A clinical trial with nomifensin, a new antidepressant drug.

An uncontrolled clinical trial with 10 depressed patients was conducted to identify the psychopathological symptoms which may be affected by nomifensin administration, and to reveal the possible adverse effects of the drug. Consistent statistically significant improvement was noted in the course of the clinical trial on all of the assessment instruments used, and - with the exception of one patient - all improved while receiving nomifensin. Most of the therapeutic changes were seen within the first three weeks of treatment, and they included improvements of depression, as well as of hostility, a symptom which usually remains unaffeCTED BY TRICYclic antidepressant drugs. To verify the favorable therapeutic effects of nomifensin in depressed psychiatric patients, a standard-controlled clinical trial is in progress; and to verify the action mechanism of nomifensin, a study employing the probenecid technique and the measurement of spinal homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5hiaa) concentration is planned.     

The assessment of potential drug interactions with a new tricyclic antidepressant drug

1 Methods for the investigation of possible interactions with tricyclic antidepressant drugs are described. These methods have been applied to a new compound, Ciba 34276-Ba, which has been shown to have antidepressant activity.

2 In five normal volunteers tested before and during treatment with Ciba 34276-Ba, no abnormalities of resting or post-exercise electrocardiographs occurred. A three-fold reduction in tyramine-responsiveness was seen in three normal subjects studied, but no potentiation of the noradrenaline pressor effect occurred. One of six patients given Ciba 34276-Ba whilst on long-term treatment with bethanidine showed loss of blood pressure control.

3 The metabolic clearance of antipyrine was unaltered in two subjects studied, showing no evidence of induction or inhibition of hepatic microsomal oxidizing enzymes by Ciba 34276-Ba.

     

Fluvoxamine, a new antidepressant drug, fails to show antiserotonin activity

Fluvoxamine, (E)-5-methoxy-4'-(trifluoromethyl)valerophenone O-2(2-aminoethyl)oxime, a new antidepressant drug inhibiting serotonin (5-HT) uptake, was studied in rats and mice in order to check whether it has any central anti-5-HT activity, as do some tricyclic antidepressants, e.g. amitriptyline and doxepin. Fluvoxamine did not influence either the 5-hydroxytryptophan-induced head twitch response in mice or the tryptamine convulsions in rats. In the hind limb flexor reflex of the spinal rat the stimulation induced by fenfluramine was inhibited, that induced by LSD was not changed. Fluvoxamine also antagonized the hyperthermia (at ambient temperature of 28 degrees C), induced in rats by fenfluramine or p-chloroamphetamine. The hyperthermia caused by m-chlorophenylpiperazine was not inhibited. Fluvoxamine did not antagonize the 5-HT pressor effect in pithed rats. It has no effect on the immobility time in the behavioural despair test in rats. The results indicate that fluvoxamine fails to show anti-5-HT activity.     

Some central effects of tiflucarbine, a new potential antidepressant drug

Tiflucarbine (TVX P 4495), a new putative antidepressant drug (AD) with a chemical novel among AD's [9-ethyl-4-fluoro-1-methyl-7,8,9,10-tetrahydrothieno (3,2-e)-pyrido(4,3-b)indole lactate], a potent inhibitor of the 5-hydroxytryptamine (5-HT) uptake, was studied in rats and mice, mostly with regard to its possible effect on the noradrenaline (NA) uptake and 5-HT postsynaptic receptors. Tiflucarbine exerted no effect on the reserpine hypothermia, attenuated the apomorphine hypothermia and enhanced the TRH-induced hyperthermia. It did not prevent tryptamine convulsions or the fenfluramine-induced hyperthermia, and inhibited the L-5-hydroxytryptophan-induced head twitches (at a high dose only). It stimulated the hind limb flexor reflex preparation of the spinal rat in cyproheptadine-reversible manner. In the behavioral despair test it shortened the immobility time. Tiflucarbine administered repeatedly enhanced the D-amphetamine-induced locomotor hyperactivity and inhibited the clonidine-induced aggressiveness. The results indicate that tiflucarbine exhibits characteristics of a poor inhibitor of the NA uptake (irrespective of its strong inhibitory effect on the 5-HT uptake), and has no effect on 5-HT2 postsynaptic receptors. When used repeatedly, it enhances--like other AD--responsiveness of the central dopamine system.     

Agomelatine,a melatonin agonist with antidepressant properties

Agomelatine (β-methyl-6-chloromelatonin), which is structurally homologous to melatonin, is a potent agonist of melatonin MT1 and MT2 receptors as well as an antagonist of serotonin 5-HT_2C receptors. Agomelatine appears to improve sleep without causing daytime sedation. It has not been found to be associated with sexual side effects and discontinuation symptoms. Three placebo-controlled trials, one of them a dose finding study and two of them pivotal trials, suggest that agomelatine is an antidepressant at doses of 25 – 50 mg/day. Agomelatine appears to be well tolerated, without sexual or cardiac adverse effects, weight gain or discontinuation syndromes. Animal studies suggest a possible neuroprotective action of agomelatine, although there are more data in favor of an anxiolytic effect. Substantially more research is needed to establish its role in the treatment of mood and circadian rhythm disorders.     

Effect of caroxazone, a new antidepressant drug, on monoamine oxidases in healthy volunteers

1 Caroxazone is a new antidepressant drug with a reversible inhibitory effect on monoamine oxidases (MAO) as previously shown experimentally in animals.

2 The effect of caroxazone on MAO was explored in healthy volunteers and compared with that of tranylcypromine and imipramine. Daily urinary excretion of tryptamine and MAO activity in platelets were assayed at various times during and after treatment and the differences from basal values were statistically analysed. In addition, caroxazone plasma levels were determined.

3 Caroxazone administered orally at doses of 300 or 600 mg/day for 12 days induced a significant, dose-dependent increase in urinary tryptamine excretion. Tranylcypromine (20 mg/day for 8 days) was even more active in this respect; imipramine (50 mg/day for 12 days) was completely inactive.

4 MAO activity in platelets was not affected by caroxazone or imipramine, but was completely inhibited by tranylcypromine.

5 Mean steady-state plasma levels of caroxazone were about 6 μg/ml and 11-12 μg/ml with the dose of 300 mg/day and 600 mg/day respectively.

6 It can be concluded that caroxazone is a MAO inhibitor in man too, at a clinically effective dose such as 600 mg/day. The fact that its MAO inhibition is not apparent in platelet preparation may be explained by its reversibility.

7 Tranylcypromine confirmed its potent irreversible MAO inhibitory effect, while imipramine lacked any effect at the tested dose.

     

Pharmacological properties of taglutimide, a new sedative-hypnotic drug

2-[Bicyclo(2,2,1)heptane-2-endo-3-endo-dicarboximido]-glutarimide (taglutimide, K-2004) proved to be a new sedative-hypnotic drug which did not produce any toxic effects when administered orally to mice even at a very high dosage. Central-nervous depression was demonstrated by a reduction in spontaneous motor activity, potentiation of the central-depressant effect of pentobarbital, antagonism of the central-stimulant effect of amphetamine after oral administration and by narcotic activity after i.v. administration of the drug. Furthermore, oral administration of taglutimide potentiated the analgesic action of morphine without being effective on its own. Only weak potentiation of chlorpromazine-induced catalepsy, but not of reserpine-induced catalepsy was observed after taglutimide pretreatment. The drug influenced neither motor co-ordination nor the toxicity of ethanol. Taglutimide exhibited no anticonvulsant activity with respect to maximum electroshock or strychnine-induced seizures. No effect on heart rate or blood pressure was demonstrable after taglutimide treatment in conscious dogs.     

Cardiovascular properties of medroxalol, a new antihypertensive drug

Medroxalol is a new antihypertensive agent that is presently undergoing clinical trial. Its cardiovascular properties were studied using spontaneously hypertensive rats (SHR), anesthetized dogs, and isolated tissues. Medroxalol produced a long-lasting fall in blood pressure when given by the oral route to SHR. It was more potent than phentolamine in antihypertensive effectiveness. Given intravenously to dogs, medroxalol reduced the blood pressure and heart rate of doses that did not greatly reduce cardiac output. The hypotensive effect of medroxalol was reduced but not abolished following alpha- and beta-adrenergic-receptor blockade. Medroxalol inhibited heart rate and blood pressure responses to isoproterenol and phenylephrine in dogs. In vitro medroxalol resembled a competitive antagonist at alpha-adrenergic receptors in rabbit aortic strips (pA2 6.09) and beta-adrenergic receptors in guinea pig atria (pA2 7.73). It was 0.02 as potent as phentolamine at alpha-receptors and 0.09 as potent as propranolol at beta-receptors. It was concluded that the principal action of medroxalol was to produce a fall in blood pressure by decreasing peripheral vascular resistance more than cardiac output. Adrenergic alpha- and beta-receptor blockade alone does more than cardiac output. Adrenergic alpha- and beta-receptor blockade alone does not satisfactorily explain the hypotension. A contribution by an active vasodilatory component appears likely.     

Neurochemical and pharmacological studies on a new 5HT-uptake inhibitor,FG4963, with potential antidepressant properties

A new phenylpiperidine derivative, FG4963, and several tricyclic antidepressants were compared in various in vitro and in vivo tests for central 5HT- and NA-uptake inhibition. FG4963 was found to be a 5HT-pump blocker with activity similar to that of chlorimipramine. FG4963 inhibited NA-uptake less than the most potent tricyclic thymoleptics.In contrast to imipramine derivatives FG4963 was a weak inhibitor of peripheral NA-uptake.FG4963 seems to produce central 5HT-potentiation without affecting organ functions regulated by the autonomic nervous system as much as tricyclic antidepressants.     

AHR-9377, a new antidepressant agent

AHR-9377 is a novel chemical structure with potential antidepressant activity. It was more potent than imipramine in mice, and equipotent with imipramine in rats in blocking tetrabenazine ptosis. Yohimbine toxicity in mice was potentiated by AHR-9377 in doses less than those of imipramine. The compound had no CNS stimulant properties as judged by behavioral observations and spontaneous motor activity determinations in rats and by its lack of effect on rectal temperature of normothermic rats. In rats made hyperthermic with d-amphetamine, however, AHR-9377, like imipramine, prolonged the hyperthermic effect. Contractions of the cat nictitating membrane that were induced by norepinephrine were potentiated by AHR-9377. Unlike iproniazid, AHR-9377 had no monoamine oxidase-inhibiting activity. Electroencephalographic analyses indicated no slowing of cortical activity and no spindle-type waves in cats after AHR-9377 administration. These data suggest that AHR-9377 is a potential antidepressant agent without sedative activity.     

Paroxetine, a selective 5-hydroxytryptamine uptake inhibitor with antidepressant properties, lacks amphetamine-like stimulus properties in an operant drug discrimination bioassay in rodents

To evaluate whether the novel antidepressant paroxetine has any possible amphetamine-like actions, rats were trained to discriminate (+)-amphetamine sulphate in a standard two lever operant drug discrimination (DD) procedure using a fixed ratio 10 schedule of food reinforcement with a quantal, lever selection, index of the amphetamine stimulus. The 'training' dose of amphetamine was 1 mg kg-1, i.p. Rats trained with this dose of amphetamine (n = 15) learned the drug discrimination rapidly over 30 training sessions and discriminative performance in these animals was subsequently maintained at a high level of accuracy (90% correct) over a prolonged time. In tests in these trained animals, amphetamine itself and the antidepressant agents nomifensine and tranylcypromine all produced clear, unequivocal dose-related generalization to amphetamine with ED50s of 0.2, 0.5 and 1.6 mg kg-1 respectively (as determined by probit analyses). In tests with paroxetine hydrochloride it was established that, over the dose range 0.3 to 10 mg kg-1, no evidence was seen of generalization to the amphetamine stimulus. These data confirm earlier studies which suggested that some antidepressants may possess abuse potential because of their ability to induce amphetamine-like internal states. In contrast, paroxetine is devoid of such properties.     

The effects of bupropion, a new antidepressant drug, and diazepam, and their interaction in man

1 The effects of single oral doses of bupropion, diazepam and the two combined, were examined in twelve (six male, six female) healthy volunteers, using a balanced cross over design and double-blind conditions. Results were analysed by analysis of variance and values of P < 0.05 taken as significant.

2 A significant reduction in signals detected in the Wilkinson vigilance test occurred after 5 mg diazepam and a similar trend occurred after 2.5 mg diazepam compared with lactose dummy. Performance after combination of bupropion 100 mg and diazepam 5 mg failed to differ from that after lactose. Bupropion alone never differed from lactose dummy. Calculation of the ratios of d' and β indicated that diazepam was reducing the subjects' ability to discriminate between signals and noise, rather than their willingness to report. Values of d' after combination of bupropion with diazepam did not differ from those after lactose.

3 Subjective effects, measured using visual analogue scales, showed that the subjects rated themselves significantly more drowsy, muzzy and dreamy after both doses of diazepam than after lactose dummy. Combinations of bupropion 100 mg with diazepam 2.5 and 5 mg resulted in ratings which never differed from lactose on any dimension. Subjects were more bored after all treatments compared with lactose and this was the only dimension where bupropion produced a significant difference. Subjective effects had largely disappeared by 6 h.

4 Tests of short term memory, reaction time and digit symbol substitution showed no significant effects, but errors in short term memory after diazepam approached significance (P = 0.092).

5 Autonomic effects: no changes were seen in blood pressure (systolic or diastolic) and pupil diameter. Significant elevation of heart rate occurred after diazepam 2.5 mg, bupropion alone and in both combinations 6 h 15 min post-treatment. This probably resulted from a spuriously low value after lactose.

6 EEG, quantitated using four filters approximating to the four clinical frequencies revealed no differences between active drug(s) and lactose at 2 h 45 min after treatment. A possible increase in fast activity occurred after bupropion 6 h 15 min post-treatment.

7 It was concluded that bupropion 100 mg administered as a single dose, while not producing significant changes in the variables measured, when co-administered with single 5 mg doses of diazepam antagonised the functional impairment and drowsiness which follow that drug.

     

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.