disease.

Naltrexone in autistic children: behavioral symptoms and attentional learning.

OBJECTIVE: To assess critically the short-term efficacy and safety of naltrexone in autistic children and its effects on discrimination learning in the laboratory. METHOD: A parallel group design was employed. After a 2-week placebo baseline period, children were randomly assigned either to naltrexone or to placebo for a period of 3 weeks followed by a one-week posttreatment placebo period. Multiple raters and rating scales were employed in a variety of conditions. Forty-one children, all inpatients, ages 2.9 to 7.8 years, completed the study. Naltrexone reduced hyperactivity and had no effect on discrimination learning in the laboratory. There was a suggestion that it had a beneficial effect on decreasing self-injurious behavior. Untoward effects were mild and transient. CONCLUSION: In the present study, naltrexone significantly reduced only hyperactivity, and no serious untoward effects were observed. The effectiveness of naltrexone in the treatment of autism and self-injurious behavior requires additional assessment in a sample of children with moderate to severe self-injurious behavior.

Haloperidol withdrawal and weight changes in autistic children.

The long-term effects of haloperidol on weight were assessed in 30 children, 25 males and 5 females, diagnosed with autistic disorder whose ages ranged from 3.08 to 8.42 years. They received haloperidol (0.25-3.50 mg/day; mean 1.26 +/- 0.84) for 6 months followed by a 4-week drug withdrawal period. Weights obtained on the last day of the 6-month haloperidol period were compared to weights obtained following drug withdrawal. There was no significant difference between the mean weights obtained on the last day of haloperidol administration (24.799 +/- 9.741 kg) compared to the mean weights at the end of the fourth week of the placebo period (24.644 +/- 9.833 kg). Weights increased during the first week of drug discontinuation (24.879 +/- 9.855 kg), but decreased during each following week of drug withdrawal. Weight was measured monthly during the 6-month haloperidol treatment period for 8 of the 30 subjects. In this subsample, weight gain was greater during the 1-month period lasting from the end of the 4-week drug withdrawal to the end of the first month after resuming haloperidol treatment than weight gain prior to drug withdrawal, between the fifth and sixth month of haloperidol treatment.

Cognitive abilities of patients with Lesch-Nyhan disease.

Parents of 42 patients with Lesch-Nyhan disease completed a questionnaire systematizing caregiver observations of the subject's behavior during a wide variety of daily events. Responses were grouped in nine categories reflecting different aspects of cognitive skills. Only 1 boy appears to have any significant generalized cognitive impairment. The patients' memory for both recent and past events is excellent, their emotional life has a normal range of reactions and is appropriate; they have good concentration, are capable of abstract reasoning, have good self-awareness, and are highly social. However, they are behind in academic ability, with only 15% at grade level for math and reading. Implications for designing educational activities, parenting or caregiver strategies, and research methodology are discussed.

Naltrexone in autistic children: a double-blind and placebo-controlled study.

A double-blind, placebo-controlled study was designed to assess critically the effects of naltrexone on behavioral symptoms and learning in autistic children, and its safety. This is a preliminary report on 18 children, ages 3.08 to 7.99 years, who completed this ongoing study. Subjects were randomly assigned to naltrexone or placebo and received daily doses over a period of 21 days. Naltrexone was superior to placebo according to blind Clinical Global Consensus Ratings (unpublished scale). However, other behavioral rating measures did not confirm this result. There was only a suggestion that naltrexone reduced fidgety and hyperactive behavior and tended to alleviate overall symptomatology in older children. Naltrexone did not appear to affect discrimination learning. Results are preliminary and, owing to the small sample size, can be considered only suggestive until this study is completed or replication is obtained from independent research.

The effects of haloperidol on discrimination learning and behavioral symptoms in autistic children.

This double-blind and placebo-controlled clinical trial in autistic children had three objectives: (a) to replicate earlier findings that haloperidol administration is associated with a significant reduction of behavioral symptoms; (b) to further assess its safety when given on a short-term basis; and (c) to assess whether it has an effect on discrimination learning. Forty-five children, 2.02 to 7.58 years old (M = 4.49), completed this crossover design, with random assignment to treatment sequences. Haloperidol was shown to be a powerful therapeutic agent when administered for 4 weeks and free of side effects; at doses ranging from 0.25 to 4.0 mg/day (M = 0.844), there was a clinically and statistically significant reduction of a variety of symptoms. Under the given conditions, the children failed to learn on either haloperidol or placebo.

Behavioral characteristics and early temperament of premature infants with intracranial hemorrhage.

Behavioral characteristics of 12 full-term and 44 premature infants with and without intracranial hemorrhage (ICH) were studied. Cranial ultrasonography prospectively documented Grade I-II ICH in 14, Grade III-IV in 19 and no ICH in 11 premature infants. Examination at corrected age of 40 +/- 2 weeks using the Neonatal Behavioral Assessment Scale showed that infants in the ICH groups had lower levels of arousal and more abnormal reflexes than full-terms. Infants with ICH III-IV displayed less optimal motor responses than full-term infants and diminished orientation responses, especially to visual stimuli. Thus, lower level of arousal, immature motoric processes, and poor visual orientation differentiated premature with ICH from full-term infants, although premature infants without these sequelae, did not differ significantly from full-term infants. The above may represent early manifestations of visual-perceptual and motor problems noted in the follow-up of ICH infants. Further, neonatal behavior was found to affect parent ratings of infant temperament (via the Bates Infant Characteristics Questionnaire) at 3 months corrected age, and the relationships between neonatal behavior and parental ratings differed depending upon the infant's gestational age and severity of hemorrhage. We conclude that neonatal behaviors are less optimal in premature infants, and least optimal in premature infants with severe intracranial hemorrhage when compared to fullterm infants.

Haloperidol in the treatment of infantile autism: effects on learning and behavioral symptoms.

In this double-blind, placebo-controlled study the administration of haloperidol resulted in significant decreases in behavioral symptoms and in general clinical improvement in 40 autistic children ages 2.33 to 6.92 years. Haloperidol also produced greater facilitation and retention of discrimination learning in the laboratory. No adverse effects were observed at therapeutic doses, which ranged from 0.5 to 3.0 mg/day or 0.019 to 0.217 mg/kg per day.

Behavior-disordered and aggressive children: new advances in pharmacotherapy.

The status of children's psychopharmacology is reviewed in the context of differences from its adult counterpart. An overview is presented of recent psychopharmacological developments in the treatment of childhood behavioral disorders. The disorders are grouped according to the potential usefulness of medication. The focus is on clinical efficacy and safety of drug usage. The effect of psychoactive drugs on cognitive functions in the laboratory is referred to, as well as the value of determining drug levels in clinical practice. It is concluded that drug administration in isolation is not the treatment of choice. Drug therapy is a valuable adjunct, however, to psychosocial interventions.

The effects of haloperidol on learning and behavior in autistic children.

The effects of haloperidol on behavioral symptoms and learning were critically assessed in autistic children in an ongoing double-blind placebo-controlled clinical trial. Children were randomly assigned to haloperidol-placebo-haloperidol or placebo-haloperidol-placebo treatment sequences. Statistically, haloperidol was significantly superior to placebo in reducing behavioral symptoms. In discrimination learning paradigm, children receiving haloperidol learned the discrimination while those on placebo did not. Discrimination attained on haloperidol was retained when the children were switched to placebo.

Pharmacotherapy for autistic children: a summary of research.

An overview of research involving pharmacotherapy in infantile autism is presented. Methodological issues relating to experimental design, rating instruments and ecological factors are considered. Classification of infantile autism and diagnostic problems are discussed. Research investigations conducted in order to define diagnostic subgroups in the etiologically heterogeneous population of autistic children are described. An attempt is made to relate biochemical findings to clinical drug response. Recent findings are presented indicating that a potent neuroleptic is able to yield simultaneously significant decrease of behavioural symptoms and improved learning under both clinical and laboratory conditions. The drug can be effective in conservative doses and administered over a period of 14 weeks without untoward effects. New research plans are introduced where attentional learning will be assessed in an operant conditioning paradigm using automated procedures.