Tacrine-propargylamine derivatives with improved acetylcholinesterase inhibitory activity and lower hepatotoxicity as a potential lead compound for the treatment of Alzheimer's disease.

A series of tacrine-propargylamine derivatives were synthesised and evaluated as possible anti-Alzheimer's disease (AD) agents. Among these derivatives, compounds 3a and 3b exhibited superior activities and a favourable balance of AChE and BuChE activities (3a: IC50 values of 51.3 and 77.6 nM; 3b: IC50 values of 11.2 and 83.5 nM). Compounds 3a and 3b also exhibited increased hAChE inhibitory activity compared with tacrine by approximately 5- and 28-fold, respectively, and low neurotoxicity. Importantly, these compounds also had lower hepatotoxicity than tacrine. Based on these results, compounds 3a and 3b could be considered as potential lead compounds for the treatment of AD and other AChE related diseases, such as schizophrenia, glaucoma and myasthenia gravis.

Acute cardiovascular response to monoamine oxidase inhibitors: a prospective assessment.

Despite the widespread use of monoamine oxidase inhibitors (MAOIs) and the well-known adverse event of hypertensive crisis, few studies have addressed the acute cardiovascular response to an MAOI dose. We prospectively measured pulse and blood pressure changes just before and at 1, 2, 3, and 4 hours after MAOI administration in 18 patients. Significant but asymptomatic increases from baseline in mean systolic and diastolic blood pressure occurred within 2 hours after MAOI administration, with return to near baseline by 4 hours. The mechanism of this reaction is unknown.

Neuromuscular effects of monoamine oxidase inhibitors.

The MAOI class of drugs is known to produce neuromuscular effects at therapeutic and toxic doses when given alone or in combination with other drugs. These effects range from muscle tension and twitches in their mild form to forceful myoclonic jerks. These effects may also be part of a more pervasive toxic syndrome that includes autonomic and mental symptoms as well. There is meager direct and substantial indirect evidence that serotonergic mechanisms play a role in mediating the neuromuscular effects of MAOIs. We have hypothesized that MAOIs produce a condition of heightened neuromuscular excitability due to a combination of increased serotonergic tone and central disinhibition of alpha-motor neuron-mediated spinal activity. Further study is needed utilizing objective pharmacologic and neurophysiologic measures.

Bipolar affective symptoms associated with use of captopril and abrupt withdrawal of pargyline and propranolol.

A woman with a family history but no personal history of depression developed bipolar symptoms associated with manipulations of her antihypertensive regimen. The author discusses hypotheses regarding the effects of these manipulations and the implications for treatment.

An open trial of pargyline in the treatment of attention deficit disorder, residual type.

Twenty-two patients who met the Utah criteria for attention deficit disorder, residual type (hyperactivity, minimal brain dysfunction in adults) received an open trial of pargyline (Eutonyl). Of these 22 patients, 13 (59%) showed a moderate to marked therapeutic response. Clinically useful features of pargyline in the treatment of attention deficit disorder, residual type are that its duration of action is greater than 24 hours and that it has not been abused. Pargyline inhibits monoamine oxidase, type B, and its therapeutic efficacy is compatible with the hypothesis that decreased phenethylaminergic function, dopaminergic function, or both play a role in the etiology of the disorder.

Pargyline-induced mania in primary affective disorder: case report.

A case is described of a 47-year-old man who developed a manic psychosis while receiving pargyline treatment for concurrent depression and hypertension. The pharmacologic actions of pargyline are discussed with regard to its partial selectivity for MAO-B and presumed action in dopamine systems, and clinicians are alerted to this uncommon drug reaction.

Selective and nonselective monoamine oxidase inhibitors: behavioral disturbances during their administration to depressed patients.

The occurrence of behavioral disturbances during four-week treatment of depressed patients with the nonselective monoamine oxidase (MAO) inhibitor, phenelzine sulfate (N = 14), the selective MAO-type A inhibitor, clorgyline (N = 12), and the partially selective MAO-type B inhibitor, pargyline hydrochloride (N = 13), was studied. Behavioral disturbances were encountered during treatment with each of the MAO-inhibiting drugs, with an overall incidence of 15% (six of 39 patients). All but one episode met criteria for mania or hypomania. Patients with bipolar illness experienced significantly greater incidences of behavioral disturbances in comparison with patients with unipolar illness (35.3% v 4.5%, respectively). The earliest latency to onset of a behavioral disturbances was 18 days, whereas the mean latencies were 22 to 26 days. Episodes of hypomania were observed after discontinuation of drug treatment in individual patients with unipolar and bipolar illness. Repeated MAO-inhibitor treatment, as part of a crossover study of clorgyline and pargyline, produced an increased severity of behavioral disturbances and a significantly shortened latency to onset.

Cardiovascular drugs and sexuality: a cardiologist's review.

In evaluating the factors of sexual dysfunction of the cardiovascular patient, the impact of drugs should be considered. Cardiovascular drugs may affect the sexuality of the patient through their effects on the CNS and peripheral nervous system, the vascular system, and hormonal changes. Such agents may impair the libidinal, erectile, and orgasmic phases of the human sexual response or may have effects that indirectly affect sexuality. Adrenergic inhibiting drugs, diuretics, vasdodilators, monoamine oxidase inhibitors, antiarrhythmics, hypolipidemics, and digitalis may affect the sexual response, with the former group having the most serious effects. These effects may interfere with the patient's compliance with medications, can cause emotional problems, and often have an undesirable impact on marital relations. Knowledge of the sexual side effects of the drugs and proper counseling of the patient are vital.

Comparative behavioral effects of clorgyline and pargyline in man: a preliminary evaluation.

The antidepressant and other behavioral effects of clorgyline, a preferential inhibitor of monoamine oxidase (MAO) type A, were compared with those of pargyline, a preferential inhibitor of MAO type B, in 16 depressed patients. In a subgroup of more severely depressed patients, clorgyline treatment for 4 weeks resulted in significant improvement on both observer-rated and self-rated scales, while minimal changes occurred during pargyline treatment. Similarly, in a crossover study that included 8 patients examined with multiple scales, clorgyline had generally greater antidepressant and antianxiety effects than did pargyline, although pargyline had some activating effects and also tended to produce more side effects. MAO type A inhibition may be more important than MAO type B inhibition for antidepressant efficacy.

Monoamine oxidase inhibitors: potential for drug abuse.

Both the amphetamines and MAO inhibitors share common clinical and pharmacological properties, namely, (i) to clinically induce euphoriant-stimulating type and psychotomimetic effects in certain individuals, and (ii) to increase, albeit by different mechanisms, the amount of functionally available neurotransmitter (catecholamines and indoleamines) at the receptor site. The present data now indicate that, like the amphetamines, the use of MAO inhibitors can be clinically associated with dependence-tolerance. Perhaps these clinical findings will converge with other clinical-biochemical data in helping to define the specific amine(s) responsible for not only the clinical effects of these drugs but also the etiopathogenesis of major psychiatric illnesses such as the affective disorders and schizophrenia.