Neonatal onset ornithine transcarbamylase deficiency: A retrospective analysis.

OBJECTIVE: A retrospective analysis of 74 cases of neonatal-onset ornithine transcarbamylase (OTC) deficiency. METHODS: The medical records of 74 of the 128 male patients referred to this center with neonatal onset OTC from 1976 to 1996 were available and analyzed. RESULTS: Initial symptoms of OTC deficiency were nonspecific and included feeding difficulties, lethargy, and "respiratory distress"; vomiting was infrequent. Respiratory alkalosis was regularly observed; the mean pH and pCO2 were 7.5 and 24 torr, respectively. Early consideration of a metabolic disorder in those neonates with a negative family history was only 9%. Sepsis was initially misdiagnosed in 50% of the cases. For all patients the mean age at onset was 63 hours. Survival was better among those who had later onset, later diagnostic studies, and diagnosis. Apart from 1 patient whose peak ammonium level was 400 micromol/L, all surviving patients had severe developmental delay. CONCLUSIONS: OTC deficiency should be suspected in term infants who have early signs of encephalopathy, particularly after the first 24 hours; a respiratory alkalosis is pathognomic of urea cycle disorders. Severe developmental delay is the usual outcome of OTC deficiency.

Long-term treatment of girls with ornithine transcarbamylase deficiency.

BACKGROUND: Ornithine transcarbamylase is an X-linked mitochondrial enzyme that catalyzes the synthesis of citrulline from carbamoyl phosphate and ornithine. A deficiency of this enzyme leads to hyperammonemia and hyperglutaminemia. In boys the disease is often fatal when its onset occurs during the neonatal period, but it is milder when onset occurs later in childhood. Heterozygous girls may be normal or may have episodes of hyperammonemic encephalopathy and decline in cognitive function. We report here on the long-term outcome in girls with ornithine transcarbamylase deficiency enrolled in studies of treatments designed to activate new pathways of waste-nitrogen excretion. METHODS: We studied 32 girls (age, 1 to 17 years) with ornithine transcarbamylase deficiency who had had at least one episode of encephalopathy. The patients were assigned to treatment that consisted of sodium benzoate, alone or in combination with sodium phenylacetate or sodium phenylbutyrate, or sodium phenylbutyrate alone. Collaborating physicians provided clinical, metabolic, and developmental data at specified intervals. RESULTS: Patients treated according to these protocols had greater than 90 percent survival at five years and maintained appropriate weight for height. The frequency of hyperammonemic episodes decreased with increasing age and with sodium phenylacetate or sodium phenylbutyrate treatment. Although the mean IQ before treatment was in the low average range, 19 of the 23 girls in whom intelligence was tested longitudinally had stable test scores. CONCLUSIONS: Girls with symptomatic ornithine transcarbamylase deficiency who are treated with drugs that activate new pathways of waste-nitrogen excretion have fewer hyperammonemic episodes and a reduced risk of further cognitive decline.

Long-term survival of patients with argininosuccinate synthetase deficiency.

OBJECTIVE: To monitor long-term survival and outcome of patients with neonatal-onset argininosuccinate synthetase deficiency (ASD) who were treated with specific therapeutic protocols designed to activate alternative pathways of waste nitrogen excretion. DESIGN: Patients for this study included 24 infants born before 1990 and rescued from hyperammonemic coma caused by neonatal-onset ASD; they were referred to this center for enrollment in ongoing clinical studies of sodium benzoate, sodium phenylacetate, and sodium phenylbutyrate. Collaborating physicians throughout the United States and Canada provided information on survival, intellectual development, intercurrent hyperammonemic episodes, and anthropometric and biochemical measurements. RESULTS: The cumulative survival rate was 87.5% at 5 years and 72% at 10 years of age. Survivors include 15 patients currently treated with high doses of sodium phenylbutyrate; two patients have withdrawn. Among the treated group, 11 are classified as severely to profoundly mentally retarded. The remaining four patients have IQ measurements in the borderline to mentally retarded range. All patients have had intercurrent hyperammonemic episodes; our data indicate that the frequency of the episodes has decreased with implementation of the current protocol. These patients are growth retarded, but most have height-for-weight z scores within 2 SD of the mean. Laboratory studies of plasma amino acids and of hematopoietic, renal, and hepatic function are within normal limits with the exception of slightly elevated serum aminotransferase values. CONCLUSION: Our results indicate that these drugs are safe and that the current protocol improves survival rates. However, survival is accompanied by mental retardation, growth retardation, risk of hyperammonemic episodes, and the necessity of lifetime adherence to strict medication and dietary management.

Behavioral pharmacology of NPC 17742, a competitive N-methyl-D-aspartate (NMDA) antagonist.

The behavioral effects of the competitive N-methyl-D-aspartate (NMDA) antagonist 2R,4R,5S-2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoate (NPC 17742) were compared with those of its parent compound, 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoate (NPC 12626), and other reference agents in a variety of operant-based tasks in rodents. In mice trained to lever press under a fixed-ratio (FR) 20 reinforcement schedule, NPC 17742 was 6.2 times more potent than NPC 12626 and equipotent with the competitive NMDA antagonist [E]-2-amino-4-methyl-5-phosphono-3-penteneoic acid (CGP 37849) in reducing rates of responding. NPC 17742 was also 3.5 and 4.5 times more potent than [+-]cis-4-phosphonomethyl-2-piperidine carboxylate (CGS 19755) and [+-] 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), respectively, and half as potent as 3SR, 4aRS, 6SR, 8aRS-6-(phosphonomethyl)-1,2,3,4,4a,5,6,7,8,8a- decahydroisoquinoline-3-carboxylate (LY 274614) in this paradigm. In rats trained to discriminate 4.0 mg/kg NPC 17742 from saline, NPC 17742 was 5.7 times more potent than NPC 12626 in substituting for NPC 17742. CGS 19755 also substituted for NPC 17742, but a maximum of only 50% NPC 17742 lever responding was observed after LY 274614 administration. In rats trained to lever press in a modified Geller-Seifter procedure, NPC 17742 and NPC 12626, like the benzodiazepine chlordiazepoxide, increased rates of punished responding. Neither tolerance nor sensitization to the anti-punishment effects were observed upon administration of NPC 17742 for 5 consecutive days. The results are consistent with NPC 17742 being a potent, systemically active compound whose behavioral effects are mediated through interaction with the NMDA receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

NPC 16377, a potent and selective sigma-ligand. II. Behavioral and neuroprotective profile.

6-[6-(4-Hydroxypiperidinyl)hexyloxy]-3-methylflavone HCI, (NPC 16377), a potent and highly selective sigma-site ligand, was evaluated in tests predictive of antipsychotic and neuroprotective potential and for toxicity. Like haloperidol, clozapine and remoxipride, and the sigma-ligands BMY 14802, ifenprodil and rimcazole, NPC 16377 reversed amphetamine-induced hyperactivity and apomorphine-induced climbing in mice. Additional evidence for antipsychotic activity was obtained in rats with NPC 16377, clozapine, BMY 14802, ifenprodil, haloperidol and rimcazole, all of which reduced conditioned avoidance responses at doses that did not reduce escape behavior. NPC 16377 did not induce catalepsy in mice, suggesting a decreased liability for producing extrapyramidal side effects. NPC 16377 extended survival time for mice exposed to a hypoxic environment. In a model of global ischemia using conscious gerbils, NPC 16377 prevented damage to hippocampal CA1 neurons after either intraperitoneal or oral administration. NPC 16377 did not disrupt prepulse inhibition or block the disruption of prepulse inhibition induced by the phencyclidine site-selective ligand (+)MK-801. In rats trained to discriminate phencyclidine from saline, NPC 16377 did not substitute for the psychotomimetic. These data are consistent with the notion that selective sigma-agents may possess antipsychotic and neuroprotective activities. Moreover, the results from prepulse inhibition and drug discrimination experiments suggest that NPC 16377 is devoid of phencyclidine-like effects.

NPC 16377, a potent and selective sigma-ligand. I. Receptor binding, neurochemical and neuroendocrine profile.

6-[6-(4-Hydroxypiperidinyl)hexyloxy]-3-methylflavone HCI (NPC 16377), a structurally novel compound, was found to be a highly potent and selective ligand for sigma-sites. Although 5-fold less potent than haloperidol and 2-fold less potent than ifenprodil to inhibit 1,3-di-o-tolylguanidine binding, NPC 16377 (IC50 = 36 nM) was more potent than alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl butanol (BMY 14802), rimcazole and the atypical antipsychotic, clozapine. A similar rank order of potency was observed when [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperdine was used as the radioligand. Like BMY, rimcazole and clozapine, NPC 16377 (IC50 = 2671 nM) had low affinity for dopamine type 2 receptors. Additionally, the compound was only weakly active in 35 additional receptor binding assays including those for serotonin2 and serotonin1C receptors. In vivo, NPC 16377 potently inhibited the binding of [3H]-(+)-N-allylnormetazocine to sigma sites after both intraperitoneal and oral administration. At doses 30-fold in excess of the ID50 to inhibit [3H](+)N-allylnormetazocine, NPC 16377 failed to displace [3H]raclopride from dopamine type 2 binding sites. Unlike haloperidol, BMY 14802, ifenprodil and clozapine, behaviorally effective doses of NPC 16377 did not increase dopamine turnover in the frontal cortex, nucleus accumbens or corpus striatum of rats. In contrast, each of these agents increased circulating levels of both adrenocorticotropin and corticosterone, but only NPC 16377 decreased circulating plasma levels of prolactin. The results of the current study are consistent with the notion that NPC 16377 is a potent, selective and orally active sigma site ligand. At behaviorally relevant doses the compound produces neuroendocrine effects both similar to, and different from, neuroleptics, other sigma-ligands and atypical antipsychotics, while having no effect on dopamine turnover. Given these data, NPC 16377 should prove to be a useful compound to explore further the physiological and functional significance of sigma-sites in brain.

Effects of strychnine-insensitive glycine receptor antagonists and sigma agents on working memory performance: comparison with dizocilpine and scopolamine.

The strychnine insensitive glycine receptor antagonists (+/-) HA 966 (2.5, 3.5, 4.25 and 5.0mg/kg) and 7 chlorokynurenic acid (5.0, 10.0, and 15.0mg/kg), the putative sigma agents NPC 16377 (5.0 and 8.0mg/kg), BMY 14802 (5.0, 7.5 and 10.0mg/kg), and ifenprodil (5.0 and 7.0mg/kg) and the reference agents scopolamine and dizocilpine [(+) MK 801] were evaluated in a nonspatial delayed matching to sample working memory task in rats. (+/-) HA 966 impaired accuracy at the longest retention interval and decreased response probability measures. 7-Chlorokynurenic acid was essentially without effect. The noncompetitive NMDA antagonist dizocilpine reduced accuracy at all retention intervals, decreased the probability of a choice response and increased the probability of an intertrial interval response. The anticholinergic agent scopolamine selectively reduced accuracy at the longest retention interval but did not affect other performance measures. Sigma agents decreased response probability measures but did not affect accuracy at any retention interval. The results support the notion that sigma agents, glycine antagonists and NMDA antagonists produce different effects in cognitive tasks including working memory performance.

N-methyl-D-aspartate antagonists and working memory performance: comparison with the effects of scopolamine, propranolol, diazepam, and phenylisopropyladenosine.

The effects of the competitive N-methyl-D-aspartate (NMDA) antagonists CPP (5 & 10 mg/kg) and NPC 12626 (25 & 40 mg/kg) and the noncompetitive NMDA antagonists phencyclidine (1, 3, & 6.25 mg/kg) and MK 801 (0.1 & 0.2 mg/kg) on performance of rats on a nonspatial delayed matching-to-sample working memory task were evaluated. At the highest dose, each NMDA antagonist reduced choice accuracy at all retention intervals. In contrast, the reference anticholinergic agent scopolamine selectively reduced accuracy at long retention intervals, suggesting that scopolamine but not the NMDA antagonists directly interfered with time-dependent working memory retention. Propranolol, diazepam, and phenylisopropyladenosine had little or no effect on choice accuracy, suggesting that noradrenergic, gamma-aminobutyric acid-diazepam, and adenosine receptors may be relatively unimportant for working memory performance as assessed in this task. The NMDA antagonists also differed from scopolamine in that doses of NMDA antagonists that reduced response accuracy also reduced response probability, altered bias (competitive antagonists only), and increased intertrial interval responding (noncompetitive antagonists only). It was concluded that NMDA antagonists disrupt cognitive functions including, but not limited to, those required for accurate working memory performance.

Photochemically induced thrombosis of the precentral cortex impairs operant variable-interval spatial delayed alternation performance by rats.

A variable-interval spatial delayed alternation memory task was used to quantify the behavioral effects of photochemically induced thrombic infarction of the precentral (frontal) cortex. Upon achieving criterion on the behavioral task, rats received thrombicischemic lesions, predominantly limited to the medial precentral cortex, induced by injection of the fluorescein dye Rose Bengal and illumination of the skull above the target area. Beginning six days after surgery, rats were retested on the memory task. Compared to Sham-operated controls (n = 5), rats with precentral cortex lesions (n = 5) demonstrated a retention interval-dependent accuracy deficit (impaired at the longest retention interval only) and slower reaction time (increased response latency). These effects were significant only during the first week of postoperative testing. Rats with lesions also demonstrated a greater probability of a choice response throughout the three postoperative test weeks. The results suggest that photochemical thrombosis in the precentral cortex produces functional, behavioral consequences in rats which can be reliably and objectively measured.

Possible cerebroprotective and in vivo NMDA antagonist activities of sigma agents.

The recent finding that ifenprodil binds with high affinity to sigma sites suggests that other sigma agents may have ifenprodil-like cerebroprotectant and functional N-methyl-D-aspartate (NMDA) antagonist effects. The present study, compared the in vivo effects of ifenprodil and the sigma agents, BMY 14802, caramiphen and haloperidol, in three tests sensitive to NMDA antagonists and purported cerebroprotectant drugs. When administered at or below the rotorod TD50 dose, all four compounds significantly increased survival time in an hypoxic environment (4% O2 in nitrogen). Caramiphen and ifenprodil (ED50 = 52 and 61 mg/kg, respectively) also blocked maximal electroshock-induced seizures, whereas BMY 14802 and haloperidol were ineffective. Finally, caramiphen (ED50 = 95 mg/kg) antagonized seizures and lethality induced by administration of NMDA (250 mg/kg, IP). BMY 14802, haloperidol and ifenprodil only partially antagonized NMDA-induced seizures, but did enhance the anticonvulsant potency of the noncompetitive NMDA antagonist, MK-801. Together, these findings suggest that sigma agents may have cerebroprotective effects.

Effects of physostigmine on operant serial discrimination/reversal learning in rats.

Two experiments examined the effects of physostigmine on acquisition and performance of operant serial reversals by rats. In Experiment 1, four groups of rats (n = 6/group) were injected with either vehicle or 0.03 mg/kg physostigmine five minutes prior to each session, or vehicle or 0.5 mg/kg physostigmine immediately after each session of a three-stimulus (bright, dim or flashing light) repeated discrimination/reversal procedure. Rats treated with physostigmine pre- or postsession learned significantly more reversals over 50 sessions than animals injected with vehicle. Experiment 2 used only two discriminative stimuli, a light and a 2,500 Hz tone. Following establishment of a stable daily reversal baseline, postsession injections of physostigmine significantly increased the number of trials to criterion on the next session compared to each subject's control baseline. Results are attributed to enhanced between-session transfer of previously learned discriminated instrumental responses by physostigmine-treated animals.

Age-related cognitive impairments as assessed with an automated repeated measures memory task: implications for the possible role of acetylcholine and norepinephrine in memory dysfunction.

Although there exists a general agreement that certain aspects of learning and memory, and certain associated neuronal systems may be impaired with aging, systematic parametric studies are needed to characterize the nature and limits of these age-related impairments and to identify the underlying neuronal mechanisms. We review a series of experiments that examined the effects of aging and experimental treatments on rats' performance of a continuous nonmatching-to-sample, working memory task. In these studies, disruption of cholinergic transmission produced robust impairments that increased with retention interval duration, but could be observed even at the shortest intervals tested. In contrast, age-related impairments were less robust. With tone and light discriminative stimuli age-related impairments were not observed under conditions that were sensitive to disruption of cholinergic transmission, but were observed with increased retention interval duration. Finally, disruption of noradrenergic transmission produced a marginal disruption of memory performance, at worst. The generality of these results, and possible implication for future studies and animal models of dementia are discussed.

Dextromethorphan inhibits NMDA-induced convulsions.

Dextromethorphan, its metabolite dextrorphan, phencyclidine, ketamine, MK-801, 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid and DL-2-amino-7-phosphonoheptanoic acid were evaluated for potency to antagonize N-methyl-D-aspartate-induced convulsions following intraperitoneal administration using male CF-1 mice. Whereas reference anticonvulsants (e.g., phenytoin) were ineffective in this model, dextromethorphan and all competitive and noncompetitive N-methyl-D-aspartate antagonists blocked seizures. The results are consistent with the interpretation that dextromethorphan elicits some of its pharmacological responses via an interaction with receptors for excitatory amino acids.