Protection against the lethal effects of pentobarbital in mice by a benzodiazepine receptor inverse agonist, 6,7-dimethoxy-4-ethyl-3-carbomethoxy-beta-carboline.

The benzodiazepine receptor inverse agonist 6,7-dimethoxy-4-ethyl-3-carbomethoxy-beta-carboline (DMCM) (1.5-15 mg/kg) was administered to mice 5 min after a lethal (LD94) injection of pentobarbital. DMCM (1.5-5 mg/kg) increased short-term (1 h) survival in a dose-dependent fashion, with an optimum survival rate more than five times greater than mice receiving pentobarbital alone. Statistically significant increases in long-term (24 h) survival were also observed after both 5 and 10 mg/kg of DMCM (34 and 33%, respectively) compared with animals receiving pentobarbital alone (6%). Two doses of DMCM (5 and 2.5 mg/kg, respectively) administered 55 min apart produced an even greater increase (58%) in 24-h survival rates. Doses of DMCM that increased 1- and 24-h survival were not lethal when administered alone, and were below the dose that produced convulsions in 50% (CD50) of the animals. The protective effects of DMCM were blocked by pretreatment with the benzodiazepine receptor agonist ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo- 4H-imidazo[1,5a][1,4]benzodiazodiazepine-3-carboxylate (Ro 15-1788), which suggests the effects of DMCM are mediated through the benzodiazepine receptor. These findings suggest that DMCM or another benzodiazepine receptor ligand with full inverse agonist qualities could prove effective as an antidote for barbiturate intoxication in man.     

In vitro characterization of benzodiazepine receptor agonists, antagonists, inverse agonists and agonist/antagonists

Using an extensively washed membrane preparation and standardized incubation conditions, the actions of benzodiazepine (BZ) receptor ligands were evaluated on [3H]flunitrazepam [+/- 10 microM gamma-aminobutyric acid (GABA)], [3H]muscimol (+/- 2.5 microM etazolate) and [35S]butyl bicyclophosphorothionate (TBPS) binding. Classical BZ receptor agonists stimulated [35S]TBPS binding and [3H]muscimol binding in the presence of etazolate. These agents also possessed ratios for [3H]flunitrazepam binding in the absence and presence of GABA (GABA ratio) of 2 to 5. BZ antagonists and inverse agonists had GABA ratios less than 1 and did not alter, or reduced, both [35S]TBPS and [3H]muscimol (+etazolate) binding. The nonsedating BZ agonist/antagonist agents CGS 9896, CL 218872, PK 8165 and PK 9084 all possessed GABA ratios between 1.1 and 1.4 and only stimulated [35S]TBPS and [3H]muscimol (+etazolate) binding to approximately 50% of the level of classical BZ agonists. The BZ partial agonists CGS 9895 and RU 39419 both were unique in that they possessed GABA ratios of 1 or less, stimulated [35S]TBPS binding and had no effect on [3H]muscimol binding (+etazolate). Therefore, by monitoring the major components of the BZ receptor complex (BZ receptor, GABA receptor and chloride channel), we were able to distinguish between different BZ drugs and to support suggestions that these drugs act via unique BZ receptor populations which possess differential couplings to the GABA receptor and chloride channel.     

Chronic benzodiazepine administration. VIII. Receptor upregulation produced by chronic exposure to the inverse agonist FG-7142.

Treatment with benzodiazepine agonists is associated with the development of behavioral tolerance and receptor downregulation, whereas antagonist administration has been reported to lead to increased activity and receptor upregulation. To determine the effects of chronic inverse agonist administration, mice were treated with FG-7142 (20 mg/kg/day) by implanted s.c. osmotic pumps for 1 to 14 days. No seizures were observed in FG-7142-exposed animals. Open-field activity was unchanged as compared to controls at days 1 and 2, but was elevated significantly at days 4 and 7. Activity was reduced below control values at day 14. Benzodiazepine receptor binding determined in vivo was unchanged for days 1, 4 and 7 within the hippocampus but was elevated at day 14. Binding remained unchanged in the cortex, cerebellum, hypothalamus and pons-medulla for the duration of drug exposure. Cortical benzodiazepine binding assessed in vitro was unchanged at days 1 and 2 but increased at days 4, 7 and 14 vs. vehicle treated controls. Binding at the gamma-aminobutyric acid site was increased at day 7 whereas binding of t-[35S]butylbicyclophosphoro-thionate was increased at days 7 and 14 of FG-7142 exposure. Maximal muscimol-slimulated [36Cl-] uptake was elevated at days 4, 7 and 14 compared to day 1 of exposure. These results demonstrate that chronic continuous exposure to FG-7142 is associated with an absence of kindled seizures and with behavioral and neurochemical changes indicative of gamma-aminobutyric acidA receptor upregulation.     

Human urocortin 2, a corticotropin-releasing factor (CRF)2 agonist, and ovine CRF, a CRF1 agonist, differentially alter feeding and motor activity

Two corticotropin-releasing factor (CRF) receptor families have been identified (CRF1 and CRF2). Whereas anxiogenic-like roles for the CRF1 receptor have been identified, behavioral functions of the CRF2 receptor remain obscure. Urocortin 2 (Ucn 2), a CRF-related peptide that selectively binds CRF2 receptors, was recently identified and recognized for its central anorectic properties. The present study tested the hypothesis that the anorexigenic mode of action of Ucn 2 differed from that of ovine CRF (oCRF), a preferential CRF1 receptor agonist. The behavioral effects of intracerebroventricular administration of Ucn 2 were compared with those of oCRF in nondeprived male Wistar rats (n=102). Ucn 2 reduced 6-h food and water intake at doses that did not induce visceral illness (0.1, 1, and 10 microg), as indicated by kaolin intake. Ucn 2 retained its potent anorectic activity in rats receiving a highly palatable cafeteria diet, preferentially reducing intake of carbohydrate (CHO)-rich items while sparing intake of mixed-fat/CHO items. In contrast to Ucn 2, oCRF (10 microg) suppressed 6-h intake of cafeteria diet-fed rats without regard to macronutrient composition. Rather, oCRF most potently suppressed intake of preferred food items. Whereas oCRF had short-onset motor-activating effects, Ucn 2 had nondose-dependent, delayed-onset motor-suppressing effects. Thus, central infusion of a CRF2 receptor agonist suppressed intake of both bland and palatable diets without inducing behavioral arousal or malaise, and the profile of anorexigenic effects qualitatively differed from those of a CRF1 receptor agonist. The results suggest the existence of distinct forms of CRF1- and CRF2-mediated anorexia.     

Benzodiazepine agonist and inverse agonist actions on GABAA receptor-operated chloride channels. I. Acute effects of ethanol

Acute exposure to ethanol was found to enhance the ability of a benzodiazepine (BZ) inverse agonist, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), to reduce muscimol-activated 36Cl- uptake by membranes isolated from mouse cerebral cortex. Pretreatment in vivo with a hypnotic dose of ethanol (but not a subhypnotic dose), or exposure to a corresponding concentration in vitro, was effective. This increase in sensitivity of gamma-aminobutyric acid receptor-operated chloride channels to the actions of DMCM was due to an increase in both the potency and efficacy of DMCM. Sensitization to DMCM was reversible and was not observed 24 hr after a single injection of ethanol. Pretreatment with ethanol (10, 50 and 100 mM) in vitro produced sensitization to DMCM in a concentration-dependent manner, similar to that produced by in vivo exposure; this increase in sensitivity did not develop if the membranes were pretreated with ethanol at 0 degrees C. Similarly, in vitro exposure to pentobarbital (200 microM) or flunitrazepam (1 microM) enhanced the actions of the inverse agonist Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a][1,4]BZ-3- carboxylate). Acute ethanol exposure did not alter low-affinity gamma-aminobutyric acidA receptor binding or muscimol action, or the ability of a BZ agonist, flunitrazepam, to augment muscimol-activated chloride flux. Ethanol exposure did not alter [3H]flumazenil (Ro15-1788) binding to central BZ receptors, its displacement by DMCM or allosteric modulation of DMCM binding by muscimol (muscimol-shift).(ABSTRACT TRUNCATED AT 250 WORDS)     

Benzodiazepine agonist and inverse agonist actions on GABAA receptor-operated chloride channels. II. Chronic effects of ethanol

Mice were made tolerant to and dependent on ethanol by administration of a liquid diet. Gamma-aminobutyric acid (GABA) receptor-dependent uptake of 36Cl- by mouse cortical microsacs was used to study the actions of benzodiazepine (BZ) agonists and inverse agonists. Chronic exposure to ethanol attenuated the ability of a BZ agonist, flunitrazepam, to augment muscimol-stimulated uptake of 36Cl- and enhanced the actions of BZ inverse agonists, Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,4]-benzodiazepine - 3-carboxylate) and DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate), to inhibit GABAA receptor-operated chloride channels. Augmentation of chloride flux by pentobarbital was not reduced by chronic ethanol exposure. Attenuation of flunitrazepam efficacy was transient and returned to control levels within 6 to 24 hr after withdrawal from ethanol, but increased sensitivity to Ro15-4513 was observed as long as 8 days after withdrawal. Chronic exposure to ethanol did not alter [3H]SR 95531 ([2-(3'-carbethoxy-2'propyl)-3-amino-6-p-methoxyphenylpyridazinium bromide] binding to low-affinity GABAA receptors or muscimol stimulation of chloride flux; and did not alter [3H]Ro15-4513 or [3H]flunitrazepam binding to central BZ receptors or allosteric modulation of this binding by muscimol (i.e., muscimol-shift). These results suggest that chronic exposure to ethanol reduces coupling between BZ agonist sites and the chloride channel, and may be responsible for the development of cross-tolerance between ethanol and BZ agonists. In contrast, coupling between BZ inverse agonist sites and the chloride channel is increased.(ABSTRACT TRUNCATED AT 250 WORDS)     

Human urocortin II, a selective agonist for the type 2 corticotropin-releasing factor receptor, decreases feeding and drinking in the rat

Corticotropin-releasing factor (CRF) has been hypothesized to modulate consummatory behavior through the Type 2 CRF (CRF(2)) receptor. However, behavioral functions subserved by the CRF(2) receptor remain poorly understood. Recently, human urocortin II (hUcn II), a selective CRF(2) receptor agonist, was identified. To study the effects of this neuropeptide on ingestive behavior, we examined the effects of centrally infused hUcn II (i.c.v. 0, 0.01, 0.1, 1.0, 10.0 micro g) on the microstructure of nose-poke responding for food and water in nondeprived, male rats. Malaise-inducing properties of the peptide were monitored using conditioned taste aversion (CTA) testing. To identify potential sites of action, central induction of Fos protein expression was examined. hUcn II dose dependently reduced the quantity and duration of responding for food and water at doses lower (0.01-1.0 micro g) than that forming a CTA (10 micro g). Effects were most evident during hours 4 to 6 of the dark cycle. Meal pattern analysis showed that hUcn II potently (0.1 micro g) increased the satiating value of food. Rats ate and drank smaller and shorter meals without changing meal frequency. Rats also ate more slowly. hUcn II induced Fos in regions involved in visceral sensory processing and autonomic/neuroendocrine regulation and resembling those activated by appetite suppressants. hUcn II is a promising neuropeptide for investigating the role of the CRF(2) receptor in ingestive behavior.     

Antinociceptive and pharmacological effects of metanicotine, a selective nicotinic agonist.

Metanicotine [N-methyl-4-(3-pyridinyl)-3-butene-1-amine], a novel neuronal nicotinic agonist, was found to bind with high affinity (K(i) = 24 nM) to rat brain [(3)H]nicotine binding sites and it generalized to nicotine in a dose-dependent manner in the drug discrimination procedure. Metanicotine produced significant antinociceptive effects in mice and rats subjected to either acute thermal (tail-flick), mechanical (paw-pressure), chemical (para-phenylquinone), persistent (Formalin), and chronic (arthritis) pain stimuli. Metanicotine was about 5-fold less potent than nicotine in the tail-flick test after s.c administration, but slightly more potent after central administration. Its duration of action was longer than that of nicotine. Nicotinic antagonists, mecamylamine and dihydro-beta-erythroidine, blocked metanicotine-induced antinociception in the different pain models. However, the antinociceptive effect was not affected by pretreatment with either naloxone or by atropine, confirming that metanicotine exerts its antinociceptive effect via nicotinic rather than either opioid or muscarinic mechanisms. In contrast to nicotine, antinociceptive effects of metanicotine were observed at doses that had virtually no effect on spontaneous activity and body temperature in mice. These data indicate that metanicotine is a centrally acting neuronal nicotinic agonist with preferential antinociceptive effects in animals. Thus, metanicotine and related nicotinic agonists may have great potential for development as a new class of analgesics.     

In vivo characterization of the pharmacodynamic interaction of a benzodiazepine agonist and antagonist: midazolam and flumazenil.

The pharmacokinetic and pharmacodynamic interaction between the benzodiazepine agonist midazolam and antagonist flumazenil was quantified in vivo in rats, using effect parameters derived from aperiodic EEG analysis. The benzodiazepine-induced increase in amplitudes in the 11.5 to 30 Hz (beta) frequency band of the EEG was used as effect measure. A competitive interaction model was derived that could describe and predict the time course of EEG effect after administration of several combinations of midazolam and flumazenil. Two approaches to derive the interaction model were evaluated. In a first experiment, rats received 10 or 20 mg/kg midazolam i.v. in 15 min during a steady-state infusion of flumazenil at a rate of 0, 0.25, 0.5 or 1 mg/kg/hr. The EEG was continuously measured and frequent blood samples were taken to determine the pharmacokinetics of the drugs. Flumazenil did not influence the pharmacokinetics of midazolam, but a significant reduction in the clearance of flumazenil was observed in the presence of midazolam. Flumazenil did not possess any intrinsic efficacy with regard to the EEG effect measure. With increasing flumazenil concentrations, a parallel shift in the concentration-EEG effect relationship of midazolam was observed, confirming the competitive nature of the interaction. An agonist-antagonist interaction model was used to quantify the interaction, yielding the pharmacodynamic parameters of midazolam [(mean +/- S.E.): Emax = 80 +/- 5 microV/sec, EC50 = 35 +/- 3 ng/ml and N = 1.1 +/- 0.2] and flumazenil: EC50 = 24 +/- 2 ng/ml and N = 1.6 +/- 0.1. In a second experiment, rats received 5 mg/kg flumazenil or placebo i.v. in 10 min during a steadystate infusion of midazolam.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neurochemical and behavioral effects of corticotropin-releasing factor in the ventral tegmental area of the rat

Corticotropin-releasing factor (CRF) is thought to have a neurotransmitter function in the mammalian central nervous system. The release of CRF into the hypothalamic-hypophyseal portal system in response to stress is known, and it has been suggested that CRF may function elsewhere in the central nervous system to promote stress-induced physiological and behavioral changes. Acute stress has been shown to activate dopamine (DA) neurons in the ventral tegmental area (VTA) that project to the prefrontal cortex. To determine whether CRF may act in the VTA to activate the mesocortical or mesolimbic DA systems, it was injected into the VTA of rats, and changes in spontaneous motor behavior and DA metabolism were measured. Intra-VTA injection of CRF produced a dose-dependent increase in horizontal and vertical photocell counts with a minimal effective dose of 0.01 and 0.1 nmol, respectively. In contrast, the minimal effective dose for CRF-stimulated motor behavior after injection into the lateral ventricles was 0.3 nmol for horizontal activity. Furthermore, in the open field, the behavioral profile of CRF (0.3 nmol) given intra-VTA differed from that observed after intraventricular injection. The motor stimulant effect of intra-VTA CRF was not blocked by pretreatment with the DA receptor antagonist haloperidol. After intra-VTA injection, CRF produced a dose-dependent decrease in DA metabolism in the prefrontal cortex. The decrease in DA metabolism in the prefrontal cortex was present at 30 and 60 min but not at 120 min after injection, and in the nucleus accumbens DA metabolism was increased only at 60 min after injection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ro 19-8022, a nonbenzodiazepine partial agonist at benzodiazepine receptors: neuropharmacological profile of a potential anxiolytic.

The partial agonist at benzodiazepine receptors, Ro 19-8022, has been characterized as a putative anxiolytic drug with an improved side effect profile. This orally active compound is a representative of a quinolizinone structure class and shows potent anticonflict activity in mice and rats. It protects rodents from convulsions induced by pentylenetetrazol, N-methyl-D-aspartic acid and maximal electroshock, as well as against audiogenic seizures, with an efficacy comparable to that of the full agonist alprazolam. No appreciable sedative or motor-impairing effects could be detected up to a very high dose (100 mg/kg) in the horizontal wire test or the rotarod performance test in mice and rats and in spontaneous behavior in monkeys. Consistent with its characterization as a partial agonist, Ro 19-8022 antagonized the motor impairment induced by the full agonists diazepam or meclonazepam measured in horizontal wire and rotarod tests in rodents, and reduced flunitrazepam-induced effects in squirrel monkeys, with an efficacy comparable to that of the benzodiazepine receptor antagonist flumazenil. After subchronic administration of Ro 19-8022 to mice, antagonist-precipitated withdrawal syndrome was dramatically weaker than after alprazolam treatment, which is indicative of a lower physical dependence liability of Ro 19-8022. Pharmacodynamic effects recorded in convulsion and reversal of motor impairment tests after i.v. administration suggest a long duration of action of this compound. Taken together, such preclinical data suggest that benzodiazepine receptor partial agonists with a neurological and behavioral profile such as that of Ro 19-8022 may offer an innovative therapeutic approach to the treatment of anxiety disorders.     

Biological mechanisms underlying the clinical effects of allergen-specific immunotherapy in asthmatic children

Introduction: Allergen-specific immunotherapy (AIT) is indicated for patients with allergic asthma and/or allergic rhinitis, and can be implemented by either subcutaneous injection (SCIT) or sublingual administration (SLIT). AIT reduces asthma symptoms, lowers the use of pharmacologic controller therapy, and decreases the need for rescue medications. SLIT appears to be safer than SCIT, but SCIT seems to be more efficacious and acts earlier in allergic asthmatic children.

Areas covered: This review looks at the pathobiology of allergic asthma as well as the role of regulatory T and B cells in allergen tolerance. It also reviews the immunological mechanisms underlying the clinical effects induced by AIT in allergic asthmatic children.

Expert opinion: AIT is very effective in allergic asthmatic children, who can significantly benefit from this particular type of immunotherapy in order to achieve a better control of their disease. AIT is also capable of modifying the natural history of allergic asthma. Furthermore, AIT can potentially represent a valuable therapeutic tool within the context of precision medicine, as recombinant allergen technology might allow the creation of targeted extracts able to be effective against specific proteins to which individual asthmatic children are allergic, thus helping to implement a personalized approach to treatment.     

Influence of taranabant, a cannabinoid-1 receptor inverse agonist, on pharmacokinetics and pharmacodynamics of warfarin

Introduction  The pharmacokinetic/pharmacodynamic effects of warfarin were assessed in the presence and absence of taranabant, an orally active, highly selective, potent, cannabinoid-1 receptor inverse agonist, which was being developed for the treatment of obesity. Methods  Twelve subjects were assigned to two open-label treatments in fixed sequence separated by a 14-day washout. Treatment A was single-dose warfarin 30 mg on day 1. Treatment B was multiple-dose taranabant 6 mg each day for 21 days (days −14 to day 7) with coadministration of singledose warfarin 30 mg on day 1. Blood samples were collected predose and up to 168 hours postdose for assay of R(+)-and S(−)-warfarin and prothrombin time/international normalized ratio (PT/INR). Results  The geometric mean ratios (GMR; warfarin+taranabant/warfarin 90% confidence interval [CI] primary endpoints) for area under the curve (AUC)_0-∞ for R(+)-and S(−)-warfarin were 1.10 (90% CI: 1.03, 1.18) and 1.06 (90% CI: 1.00, 1.13), respectively. The GMRs (warfarin+taranabant/warfarin) for the maximum plasma concentration (C_max) of S(−)-and R(+)-warfarin were 1.16 (90% CI: 1.05, 1.28) and 1.17 (90% CI: 1.07, 1.29), respectively. For R(+)-and S(−)-warfarin, the 90% CIs for AUC_0-∞ GMRs fell within the prespecified bounds. Taranabant did not produce a clinically meaningful effect on PT/INR. Conclusion  No clinically significant alterations of the pharmacokinetics of R(+)-and S(−)-warfarin were seen following coadministration of multipledose taranabant 6 mg and single-dose warfarin 30 mg.     

Acute and chronic effects of corticotropin-releasing factor on schedule-controlled responding and neurochemistry of pigeons

Key pecking by pigeons was maintained under various schedules of food presentation. Acute i.c.v. administration of corticotropin-releasing factor (CRF) (3.0-30.0 micrograms/kg) decreased responding in both components of a multiple 3-min fixed-interval, 30-response fixed-ratio schedule and under a multiple fixed-ratio schedule in which responding during one component was punished by shock delivery. The rate-decreasing effects of intermediate doses of CRF were blocked by the CRF antagonist alpha-helical CRF9-41 under the multiple fixed-internal fixed-ratio schedule, with 10.0 micrograms/kg of the antagonist producing a more complete reversal than 30.0 micrograms/kg. The rate-reducing effects of 10.0 and 30.0 micrograms/kg of CRF disappeared rapidly when CRF was administered daily, with complete restoration of responding occurring by the 4th day of chronic administration. Acute effects were recovered when CRF administration was discontinued for 7 to 14 days. Analyses of cerebrospinal fluid revealed that behaviorally active doses of CRF produced large, dose-dependent increases in levels of the serotonin metabolite 5-hydroxyindoleacetic acid and in the dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid; smaller increases also occurred in the levels of 3-methoxy-4-hydroxyphenylethylene glycol, the metabolite of norepinephrine. Chronic administration of 30 micrograms/kg of CRF for a 4-day period did not reveal any change in metabolite levels when compared to those obtained after acute administration, with the exception of 3-methoxy-4-hydroxyphenylethylene glycol which approached control levels after chronic CRF. These results indicate that, as is the case with mammals, CRF has potent behavioral and neurochemical activity in avian species and that tolerance occurs rapidly to the behavioral effects.     

The effects of alprazolam on corticotropin-releasing factor neurons in the rat brain: acute time course, chronic treatment and abrupt withdrawal.

Considerable evidence indicates that corticotropin-releasing factor (CRF) is responsible for integrating not only the endocrine, but the autonomic and behavioral responses of an organism to stress. We have investigated the time course of action of the anxiolytic triazolobenzodiazepine, alprazolam, on the activity of the hypothalamic-pituitary-adrenal (HPA) axis and of CRF neurons after acute and chronic administration. In addition, because many of the signs and symptoms observed in animals and humans after abrupt discontinuation of benzodiazepines resemble the stress response, we examined the effect of alprazolam withdrawal on CRF neurons and HPA axis activity. Alprazolam decreases CRF concentrations in the locus coeruleus between 0.5 and 3.0 h following acute injection. The half-life of alprazolam in rats is less than 1 h in both plasma and brain. Similarly, chronic (14 days) alprazolam administration also results in decreased CRF concentrations in the locus coeruleus. CRF concentrations return to control values 24 h after abrupt withdrawal. Moreover, abrupt alprazolam withdrawal results in increased plasma adrenocorticotrophic hormone and corticosterone concentrations and decreased anterior pituitary CRF receptor concentrations 24 h after drug discontinuation. These indices return to control values by 48 h postwithdrawal. These results support the hypothesis that both acute and chronic alprazolam administration alters CRF-containing neurons innervating the locus coeruleus. Additionally, abrupt alprazolam withdrawal profoundly activates the HPA axis.     

Corticorelin, a synthetic human corticotropin-releasing factor analog, for the treatment of peritumoral brain edema

Corticorelin is a synthetic analog of the naturally occurring human peptide corticotropin-releasing factor (CRF). Several studies have indicated the ability of CRF to reduce the brain edema caused by brain tumors. Peritumoral brain edema (PBE), caused by an intracerebral tumor, manifests several features of vasogenic edema, which is a type of edema characterized by disruption of the blood-brain barrier. Traditionally, PBE has been treated using corticosteroids, primarily dexamethasone. Introduced more than four decades ago, dexamethasone revolutionized the treatment of PBE, but the side effects and withdrawal symptoms associated with corticosteroids propelled the investigation of other drugs. Clinical trials with the synthetic human CRF (hCRF) corticorelin (Xerecept, NEU-3002; Celtic Pharmaceutical Holdings) have indicated that this drug has a distinct advantage over classical corticosteroids in the treatment of PBE. Fewer and/or milder side effects have been reported for corticorelin compared with dexamethasone, although at higher doses of corticorelin several side effects, including hypotension and transient flushing, have been reported. Nevertheless, corticorelin was reasonably well tolerated in patients and healthy volunteers, and may be a good candidate for reducing PBE and associated neural damage, as well as improving neurological symptoms.     

Acute alertness-promoting effects of a novel histamine subtype-3 receptor inverse agonist in healthy sleep-deprived male volunteers

The alertness-promoting effect of MK-0249 (10 or 50 mg), a histamine subtype-3 receptor (HRH3) inverse agonist (IA), was evaluated in the stimulant reference sleep deprivation model (SRSDM) using a double-blind, double-dummy, placebo- and modafinil- (200 mg) controlled, four-period crossover design in 24 healthy young men. The two primary hypotheses were related to sleep latency (first appearance of one epoch of stage 2, 3, or 4 or REM sleep, as detected using polysomnography (PSG)) at 8:00 AM on day 2. Statistically significant increases in sleep latency were observed in association with the use of modafinil 200 mg (9.07 min; P < 0.0001), MK-0249 50 mg (5.17 min; P = 0.008), and MK-0249 10 mg (5.45 min; P = 0.005) at the maintenance of wakefulness test (MWT) at 8:00 AM. Sleep latency was higher when averaged over all MWT time points (P < 0.0001 for modafinil and for both doses of MK-0249). The alertness-promoting effect with the use of MK-0249 in the SRSDM suggests that HRH3 IAs may be effective in disorders involving excessive somnolence.     

Behavioral effects of U-78875, a quinoxalinone anxiolytic with potent benzodiazepine antagonist activity.

U-78875 (3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(1-methylethyl) imidazo[1,5-a]-quinoxalin-4(5H)-one) is a chemically novel compound with a high affinity for the benzodiazepine receptors. It has anticonflict effects in both the Vogel and Cook-Davidson models of anxiety, with a potency similar to that of diazepam (1-3 mg/kg, i.p.). In unanesthetized rats implanted with cortical electrodes for EEG recording, i.p. injections of U-78875 (3-10 mg/kg) increased the EEG power density in frequencies above 12 Hz, and decreased EEG power at lower frequencies. This EEG effect is similar to that of diazepam, and was completely antagonized by pretreatment with flumazenil. In animal models measuring central nervous system depression, U-78875 is much weaker than diazepam. It produced minimal impairment of rotarod performance in rats at doses up to 30 mg/kg, but at lower doses completely reversed the impairment from 10 mg/kg of diazepam. In rats trained to avoid shocks in a shuttle box, U-78875 (3-10 mg/kg) increased avoidance responses and antagonized the suppression of avoidance from diazepam (10 mg/kg). In the mouse one-trial passive avoidance task, pretreatment with U-78875 (1-10 mg/kg) before training produced no anterograde amnesia, but completely blocked the amnesic effect from diazepam (10 mg/kg). The diazepam antagonist potency for U-78875 is 10 to 100 times that of flumazenil. This unusual profile of mixed agonist/antagonist activities suggests U-78875 to be a unique anxiolytic agent with a minimum of central nervous system depression.