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PubMed1982

To the pharmacological profile of maprotiline.

Experimental EEG study of sleep-vigil cycles in rats with implanted brain electrodes showed that maprotiline has lower inhibitory effects on the REM sleep, sleep onset and mean duration of sleep cycles than imipramine. Maprotiline reveals significantly lower cardiotoxicity than imipramine and amitriptyline in the test on chick embryo heart. Embryotoxicity risk, evaluated on chick embryo by the method CHEST is significantly lower in maprotiline than in imipramine, nortriptyline and amitriptyline.

Abnormalities, Drug-Induced↗

PubMed1982

[Drug hydroxylation disorders (debrisoquin type) in a random sample of the Swiss population].

The hydroxylation phenotype was determined in a sample of the Swiss population consisting of 222 normal unrelated subjects (131 women, 91 men). Following oral administration of a single dose of 19 mg debrisoquine, urine was collected for 8 hours. Urinary concentrations of parent compound and its major metabolite (4-hydroxydebrisoquine) were measured with GLC and their molar ratio ("metabolic ratio", MR) was calculated and plotted as a frequency distribution histogram. The frequency distribution of the MR was clearly bimodal, exhibiting two clusters of MR's of 0.1 to 1.0 and 20 to 100, respectively. Using probit analysis, the antimode was found at an MR of 12.6 Consequently, 22 subjects (16 women, 6 men), representing 10% of the population studied, were, with an MR of greater than 12.6, considered to be poor hydroxylators (PM). The families of two subjects, established as PMs in the population study, were also investigated. One family was found to be the first known pairing of homozygous PM parents with all 6 offspring exhibiting the PM phenotype. In both families the pattern was consistent with an autosomal recessive mode of inheritance for the two alleles E (extensive) and N (none) respectively. Clinical consequences of the PM phenotype known to date are summarized. Since some drugs typically used for longterm treatment (such as perhexiline, phenytoin, nortriptyline, guanoxan) are subject to the same hydroxylation pathway, PM patients are likely to be at higher risk of drug toxicity. This relationship has been well documented for perhexiline-induced neuropathy. Conversely, it is conceivable that with the use of prodrugs which have to be hydroxylated to the active compound, PM subjects might turn out to be "non-responders".

Adolescent↗

PubMed1980

[Neurochemical and electroencephalographical studies on the central actions of mianserin (author's transl)].

A new antidepressant, mianserin (GB-94, Organon), and other known antidepressants, imipramine (IMP), desipramine (DPM), chlorimipramine (CIP), amitriptyline (ATP) and nortriptyline (NTP) were orally administered to respective groups of 25 mice for consecutive weeks, and changes in monoamine metabolisms in the brain were investigated, neurochemically. On the basis of significant difference from the control group, mianserin 20 mg/kg and DPM 20 mg/kg produced no change of the brain contents of DA and 5-HT; IMP 50 mg/kg and CIP 40 mg/kg did not alter NA and DA values, but did decrease 5-HT levels; ATP 30 mg/kg increased only the amount of NA, left unchanged the DA and 5-HT levels, and NTP 20 mg/kg raised the levels of DA and 5-HT, but had no effect on NA. Mianserin, IMP and DPM all facilitated the decrease of both NE and DA as induced by pre-administration of alpha-methyltyrosine, the substance known to reduce the level of catecholamines. Both NTP and CTP showed no notable effect. ATP suppressed the reduction of the DA level. Accumulation of 5-HIAA induced 1 hour after treatment with probenecid 250 mg/kg was enhanced by mianserin 20 mg/kg, NTP 20/kg and IMP 25 mg/kg, but was not significantly affected by CIP, DPM and ATP. These results suggest that mianserin activated both the NE and 5-HT metabolic systems, IMP activated the NE system in general, but activated the 5-HT system only at low doses and tended to suppress the formation of 5-HT, in high doses; CIP had no effect on the NE system and suppressed 5-HT system, in high doses. The arousal response of hippocampal EEG in the chronic EEG of the rabbit, induced by physostigmine 0.05 mg/kg, i.v., was suppressed by IMP, ATP and CIP, while DMP and NTP were uneffected. Mianserin, rather maintained and prolong the arousal reaction. Observations made on arousal and sleep phases in long time recording of chronic spontaneous EEG in the rat showed a dose-dependent shortening of the para-sleep phase by mianserin in doses over 30 mg/kg and IMP in doses over 5 mg/kg. ATP 15 mg/kg showed a tendency to shorten the para-sleep. Hippocampal and cerebral cortical EEGs at arousal and slow wave stages were analyzed using a signal processor. The power spectra thus obtained showed no significant difference between the effects of mianserin and IMP.

Amines↗

PubMed1980

The effect of dibenzazepines (tricyclic antidepressants) on cerebral capillary permeability in the rat in vivo.

The degree of equilibration of [3H]water across the cerebral capillary was evaluated by measuring its cerebral extraction fraction (Ew) by using a dual label radioactive tracer technique. All tricyclic antidepressants (125 mumol/kg i.p. at 5 min) increased Ew as compared to base line. The rank order of the drugs in producing this response was doxepin greater than amitriptyline greater than imipramine greater than nortriptyline greater than desmethylimipramine greater than protriptyline. The effect of amitriptyline, the prototype tricyclic for this study, was rapid in onset (maximal effect within 5 min), reversible (duration 15 min), dose-dependent and generalized throughout the brain. Amitriptyline also induced a marked increase in the cerebral extraction fraction of [3H]ethanol. A difference in the time course of the drug effect on these two tracers indicated that the elevation in E was due to the increase in cerebral capillary permeability to both polar and lipid soluble substances. This work demonstrates that tricyclic antidepressants have important central effects on non-neuronal tissue.

Amitriptyline↗

PubMed1980

Clomipramine: plasma levels, side effects and outcome in obsessive-compulsive neurosis.

The relationship between plasma levels of clomipramine and desmethylclomipramine and clinical response was studied in a group of patients with obsessive-compulsive neurosis. In general the response was best in the middle range of plasma concentrations, showing the inverted U curve well recognized with nortriptyline. However, the results of this study suggest that the response of compulsive rituals correlates with levels of plasma clomipramine, while depression appears to correlate with plasma levels of desmethylclomipramine. The former relationship may be the stronger. There may also be some relationship between side effects and relative plasma levels of clomipramine and desmethylclomipramine.

Adolescent↗

PubMed1995

Acute treatment with antidepressant drugs selectively increases the expression of c-fos in the rat brain.

Rats were treated acutely, ip, with saline vehicle or an antidepressant: iprindole (15 mg/kg), nortriptyline (15 mg/kg), A75200 (10 mg/kg), fluoxetine (15 mg/kg), desipramine (10 mg/kg), bupropion (20 mg/kg) or tranylcypromine (7.5 mg/kg). Mapping the neuroanatomical distribution at 64 sites of the immediate early gene, c-fos revealed several patterns: first, increased counts of Fos-like neurons were found in all but one instance; second, drugs which had dopaminergic effects (bupropion and tranylcypromine) were more likely to potentiate c-fos reactivity than were the other drugs; third, Fos-like counts were more likely to be significantly elevated in structures bordering brain ventricles; fourth, only in the central amygdala were the Fos-like counts higher in all seven drug groups relative to the saline group. It remains to be seen whether or not this shared substrate is therapeutically significant.

Amygdala↗

PubMedDate not supplied

Deafferentation pain exacerbated by subarachnoid lidocaine and relieved by subarachnoid morphine. Case report.

BACKGROUND AND OBJECTIVES: Neuropathic pain syndromes are often resistant to traditional pharmacologic treatment. The authors describe a patient with chronic deafferentation pain of the legs associated with peripheral neuropathy that was refractory to multidisciplinary pain clinic management. METHODS: Numerous medications had been tried, including nortriptyline, mexiletine, and oral and parenteral opioids. Spinal cord stimulation was also ineffective, despite a satisfactory pattern of stimulation-induced paresthesias. For diagnostic purposes, differential spinal anesthesia with lidocaine and morphine was performed, with evoked potential monitoring used to evaluate the intensity of spinal anesthetic block. RESULTS: Paradoxically, lidocaine spinal anesthesia exacerbated pain, whereas subarachnoid morphine provided rapid pain relief. Long-term pain control has been maintained with an implanted spinal infusion pump. CONCLUSIONS: Evoked potential data acquired during lidocaine spinal anesthesia and the rapid pain relief provided by subarachnoid morphine suggest that deafferentation pain may involve segmental, opioid-sensitive dorsal horn pain generators. The long-term pain relief afforded the patient demonstrates that subarachnoid opioids may be efficacious for some forms of neuropathic pain.

Adult↗

PubMedDate not supplied

Tissue distribution and metabolism of amitriptyline after repeated administration in rats.

Plasma concentration, tissue distribution, and metabolism of amitriptyline (AMI) in rats pretreated with AMI (20 mg/kg/day, ip dose, for 7 days; treated) were compared with control rats. Plasma concentrations of AMI after intravenous administration (2 and 10 mg/kg) to the treated rat were significantly higher than those to the control rat in both doses. The difference in the plasma concentration between both groups may be caused by a change of tissue distribution of AMI, because the blood cell-to-plasma concentration ratio and the tissue-to-blood concentration ratio values for various tissues in the treated rat were smaller than those in the control, respectively. The plasma unbound fraction of AMI in the treated rat was significantly smaller (p < 0.05). alpha 1-Acid glycoprotein concentration in plasma of the treated rat was approximately twice that in the control rat. These results suggest that the decrease of tissue distribution of AMI in the treated rat may be caused by the decrease in the plasma unbound fraction of AMI with the increase of alpha 1-acid glycoprotein in plasma. The area under the plasma concentration-time curve for AMI and its main metabolite, nortriptyline, in the treated rat after intraportal administration of AMI was 1/3 and 3-fold those in the control rats, respectively. On the other hand, the hepatic intrinsic clearance (CLH,Int) of the unbound drug in the treated rat was approximately twice that of the control, suggesting that the increase of the (CLH,Int) by repeated administration of AMI may result in the induction of oxidative metabolism.

Amitriptyline↗

PubMedDate not supplied

[Effects of antidepressants on cognitive functions. Review of the literature].

In this review the authors propose to study the impact of antidepressants on attention, memory and motor functions in healthy volunteers and depressed patients on single and long-term administration. After reviewing the principal cognitive functions, we examine the actual investigation means to conclude that the Critical Flicker Fusion Test (CFFT) is one of the most drug-sensitive tests. It permits a categorization in: sedative antidepressants that in single administration lower CFFT; compounds with no effect on CFFT and no deleterious cognitive effect; and finally substances that raise CFFT and may have psychostimulating properties. On single administration amitriptyline is the most sedative antidepressant on attention or motor level. It seems to produce negative effects on memory level. However, experimental trials give contradictory results. Imipramine in single administration also has sedative effects on memory and car driving capacity. However divergent results of experimental trials do not allow any conclusions of a clearcut negative cognitive effect. Memory impairments with imipramine appear at administration levels of 150 mg. Mianserin has a sedative impact on attention and motor level at low doses (10 mg). Among the tricyclics, nortriptyline has a highly dose dependent sedative effect that has been shown on attention tests (Time Reaction:TR, Digit Symbol Substitution Test: DSST). Among non-tricyclic compounds, doxepine lowers attention and motor performances. Maprotiline (75 mg) lowers CFFT and has a dose dependent effect. Trazodone also has a negative impact on attention tests. Finally viloxazine lowers CFFT but does not impair other attention or motor tests on a 100 mg doses. Buspirone, lofepramine, midalcipran and zimelidine are antidepressants with no effect on CFFT and do not have any positive or negative cognitive effect. On the other hand nomifensine, paroxetine and fluoxetine raise CFFT in healthy volunteers on single administration. Improvement of CFFT performances was found in an isolated manner for nomifensine and paroxetine on 30 mg doses with no other memory or motor effects. MAO-Inhibitors do not impair attention or motor function; thus moclobemide has no negative impact on memory, attention or car driving tests. Cognitive impact of antidepressants in depressive patients seems the same with those of healthy volunteers on single administration. In long-term administration antidepressants have different effects in healthy and depressed subjects. In healthy volunteers cognitive effects of most compounds are normalized after the second week of treatment. However, attention and motor performances with amitriptyline are normalized after 3 weeks of treatment. Sedative motor or cognitive effects of imipramine do not exceed 8 days.(ABSTRACT TRUNCATED AT 400 WORDS)

Antidepressive Agents↗

PubMed1994

Depression in the elderly.

Depression is a common psychiatric problem in old age. The magnitude of the problem will become greater as this segment of the population grows. Depression is often overlooked in the elderly, contributing to a greater risk of suicide in this group than in younger patients. Depression may be masked by hypochondriasis or somatization. Special problems in diagnosis include bipolar disorder, pseudodementia, pathological grief, and organic mood disorder as related to medications or physical illness. Pharmacokinetic changes with aging need to be kept in mind by physicians treating the elderly with antidepressant medications. Tricyclic antidepressants are the traditional first line pharmacologic agents. Tricyclics with a low side effect profile, such as desipramine or nortriptyline, are generally preferred. However, newer medications including serotonin reuptake inhibitors and bupropion are becoming more widely used. Other medications, including monoamine oxidase inhibitors, lithium, and stimulants, also have a place in the treatment of depression in old age. Electroconvulsive therapy is a useful treatment for patients with treatment-resistant or psychotic depression. Psychotherapy in the elderly has not been well studied, but is believed to be effective if patients are properly selected for therapy and appropriate modifications are made.

Aged↗

PubMed1993

[Indications for antidepressive agents in relation to diseases of the cardiovascular system].

Antidepressants, in particular tricyclic ones (TCA), and inhibitors of monoaminooxidase (IMAO) exert a number of undesirable cardiovascular effects. TCA and IMAO frequently cause postural hypotension (PH). IMAO administration is associated with the risk of hypertensive crisis. TCA raises the heart rate and can cause abnormalities in the conduction of the cardiac excitation. TCA are contraindicated after myocardial infarction and are the cause of death after overdosage. When PH is undesirable, in hypertension and cardiac insufficiency the following safe antidepressants are recommended: nortriptyline, mianserine, trazodone and viloxazine. In abnormalities of conduction of the cardiac excitation and after myocardial infarction only mianserine, trazodione and viloxazine are recommended. With regard to cardiovascular toxicity, antidepressants from the series of selective inhibitors of serotonin reabsorption are very promising: fluvoxamine, fluoxetine, citalopram, paroxetine and sertraline. The same applies also to the reversible IMAO type A moclobemide.

Antidepressive Agents↗

PubMed1993

[Therapeutic drug monitoring with the help of serum concentration measurements. How are the analytic results distributed in a population?].

Therapeutic drug monitoring includes measurement of serum concentrations of drugs when this is possible and appropriate. A therapeutic range is defined for populations where the serum levels represent an optimal relationship between clinical effects and side effects for most of the individuals in the population. Compared with the rest of the population, some individuals are atypical, both with respect to response to and elimination of drugs. Therapeutic drug monitoring makes individualization of dosages in these individuals easier, but often requires extra effort. Compilation of serum level measurements for different drugs for a period of six months showed that the tailoring of digitoxin, carbamazepine, lithium and phenobarbital is as close to optimal as can be expected for a population. For amitriptyline, digoxin and theophylline, a considerable increase in clinical effect within a population of users could probably be achieved by bringing more individual serum levels from the subtherapeutic into the therapeutic range. Nor does the therapeutic potential of phenytoin, nortriptyline and valproate seem to be fully utilized.

Blood Chemical Analysis↗

PubMed1993

Interaction of tricyclic drug analogs with synaptic plasma membranes: structure-mechanism relationships in inhibition of neuronal Na+/K(+)-ATPase activity.

Perturbations of rat brain synaptic plasma membrane (SPM) bilayer structure and Na+/K(+)-ATPase activity were correlated for drugs that are structurally related and exhibit similar toxicological side effects but belong to different pharmacological classes. Na+/K(+)-ATPase IC50 values decrease linearly with increasing octanol/water partition coefficients (log-log plot) for a series of dimethylethylamine-containing drugs (i.e., chlorpromazine, amitriptyline, imipramine, doxepin, and diphenhydramine), emphasizing hydrophobicity in inhibition. However, nortriptyline and desipramine are 1.2 log units less hydrophobic than their N-methylated parent drugs but more potent inhibitors. To investigate this, bilayer surface structure was examined by the binding of the fluorophore 1-anilinonaphthalene-8-sulfonic acid (ANS) to SPMs. The dissociation constant and wavelength maximum of ANS are invariant with drug binding; however, the limiting fluorescence intensity of ANS (F infinity) is increased. Such data indicate that these cationic drugs bind to the membrane surface, increasing the number but not the polarity of ANS binding sites by cancelling charge at anionic phospholipid groups. More importantly, there is a close linear correlation between the concentrations of drugs necessary to increase F infinity by 40% and the IC50 values, with full compensation for the N-demethylated drugs. This correlation implies that drug-induced increases in SPM-bound ANS fluorescence are a better predictor of Na+/K(+)-ATPase inhibition than are octanol/water partition coefficients and that electrostatic interactions are also involved in inhibition. Furthermore, it points toward similar mechanisms of biomembrane surface interaction governing both inhibition and fluorescence change that are common to these drugs. K(+)-dependent p-nitrophenylphosphatase activity is inhibited with the same potency as Na+/K(+)-ATPase activity, indicating that inhibition may involve drug interaction near the K+ binding sites. Furthermore, chlorpromazine, diphenhydramine, and dimethylaminopropyl chloride alter K(+)-activation of K(+)-dependent p-nitrophenylphosphatase, progressing from noncompetitive through mixed to competitive inhibition as their hydrophobicity changes, and these mechanisms are consistent with steric hindrance of K+ binding. In contrast to the ANS data, decreases in 1,6-diphenyl-1,3,5-hexatriene fluorescence anisotropy induced by these drugs do not correlate with Na+/K(+)-ATPase inhibition, and drug N-demethylation enhances inhibition without altering anisotropy; both findings indicate that Na+/K(+)-ATPase activity is not predominantly influenced by changes in bulk fluidity. Taken together, these data suggest that electrostatic interactions at the biomembrane surface between the protonated amino group of the drug and anionic groups on the enzyme and/or phospholipids near the K+binding sites are crucial to inhibition and that drug hydrophobicity modulated the number and orientation of these interactions.

Animals↗

PubMed1993

Review of the cardiovascular effects of heterocyclic antidepressants.

We review the effects of heterocyclic antidepressant compounds on the cardiovascular system. It has been shown that tricyclic antidepressants (TCAs) slow intraventricular conduction, and this can be seen on a standard ECG as the increased QRS, PR, and QTc intervals. This prolonged conduction is dangerous to patients in two conditions. In overdose, delayed conduction may lead to a complete heart block or ventricular reentry arrhythmias. Either of these complications, or a combination of both, may lead to death. When treated with TCAs at therapeutic plasma levels, depressed patients with preexisting conduction disease, particularly bundle-branch block, are at higher risk to develop symptomatic A-V block than depressed patients free of conduction disorders. Clinically, the effects of TCAs on conduction does not differ significantly within the family of drugs. Who gets complications is much more a function of severity of the patient's preexisting cardiac condition. The most common cardiovascular effect of TCAs is orthostatic hypotension. Postural hypotension is more dangerous in elderly patients because it may lead to falls that cause serious physical injuries. Severe orthostatic hypotension is more likely to develop in depressed patients with left ventricular impairment and/or in patients taking other drugs like diuretics or vasodilators. Nortriptyline has been shown to cause significantly less serious postural blood pressure drops, an important difference between this drug and other TCAs. Another cardiovascular effect of TCAs is that they reduce ventricular arrhythmias. They share this property with Type 1A antiarrhythmic compounds, and a variety of Type 1 antiarrhythmics have recently been shown to increase mortality in postmyocardial infarction patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Amoxapine↗

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↗

PubMed1977

Simultaneous measurement of secondary and tertiary tricyclic antidepressants by GC/MS chemical ionization mass fragmentography.

We present a method for measuring seven commonly used tricyclic antidepressants in plasma. This method is suitable for monitoring therapeutic concentrations and for screening drug overdoses in cases where the identity of the abused tricyclic antidepressant may not be known. Drugs from alkalinized plasma are extracted into hexane in one step; two injections into the gas chromatograph/mass spectrometer follow. The tertiary amines (amitriptyline, doxepin, and imipramine) are analyzed by direct injection; the secondary amines (nortriptyline, desmethyldoxepin, desipramine, and protriptyline) are analyzed after derivitization with trifluoroacetic anhydride. Clomipramine and desmethyltrimipramine are suitable internal standards. Chemical ionization mass fragmentography, with methane as the reactant gas, is used. While maintaining specificity for these drugs, concentrations in human plasma ranging from 5 to 500 microng/liter can be measured. The coefficients of variation are about 4 to 11%.

Antidepressive Agents, Tricyclic↗

PubMed1996

Efficacy and tolerability of antidepressant therapy in the old-old.

As the number of elderly increases worldwide, there will be a concurrent increase in the absolute number of people over 70 years of age who suffer from major depressive disorders. There is a paucity of research in this old-old population, although each of the following drugs has been studied in at least one clinical drug trial: amitriptyline, bupropion, dothiepin, fluoxetine, mianserin, nortriptyline, paroxetine, and sertraline. The results to date, though limited, suggest similar efficacy and greater tolerability of serotonin selective reuptake inhibitors compared with tricyclic antidepressants in the elderly.

Age Factors↗

PubMed1977

Therapeutic monitoring of tricyclic antidepressants in plasma by gas chromatography.

We describe a comprehensive gas chromatographic analysis for therapeutic concentrations of amitriptyline, nortriptyline, imipramine, desipramine, doxepin, and desmethyldoxepin in plasma, with use of a nitrogen detector. All these drugs are extracted and chromatographed under identical conditions. Each tertiary amine tricyclic is well resolved from its secondary amine metabolite on a mixed-phase column and the concentrations of both are determined simultaneously, without derivatization. The lower limit of sensitivity is 10 microgram/liter of plasma (2-ml sample). Analytical recoveries of the tertiary and secondary amines are 100 and 80%, respectively. Between-run CV's for all of the drugs ranged between 5 and 7%.

Antidepressive Agents, Tricyclic↗