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PubMed1986

Current concepts in clinical therapeutics: major affective disorders, Part 1.

The epidemiology, pathophysiology, diagnosis and clinical features, and treatment of unipolar (depressive) and bipolar (manic-depressive) affective disorders are described. Disturbances of mood are the most common psychiatric disorders in adults, with 18-23% of women and 8-11% of men having at least one major depressive episode. Genetic factors are important in both depression and manic-depressive illness. Depression is characterized by a persistent dysphoric mood accompanied by feelings of sadness or hopelessness nearly every day for at least two weeks. The essential feature of a manic episode is an elevated, expansive, or irritable mood associated with symptoms such as hyperactivity and lack of judgment. Treatment involves nonpharmacologic and pharmacologic interventions. Psychotherapy in patients with depression is most useful in improving social functions, while antidepressant drugs reduce relapse rates. Electroconvulsive therapy is indicated in depressed patients at immediate risk of suicide or extreme incapacitation. Tricyclic antidepressants (amitriptyline, imipramine, doxepin, notriptyline, desipramine, trimipramine), second-generation antidepressants (maprotiline, amoxapine, trazodone, bupropion), monoamine-oxidase inhibitors (phenelzine, isocarboxazid, tranylcypromine, pargyline), and lithium are useful in treating patients with affective disorders. Tricyclic agents are the mainstay of treatment for depression; newer second-generation agents should be used in specific subgroups of patients. Lithium is the drug of choice for prophylaxis in bipolar patients, whereas combinations of lithium and tricyclic agents are useful during acute episodes of depression in bipolar patients. Major affective disorders occur commonly and require a careful balance of pharmacologic and nonpharmacologic interventions for proper therapy.

Antidepressive Agents↗
PubMed1985

Effects of adrenalectomy on gonadal hormone-induced changes in hepatic microsomal carboxylesterase activities in rats.

Hepatic microsomal carboxylesterase (E.C. 3.1.1.1) showed a different capacity for the hydrolysis of various substrates in rats. Adrenalectomy in castrated male rats slightly decreased the activities towards p-nitrophenyl-acetate and malathion. The magnitude of testosterone-induced changes in the hydrolase activities by liver microsomes in adrenalectomized-castrated male rats was markedly decreased castrated male rats. However, when 5 alpha-dihydrotestosterone was administered to adrenalectomized-castrated male rats, malathion and p-nitrophenylacetate hydrolase activities were significantly increased. But in all cases, isocarboxazid and acetanilide hydrolase activities were not affected by physiological states. These results suggest that hepatic microsomal carboxylesterases may be, at least in part, regulated by adrenal gland and gonadal hormones which exert different effects on the several isozymes of carboxylesterases.

Adrenalectomy↗
PubMedDate not supplied

Localization and characterization of meperidine esterase of rats.

Meperidine esterase of the rat was studied. The enzyme activity was found in the liver microsomes but not in brain tissue or blood. The enzyme had an optimal activity between pH 8.0 to 9.5 and a temperature of 53 degrees-55 degrees C. The heat of activation was found to be 4.6 X 10(6) cal/mol and the KM 1.2 X 10(-4) M. The esterase activity of older male rats (200-350 g) was significantly higher than that of the younger group (150-175 g). There was no significant difference in specific activity of hepatic meperidine esterase between male and female rats, and between rats fasted for 20 hr and phenobarbital- and benzopyrene-treated rats and their respective control groups. However, the liver weight and the microsomal protein yield per g of liver of fasted rats were significantly smaller, and those of phenobarbital- and benzopyrene-treated rats were significantly larger, than those of the control group. The overall enzyme activity per liver of phenobarbital- and of benzopyrene-treated rats was therefore significantly increased. The specific enzyme activities in microsomes prepared by ultracentrifugation and by calcium aggregation were not significantly different, although the ultracentrifugation method resulted in a higher yield of hepatic microsomal protein. The enzyme activities in microsomes prepared by ultracentrifugation/or calcium aggregation and frozen at -20 degrees C up to 22 days were not significantly different from those of freshly prepared microsomes. The enzymatic activity was inhibited by cocaine hydrochloride, isocarboxazid, neostigmine methyl sulfate, alpha-naphthyl acetate, p-nitrophenyl acetate, paraoxon, propoxyphene hydrochloride, phenelzine sulfate, physostigmine sulfate, SKF 525-A, tranylcypromine sulfate, fluoride ions, methanol, and ethanol.

Animals↗
PubMed1978

Sensitization to the generalized Shwartzman reaction by catechol-O-methyltransferase inhibitors.

The generalized Shwartzman reaction (GSR) was produced by a single injection of endotoxin in male rats pretreated with catechol-o-methyltransferase (COMT) inhibitors (tropolone, pyrogallol). Such a result was not obtained with inhibitors (pargyline, phenelzine, isocarboxazide) of the monoamine oxidase (MAO). The inhibitors of the COMT were found to enhance the action of endotoxin on the coagulation system such as evidenced by the increased consumptions of Hageman factor, fibrinogen, and platelets. Tropolone-treated rabbits did not require exogenous stimulation of alpha-adrenergic receptor sites by norepinephrine to localize thrombi in the glomerular capillaries when Hageman factor was activated by ellagic acid and fibrinolysis inhibited by epsilon-amino-caproic acid. It is concluded that interference with the degradation of circulating catecholamines results in sensitization to the generalized Shwartzman reaction.

Animals↗
PubMed1983

Inhibited female orgasm resulting from psychotropic drugs. A clinical review.

Female orgasm inhibition associated with psychotropic agents was reported ten years after the first report of ejaculatory disturbance in the male resulting from psychotropic drugs. To date, the psychotropic agents that have been reported to inhibit female orgasm include antipsychotic agents (thioridazine and trifluoperazine), monoamine oxidase inhibitors (phenelzine, isocarboxazid and tranylcypromine) and tricyclic antidepressants (amoxapine, clomipramine and amitriptyline). As awareness of this sexual side effect of psychotropic drugs grows, more drugs undoubtedly will be added to the list. Physicians should be alert to the underreporting of sexual side effects by female patients and should solicit such information from them.

Adult↗
PubMed1980

Drug-induced liver injury and microsomal arylamidase activity in needle biopsy of human liver.

The relation between the activities of arylamidase (one of the non-specific carboxylesterases) located exclusively in smooth endoplasmic reticulum (SER), and microscopical changes of the hepatocytes, was studied in three patients treated with phenobarbital and twenty-five patients injured by various other drugs. A micro-method was used for the determination of the enzyme activity in small pieces of liver (5-15 mg) obtained by needle biopsy. The arylamidase activity in seven normal livers was 0.43 +/- 0.05 (SD) nmol benzylhydrazine/micron protein/hr formed from isocarboxazid. The mean value in the livers treated with phenobarbital was statistically different from the value before phenobarbital treatment (P less than 0.05). Of sixteen cytotoxic type samples, seven showed low activity and eight high activity, respectively. Of the seven mixed-type samples, three showed mildly low activity and four normal activity. The frequency of the cytotoxic type is statistically different from that of the cholestatic (mixed and pure cholestatic) type comparing the abnormal activity with normal activity (P less than 0.05). The degree of enzyme activity was related to changes such as pyknosis, enlarged nuclei and centrilobular zonal necrosis. The ultrastructure of the material taken from three patients after phenobarbital treatment and one patient with ibuprofen-induced injury showed prominent increase and vesiculation of SER respectively. The study shows that drug-induced liver injury is closely related to the activity of SER, and that the changes in hepatocytes in cytotoxic type may result from the functional abnormality of SER.

Adult↗
PubMedDate not supplied

Species differences in the induction of hepatic microsomal carboxylesterases caused by dietary exposure to di(2-ethylhexyl)phthalate, a peroxisome proliferator.

The ability of di(2-ethylhexyl)phthalate (DEHP), a very widely used commercial plasticizer, to induce hepatic microsomal carboxylesterase isozymes in rats, mice (C5BL/6 and DBA/2 strains), and hamsters was studied by measuring hydrolase activities and by immunoblotting analysis using specific antibodies. Animals were given 2% (v/w) DEHP in the diet for 7 days. In rats, p-nitrophenyl acetate, isocarboxazid, and butanilicaine hydrolase activities and the contents of RL1, RL2, and RH1 in liver microsomes were all increased, but acetanilide hydrolase activity was not increased. In hamsters, the only significant change was a slight increase of butanilicaine hydrolase activity. In mice, butanilicaine hydrolase was strongly induced in both the C57BL/6 (7.35-fold) and DBA/2 (4.96-fold) strains. The anti-RL1 and RH1 antibody-reactive proteins in C57BL/6 mouse liver microsomes were increased, but the extent of induction was much less than that of butanilicaine hydrolase activity. The butanilicaine hydrolysis seems to be catalyzed by not only anti-RL1 reactive protein, but also some other carboxylesterase in C57BL/6 mouse. Anti-RL1 antibody inhibited the DEHP-induced butanilicaine hydrolase activity by > 50%. The results strongly suggest that multiple carboxylesterase isozymes were induced in mouse hepatic microsomes by dietary exposure to DEHP.

Animals↗
PubMed1993

[Drug treatment of anorexia nervosa and bulimia nervosa. A review].

With the apparent increase in prevalence of anorexic and bulimic eating disorders, the search for effective treatments for these disorders has been intensified in recent years. In this review the results of psychopharmacological studies of patients with anorexia or bulimia nervosa are presented and analysed. The focus of this review is on controlled studies. Although a variety of psychopharmacological substances has been tested in patients with anorexia nervosa, the outcome of controlled studies has been generally disappointing. A possible differential therapy effect of cyproheptadine needs replication: in one study it enhanced body weight gain in non-bulimic anorexics, while it appeared to hinder weight gain in bulimic anorexics. The issue of prophylaxis of osteoporosis in chronic low-weight anorexics has received increasing attention in recent years, and pharmacological prophylaxis appears indicated in this patient group. The results of psychopharmacological treatment studies of patients with bulimia nervosa have overall been more favourable than those of anorexic patients. Statistically significant effects concerning the reduction of bulimic or depressive symptoms in bulimia nervosa has been demonstrated for tricyclic antidepressants (imipramine, desipramine), serotonergic agents (fluoxetine, d-fenfluramine), non-selective monoamine-oxydase-inhibitors (isocarboxazide, phenelzine) and trazodone. The antibulimic effect appears not to be associated with the antidepressant effect. Theoretical, methodological and practical issues concerning pharmacological treatment of anorexic and bulimic eating disorders are presented and discussed.

Anorexia Nervosa↗
PubMed1993

Recent pharmacologic advances in antidepressant therapy for the elderly.

Major depression is a common, serious, and potentially life-threatening illness in the elderly. Moreover, this population is perhaps the most difficult to treat effectively and safely for this disease. Changes in physiology associated with advancing age produce clinically significant differences in drug metabolism and pharmacokinetics in these patients versus younger individuals. The elderly are also more likely than young patients to receive treatment for multiple illnesses. This fact increases the potential for serious pharmacodynamic and pharmacokinetic drug-drug interactions. The practicing clinician now has five distinct classes of antidepressant medications that may be used for treating depression in the elderly: tricyclic antidepressants (TCAs; e.g., desipramine, nortriptyline), monoamine oxidase inhibitors (MAOIs; e.g., isocarboxazid, tranylcypromine), selective serotonin reuptake inhibitors (SSRIs; i.e., fluoxetine, sertraline, and paroxetine), aminoketones (i.e., bupropion), and triazolopyridines (i.e., trazodone). Although all are effective antidepressants, the SSRI class may be the best choice for the treatment of elderly depressed patients, based on a number of considerations. SSRIs have a broad spectrum of antidepressant activity, being effective in different types of major depressive episodes (e.g., melancholic, atypical), have a wide therapeutic index, and are free of many potentially serious adverse effects associated with other antidepressants, such as central nervous system and cardiovascular toxicity (TCAs, bupropion), orthostatic hypotension (TCAs, MAOIs, and trazodone), and sedation (TCAs, trazodone). While SSRIs as a group share a common presumed mechanism of action, there are clinically important differences among the members of this class. First, the pharmacokinetics of sertraline are the same in both elderly and younger patients, whereas elderly, in comparison with younger, patients develop higher plasma levels of fluoxetine (and its active metabolite, norfluoxetine) or paroxetine, when given the same dose. Second, the SSRIs differ in their potential for pharmacokinetic interactions with other psychotropic and nonpsychotropic drugs. Fluoxetine, norfluoxetine (the major metabolite of fluoxetine), and paroxetine are potent inhibitors of the hepatic isoenzyme P450 IID6, whereas sertraline has much weaker inhibitory effects on its activity. Inhibition of P450 isoenzymes can cause potentially dangerous increases in the plasma levels of a large number of drugs, including TCAs, neuroleptics, and mood stabilizers, such as carbamazepine. Thus, sertraline has several characteristics that offer advantages over other members of this class of antidepressants for the treatment of the elderly patient with major depression.

Age Factors↗
PubMedDate not supplied

[Pharmacologic treatment of bulimia].

The rationale for pharmacological treatment of bulimia nervosa is summarized and a review of controlled therapeutic trials shows contradictory results. A number of antidepressant agents (tricyclics: imipramine, desipramine, amitriptyline; IMAO: phenelzine, isocarboxazide; trazodone; fluoxetine) appear more effective than placebo in double-blind controlled trials of 6 to 16 weeks. In similar studies, other antidepressants (mianserine, fluvoxamine) are ineffective. Improvement reported is often incomplete and the low percentage of patients totally abstinent at the end of treatment appears of poor pronostic value for long-term outcome. Methodological limitations of existing studies are discussed, and some psychopathological factors to consider in the assessment of therapeutic response are proposed.

Antidepressive Agents↗
PubMed1996

Modulation of [3H]quinpirole binding in brain by monoamine oxidase inhibitors: evidence for a potential novel binding site.

[3H]Quinpirole is a dopamine agonist with high affinity for the D2 and D3 dopamine receptor subtypes. A variety of drugs, most notably monoamine oxidase inhibitors (MAOls), inhibit the binding of [3H]quinpirole, but not [3H]spiperone or [3H](-)N-n-Propylnorapomorphine, in rat striatal membranes by a mechanism that does not appear to involve the enzymatic activity of MAO. This study extends the characterization of MAOI-displaceable [3H]quinpirole binding in rat brain. Clinically antidepressant MAOIs exhibited selectivity between sites labeled by [3H]quinpirole and [3H]spiperone as did a number of structurally related propargylamines and N-acylethylenediamine derivatives and other drugs such as debrisoquin and phenylbiguanide. The MAOIs clorgyline and Ro 41-1049 were the most potent. Anti-depressant MAOIs inhibited [3H]quinpirole binding with the following rank order of potency: phenelzine > pargyline > tranyl-cypromine > isocarboxazid > nialamide > moclobemide. In striatal membranes, MAOI Ro 41-1049 inhibited [3H]quinpirole binding with similar potency at a variety of incubation temperatures (4-37 degrees C), assay tissue concentrations (5-20 mg original wet weight/ml), and time points (2 min-4 hr) and in the presence or absence of K+, Mg2+, Ca2+ ions, ascorbate, EDTA and NaCl. The regional distribution of Ro 41-1049-displaceable [3H]quinpirole binding in brain paralleled that of D2-like receptors. These data suggest that MAOIs interact with a novel binding site that is labeled by [3H]quinpirole or that modulates [3H]quinpirole binding. This site may be associated with D2-like dopamine receptors.

Animals↗