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PubMed1986

Effects of combined administration of diazepam and imipramine hydrochloride in rats.

The effects of daily oral administration of imipramine hydrochloride (5-[3-(dimethylamino)propyl]-10,11-dihydro-5H-dibenz-[b,f]azepine monohydrochloride; 50 mg/kg) and/or diazepam (7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one ; 5 mg/kg) in a 1% aqueous solution of carboxymethylcellulose sodium salt (CMC) on the body weight, organ weights, and activities of various enzymes, including drug metabolizing enzyme systems were investigated in rats during a 15-day period. The plasma concentrations of imipramine and desipramine were also determined. In addition, the effect of a single intravenous administration of imipramine hydrochloride (5 mg/kg) on the plasma concentration-time profiles of imipramine and desipramine was investigated in rats given the same drug treatments. The plasma concentration-time profiles of imipramine and desipramine were analyzed pharmacokinetically. The rats treated with imipramine hydrochloride showed a greater inhibition of body weight gain than those treated with diazepam, and those treated with imipramine hydrochloride and diazepam simultaneously showed a body weight gain similar to those treated with imipramine hydrochloride alone. No significant differences in organ weight (per 100 g of body weight) were found. The imipramine hydrochloride plus diazepam treatment group showed a greater increase in drug-metabolizing enzyme activities than the imipramine hydrochloride treatment group, but the difference was not statistically significant. However, the plasma levels of imipramine and desipramine after oral administration for 15 d suggested that the imipramine hydrochloride plus diazepam treatment group did not show increased imipramine metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Complete 1H and 13C NMR spectral assignment of N-aralkylsulfonamides, N-sulfonyl-1,2,3,4-tetrahydroisoquinolines and N-sulfonyl-2,3,4,5-tetrahydro-1H-2-benzazepines. Conformational analysis of N-[((3',4'-dichlorophenyl)methyl)sulfonyl]-3-methyl-2,3,4,5-tetrahydro-1H-2-benzazepin.

The complete and unambiguous assignment of the 1H NMR and 13C NMR spectra of 26 N-aralkylsulfonamides, N-sulfonyl-1,2,3,4-tetrahydroisoquinolines and N-sulfonylbenz[c]azepines was performed on the basis of APT, DEPT, homonuclear (gs-COSY) and 1H-detected heteronuclear one-bond (gs-HMQC) and long-range (gs-HMBC) correlation experiments. The methylated 2,3,4,5-tetrahydro-1H-2-benzazepine derivative 26 adopts a chair conformation as determined by 1H-1H coupling analysis and gamma-gauche effects. This is supported by a single-crystal X-ray structure analysis.

Journal Article↗
PubMed1994

NMR and molecular modelling based conformational analysis of some N-alkyl 1- and 2-benzazepinones: useful central nervous system agent design motifs.

Variable temperature 1H NMR lineshape analyses and 13C NMR spin-lattice relaxation time studies were undertaken to characterise the conformationally dynamic N-alkyl 1- and 2-benzazepinones 1 and 2. For 1, dynamic interchange between two mirror-image puckered forms of the azepine ring occurs with a barrier of 56 kJ mol-1. There is a significantly greater degree of ring flexibility in the case of 2. Molecular modelling studies were used to examine the degree of sidechain flexibility in these compounds.

Benzazepines↗
PubMed2000

Oxcarbazepine for Treatment of Partial Epilepsy: A Review and Recommendations for Clinical Use.

Recent trials and extensive postmarketing use confirm the efficacy and safety of oxcarbazepine (OXC) as a first-line treatment for adults and children with simple partial seizures, complex partial seizures, and partial seizures evolving to secondarily generalized seizures. OXC undergoes reductive metabolism at its keto moiety to form 10-hydroxy-10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide (MHD), which is glucuronidated and excreted in the urine, with minimal involvement of the hepatic cytochrome P450-dependent enzymes. OXC has some drug interactions, and does not require titration, allowing for better tolerability. Titration for monotherapy and adjunctive therapy of OXC could begin at 150 mg/day and be increased by 150 mg every 2-3 days until the target dose of 900-1200 mg/day is reached. If necessary, one can go faster and start with up to 600 mg/day and titrate with weekly increments up to 600 mg/day if necessary for seizure control. Conversion to monotherapy can be done overnight or gradually. For gradual conversion, use the recommended titration of OXC and withdraw the baseline antiepileptic drugs gradually by 25%, starting at Day 14 or earlier in case of baseline tolerability issues. Consider reducing the dose of the primary antiepileptic drug during adjunctive therapy in case of adverse events or increase the dose of OXC in case of incomplete seizure control. In children OXC should be started at 8-10 mg/kg/day in two or three divided doses. If clinically indicated the dose can then be increased by 10 mg/kg/day in weekly intervals with final doses up to 30-46 mg/kg/day. Dose adjustment may be necessary in very young children (age 2-5 years) and in patients with renal dysfunction, based on renal clearance. However no adjustment of OXC dose is needed in patients with mild to moderate hepatic dysfunction. OXC has a number of advantages which include rapid titration, no need for safety monitoring (except for uncommon and mostly asymptomatic hyponatremia), a low potential for drug-drug interactions (except for those possibly impairing the effectiveness of oral contraceptives and increasing the serum concentration of phenytoin), a rash rate of less than 5%, similar efficacy and similar or better tolerability and safety compared with first-generation antiepileptic drugs. OXC is a valuable alternative to current treatment options.

Journal Article↗
PubMed1980

Review of experimental studies on nitrosourea derivatives in Japan.

Four antitumor nitrosourea derivatives under development in Japan are described. Among these, GANU and MCNU, having very similar structures to chlorozotocin, are water-soluble compounds, and CDL-7 and EBNU are rather insoluble in water. The latter two are before clinical trials, and like other nitrosourea derivatives, have a marked antitumor activity in mouse leukemia L1210. Though GANU and MCNU are in the stage of clinical studies, it seems premature to draw conclusions about them. Antitumor activity and pharmacologic studies on four nitrosourea compounds under development in Japan are reviewed. These compounds are: 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea (GANU), 1-(2-chloroethyl)-3-(methyl-alpha-D-glucopyranos-6-yl)-1-nitrosourea (MCNU), DL-1(2-chloroethyl)-3-(hexahydro-2-oxo-azepin-3-yl)-1-nitrosourea (CDL-7), and 1,1'-ethylene-bis(1-nitrosourea) (EBNU).

Animals↗
PubMed1987

Facilitation of serotonin (5-HT) release in the rat brain cortex by cAMP and probable inhibition of adenylate cyclase in 5-HT nerve terminals by presynaptic alpha 2-adrenoceptors.

Stimulation-evoked tritium overflow was examined in superfused rat brain cortex slices (stimulus: electrical impulses; 3 Hz) and synaptosomes (stimulus: potassium 12 mmol/l) preincubated with 3H-5-HT. 1. In slices and synaptosomes, the evoked 3H overflow was facilitated by forskolin and 8-Br-cAMP, but was not affected by AH 21-132 (an inhibitor of cAMP phosphodiesterase; cis-6-(p-acetamidophenyl)-1,2,3,4,4a,10b-hexahydro-8,9-dimethoxy-2-methylbenzo [c] [1,6]-naphthyridine). In the presence of AH 21-132, the facilitatory effect of forskolin on evoked overflow was increased. 2. In slices, AH 21-132 or combined administration of forskolin plus AH 21-132 did not change the percentage of basal or evoked 3H overflow represented by unmetabolized 3H-serotonin (about 30% and 60%, respectively). 3. In slices, cocaine or 6-nitroquipazine, an inhibitor of serotonin uptake, did not influence the increase in evoked overflow produced by forskolin plus AH-21-132. Forskolin plus AH 21-132 did not alter the inhibitory effect of serotonin (examined in the presence of 6-nitroquipazine) and the facilitatory effect of metitepin (a serotonin receptor antagonist) on evoked 3H overflow, but considerably decreased the inhibitory effect of clonidine or B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo-[5,4-d]-azepine). The present results suggest that the serotoninergic nerve terminals in the rat brain cortex are endowed with an adenylate cyclase, which is negatively coupled to the presynaptic alpha 2-adrenoceptors, but is not linked to the presynaptic autoreceptors.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1987

Cardiovascular effects in rats of alpha 1 and alpha 2 adrenergic agents injected into the nucleus tractus solitarii.

The cardiovascular effects of selective alpha 1 and alpha 2 agonists and antagonists injected into the nucleus tractus solitarii (NTS) were studied in urethane-anesthetized rats. Methoxamine (0.3-3 micrograms) injected bilaterally into the NTS caused a dose-dependent increase in blood pressure and heart rate. Phenylephrine (6 micrograms) and an imidazolidine derivative St 587 (3 micrograms) similarly injected also produced an increase in blood pressure, whereas alpha-methylnoradrenaline and an azepine derivative B-HT 920 (1 and 3 micrograms) caused a decrease in blood pressure and heart rate. The pressor response to methoxamine (1 microgram) was markedly inhibited by prazosin (0.3 microgram) injected into the same sites or hexamethionum (25 mg/kg, i.v.). Prazosin (0.3 microgram) alone injected bilaterally into the NTS did not affect the blood pressure, while yohimbine (0.1 microgram) similarly injected increased the pressure. These results suggest that in the rat NTS there exist alpha 1 adrenoceptors responsible for an increase in arterial pressure. The NTS alpha 2 adrenoceptors seem to be involved in the tonic regulation of arterial pressure.

Adrenergic alpha-Agonists↗
PubMed1981

Organic and inorganic calcium antagonists reduce vasoconstriction in vivo mediated by postsynaptic alpha 2-adrenoceptors.

The influence of various calcium antagonists and divalent metal cations on the pressor responses induced by the selective alpha 1-adrenoceptor agonist methoxamine and the selective alpha 2-adrenoceptor stimulating agent B-HT 920 (2-amino-6-allyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]-azepine) was studied in pithed rats. 1. The calcium antagonists verapamil, D 600 and nifedipine, when given intraarterially (i.a.) in doses up to 1 mg/kg did not influence the pressor effects of methoxamine. Only higher amounts of these calcium antagonistic drugs (1 - 3 mg/kg i.a.) somewhat reduced this pressor response. 2. The vasoconstriction due to B-HT 920, as reflected by the increase in diastolic pressure, was markedly inhibited by verapamil, D 600 and nifedipine in a dose-dependent manner. In low doses a parallel displacement to the right was observed, whereas in higher amounts the shift was non-parallel. 3. The divalent cations MN2+, Ni2+ and Co2+ (0.05 - 0.15 mmol/kg i.a.) hardly affected the pressor effect of methoxamine, whereas B-HT 920-induced vasoconstriction was highly sensitive to these metal ions. La3+ and Mg2+ were ineffective. 4. The calcium antagonists verapamil, D 600 and nifedipine displayed only minor affinities for [3H]prazosin (alpha 1) as well as [3H]clonidine (alpha 2) binding sites of rat brain membranes. 5. It is concluded that an influx of extracellular Ca2+ is necessary for the vasoconstriction in vivo initiated by stimulation of vascular postsynaptic alpha 2-adrenoceptors. On the other hand, vasopressor responses to alpha 1-adrenoceptor stimulation are not directly dependent on a transmembrane influx of calcium ions.

Adrenergic alpha-Agonists↗
PubMed1992

Quantification of SCH 39166, a novel selective D1 dopamine receptor antagonist, in rat brain and blood.

A gas chromatographic method for measuring concentrations of a novel D1 antagonist SCH 39166 [(-)-trans-6,7,7a,8,9-13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5- H-benzo[d]naphto(2,1-6)azepine] in rat brain and plasma was developed. The method was applied to descriptive pharmacokinetics of two subcutaneous doses of SCH 39166 (0.25 mg/kg and 2.5 mg/kg). For comparison, concentrations of the "prototype" D1 antagonist SCH 23390 (0.25 mg/kg, SC) [R-(+)-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1-H-3-benzazepine] were also measured in plasma and brain. SCH 23390 (0.25 mg/kg, SC) had a very short elimination half-life of about 30 min in plasma, and disappeared in a slightly slower manner from striatum and cortex. SCH 39166 (0.25 and 2.5 mg/kg, SC), however, had a longer elimination half-life of about 1.5-2.5 h in plasma and brain. Interestingly, the 2.5 mg/kg dose of SCH 39166 produced only two-to five-fold increases in maximum concentrations in plasma and brain compared to the 0.25 mg/kg dose. The reason for this is not clear. The ability of these two doses of SCH 39166 to induce catalepsy in the bar test was also evaluated. It was found that SCH 39166 in these two doses, unlike SCH 23390, was not cataleptic. In conclusion, these pharmacokinetic features of SCH 39166 in the rat should be useful when designing experiments with this novel selective D1 antagonist. Furthermore, the longer elimination half-life of SCH 39166 makes it a more useful probe in pharmacodynamic comparisons of D1 receptor antagonists and classical as well as atypical neuroleptics.

Animals↗
PubMed1994

Savoxepine fails to selectively influence glucose metabolism in the rat limbic system.

The [14C]-2-deoxyglucose method was used to map the in vivo metabolic response of glucose to savoxepine, a novel tetracyclic cyano-dibenzoxepino-azepine. Savoxepine is reported to have higher affinity for dopamine (DA) receptors in the hippocampus than in the striatum and hence should have dose-dependent, anatomically selective actions. Two doses of savoxepine (0.05 mg/kg and 0.5 mg/kg) were compared with haloperidol (1 mg/kg) to test the hypothesis that low doses of savoxepine would display a selective action on limbic brain areas. Results failed to show that low dose savoxepine selectively modifies glucose utilization in the limbic system as previous biochemical studies suggested. In fact, low doses of the drug displayed a potent activity quite similar to haloperidol in effect and localization. The low dose did not produce significantly altered glucose metabolism in the nucleus accumbens or in the lateral habenular nucleus as observed with most other neuroleptics, suggesting a lack of antipsychotic action at this dose. Our findings demonstrate the difficulty of designing a neuroleptic with a preferential blockade of limbic DA receptors and point to the need for functional assessment of regional receptor binding differences.

Animals↗
PubMed1988

Protective effects of a leukotriene inhibitor in an experimental massive hepatic cell necrosis model.

When heat-killed Propionibacterium acnes was intravenously injected into mice and seven days later, a small amount of gram-negative lipopolysaccharide was also intravenously injected, most of them died of massive hepatic cell necrosis. However, when azelastine hydrochloride, a leukotriene antagonist chemically known as 1(2H)-phthalazinone, 4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepine-4-yl)-, monohydrochloride, or AA861, 2-(12-hydroxydodeca-5, 10-diynyl)-3,5,6-trimethyl-1, 4-benzoquinone, a specific inhibitor of 5-lipoxygenase, was administered during this experimental induction of massive hepatic cell necrosis, the survival rate of the mice increased and the histological changes of the liver improved remarkably. These results suggested that leukotriene may be important for the induction of massive hepatic cell necrosis in our experimental model.

Animals↗
PubMed1998

Influence of catecholamine receptor agonists and antagonists on the ultradian rhythm of the EEG in the posterior hypothalamus.

The power of delta and theta frequency bands of the EEG in the posterior hypothalamus of the rat fluctuates according to an ultradian rhythm. To investigate, whether catecholamine receptor ligands influence the ultradian EEG rhythm, drugs were applied intracerebroventricularly into the lateral ventricle of anaesthetized rats. Injection of the alpha1-adrenoceptor agonist (+/-)-methoxamine (150 nmol) abolished, while 25 nmol of the compound prolonged the cycle duration of the rhythmic changes in the delta and theta frequency bands. Injected into the lateral ventricle, the alpha2-adrenoceptor agonists 6-ethyl-5,6,7,8-tetrahydro-4H-oxazol[4,5-d] azepin-2-amine (B-HT 933) or clonidine (150 nmol each) prolonged the duration of the cycles of both frequency bands. The beta1/2-receptor agonists (+/-)-orciprenaline (300 nmol) and (R)-(-)-isoprenaline (150 nmol) slowed down the cycle durations of both frequency bands. The beta1-receptor agonist (+/-)-xamoterol (300 nmol) also prolonged the cycle durations of the delta and theta frequency bands. The beta1-receptor antagonist (S)-(-)-atenolol was ineffective (150 and 300 nmol). The beta2-receptor agonist (+/-)-salbutamol (300 nmol) shortened the duration of the ultradian rhythm in the two frequency bands, while the beta2-receptor antagonist (+/-)-1-[2,3-(dihydro-7-methyl-1 H-inden-4-yl) oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI 118,551) (300 nmol) exerted the opposite effect. On the other hand, the D1 receptor agonist (+/-)-1-phenyl-2,3,4,5-tetrahydro-1H)-3-benzazepine-7,8-diol (SKF 38393) and the D2 agonist (4aR,8aR)-(-)-quinpirole (150 nmol each) slowed down the frequency of the ultradian rhythm. The powers of alpha and beta frequency bands were not significantly influenced by the catecholamine receptor ligands used in this study. The findings suggest that, in the posterior hypothalamus, the ultradian rhythm of the delta and theta frequency bands are prolonged when beta1-receptors are stimulated and shortened on stimulation of beta2-adrenoceptors. Endogenous catecholamines released from their neurons seem to shorten the duration of the rhythmic fluctuations by stimulating beta2-receptors and to slow down the frequency of the cyclic fluctuations by stimulating alpha2-adrenoceptors. The ultradian rhythm is also slowed down on stimulation of D1 and D2 receptors by endogenous dopamine. Together with previous observations, the results indicate that the ultradian EEG rhythm is susceptible to modulatory mechanisms mediated by catecholaminergic neurons.

Activity Cycles↗
PubMed2000

[Oxcarbazepine (Trileptal). An effective and well tolerated new drug as first choice in treatment of focal seizures].

Oxcarbazepin (OXC; 10,11-dihydro-10-oxo-5H-dibenz-[b,f]azepin-5-carboxamid, trade name Trileptal) is a new antiepileptic drug for treatment of mono- and adjunctive therapy of partial seizures with or without secondary generalization for adults and children above 6 years of age. It was developed through structural variation of carbamazepine. Extensive postmarketing use includes more than 200,000 patient years. The mechanism of action mainly involves blockage of sodium currents. The recommended daily starting dose of oxcarbazepin for both mono- and adjunctive treatment is 8-10 mg/kg (600 mg/day for adults) in two doses and can be titrated according to clinical benefit up to 2400 mg/day. Oxcarbazepin undergoes reductive metabolism at its keto moiety to form MHD, which is glucuronidated and excreted in the urine, with minimal involvement of the hepatic cytochrome P450-dependent enzymes. Thus, OXC has limited drug interactions and does not require slow titration, allowing for better tolerability. Oxcarbazepin compares favorably to presently available new anticonvulsants of the second generation for two reasons: it is available immediately for both mono- and adjunctive therapy in adults and children, and extensive postmarketing experience from many countries is already available. In addition, OXC has been thoroughly tested in an unusually large clinical development program and been shown to be similarly effective as standard antiepileptic drugs.

Adult↗
PubMed2000

Activation of striatal group II metabotropic glutamate receptors has a differential effect on dopamine-D1 and -D2 receptor antagonist-induced hypokinesia in the rat.

Motor function of group II metabotropic glutamate receptors was investigated by quantifying motor effects of bilateral infusions of the preferential group II metabotropic glutamate receptor agonist (2S,3S,4S)-alpha-carboxycyclopropyl-glycine (15, 30, 60 nmol/0.5 microl) into the striatum of conscious rats. (2S,3S,4S)-alpha-carboxycyclopropyl-glycine reduced spontaneous sniffing activity in an experimental chamber, but did not affect spontaneous locomotor (line crossings) or exploratory behaviour (rearings, hole visits) in an open field equipped with a hole-board. Intrastriatal infusion of the selective group III metabotropic glutamate receptor agonist L-2-amino-4-phosphobutyric acid (15, 30, 60, 120 nmol/0.5 microl) did not influence spontaneous motor behaviour. Intrastriatal infusion of (2S,3S,4S)-alpha-carboxycyclopropyl-glycine (15 nmol/0.5 microl and 30 nmol/0.5 microl) further depressed spontaneous motor behaviour in rats pretreated with the dopamine-D1 receptor antagonist (-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H- benzo[d]naphtho-(2,1-b)azepine, but not if rats were pretreated with the preferential dopamine-D2 receptor antagonist haloperidol. It appears likely that the depression of spontaneous motor behaviour evoked by the preferential group II agonist (2S,3S,4S)-alpha-carboxycyclopropyl-glycine is mediated by activation of group II metabotropic glutamate receptors, since activation of group I metabotropic glutamate receptors has been shown to stimulate motor behaviour, and activation of group III metabotropic glutamate receptors had no effect, as shown in this study. Therefore, it is reasonable to speculate that the striatum may contribute to the motor-depressant effects of systemically applied group II metabotropic glutamate receptor agonists, as reported by us recently. The present findings further suggest that a functional dopamine-D1 antagonism contributes to the motor effects of group II metabotropic glutamate receptor agonists.

Amino Acids, Dicarboxylic↗
PubMed1985

Interaction of pitrazepin with the GABA/benzodiazepine receptor complex and with glycine receptors.

Pitrazepin (3-(piperazinyl-1)-9H-dibenz(c,f)triazolo(4,5-a)azepin) is a new GABAA receptor antagonist reported to antagonize electrophysiological effects of GABA. We have investigated in some detail the interaction of pitrazepin with the GABA/benzodiazepine receptor chloride channel complex. Pitrazepin was found to be a competitive inhibitor of the GABAA receptor which is coupled to [3H]diazepam and [35S]TBPS binding sites; the KI value obtained by Schild analyses was 80 nM. Although pitrazepin interacted weakly with BZ receptors the compound did not affect the chloride gating mechanism (labelled with [35S]TBPS or [3H]avermectin B1a). Further, pitrazepin was a non-selective GABA antagonist since glycine receptors, labelled with [3H]strychnine, were affected at low concentrations (the KI values in rat brain-stem were 71-110 nM).

Animals↗
PubMed1989

Anticonvulsant activity of the glial GABA uptake inhibitor, THAO, in chemical seizures.

The antiseizure activity of the glia-selective GABA uptake inhibitor, 5,6,7,8-tetrahydro-4H-isoxazolo[4,5-c]azepin-3-ol (THAO), was evaluated in rats in models of acute chemoconvulsion. In these experiments, intracerebroventricular administration of the drug 30 min prior to testing in doses between 100-750 micrograms provided protection against maximal pentylenetetrazol seizures and increased the latency to isonicotinic acid hydrazide seizures. Pentylenetetrazol seizure thresholds, in contrast, were not significantly elevated. The ability of THAO to suppress tonic but not generalized minor seizures suggests that it may block seizure spread.

Animals↗
PubMed1990

Effects of azelastine on contraction of guinea pig tracheal smooth muscle.

Azelastine [4-(p-chlorobenzyl)-2-(hexahydro-1-methyl-1H-azepine-4-yl)-1(2H)-phthalazinone hydrochloride] is a new anti-asthmatic drug. We examined the mechanism of its inhibitory action on guinea pig tracheal smooth muscle contraction by measuring membrane potential and isometric force using intracellular microelectrodes and a micro-force transducer. The mean resting membrane potential of guinea pig tracheal muscle cells was -54 mV. Perfusion with 20 mM tetraethylammonium (TEA) caused membrane depolarization and elicited spontaneous action potentials. Azelastine (1-100 microM) suppressed both the amplitude and maximal rate of rise of the action potentials in a concentration-dependent manner. Complete abolition occurred at 100 microM. Similarly, azelastine (0.1-100 microM) inhibited and abolished 50 mM KCl-induced contractions. These results suggest that azelastine may inhibit voltage-dependent Ca2+ channels. Next, pretreatment of tracheal muscle (for 15 min) with azelastine (0.01-100 microM) inhibited subsequent acetylcholine (ACh) (0.01-100 microM)-induced contractions. Azelastine, 100 microM, completely abolished the ACh-induced contractions. In contrast, high concentrations of Ca2+ channel antagonists diltiazem (10-100 microM) or nifedipine (20 microM), and Ca2(+)-free solution, only partially depressed the ACh contractions suggesting that azelastine has an additional effect on intracellular Ca2+ release. In Ca2(+)-free solution (containing 0.5 mM EGTA), azelastine (1-100 microM) depressed and abolished the transient contractions induced by 10 microM ACh. We conclude that azelastine inhibits airway constriction by inhibiting both voltage-sensitive Ca2+ slow channels on the cell membrane and Ca2+ release from a intracellular storage site.

Action Potentials↗
PubMed1995

Discriminative stimulus effects of esteratic local anesthetics in squirrel monkeys.

A number of esteratic local anesthetics serve as positive reinforcers and produce cocaine-like discriminative stimulus effects in animals. It has been suggested that the affinity of these compounds for a site on the dopamine transporter, and not their local anesthetic actions, is responsible for these abuse-related behavioral effects. In the present study, three local anesthetics previously shown to be self-administered in animals were examined in squirrel monkeys trained to discriminate cocaine (0.3 mg/kg) from saline in a two-lever, food-reinforced procedure. Dimethocaine (0.1-3.0 mg/kg) fully and dose-dependently substituted for cocaine. Doses of dimethocaine (1.7 mg/kg) and cocaine (0.3 mg/kg) which produced full (> 80%) substitution for cocaine were administered in combination with the dopamine D1 receptor antagonist SCH 39166 ((-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H -benzo [d]naphtho-(2,1-b)azepine) and the dopamine D2 receptor antagonist raclopride (both at 0.003-0.03 mg/kg). SCH 39166 fully blocked the cocaine-like discriminative stimulus effects of dimethocaine and cocaine, but raclopride produced only partial antagonism of cocaine-lever selection. In addition, there was some evidence that raclopride blocked cocaine-lever responding produced by a lower dose of dimethocaine. In substitution studies, neither procaine (1-10 mg/kg) nor chloroprocaine (1-30 mg/kg) produced cocaine-like effects. These results support a role for dopamine in the behavioral effects of some local anesthetics.

Aminobenzoates↗