Comparison of the doubly labeled water (2H2(18)O) method with indirect calorimetry and a nutrient-balance study for simultaneous determination of energy expenditure, water intake, and metabolizable energy intake in preterm infants.

The doubly labeled water method was compared with indirect calorimetry and a nutrient-balance study for simultaneous determination of rates of CO2 production, energy expenditure, and water intake over 5 days in four preterm infants. Additionally, metabolizable energy (ME) intake estimated using the isotope procedure (as energy expenditure plus an estimate for energy deposition based on weight gain), was compared to ME intake measured in the balance study. Compared to values obtained by traditional methods, calculated CO2 production, energy expenditure, and water intake differed by -1.4 +/- 4.8% (SD), +0.3 +/- 2.6%, and +5.7 +/- 1.4%, respectively; the difference in water intake was significant (p less than 0.05). Calculated ME intakes were 5.3 +/- 19.3% less than measured intakes, but the difference was not significant. These findings indicate that the doubly labeled water method can provide accurate information on rates of CO2 production, energy expenditure, and water intake in preterm infants, but individual estimates of ME intake may be subject to substantial error.

The action of dazopride to enhance gastric emptying and block emesis.

The substituted benzamide derivatives, dazopride and metoclopramide, enhanced field stimulation-induced contractions of guinea-pig stomach strips and gastric emptying in the guinea-pig after peripheral, intracerebroventricular and intrahypothalamic injection. In the isolated vagal nerve preparation from the rabbit, both compounds were shown to be 5-hydroxytryptamine M-receptor antagonists. Dazopride and metoclopramide were equipotent in antagonising cisplatin-induced emesis in the ferret, whereas metoclopramide was approximately 200 times more potent than dazopride in antagonising the emesis caused by the dopamine agonist 2-di-n-propylamino-5,6-dihydroxytetralin in the marmoset. In behavioural tests which indicate dopamine receptor antagonism in the rat, metoclopramide induced catalepsy, antagonised amphetamine-induced stereotypy and the hyperactivity induced by the intrastriatal injection of dopamine, caused body asymmetry on unilateral injection into the striatum and also antagonised apomorphine-induced climbing and circling behaviour in the mouse. In contrast, dazopride had little or no action in these tests and failed to displace [3H]spiperone in radioligand binding assays. The use of dazopride provides evidence to dissociate a dopamine receptor blockade from an ability to facilitate gastric emptying and to antagonise cisplatin-emesis, and indicates that antagonism of 5-hydroxytryptamine M-receptors is the essential basis of action for dazopride and plays an important role in the actions of metoclopramide.

Synthesis and dopaminergic properties of some exo- and endo-2-aminobenzonorbornenes designed as rigid analogue of dopamine.

Stereospecific syntheses of exo-2-amino-5,6-dihydroxybenzonorbornene (11f), exo-2-amino-6,7-dihydroxybenzonorbornene (11h), exo-2-amino-7,8-dihydroxybenzonorbornene (11g), and endo-2-amino-6,7-dihydroxybenzonorbornene (14d), rigid analogues of dopamine, are described. Compounds 11 h and 14d, their N-methyl (11i and 11j) and N,N-dimethyl (14i and 14j) derivatives, and compounds 11f and 11g were inactive as dopamine agonists when evaluated for dopaminergic activity by their ability to induce stereotyped behavior in mice after subcutaneous injection and by their ability to cause hyperactivity in rats after bilateral injection into the nucleus accumbens. However, compounds 11f, 11g, 11h, and the N-methyl derivatives 11i and 14d were all effective in displacing [3H]-2-amino-6,7-dihydroxytetralin ([3H]ADTN) and [3h[-N-n-propylnorapomorphine ([3H]NPA) from rat striatal membranes.

5,7-Dihydroxy-2-aminotetralin derivatives: synthesis and assessment of dopaminergic and adrenergic actions.

Replacement of the catechol 3,4-dihydroxylation pattern of certain adrenergic beta-phenethylamines by a resorcinol 3,5-dihydroxylation pattern has led to a greater selectivity of adrenergic agonist effects in certain molecules. This strategy has been applied to a series of dopaminergic agents derived from 2-aminotetralin, leading to a 5,7-dihydroxylation pattern. Traditional literature approaches to formation of a tetralin ring with this oxygenation pattern failed. A method was used which involved cyclization of 3,5-dimethoxybenzylsuccinic acid derivatives with pyridinium poly(HF) and subsequent modification of the tetralin ring. The resorcinol-derived 2-aminotetralins were less potent and less active dopaminergic agents than their catechol-derived isomers (5,6-dihydroxy and/or 6,7-dihydroxy). Certain of the subject compounds demonstrated alpha- and beta 1-adrenoceptor activating properties.

Differential effect of benserazide (Ro4-4602) on the concentration of indoleamines in rat pineal and hypothalamus.

1 Low doses (50 and 80 mg/kg) of benserazide (Ro4-4602), an aromatic amino acid decarboxylase inhibitor, markedly reduced 5-hydroxytryptamine and melatonin in the rat pineal gland without affecting hypothalamic 5-hydroxytryptamine. 2 This differential effect shows that inhibition of the pineal gland decarboxylase activity is possible, and confirms that the rat pineal gland is accessible to peripherally acting agents.

Use of the intracerebral injection technique to elucidate mechanisms of apomorphine climbing and its antagonism in the mouse.

Climbing behavior induced by peripherally administered apomorphine in the mouse was reduced by 0.25-10 microgram bilateral intra-accumbens fluphenazine, (+/-) and (-) sulpiride and by serotonin, but not by (+)sulpiride, dl-propranolol, phentolamine, atropine or methysergide. A specific antagonism of climbing could not be shown when fluphenazine was injected into the striatum, hypothalamus, thalamus, reticular formation, frontal cortex or cerebellum, but was apparent when a large dose of fluphenazine was placed below (but not above) the accumbens nucleus. 6-Hydroxydopamine denervation of the nucleus accumbens did not alter the climbing antagonism afforded by fluphenazine, although sulpiride was three-fold more effective following denervation. The data indicates an accumbens involvement in the climbing phenomenon, that sulpiride more effectively antagonises climbing after accumbens denervation and that the presumed dopamine agonist-antagonist interaction in the accumbens, which controls climbing, may also involve serotonergic function. The studies emphasise the value of the intra-cerebral injection technique to an analysis of drug action in the mouse.

Dopamine D2 receptor occupancy in vivo by the novel atypical antipsychotic olanzapine--a 123I IBZM single photon emission tomography (SPET) study.

We have studied striatal D2 dopamine binding in schizophrenic patients treated with the novel atypical antipsychotic drug, olanzapine. 123I iodobenzamide (IBZM) single photon emission tomography (SPET) was used to estimate striatal dopamine D2 receptor binding in vivo. Patients were recruited from a prospective, double blind controlled trial of olanzapine versus haloperidol treatment. In vivo striatal D2 binding data from olanzapine treated patients (n = 6) were compared with previously reported data from typical antipsychotic responsive (n = 10); clozapine (n = 10); and risperidone (n = 6) treated patient groups. Mean % Brief Psychiatric Rating Scale score (BPRS) improvement following olanzapine treatment was 49% (SD 44). The hypothesis that clinical improvement in olanzapine treated patients would be associated with higher mean striatal D2 binding of 123I IBZM (reflecting lower levels of D2 occupancy) than typical antipsychotic (1.25 +/- 0.05) or risperidone (1.24 +/- 0.04) treatment was confirmed. Olanzapine treated patients had similar levels of striatal D2 binding in vivo (1.41 +/- 0.06) as those treated with clozapine (1.49 +/- 0.04). This preliminary evidence suggests olanzapine is another atypical antipsychotic drug in which therapeutic response is not associated with a high degree of striatal D2 receptor occupancy in vivo.

Climbing behaviour induced by apomorphine in mice: a potential model for the detection of neuroleptic activity.

Apomorphine and the putative dopamine agonist, 2-(N, N-dipropyl)-amino-5, 6-dihydroxytetralin induced dose-dependent climbing behaviour in the mouse which was measured in wire mesh lined cages as the percentage of time spent climbing in the 30 min period following the first climb and as the maximum time spent in a single climb throughout the drug effect. These These two measures were generally found to parallel excepting when the interacting agent caused muscular hypotonia. All potential interacting agents were given as pretreatments to determine changes in motor function which may interfere with the climbing induced by 1.0 mg/kg s.c. apomorphine. The possibility of a change in the apomorphine response to a sterotyped biting, which would also interfere with climbing, was also considered. Excluding these non-specific changes, climbing behaviour was shown to be antagonised, dose-dependently, by low doses of typical and atypical neuroleptic agents (haloperidol, fluphenazine, loxapine, pimozide, oxiperomide, clozapin, thioridazine, sulpiride, tiapride and metoclopramide) but not specifically by other psychoactive agents. Climbing behaviour was modified by serotonergic agents; the agonist quipazine reduced or abolished, whilst the antagonists, methysergide and cyproheptadine, enhanced the response. Picrotoxin specifically reduced climbing behaviour but sodium valproate exerted non-specific effects, precluding conclusions as to a GABA involvement. Cholinergic and noradrenergic involvements with climbing were also apparently eliminated by the ineffectiveness of atropine, aceperone, piperoxan and propranolol. The involvement of serotonin with climbing was extended to the actions of the neuroleptics: the antagonistic effects of typical neuroleptics (haloperidol, fluphenazine, loxapine) were markedly enhanced by combination with methysergide or cyproheptadine whilst the effects of clozapine, sulpiride and thioridazine were significantly reduced. The actions of metoclopramide, oxiperomide, pimozide and tiapride were not generally modified by such combinations. These differences are discussed in terms of differential abilities to induce extrapyramidal disturbances and the mouse climbing model is forwarded as a test with potential to detect antipsychotic agents of different activity spectra.

The mesolimbic system, denervation and the climbing response in the mouse.

Bilateral intra-accumbens 6-OHDA (2 micrograms in the presence of DMI and tranylcypromine, 14th postoperative day) enhanced the climbing responses of mice to apomorphine and 2-(N,N-dipropyl)amino-5,6-dihydroxytetralin causing parallel shifts of the normal log dose-response curves to the left. The enhancement of the apomorphine response was shown to be dependent on the dose of 6-OHDA, 0.5 micrograms being threshold and 2 micrograms maximum. Increased climbing was apparent by the 5th postoperative day, maximum by the 10th day, and was then maintained throughout the experimental period (6-8 weeks). 0.25-2 micrograms intra-accumbens 6-OHDA caused dose-related decreases in the dopamine content of mesolimbic areas (nucleus accumbens and tuberculum olfactorium) without causing significant changes in mesolimbic noradrenaline or striatal dopamine. In the absence of DMI/tranylcypromine, 2 and 4 micrograms 6-OHDA also decreased mesolimbic noradrenaline and striatal dopamine content. 16 micrograms 6-OHDA injected into the striatum (after DMI/tranylcypromine) decreased the striatal dopamine content by 85% (without altering mesolimbic dopamine or noradrenaline content) but this treatment failed to modify apomorphine climbing (2nd-12th postoperative days). Haloperiod, sulpiride, thioridazine, clozapine ad metoclopramide each caused a dose-dependent decrease in apomorphine climbing in both normal and 6-OHDA-treated mice. Haloperidol and metoclopramide were approximately equipotent in both groups of animals whilst sulpiride and thioridazine were approximately 4x more potent in the 6-OHDA-treated mice (the development of muscular hypotonia made an interpretation of clozapine effects difficult). The data indicate that an important role for the mesolimbic nucleus accumbens in the mediation of apomorphine climbing, and indicate that the antagonism by sulpiride and thioridazine may be specifically increased when mesolimbic mechanisms are rendered 'supersensitive'.

EKG abnormalities in pediatric patients with myotonic dystrophy.

Electrocardiographic (EKG) abnormalities are frequent in patients with myotonic dystrophy; cardiac complications may lead to significant morbidity and mortality. The charts of 17 pediatric patients with myotonic dystrophy were reviewed to ascertain the frequency of EKG abnormalities and cardiovascular symptoms. Fifteen of 17 patients had abnormal EKGs with sinus bradycardia being the most common abnormality. Only 1 of 17 patients had cardiovascular symptoms. Four patients had moderate to severe weakness and 3 of them had a conduction disturbance (i.e., first-degree AV block or intraventricular conduction delay). Two of the remaining 13 patients with mild weakness had conduction disturbances. No pediatric patients had progressive EKG abnormalities during follow-up. Baseline EKG study of pediatric patients with myotonic dystrophy is recommended because abnormalities are frequent and usually asymptomatic. Frequent follow-up EKGs are probably unnecessary unless the patient is symptomatic or has heart block.

Torticollis acquired in late infancy due to a cerebellar gangliocytoma.

Torticollis in infancy is a common disorder and is typically benign and self-limiting. However, in some instances it is the presentation of serious disease. A critical distinction is whether the condition is congenital or acquired. We present a case of acquired late infantile torticollis caused by a cerebellar gangliocytoma that underscores the importance of making this determination prior to initiating a treatment plan. A gangliocytoma presenting with torticollis has not been previously described.

Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy.

OBJECTIVE: To evaluate the efficacy and safety of ezogabine (United States adopted name)/retigabine (international nonproprietary name) (EZG[RTG]) 1,200 mg/day as adjunctive treatment in adults with drug-resistant epilepsy with partial-onset seizures with or without secondary generalization. METHODS: RESTORE 1 was a multicenter, randomized, double-blind, parallel-group trial. Following a prospective 8-week baseline phase, patients entered an 18-week double-blind treatment period (6-week forced dose titration to EZG[RTG] 1,200 mg/day in 3 equally divided doses or placebo, followed by a 12-week maintenance phase). Results were analyzed on an intent-to-treat basis for the entire 18-week period and for patients reaching the maintenance phase. RESULTS: In 306 patients randomized, 305 received EZG(RTG) 1,200 mg/day (n = 153) or placebo (n = 152). Median percent reduction in total partial-seizure frequency was 44.3% vs 17.5% (p < 0.001) for EZG(RTG) and placebo, respectively, during the 18-week double-blind period; responder rates (≥50% reduction in total partial-seizure frequency from baseline) were 44.4% vs 17.8% (p < 0.001). In 256 patients (EZG[RTG], 119; placebo, 137) entering the 12-week maintenance phase, median percent reduction in seizure frequency for EZG(RTG) vs placebo was 54.5% and 18.9% (p < 0.001), respectively; responder rates were 55.5% vs 22.6% (p < 0.001). The proportion of patients discontinuing due to treatment-emergent adverse events (TEAEs) was 26.8% (EZG[RTG]) vs 8.6% (placebo). Dizziness, somnolence, fatigue, confusion, dysarthria, urinary tract infection, ataxia, and blurred vision were the most common TEAEs reported by more patients treated with EZG(RTG) than placebo. CONCLUSIONS: This study demonstrates that EZG(RTG) is effective as add-on therapy for reducing seizure frequency in patients with drug-resistant partial-onset seizures. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that EZG(RTG) 1,200 mg/day is effective as adjunctive therapy in adults with partial-onset seizures with or without secondary generalization.

Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy.

OBJECTIVE: This study assessed the efficacy and safety of the neuronal potassium channel opener ezogabine (US adopted name; EZG)/retigabine (international nonproprietary name; RTG) as adjunctive therapy for refractory partial-onset seizures. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled trial in adults with ≥4 partial-onset seizures per month receiving 1 to 3 antiepileptic drugs. EZG (RTG) or placebo, 3 times daily, was titrated to 600 or 900 mg/d over 4 weeks, and continued during a 12-week maintenance phase. Median percentage seizure reductions from baseline and responder rates (≥50% reduction in baseline seizure frequency) were assessed. RESULTS: The intention-to-treat population comprised 538 patients (placebo, n = 179; 600 mg, n = 181; 900 mg, n = 178), 471 of whom (placebo, n = 164; 600 mg, n = 158; 900 mg, n = 149) entered the maintenance phase. Median percentage seizure reductions were greater in EZG (RTG)-treated patients (600 mg, 27.9%, p = 0.007; 900 mg, 39.9%, p < 0.001) compared with placebo (15.9%). Responder rates were higher in EZG (RTG)-treated patients (600 mg, 38.6%, p < 0.001; 900 mg, 47.0%, p < 0.001) than with placebo (18.9%). Treatment discontinuations due to adverse events (AEs) were more likely with EZG (RTG) than with placebo (placebo, 8%; 600 mg, 17%, 900 mg, 26%). The most commonly reported (>10%) AEs in the placebo, EZG (RTG) 600 mg/d, and EZG (RTG) 900 mg/d groups were dizziness (7%, 17%, 26%), somnolence (10%, 14%, 26%), headache (15%, 11%, 17%), and fatigue (3%, 15%, 17%). CONCLUSIONS: In this dose-ranging, placebo-controlled trial, adjunctive EZG (RTG) was effective and generally well tolerated in adults with refractory partial-onset seizures. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that adjunctive EZG/RTG reduces the occurrence of partial-onset seizures.