A comparison of the inhibitory effects of new non-tricyclic amine uptake inhibitors on the uptake of norepinephrine and 5-hydroxytryptamine into synaptosomes of the rat brain

The effects of new non-tricyclic amine uptake inhibitors, FS32 and FS97, on the uptake of [³H]-norepinephrine (NE) into the hypothalamic synaptosomes and [³H]-5-hydroxytryptamine (5-HT) into whole brain synaptosomes were studied. Their effects were compared with those of tricyclic antidepressants. The uptake of [³H]-NE was inhibited competitively by FS32 and FS97 with a respective K_i value of 6.5 × 10^?7 M and 3.8 × 10^?7 M. The potency of FS32 and FS97 to inhibit this uptake was almost comparable to that of clomipramine and imipramine, respectively. In the case of [³H]-5-HT uptake, FS32 and FS97 also showed competitive inhibition with a respective K_i value of 2.9 × 10^?6 M and 5.9 × 10^?6M. The ability of FS32 to inhibit [³H]-5-HT uptake was almost equal to that of nortriptyline, while FS97 was two times more potent than iprindole in inhibiting this uptake.     

Some neurochemical properties of pramiracetam (CI-879), a new cognition-enhancing agent

The present study was initiated to examine the effect of pramiracetam sulfate [N-[2-[bis(1-methylethyl)amino]ethyl]-2 oxo-1-pyrrolidineacetamide sulfate (1:1)] (PR), a new cognition-activator agent, on various neurochemical parameters in order to gain some insight into the mechanism of action of this agent. PR (100 mg/kg i.p.) did not alter the concentration of norepinephrine, dopamine (DA), serotonin (5-HT), 5-hydroxyindoleacetic, and homovanillic acid in various brain areas. The agent also did not alter d-methamphetamine-induced changes in monoamine metabolism nor prolactin concentration in rat serum. PR did not exhibit any affinity in vitro for dopaminergic, adrenergic, serotoninergic, GABAergic, muscarinic, adenosine (IC₅₀ > 10 μM), and benzodiazepine receptors (IC₅₀ > 1 μM) binding sites. It may be concluded that the mechanism of action of pramiracetam does not appear to be due to a direct action upon DA and 5-HT neurotransmitter systems or various brain receptors. PR (44 and 88 mg/kg i.p.) caused a significant increase in the rate of sodium-dependent high-affinity choline uptake (HACU) into rat hippocampal synptosomes in vitro. This was specific as no effect was observed in cerebral cortex and corpus striatum. These results would seem to indicate that PR is accelerating hippocampal acetylcholine turnover and thus septal-hippocampal cholinergic neuronal impulse flow. This effect could be at least partially responsible for the enhancement of cognition processes observed for this agent.     

Fluradoline (HP 494), a centrally acting analgesic with antidepressant properties: Antidepressant pharmacology

Fluradoline (HP 494), a tricyclic dibenz (b, f) oxepine derivative with an analgesic profile, was tested for antidepressant activity. After oral administration, fluradoline was twice as potent as imipramine and similar in potency to desmethylimipramine in blocking tetrabenazine-induced ptosis. Like standard antidepressants, fluradoline selectively increased response rates for electrical stimulation of the median forebrain bundle using internal capsule-lesioned rats. Response rates in nonlesioned rats were unaffected. There was partial protection against yohimbine toxicity and no potentiation of 5-hydroxytryptophan-induced seizures in mice. When administered to squirrel monkeys, the EEG profile from cortically-placed electrodes resembled that found for imipramine. Using in vivo and in vitro techniques, it was shown that fluradoline was not a monoamine oxidase inhibitor; however, the compound did block the reuptake of norepinephrine, serotonin and dopamine in brain homogenates. These results suggest that in addition to the analgesic profile, there is a concomitant antidepressant profile which may enhance the spectrum of activity of fluradoline.     

The effect of bupropion,a new antidepressant drug,and alcohol and their interaction in man

Summary The effects of bupropion and ethanol were examined alone and in combination in a placebo controlled, double-blind, crossover study in 12 healthy volunteers. Results were subjected to analysis of variance and differences ofp<0.05 taken as significant. In the main study using the Wilkinson auditory vigilance test, no active treatment or combination of treatments produced significant change compared with placebo. However, when compared with bupropion 100 mg, vigilance was significantly impaired by 32 ml alcohol alone though not when combined with bupropion. No significant changes in reaction time or short term memory occurred. Visual analogue scales indicated that the subjects were mentally slower after alcohol 32 ml than after placebo. Combination of bupropion 100 mg with alcohol 32 ml abolished this difference. A similar pattern occurred with group ratings indicating mental sedation. Subjects were clearly able to differentiate between the 16 ml and 32 ml doses of alcohol when assessing their degree of inebriation. Combination of bupropion with alcohol made no difference to the ratings of inebriation. The top dose of alcohol tended to increase energy in the low frequency EEG bands. Combination of the top alcohol dose with bupropion, however, produced a significant reversal with lowered energy in the 4–7.5 Hz band. Combination of bupropion with alcohol failed to change the blood alcohol concentration achieved.     

Effects of imipramine,bupropion, chlorpromazine,and clozapine on differential-reinforcement-of-low-rate (DRL) > 72-Sec and > 36-sec schedules in rat

The hypothesis that a DRL schedule requiring a long pause (> 72 sec) specifically identifies antidepressant drugs was evaluated in rats pressing a lever for food reinforcement. The tricyclic antidepressant imipramine decreased responses and increased reinforcements as previously shown. However, the antipsychotics chlorpromazine and clozapine had a similar effect, as did prefeeding, and the atypical antidepressant bupropion increased responses and decreased reinforcements. Because mean baseline reinforcement rate was lower than in previous studies showing drug class specificity, the DRL requirement was reduced to > 36 sec and the drugs were tested again; effects were qualitatively similar to those in DRL > 72 in the first part of the study. The results suggest that a drug-induced reduction in responses could account for the increase in reinforcements, that if drug class specificity exists it may occur only when baseline response and reinforcement rates are confined to a narrow range, that the failure of previous studies to show antidepressant type effects with nonantidepressants could have resulted from choice of drugs and doses, and that the type of reinforcer could be an important factor.     

Pharmacokinetics of bupropion,a novel antidepressant agent,following oral administration to healthy subjects

Summary The pharmacokinetics of bupropion hydrochloride, a structurally novel antidepressant agent, have been studied in healthy male and female subjects following administration of single oral doses of 50, 100 and 200 mg. Plasma drug concentrations were determined directly by a specific radioimmunoassay (r. i. a.), while urinary measurements required a prior solvent extraction to remove substances interfering in the assay. Bupropion appeared rapidly in the plasma, suggesting good absorption. Drug plasma concentration-time data were fitted well to a two-compartment open model of drug disposition by use of the computer program NONLIN. By comparison of AUC, C_max and t_max values, the pharmacokinetics of bupropion were found to be linear across the 50–200 mg dose range in both sexes. When the data were normalized for subjects' body weights, no differences between pharmacokinetic parameters for male and female subjects were found. Mean disposition half-lives across treatments were 1.2–1.4 h for t_{1 2} and 10.7–13.8 h for the t_{1 2}. Bupropion was extensively bound (85%) to human plasma proteins over a wide drug concentration range. Less than 1% of a 200 mg oral dose of bupropion hydrochloride appeared in the urine of 16 subjects as unchanged drug, indicating extensive metabolism of the parent compound.     

Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: a randomized, double-blind, placebo-controlled study

AIMS: To assess the analgesic efficacy of topical administration of 3.3% doxepin hydrochloride, 0.025% capsaicin and a combination of 3. 3% doxepin and 0.025% capsaicin in human chronic neuropathic pain. METHODS: A randomized, double-blind, placebo-controlled study of 200 consenting adult patients. Patients applied placebo, doxepin, capsaicin or doxepin/capsaicin cream daily for 4 weeks. Patients recorded on a daily basis overall pain, shooting, burning, paraesthesia and numbness using a 0-10 visual analogue scale during the week prior to cream application (baseline levels) and for the 4 week study period. Side-effects and desire to continue treatment were also recorded. RESULTS: Overall pain was significantly reduced by doxepin, capsaicin and doxepin/capsaicin to a similar extent. The analgesia with doxepin/capsaicin was of more rapid onset. Capsaicin significantly reduced sensitivity and shooting pain. Burning pain was increased by doxepin and by capsaicin and to a lesser extent by doxepin/capsaicin. Side-effects were minor. One patient requested to continue placebo cream, 17 doxepin cream, 13 capsaicin and 9 the combination of doxepin and capsaicin. CONCLUSIONS: Topical application of 3.3% doxepin, 0.025% capsaicin and 3.3% doxepin/0. 025% capsaicin produces analgesia of similar magnitude. The combination produces more rapid analgesia.     

Cardiocirculatory effects of Ro 11-2464, a selective 5-HT (serotonin) uptake inhibitor,in healthy volunteers

Summary The imipramine derivative Ro 11-2465, a potent, selective 5-HT (serotonin) uptake inhibitor, is being developed as an antidepressant agent. The effects of Ro 11-2465 on heart rate, blood pressure, electrocardiogram and systolic time intervals were assessed in nine normotensive volunteers. Ro 11-2465 1 and 2 mg and a placebo were given in a single blind, cross over design study. The placebo did not induce any significant changes. With Ro 11-2465, the ECG-intervals (P,PQ,QRS,QTc) did not change, the blood pressure increased 3–6 h after administration of either dose, and the heart rate was increased 4–6 h after the 2 mg dose. There was also evidence of increased ventricular automaticity in one subject. The total electromechanical systole (QS₂-index) was significantly shortened 4–8 h after administration of 2 mg, whereas neither 1 mg the dose nor the placebo had any such effect. This finding suggests the presence of a positive inotropic effect, which is probably due to a stimulatory effect of serotonin, and is not mediated by an adrenergic mechanism. The findings suggest that Ro 11-2465, as a potential new tricyclic antidepressant, might have favourable cardiocirculatory side effects, particularly in patients with pre-existing heart disease.     

Transdermal delivery of imipramine hydrochloride: development and evaluation (in vitro and in vivo) of reservoir gel formulation

The in vitro permeation studies of imipramine hydrochloride (IMH) reported earlier from our laboratory showed that a combination of menthol (2.5% w/v) and oleic acid (2.5% w/v) worked well in terms of safety and efficacy. The main objective of this study was to evaluate the in vivo performance of this combination; in order to do that, penetration enhancers were incorporated in a hydro-alcoholic gel of hydroxypropylmethyl cellulose along with IMH and used as the drug matrix in a reservoir transdermal patch. A stability study of IMH gel was performed at 40 degrees C/75% RH for 2 months. The results of this study indicate that gels of IMH stored at 40 degrees C/75% RH turned yellow brown in 2 months and the small change in viscosity of gel at 40 degrees C/75% RH had an insignificant effect on the release rate of IMH from the gel (p>0.05). The in vivo performance of the gel was tested in rats using a reservoir transdermal patch, which consisted of a backing membrane, drug matrix and retaining membrane with an area of 12.5 cm2. Plasma concentrations of 3 microg/ml of IMH were achieved and in a histopathological study 24 h occlusion was found to be safe.     

CGP 4718 A, a new potential antidepressant with a dual mode of action

The ergolene derivative MPME (PTR 17402; (5R,8R)-8-(4-p-methoxyphenyl)-1-piperazynylmethyl-6- methylergolene], a dopamine (DA) receptor agonist acting mainly at DA D-1 receptors linked to dotted types of forebrain DA nerve terminals, induces a characteristic behavioural syndrome consisting of increased locomotion, head-bobbing and sniffing activity without oral stereotypies or increased rearing. Haloperidol and cis-flupenthixol, nonselective DA receptor antagonists, but not selective D-2 receptor antagonists such as remoxipride and sulpiride, could significantly counteract the locomotion and head-bobbing behaviour induced by MPME. In contrast, the sniffing behaviour induced by MPME was only marginally affected by haloperidol and cis-flupenthixol pretreatment. These results suggest that activation of D-1 receptors in the forebrain mainly linked to the dotted types of DA nerve terminals in the striatum, and in the limbic forebrain, can result in behavioural effects which differ from those caused by stimulation of D-2 receptors located mainly within the diffuse types of DA nerve terminal systems.     

Biochemical characteristics of a potential antidepressant, 2-(7-indenyloxymethyl)morpholine hydrochloride (YM-08054-1)

The effects of potential antidepressant, 2-(7-indenyloxymethyl)morpholine hydrochloride (YM-08054-1), on uptake, release and oxidative deamination of catecholamines and serotonin [5-hydroxytryptamine(5-HT)] were studied in vitro with rat brain, and compared with the effects of several tricyclic antidepressants and viloxazine a structural analogue of YM-08054-1. YM-08054-1 at concentrations of less than 1 μM. considerably inhibited 5-HT uptake by synaptosomes from rat whole brain as well as noradrenaline (NA) uptake by synaptosomes from rat hippocampus, similar to amitriptyline. Viloxazine and iprindole were weak inhibitors in both uptake reactions. In the release of either [¹⁴C] -5-HT from [¹⁴C]-5-HT-prelabeled hypothalamic slices or [¹⁴C]NA from [¹⁴C] NA-prelabeled hippocampal slices, YM-08054-1 and amitriptyline were much less potent than such typical potent releasers as methamphetamine and tyramine. YM-08054-1 was also found to be a weak inhibitor of both type A and type B monoamine oxidases, whereas the tricyclic antidepressants preferentially inhibited the type B enzyme. These biochemical results indicate that YM-08054-1 may be an amitriptyline-like antidepressant, but distinct from viloxazine.     

Antiserotoninergic properties of maprotiline and a new antidepressant,oxaprotiline: Two selective na uptake inhibitors

Antiserotoninergic effects of maprotiline and its hydroxy derivative oxaprotiline (Ba 49802 B), two selective inhibitors of NA uptake, and clinically active antidepressants were investigated in several functional tests and also in in vivo ³H-spiperone binding assay in the rat. In some tests comparisons with amitriptyline, mianserin, and fluoxetine, which are antidepressants of different qualities, were also done. After single doses up to 30 mg/kg neither maprotiline nor oxaprotiline inhibited L-5-HTP-induced head twitch in mice or tryptamineinduced paw clonus in the rat. Maprotiline, however, but not oxaprotiline, significantly reduced the hyperthermic response to LSD in rabbits and blocked to nearly 90% the ³H-spiperone labeled 5-HT receptors in the rat frontal cortex at a dose of 30 mg/kg. Moreover, maprotiline also reduced the response of mice to L-5-HTP after daily administration of 25 mg/kg over 10 days. No change in the responsiveness of mice to L-5-HTP was observed after the same treatment with oxaprotiline. In agreement with other observations, mianserin and amitryptiline displayed clear-cut antiserotoninergic effects, whereas fluoxetine potentiated the effects of tryptamine and LSD. The results of this study indicate that, although chemically closely related, maprotiline and oxaprotiline distinctly differ in respect to their action on 5-HT receptors. Maprotiline exerts 5-HT receptor blocking effects that appear to increase upon repetitive administration in mice. Oxaprotiline, by contrast, is devoid of them. Comparative experimental and clinical investigations of maprotiline and oxaprotiline may, therefore, provide a clue as to the importance of 5-HT receptor blocking properties for antidepressant profile of action of drugs.     

Diphenylpyraline, a histamine H1 receptor antagonist, has psychostimulant properties

Diphenylpyraline hydrochloride (DPP) is used clinically as an antihistamine drug, but its neurobiological effects are not completely understood. Voltammetry and microdialysis were used to investigate potential actions of DPP on the dopamine system. Voltammetric monitoring of dopamine signals in mouse nucleus accumbens slices showed that DPP (10 microM) markedly inhibited dopamine uptake. There was a 20-fold increase in apparent Km for dopamine uptake, while Vmax was unchanged. Microdialysis experiments demonstrated that DPP (5 mg/kg, i.p.) elevated extracellular dopamine levels (approximately 200%) in mouse nucleus accumbens. DPP (5 and 10 mg/kg) also induced locomotor activation. All of the effects of DPP were comparable with those of cocaine. Taken together, these results indicate that DPP acts as a competitive dopamine transporter inhibitor similar to cocaine.     

Biochemical profile of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug

The present study of midalcipran (F 2207), 1-phenyl-1-diethyl-aminocarbonyl-2-aminomethyl-cyclopropane(Z)hydrochloride, was undertaken to determine its biochemical profile.

The properties of midalcipran, in inhibiting the uptake of monoamines were tested and compared with that of imipramine. In vitro, midalcipran was found to inhibit the uptake of radiolabelled serotonin and noradrenaline (IC₅₀ = 203 and 100 nM, respectively), but not that of dopamine, into brain slices. Hyperthermia induced by the centrally-acting displacers of monoamines, H77/77 and H75/12, were almost equipotently antagonized by midalcipran, confirming the inhibition of the uptake of serotonin and noradrenaline by midalcipran in vivo (ID₅₀ = 11 and 4.8 mg/kg, respectively). Midalcipran showed no inhibition of the activity of monoamine oxidase in vitro or in vivo. The interaction between midalcipran and neurotransmitter receptors and binding sites in the CNS was studied in the rat in comparison with imipramine and desipramine. In contrast to these two antidepressant drugs, midalcipran showed no affinity for alpha- or beta-adrenoceptors, muscarinic, histaminergic H₁, dopaminergic D₂ or serotonergic 5-HT₂ receptors, suggesting a general absence of anticholinergic, sedative and other side-effects. Midalcipran was equipotent with imipramine at inhibiting the binding of [³H]imipramine. Chronic administration of midalcipran to rats did not alter the number of beta-adrenergic receptors in the cortex, in contrast to imipramine and desipramine which decreased the binding of beta-adrenoceptors.

Thus midalcipran appears to act exclusively presynaptically, inhibiting the uptake of serotonin and noradrenaline. This activity, coupled to the total absence of interaction at postsynaptic sites, suggests that midalcipran may be a useful and novel antidepressant drug.     

Preferential inhibition of type B-MAO by new compounds, 1-[3-(dimethylamino)propyl]-5-methyl-3-phenyl-1H-indazole(FS32) and its N-desmethylated derivative (FS97)

The effects of new compounds, FS32 and FS97, on two forms of monoamine oxidase(MAO), type A-MAO and type B-MAO, were studied. Both FS32 and FS97 inhibited type B-MAO effectively while they inhibited type A-MAO to a lesser extent. Type B-MAO was also more susceptible to inhibition by classical tricyclic antidepressants. Kinetic studies have revealed that both FS32 and FS97 are competitive and reversible inhibitors of type A- and type B-MAO.     

Clinical pharmacology of sibutramine hydrochloride (BTS 54524), a new antidepressant, in healthy volunteers.

The cardiovascular, anticholinergic and central effects of single doses of 30, 45 and 60 mg of sibutramine hydrochloride (BTS 54524), a new potential antidepressant, were compared with amitriptyline (50 mg) and placebo given at weekly intervals in a randomised design to six healthy male volunteers. Sibutramine was associated with increases in both supine heart rate and systolic blood pressure at 1, 2 and 6 h after 60 mg (P less than 0.05). Amitriptyline caused a significant 50-60% decrease in salivation compared with placebo at 2 and 6 h but there were no changes with sibutramine. No significant changes in pupil size were detected with either drug. Visual analogue rating scales (VARS) revealed significant drowsiness with amitriptyline but neither sedative nor stimulant effects with sibutramine. Impairments of simple auditory and visual reaction times, visual two-choice reaction time, finger tapping and trail making, measured using an automated test battery, occurred with amitriptyline compared with sibutramine. If sibutramine proves to be an effective antidepressant it should be devoid of anticholinergic or central depressant effects. Chronic dosage studies are indicated to evaluate the clinical significance of its cardiovascular effects.     

Biochemical and pharmacologic properties of 2614W94, a reversible,competitive inhibitor of monoamine oxidase-A

2614W94 [3-(1-trifluoromethyl)ethoxyphenoxathiin 10,10-dioxide] is a selective, reversible inhibitor of monoamine oxidase-A with a competitive mechanism of inhibition and a K_i value of 1.6 nM with serotonin as substrate. In pretreated rats, the ED₅₀ value after single oral dosing was 1.7 mg/kg, similar to an ED₅₀ value of 1.1 mg/kg estimated in the 5-hydroxytryptophan potentiation test. Maximal inhibition of monoamine oxidase-A (MAO-A) was observed by 0.5 h after dosing, suggesting rapid transport to brain. Inhibition in brain was maintained for several hours, followed by a gradual reversal with a half-time of 7.2 h. Brain levels of parent compound were higher than plasma levels at all times after dosing. No significant inhibition of MAO-B was observed. After preincubation of MAO with 2614W94 at 37°C, the inhibition was reversed by dialysis. Concentrations of serotonin, norepinephrine, and dopamine were clearly elevated in brains of rats after single oral doses, whereas levels of MAO metabolites were decreased. In a rat model designed to show blood pressure elevations in response to a threshold dose of orally administered tyramine, 2614W94 compared well with moclobemide, an MAO-A selective inhibitor that has not been associated with problems relating to dietary tyramine. The two stereoisomers of 2614W94 were both potent MAO-A inhibitors. In vitro and in vivo properties of 2614W94 suggest that this compound and its close analogs are among the most potent MAO-A inhibitors known and that they may have therapeutic potential as safe new antidepressant/anxiolytic agents. Drug Dev. Res. 45:1–9, 1998. © 1998 Wiley-Liss, Inc.     

Involvement of nitric oxide (NO) signaling pathway in the antidepressant action of bupropion, a dopamine reuptake inhibitor

The present study was undertaken to elucidate the alterations in various behavioral and neurochemical basis of antidepressant action of bupropion [(+/-)-alpha-t-butylamino-3-chloropropiophenone], a dopamine reuptake inhibitor and to elucidate the possible mechanism of its action. The involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant action of bupropion was investigated besides its actions on various brain transmitters like norepinephrine, dopamine and homovanillic acid. Bupropion (10, 15, 20 and 40 mg/kg., i.p.) dose dependently inhibited the immobility period in mice in both forced swim test and tail suspension test. ED(50) values of bupropion in reducing the immobility period was found to be 18.5 and 18 mg/kg i.p., in forced swim test and tail suspension test, respectively. Bupropion (10, 20 and 40 mg/kg., i.p.) reversed the reserpine-induced behavioral despair also. When different doses (10, 15, 20 and 40 mg/kg., i.p.) of bupropion were tested for locomotor activity, it (15, 20 and 40 mg/kg., i.p.) increased locomotor activity. At 20 and 40 mg/kg doses the drug showed hypothermia. The neurochemical analysis of brain samples revealed that bupropion dose dependently (10-40 mg/kg., i.p.) increased the brain contents of dopamine and homovanillic acid in the mouse whole brain. The levels of norepinephrine were also increased at 20 mg/kg dose. The antidepressant-like effect of bupropion (20 mg/kg., i.p.) was prevented by pretreatment with L-arginine (750 mg/kg., i.p.) [substrate for nitric oxide synthase (NOS)]. Pretreatment of mice with 7-nitroindazole (25 mg/kg., i.p.) [a specific neuronal nitric oxide synthase (nNOS) inhibitor] produced potentiation of the action of subeffective dose of bupropion (10 mg/kg i.p.). In addition, treatment of mice with methylene blue (10 mg/kg., i.p.) [direct inhibitor of both nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC)] potentiated the effect of bupropion (10 mg/kg., i.p.) in the forced swim test. Furthermore, the reduction in the immobility period elicited by bupropion (20 mg/kg., i.p.) was also inhibited by pretreatment with sildenafil (5 mg/kg., i.p.) [phosphodiesterase 5 inhibitor]. The study indicated that bupropion possesses antidepressant activities in different animal models of depression through its dopaminergic and/or by modulating the L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway.