Safety, pharmacokinetics and use of the novel NK-1 receptor antagonist maropitant (Cerenia) for the prevention of emesis and motion sickness in cats.

The present study characterizes the safety, pharmacokinetics, and anti-emetic effects of the selective NK-1 receptor antagonist maropitant in the cat. Safety of maropitant was determined following 15 days of subcutaneous (SC) administration at 0.5-5 mg/kg. Maropitant was well tolerated in cats at doses that exceeded the efficacious anti-emetic dose range of the drug by at least a factor of 10 and adverse clinical signs or pathological safety findings were not noted at any dose.The pharmacokinetics of maropitant in cats were determined following single dose oral (PO), intravenous (IV) and SC administration. Maropitant had a terminal half-life of 13-17 h and a bioavailability of 50 and 117% when administered PO and SC, respectively. Efficacy was determined against emesis induced either by xylazine or by motion. A dosage of 1 mg/kg maropitant administered IV, SC or PO prevented emesis elicited by xylazine. The compound had good oral antiemetic activity and a long (24 h) duration of action. Maropitant (1.0 mg/kg) was highly effective in preventing motion-induced emesis in cats. These studies indicate that the NK-1 receptor antagonist maropitant is well tolerated, safe and has excellent anti-emetic properties in cats.

Preclinical studies characterizing the anti-migraine and cardiovascular effects of the selective 5-HT1D receptor agonist PNU-142633.

The present study describes the preclinical pharmacology of a highly selective 5-HT1D receptor agonist PNU-142633. PNU-142633 binds with a Ki of 6 nm at the human 5-HT1D receptor and a Ki of> 18 000 nm at the human 5-HT1B receptor. The intrinsic activity of PNU-142633 at the human 5-HT1D receptor was determined to be 70% that of 5-HT in a cytosensor cell-based assay compared with 84% for that of sumatriptan. PNU-142633 was equally effective as sumatriptan and a half-log more potent than sumatriptan in preventing plasma protein extravasation induced by electrical stimulation of the trigeminal ganglion. Like sumatriptan, PNU-142633 reduced the increase in cat nucleus trigeminal caudalis blood flow elicited by electrical stimulation of the trigeminal ganglion compared with the vehicle control. The direct vasoconstrictor potential of PNU-142633 was evaluated in vascular beds. Sumatriptan increased vascular resistance in carotid, meningeal and coronary arteries while PNU-142633 failed to alter resistance in these vascular beds. These data are discussed in relation to the clinical findings of PNU-142633 in a phase II acute migraine study.

The nature and correlates of underachievement among elementary schoolchildren in Hong Kong.

This study investigated for the first time several characteristics of underachievement in a large sample of Hong Kong elementary schoolchildren. More males were identified as underachievers than females, but the ratio was substantially less than the two-to-one rate typically found in the American literature. The stability and persistence of underachievement increased during the elementary school years, and the stability of underachievement tended to be higher in subject matter that was relatively more difficult, which varied with gender. Underachievement became more specific to particular academic subjects rather than more general across the elementary grades. Parents and teachers, but not the children themselves, perceived that underachievers were more capable than same-grade nonunderachievers (who score lower on ability tests), although this awareness is more likely directed at male than female underachievers, which has been observed in other samples. In grades 1-4, teachers provided extra mentoring, communications, and support to underachievers. Thereafter, underachievers became more disruptive, impatient, and aggressive in school and perhaps at home. At that point, teachers became less supportive, offered less extra mentoring, and applied greater behavioral control over underachievers. Underachieving children also perceived that their parents became less supportive and used more discipline in grades 5-6 relative to grades 3-4. These correlates of underachievement suggests the existence of a syndrome of underachievement that separates underachievers from children who have the same grades but lower mental ability.

The future of applied child development research and public policy.

After reviewing a brief general history of applied child development research, this paper suggests that in the future we should study questions that society needs to answer as well as questions that might contribute to theory, and that our research methods need to be adjusted to match these types of questions. Further, academics are urged to broaden their audience from a nearly exclusive focus on other academics to a focus on the three ps--practitioners, policymakers, and the public--and to recognize that scholarship is packaged differently for these audiences. Finally, it is suggested that applied child development research should market as well as sell, partner with nonacademic groups, disseminate results more vigorously, and focus efforts on local as well as national issues.

Trigeminal ganglion elicited increases in nucleus trigeminal caudalis blood flow: a novel migraine model.

We developed an assay which predicts the antimigraine efficacy of sumatriptan. Our assay is based on two assumptions: (1) electrical stimulation of the trigeminal ganglion mimics the neurogenic inflammatory process and (2) stimulation-induced increases in n. trigeminal caudalis blood flow reflect activation of a large population of neurons. Briefly, the trigeminal ganglion was electrically stimulated for 30 s periods at 1 and 10 Hz before and after administration of saline or the antimigraine compound sumatriptan in chloralose-anesthetized cats. Sumatriptan blunted the increase in blood flow following stimulation of the trigeminal ganglion. These data suggest that the n. trigeminal caudalis blood flow model may be useful in identifying antimigraine compounds.

Pharmacological characterization of U-101387, a dopamine D4 receptor selective antagonist.

Dopamine D2-like receptors play an important role in the pharmacotherapy of psychotic disorders. Molecular and cellular techniques have identified distinct gene products (D2-long, D2-short, D3 and D4) displaying the D2 receptor pharmacology. However, the contribution of each subtype in antipsychotic effects of or their physiological role remain unclear. Here we describe the pharmacological effects of a selective D4 antagonist, U-101387. U-101387 displayed moderately high affinity (Ki = 10 nM) and selectivity for the dopamine D4.2 receptor expressed in clonal cell lines. It lacked measurable affinity for not only other dopamine receptors but also noradrenalin, serotonin and histamine receptor families (Ki > 2000 nM). It fully and dose-dependently antagonized quinpirole-induced cAMP inhibition (without producing any effect by itself) in stably transfected cells. U-101387 also displayed excellent oral bioavailability, brain penetration and other pharmacokinetic characteristics. Unlike classical neuroleptics (e.g., haloperidol), U-101387 neither blocked acute behavioral effects of amphetamine or apomorphine nor did it alter spontaneous locomotion by itself. Additionally, U-101387 was without effect in behavioral and biochemical tests predictive of extrapyramidal and neuroendocrine side effects. Consistent with the lack of autoreceptor function of D4, acute administration of U-101387 failed to alter dopamine neuronal firing by itself or reverse the inhibition produced by dopamine agonists and to affect monoamine turnover in areas innervated by the mesencephalic or hypothalamic dopamine neurons. However, U-101387 potently induced c-fos mRNA expression in the infralimbic/ventral prelimbic cortex to a level similar to that produced by the atypical antipsychotic, clozapine. This is consistent with the predominantly cortical distribution of the D4 receptor. Taken together, these results demonstrate that the D4-selective antagonist, U-101387, produces effects that are distinct from those of the nonselective D2 antagonists as well as D3-preferring agents. U-101387 offers a unique tool to understand the role of dopamine D4 receptors in diseases involving central dopamine systems.

Role of serotonergic neurons in the maintenance of the 10-Hz rhythm in sympathetic nerve discharge.

We studied the effects of serotonin (5-HT)-receptor agonists and antagonists on the naturally occurring 10-Hz rhythm in sympathetic nerve discharge (SND) of urethan-anesthetized, baroreceptor-denervated cats. Intravenous doses of the 5-HT1A-receptor agonists 8-hydroxy-2(di-n-propylamino)-tetralin (8-OH-DPAT) and U-93385E, which inhibit the firing of serotonergic medullary raphe neurons, decreased the power in the 10-Hz band of SND without affecting the power at frequencies < or = 6 Hz. The inhibitory effects of 8-OH-DPAT and U-93385E were reversed by the 5-HT1A-receptor antagonists spiperone and WAY-100135. Microinjection of 8-OH-DPAT into medullary raphe nuclei also selectively eliminated the 10-Hz rhythm in SND. Intravenous administration of the 5-HT2-receptor antagonist methysergide blocked the 10-Hz rhythm in SND, whereas the 5-HT2-receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane increased peak frequency and power in the 10-Hz band of SND. Microinjection of N-methyl-D-aspartic acid into the medullary raphe also enhanced the 10-Hz rhythm in SND. These data support the view that the naturally occurring discharges of serotonergic medullary raphe neurons preferentially enhance the 10-Hz rhythm in SND.

Rapid and long duration tolerance to the vagal bradycardic effects of 5-HT1A receptor agonists.

Administration of a single dose of the 5-HT1A receptor high intrinsic agonist U-93385E (either 0.3, 1.0 or 3.0 mg/kg, i.v.) results in a 20-30% decrease in heart rate. In contrast, cumulative dosing of U-93385E (0.01-3.0 mg/kg, i.v.) failed to lower heart rate in the spinal cat. Similarly, infusion of 1 mg/kg of U-93385E over a 2 h period failed to lower heart rate and prevented a bradycardic effect of a single bolus dose of U-93385E or flesinoxan. In contrast, the alpha 2-receptor agonist clonidine decreased heart rate in animals receiving the U-93385E infusion. Single bolus doses of flesinoxan or U-93385E failed to decrease heart rate in cats treated for 7 days with U-93385E (3 mg/kg, b.i.d.) and then saline for 3 days. Similarly, U-93385E failed to lower heart rate 12 days following a 14 day infusion of U-93385E (1 mg/kg per day). These data indicate that a rapid and long duration tolerance develops to the vagal bradycardia produced by 5-HT1A receptor agonists.

Effects of inhibitory amino acids on the frequency components in sympathetic nerve discharge.

The effects of the GABA antagonist picrotoxin and the glycine antagonist strychnine on the frequency components in sympathetic inferior cardiac nerve activity were observed. Picrotoxin (0.03-1.0 mg/kg) increased power in the 10-Hz component of sympathetic activity and produced a dramatic shift in the rhythm to higher frequencies. Only small changes were noted in the 2- to 6-Hz component. Strychnine produced a small generalized increase in power in both frequency bands in sympathetic activity. These data suggest that GABA may play an important role in the generation and maintenance of the 10-Hz rhythm in sympathetic activity while glycine likely inhibits activity at a site of convergence of the two rhythms in sympathetic activity.

Tolerance development to the vagal-mediated bradycardia produced by 5-HT1A receptor agonists.

The purpose of this study was to characterize the bradycardic effects of 5-hydroxytryptamine (5-HT)1A receptor agonists in the chloralose-anesthetized spinal cat and to determine if tolerance develops to the bradycardia produced by these drugs. 5-HT1A receptor agonists studied included 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), buspirone, gepirone, flesinoxan and U-93385E (cis-(3aR)-(-)-2,3,3a,4,5,9b-hexahydro-3-propyl-1H-benz[e]indole-9 - carboxamide). These compounds reduced heart rate by 20 to 30% in the spinal cat and lowered arterial blood pressure. The hypotension resulted from a decrease in cardiac output. Atropine reversed and vagotomy prevented the bradycardia produced by a single dose of U-93385E. The decrease in heart rate produced by i.v. bolus doses of flesinoxan or U-93385 was reversed by administration of the 5-HT1A receptor antagonists spiperone or WAY 100135. Administration of a single dose of U-93385E (either 0.3, 1.0 or 3.0 mg/kg i.v.) resulted in a 20 to 30% decrease in heart rate. In contrast, cumulative dosing of U-93385E (0.01-3.0 mg/kg i.v.) failed to lower heart rate in the spinal cat. Similarly, infusion of 1 mg/kg of U-93385E over a 2-hr period failed to lower heart rate and prevented a bradycardic effect of a single bolus dose of U-93385E or flesinoxan. In contrast, the alpha-2 receptor agonist clonidine decreased heart rate in animals receiving the U-93385E infusion. Finally, single bolus doses of flesinoxan or U-93385E failed to decrease heart rate in cats treated for 7 days with U-93385E and then saline for 3 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of U-92016A as a selective, orally active, high intrinsic activity 5-hydroxytryptamine1A agonist.

The purpose of the present study was to characterize U-92016A [(+)-R)-2-cyano-N,N-dipropyl-8-amino-6,7,8,9-tetrahydro-3H-benz[e] indole] as a 5-hydroxytryptamine (5-HT)1A receptor agonist and to compare its activity with that of standard 5-HT1A receptor agonists. U-92016A binds with high affinity to human 5-HT1A receptors expressed in Chinese hamster ovary cells (Ki = 0.2 nM). Radioligand binding studies also indicate that U-92016A is selective for the 5-HT1A receptor over other biogenic amine receptors. In Chinese hamster ovary cells expressing the human 5HT1A receptor, U-92016A decreased the forskolin-induced increase in cyclic AMP synthesis and had an intrinsic activity of 0.82 relative to 5-HT. U-92016A potently decreased rectal temperature in mice. The maximum temperature decrease was significantly greater than that observed for 8-hydroxy-di-n-propyl aminotetralin, buspirone, gepirone, ipsapirone or flesinoxan. U-92016A also elicited the 5-HT-mediated syndrome in rats and resulted in a dose-related decrease in 5-hydroxytryptophan accumulation. The compound also decreased arterial blood pressure in spontaneously hypertensive rats and inhibited sympathetic nerve activity in cats. In these assays U-92016A displayed excellent potency and a long duration of action. U-92016A also inhibited the firing of dorsal raphe 5-HT neurons and was active in two social interaction assays. The p.o. bioavailability of U-92016A was calculated to be 45%. Taken together, these data indicate that U-92016A is a metabolically stable, p.o. active 5-HT1A receptor agonist with an exceptionally high degree of intrinsic activity.

Pharmacology of a mixed 5-hydroxytryptamine1A/dopamine agonist.

U-67413B (4-hydroxydipropylaminodihydrophenalene) bound with high affinity to both 5-hydroxytryptamine (HT)1A and D2-dopamine (DA) receptor sites. U-67413B depressed 5-HT and DA cell firing rates and depressed synthesis of both neurotransmitters. The drug depressed mouse body temperatures by an amount similar to that for buspirone, gepirone and ipsapirone, but less than that for 8-hydroxy-N,N-dipropyl-2-aminotetralin. In rats, it produced the 5-HT1A behavioral syndrome. In contrast to 5-HT1A agonists having DA antagonist effects, U-67413B mildly depressed rather than stimulated firing rates of noradrenaline (NA) neurons in the locus ceruleus by a non-alpha-2 receptor mechanism. In behavioral tests designed to measure anxiolytic activities, U-67413B was a slightly more effective anxiolytic than standard 5-HT1A anxiolytics (buspirone, gepirone and ipsapirone). The data are consistent with the hypothesis that effects of 5-HT1A agonists on NA neuron activity are mediated through effects on dopaminergic mechanisms, and that effects on NA neurons could modulate anxiolytic activities of 5-HT1A agonists.

Characterization of the serotonin1A receptor antagonist activity of WAY-100135 and spiperone.

The effects of the putative serotonin (5-HT)1A receptor antagonists WAY-100135 (WAY) and spiperone on the neuronal activity recorded from medullary and dorsal raphe 5-HT neurons and the inferior cardiac sympathetic nerve were investigated in chloralose anesthetized cats. We also determined the effectiveness of WAY and spiperone to antagonize the sympathoinhibitory effects of the 5-HT1A agonist 8-hydroxy-(2-di-n-propylamino)tetralin (8-OH DPAT). Intravenous administration of both WAY and spiperone produced a dose-related inhibition of the firing of medullary 5-HT neurons. WAY also inhibited firing of serotonergic neurons in the dorsal raphe nucleus. WAY treatment had no significant effect on inferior cardiac sympathetic nerve discharge (SND), whereas spiperone treatment caused a small, but significant, increase in SND. WAY treatment did not significantly affect 8-OH DPAT-induced inhibition of unit firing. Spiperone, however, did display antagonist activity at the presynaptic autoreceptor site. WAY and spiperone pretreatments resulted in significant rightward shifts in the 8-OH DPAT inhibition of SND dose-response curves and reversed the depressant effects of 8-OH DPAT. These results suggest that WAY and spiperone act as 5-HT1A antagonists postsynaptically, but WAY appears to have more potent agonist efficacy at the 5-HT1A presynaptic autoreceptor site in the cat. However, because all drugs were administered intravenously, conclusions regarding direct effects of WAY and spiperone on 5-HT1A receptors must be made cautiously.

Impairment of baroreceptor reflexes following kainic acid lesions of the lateral tegmental field.

We examined the effects of kainic acid lesions of the lateral tegmental field on baroreceptor function in the anesthetized cat. Kainic acid lesions prevented the reflex inhibition of inferior cardiac sympathetic nerve activity observed during an increase in blood pressure. The temporal locking of sympathetic slow waves to the cardiac cycle was also abolished following tegmental field lesions. Finally, the periodicity of sympathetic nerve discharge shifted to a higher frequency range following kainic acid lesions. These observations are consistent with the conclusion that lesions of the lateral tegmental field impair baroreceptor reflexes.

Synthesis and biological activity of cis-(3aR)-(-)-2,3,3a,4,5,9b-hexahydro- 3-propyl-1H-benz[e]indole-9-carboxamide: a potent and selective 5-HT1A receptor agonist with good oral availability.

The synthesis and biological activity of cis-(3aR)-(-)-2,3,3a,4,5,9b- hexahydro-3-propyl-1H-benz[e]indole-9-carboxamide ((-)-3a), U93385, is described. The cis racemate and its enantiomer as well as the corresponding trans enantiomers were also synthesized and evaluated. The synthesis of these analogs was achieved via either a four-step conversion of the 9-hydroxy precursor into 9-carboxamide or an alternative synthesis using the (R)-alpha-methylbenzyl group as the chiral auxiliary. The cis racemate (+/-)-3a, was found to be a selective and potent 5-HT1A receptor agonist with the activity residing in the cis-(3aR)-enantiomer, (-)-3a. The cis-(3aS)-enantiomer (+)-3a and trans-(3aR)-enantiomer (-)-3b displayed partial 5-HT1A agonist activity whereas the other trans-(3aS)-enantiomer (+)-3b showed no activity. The enantiomer (-)-3a was found to be selective in both in vitro and in vivo biochemical/behavioral assays. This compound potently reduced rectal temperature in mice, decreased the firing rate of rat midbrain serotonergic neurons, and suppressed rat brain 5-HT synthesis. This compound also reduced sympathetic nerve discharge and blood pressure in the anesthetized cat and showed activity in the forced swim assay in mice. It exhibited good oral activity in behavioral and biochemical assays and, in fact, had a 46% oral availability in the rat when comparing blood levels of parent drug after iv and po administration. This compound has demonstrated a potential for anxiolytic and antidepressant activity and is currently undergoing clinical evaluation.

Novel 2-substituted tetrahydro-3H-benz[e]indolamines: highly potent and selective agonists acting at the 5-HT1A receptor as possible anxiolytics and antidepressants.

The synthesis of (+)-(R)-2-cyano-N,N-dipropyl-8-amino-6,7,8,9-tetrahydro-3H- benz[e]indole [(R)-14, U92016A], a potent 5-HT1A agonist, and related analogs is described. In vitro binding studies show that the (R)-enantiomers of this series possess the highest potency for the 5-HT1A receptor. In vivo hypothermia correlates with this, with the (R)-enantiomers causing a greater temperature drop than the (S)-enantiomers. The most active compound in 5-HT1A binding and in the in vivo models was (R)-14, which was found to be highly potent as an agonist in single cell firing studies, as well as potent and of very high intrinsic activity in mouse hypothermia and the sympathetic nerve discharge (SND) models. An in vivo duration of action study, following SND, showed (R)-14 to possess a long duration of action. The synthesis via a nitrene insertion, determination of absolute configuration, and biological activities of this series is described.

Lateral tegmental field involvement in the central sympathoinhibitory action of 8-OH-DPAT.

This study examined the effects of kainic acid and NMDA microinjections into the lateral tegmental field on the sympatholytic effect of the 5-HT1A agonist 8-OH-DPAT. Kainic acid has been reported to destroy cell bodies while leaving fibers of passage intact while NMDA excites the cell bodies but not the axons of neurons. Microinjection of kainic acid was found to block the usual sympatholytic effect of 8-OH-DPAT but not the sympathoinhibition produced by the alpha 2 agonist clonidine. Microinjection of NMDA elicited profound pressor responses related to an increase in sympathetic activity. Sympatholytic effects of 8-OH-DPAT and clonidine were transiently overridden by microinjections of NMDA, but not glutamate. A role for the lateral tegmental field in the generation of sympathetic tone and in the sympatholytic mechanism of 8-OH-DPAT is supported by the chemical lesion and stimulation studies.