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PubMed1997

In pursuit of drugs for American trypanosomiasis: evaluation of some "standards" in a mouse model.

Forty-nine "standard" compounds known to be useful in the treatment of other diseases were tested for their suppressive activity against the trypomastigotes of Trypanosoma cruzi-infected mice. The most active was the antidepressant protriptyline, which was almost three times as effective as the reference drug, nifurtimox. A major value of the present data is to demonstrate the refractoriness of the T. cruzi parasite against many of the drug standards that have known biological activity.

Animals↗

PubMed1985

Undiagnosed sleep apnea in patients with essential hypertension.

The prevalence of sleep apnea was studied in 46 middle- and older-aged men with "essential hypertension." Thirty-four age- and weight-similar normotensive men were also studied. Fourteen hypertensive men and three controls had sleep apnea syndrome, as defined as greater than ten apneas per hour of sleep. Hypertensive men with apnea tended to be more overweight and slightly older than the hypertensive men without apnea, but differences were not statistically significant. Individual men with apnea could not be distinguished by their answers on a questionnaire that elicited symptoms related to apnea. Seven hypertensive men with apnea were treated with protriptyline and one with uvulopalatopharyngoplasty, and apnea index (apneas per hour) decreased by 77% from pretreatment levels while mean blood pressure decreased from 149/95 mm Hg to 139/90 mm Hg. Undiagnosed sleep apnea syndrome may be associated with systemic hypertension in many middle- and older-aged men. In some, sleep apnea syndrome could be the cause of hypertension, and in others it may contribute to hypertension of another cause.

Adult↗

PubMed1986

Bethanechol chloride can reverse erectile and ejaculatory dysfunction induced by tricyclic antidepressants and mazindol: case report.

A 43-year-old man who experienced profound dose-related erectile and ejaculatory dysfunction without loss of libido on three separate antidepressants and on the anorectic agent mazindol is described. Bethanechol chloride 20 mg p.o., taken 1 to 2 hours prior to sexual activity, permitted satisfactory erection and ejaculation during sexual intercourse, while the patient continued to take protriptyline or mazindol. Bethanechol chloride may prove to be of use in treating sexual dysfunction associated with drugs or conditions which increase sympathetic tone.

Adult↗

PubMed1979

The effect of tricyclic antidepressants on cerebral fluid dynamics.

Tricyclic antidepressants are thought to act primarily via effects on adrenergic neurotransmitters. Recent research supports the concept that a major function of the central adrenergic system is the modulation of cerebral fluid dynamics. Based on this concept, studies in the rat were conducted to assess the effects of these drugs on cerebral capillary permeability and flow by quantitating changes in the extraction fraction of water (Ew). Amitriptyline and nortriptyline produced significant increased in Ew for the total forebrain (from control values of 0.67 to experimental values as high as 0.99) while protriptyline had no effect on Ew. The amitriptyline-induced increase in Ew occurred at doses which produced plasma levels (500 ng/ml) near the range defined as therapeutic in depression studies. The magnitude of the effect was similar for both amitriptyline and nortriptyline representing a 35--40% increase over control values. The effects were uniformly observed throughout the forebrain: rostral telencephalon, caudal telencephalon, and diencephalon.

Amitriptyline↗

PubMed1979

Plasma levels of tricyclic antidepressants and clinical efficacy: review of the literature -- part II.

The authors have critically reviewed the literature regarding the relationship between plasma levels of tricyclic antidepressant and their clinical efficacy. When available, drug-drug interactions, pharmacokinetics, and other factors influencing plasma levels of tricyclic antidepressants are discussed. Although many studies are confounded by significant methodological and statistical problems, it appears to these reviews that the available evidence suggests a curvilinear relationship between nortriptyline plasma levels and antidepressant efficacy in tricyclic responsive endogenously depressed inpatients, with maximal therapeutic efficacy achieved with notriptyline plasma levels between 50-175 ng/ml. The evidence for imipramine supports a linear relationship between plasma levels of imipramine plus desmethylimipramine and clinical response in nondelusional endogenously depressed tricyclic responsive inpatients. For amitriptyline, the picture is less clear. However, with the exception of one well-controlled study, the available evidence suppprts some significant relationship between amitriptyline plus nortriptyline plasma levels and antidepressant efficacy in tricyclic respoonsive endogenously depressed patients, but it is not clear as to whether this is a linear relationship or a curvilinear one. For the other antidepressants: protriptyline, desmethylimipramine, doxepin, clomipramine, maprotiline, and butriptyline, a significant relationship (if any) awaits further elucidation. It is important to point out that these plasma level relationships probably do no generalize to other types of depressions (e.g. neurotic, characterological, delusional, acute situationa, etc.) and clearly do not apply to every endogenous tricyclic responsive patient. /owever, it appears that, in general, a clinician will obtain therapeutic efficacy for endogenously depressed patients if these guidelines are followed. The actual therapeutic levels will depend on the assay's sensitivity and specificity and may vary from center to center, illustrates the importance of each center defining its own therapeutic limits, or conversely all centers adoptina a universal reproducible assay methodology for each compound measured. Despite these limitations, these reviewers feel that routine monitoring of plasma levels of the tricyclic antidepressants is a useful method to maximize therapeutic efficacy and prvent undue side effects, as well as to insure good medication compliance.

Antidepressive Agents, Tricyclic↗

PubMedDate not supplied

Metabolism of rat brain phospholipids after prolonged treatment with psychotropic drugs.

Adult and newborn rats were treated with psychotropic drugs: neuroleptics (fluphenazine, benperidol, pimozide, thiotixen), an ataractic (oxazepam) and an anti-depressant (protriptyline) for periods up to one year or longer. The body weight was monitored, and brain weight, total cerebral lipid content, content of individual phospholipids, incorporation of 32P into individual phospholipids, and the fatty acids composition of phosphatidylethanolamine were measured. The prolonged treatment with neuroleptics and an antidepressant, but not with oxazepam, produced profound, often biphasic or multiphasic changes in the biochemistry of phospholipids. These changes should be taken into account in discussion of the mechanism of action and side-effects of prolonged treatment with antidepressants and neuroleptics.

Animals↗

PubMedDate not supplied

L-tryptophan in the treatment of impaired respiration in sleep.

15 subjects (mean age: 48.2 yr; 13 males, 2 females) with sleep apnea (12 obstructive, 3 central) were treated with an average dose of 2500 mg L-tryptophan (L-T) at bedtime. Comparison of pre- and post-drug polysomnograms showed significant improvement in obstructive sleep apnea but not with central sleep apnea. Most dramatic improvement is seen in subjects with obstructive sleep apnea in non-REM sleep only, but severity of apnea appears to be the most important factor determining improvement. L-T increased REM time and shortened REM latency but had no other significant effects on sleep architecture. Serotoninergic activity with a defect in feedback control of tryptophan-serotonin metabolism is postulated as a potential mechanism in the pathophysiology of obstructive sleep apnea. The enhanced usefulness of L-T in combination with protriptyline is predicted based on early preliminary work at the OSU Sleep Center. The Potential influence of dietary intake on respiratory automaticity is reviewed.

Clinical Trials as Topic↗

PubMed1980

Sleep-induced ventilatory dysfunction in Down's syndrome.

Three patients with Down's syndrome demonstrated severe sleep-induced ventilatory failure characterized by Cheyne-Stokes respiration with superimposed obstruction of the upper airway. Anatomic otolaryngologic factors were present in two of the three patients, implicating both mechanical and CNS factors in the pathogenesis of this phenomenon. Administration of protriptyline hydrochloride elicited considerable improvement in one case. Occult sleep-related ventilatory failure may account for the previously unexplained tendency for pulmonary hypertension to develop in patients with Down's syndrome.

Adolescent↗

PubMed1981

Liquid-chromatographic analysis for common tricyclic antidepressant drugs and their metabolites in serum or plasma with the technicon "FAST-LC" system.

We describe a single procedure for assay of seven tricyclic antidepressant drugs and metabolites in serum or plasma: protriptyline, nortriptyline, amitriptyline, desmethyldoxepin, doxepin, desipramine, and imipramine. With the Technicon "FAST-LC" system, samples are aspirated directly into the unit and pretreated via double extraction; the concentration of each drug is then determined by "high-performance" liquid chromatography. Final chromatograms are monitored at 205 nm, at analysis rates of 7.5 samples/h. Concentration and absorbance are linearly related for each drug from 0 to 1400 micrograms/L. Day-to-day CVs averaged 5 to 6% for each drug, and there is good correlation of FAST-LC values with those obtained by gas-chromatographic methods. Total sample volume is 750 microliters.

Amitriptyline↗

PubMed1976

Structure-activity relationships among desmethyl derivatives of neuroleptics and antidepressants for substrate specificty to indolethylamine N-methyltransferase from rabbit lung.

Desmethylperazine (norperazine) and desmethylprochlorperazine (norprochlorperazine), like nor1- and nor2chlorpromazine, are excellent substrates for indolethylamine N-methyltransferase (NMT) and also inhibit the formation of dimethyltryptamine (DMT) from N-methyl-tryptamine (NMT). Nortriptyline and protriptyline, antidepressant compounds which like NMT contain a secondary amino group, also serve as substrates for INMT but lack in inhibitory effect on DMT formation.

Animals↗

PubMed2002

Drug treatments for obstructive sleep apnoea.

BACKGROUND: The treatment of choice for moderate to severe obstructive sleep apnoea (OSA) is continuous positive airway pressure (CPAP) via a mask during sleep. However this is not tolerated by all patients and its role in mild OSA is not proven. Drug therapy has been proposed as an alternative to CPAP in some patients with mild to moderate sleep apnoea. The mechanisms by which drugs might reduce OSA include; a reduction in the proportion of rapid eye movement (REM) sleep (during which apnoeas tend to be more frequent), an increase in ventilatory drive or an increase in upper airway muscle tone during sleep. OBJECTIVES: To determine the efficacy of drug therapies in the treatment of sleep apnoea. SEARCH STRATEGY: Searches were carried out on the Cochrane Airways Group RCT Register. Additional hand searching was performed as relevant. SELECTION CRITERIA: Double blind, randomised placebo controlled trials were included, involving patients with confirmed obstructive sleep apnoea. Trials were excluded if continuous positive airways pressure, mandibular devices or oxygen therapy were used. No restriction was placed upon publication language or trial duration. DATA COLLECTION AND ANALYSIS: A total of 51 references were identified by electronic searches. 42 studies were retrieved for selection and 9 trials were included in the review. The results for 91 patients were available. No response for further information was forthcoming from the study authors. Results were expressed as (WMD) and 95% Confidence Intervals (95% CI) MAIN RESULTS: Only acetazolamide reduced the Hypopnoea Index (1 crossover trial of 9 patients, Weighted Mean Difference -24; 95%Confidence Intervals (95% CI): -4, -44). However there was no symptomatic response and the drug was poorly tolerated. Protriptyline led to a symptomatic improvement (improved vs not improved) in two out of three crossover trials (13 patients, Peto Odds Ratio 29.2; 95%CI 2.8, 301.1) but there was no change in the apnoea frequency. No beneficial effects were found for medroxy progesterone, clonidine, buspirone, aminophylline, theophylline or sabeluzole. REVIEWER'S CONCLUSIONS: The data available do not support the use of drugs as a therapy for OSA. Although the studies examined had limitations there was little to justify further trials of these particular drugs.

Humans↗

PubMed1997

Capillary electrophoretic separation of tricyclic antidepressants using charged carboxymethyl-beta-cyclodextrin as a buffer additive.

Charged carboxymethyl-beta-cyclodextrin was successful in the capillary electrophoretic separation of a series of tricyclic antidepressants. The cyclodextrin alone was successful in the separation of carbamazepine, protriptyline, desipramine, clomipramine, and opipramol using a 3-(trimethoxysilyl)propyl methacrylate capillary coating to reduce the electroosmotic flow. The ideal buffer pH was found to be in the range of 6-7 and the ideal cyclodextrin concentration to be 10 mM. All nine antidepressants were resolved using the charged cyclodextrin in the micellar electrokinetic chromatography (MEKC) mode with sodium dodecyl sulfate as the surfactant. Neither the cyclodextrin nor the surfactant alone were successful in resolving the whole series of compounds under investigation but a combination of both produced the separation. Separations were performed on a linear polyacrylamide coated capillary. The ideal pH of the buffer was in the range of 5-7.

Antidepressive Agents, Tricyclic↗

PubMed1998

Enhanced separation of antidepressant drugs using a polymerized nonionic surfactant as a transient capillary coating.

The separation of seven structurally similar antidepressant drugs (amitriptyline, nortriptyline, imipramine, desipramine, protriptyline, doxepin, and nordoxepin) was achieved in under 15 min using a novel nonionic micelle polymer, poly(n-undecyl-alpha-D-glucopyranoside) (PUG) by use of capillary zone electrophoresis (CZE). Systematic studies with varying polymer concentration, pH, and percent organic modifier were conducted in order to find the optimum conditions for baseline separation of the seven tricyclic antidepressants. In addition, equations for capacity factor were used to estimate the extent of what was initially thought to be micelle analyte interaction. A series of calculations show that a modified CZE system (PUG-CZE) was the actual mode of separation. Thus, our study concluded that PUG functioned in a non-electrokinetic chromatography mode.

Antidepressive Agents↗

PubMedDate not supplied

Bethanidine sulfate in paroxysmal ventricular tachycardia: toxicity and antifibrillatory actions.

Programmed ventricular stimulation was used to test oral bethanidine sulfate in 10 patients with life-threatening ventricular arrhythmias. These patients had previously documented, recurrent, sustained ventricular tachycardia (VT) and/or ventricular fibrillation (VF) complicating stable heart disease. During control electrophysiologic studies, VT could be induced in all 10 patients: 6 with nonsustained VT, 3 with sustained VT, and 1 with VT/VF. After control, bethanidine 20-30 mg/kg was administered orally and beginning 60 minutes later, programmed ventricular stimulation was repeated. After bethanidine administration, VT could be induced in nine patients; in four, the VT was essentially unchanged from that induced during control studies. In four others, worse VT was induced after bethanidine. The remaining two patients had a potentially beneficial response to the drug. Bethanidine was poorly tolerated: seven patients had symptomatic orthostatic hypotension that persisted for several days despite concurrent protriptyline therapy. Furthermore, in four patients, spontaneous VT or VT/VF occurred 3-8 hours after the last dose. Nausea, vomiting, flushing, and blood pressure elevation were also noted. Bethanidine sulfate in the dosages used usually does not prevent the induction of VT by programmed ventricular stimulation and frequently causes serious toxicity. These findings suggest that the drug would be ineffective and poorly tolerated for long-term therapy in patients with serious ventricular arrhythmias.

Administration, Oral↗

PubMed1976

Electron beam ionization mass fragmentographic analysis of tricyclic antidepressants in human plasma.

A method for the measurement, in human plasma, of all tertiary and secondary tricyclic antidepressants prescribed in the United States is described. The method uses electron beam ionization GLC-mass spectrometry, employing a computer-controlled multiple-ion detector. This method, mass fragmentography, is used with internal standards for each drug. Plasma levels to as low as 10 ng/ml of the following drugs can be measured: amitriptyline, nortriptyline, doxepin, desmethyldoxepin, imipramine, desipramine, and protriptyline. Deuterium-labeled amitriptyline and imipramine are used as internal standards for those two drugs; for the other drugs, deuterated amitriptyline, nortriptyline, desmethyldoxepin, or desipramine is used. The method can measure up to 15 samples/hr, making it practical for large-scale studies of these drugs in patients. Spectra of each drug and examples of their analysis are given.

Adult↗

PubMed1978

Analysis of tricyclic antidepressants in human plasma by GLC--chemical-ionization mass spectrometry with selected ion monitoring.

A method is described for the analysis of amitriptyline, doxepin, imipramine, nortriptyline, desmethyldoxepin, desipramine, and protriptyline in human plasma utlizing GLC-chemical-ionization mass spectrometry with selected ion monitoring. The assay is highly specific and is quantitative to at least 1 ng/ml with a standard error typically less than 5%. Representative concentrations of the parent compounds and their monodemethylated metabolites, as meeasured in plasma samples from patients under treatment with tertiary amine tricyclic antidepressants, are given.

Antidepressive Agents, Tricyclic↗

PubMedDate not supplied

Modulation by antidepressant drugs of CNS postsynaptic alpha 2-adrenoceptors mediating mydriasis in the rat.

The modulation of central postsynaptic alpha 2-adrenoceptors mediating mydriasis in the pentobarbitone-anaesthetized rat was studied after the acute and short/long-term administration of antidepressant treatments (drugs, electroshock). The acute administration of cyclic antidepressant drugs (2.5 mg/kg, i.v.) resulted in different mydriatic effects (amitriptyline greater than protriptyline approximately imipramine greater than clomipramine greater than nortriptyline greater than desipramine approximately maprotiline) which were attenuated (17-55%) by idazoxan (1 mg/kg, i.v., 5 min) and reserpine (5 mg/kg, s.c., 18 h) indicating that, besides the well-known anticholinergic properties of some of these drugs, their mydriatic effects are due in part to activation of alpha 2-adrenoceptors (through endogenous noradrenaline). In contrast, the long-term (7-21 days) but not the short-term (1-4 days) administration of cyclic antidepressant drugs (2.5-10 mg/kg, i.p.), MAO inhibitors (1 mg/kg, i.p.), lithium (20 mg/kg, i.p.) and electroshock (150 mA, 63 Hz, 8 ms during 300 ms) resulted in dose- and time-dependent reductions of the dose-pupillary response curve for clonidine (ED50 increased 1.2-2.0-fold; Emax decreased by 9-29%) which indicated desensitization of postsynaptic alpha 2-adrenoceptors. In line with these findings, treatment for 7 days with clonidine (0.1-1 mg/kg, i.p.) or idazoxan (3-10 mg/kg, i.p.) led to an opposite modulation (down- and up-regulation) of the dose-pupillary response curve for clonidine. The main results demonstrate that cyclic antidepressant drugs, through indirect mechanisms which involve endogenous noradrenaline, can modulate the sensitivity of brain postsynaptic alpha 2-adrenoceptors mediating mydriasis in the rat.

Anesthesia↗

PubMed1976

Effects of thymoleptics on behaviour associated with changes in brain dopamine. I. Potentiation of dopa-induced gnawing of mice.

The thymoleptics imipramine, desipramine, protriptyline, nortriiptyline, chlorimipramine and amitriptyline all potentiate gnawing of mice induced by Dopa following decarboxylase inhibitior Ro 4-4602. The gnawing behavior is probably associated with the increase in brain dopamine resulting from this treatment. Thymoleptics also affect other types of behaviour associated with brain dopamine. The relevance of these effects to clinical antidepressive effect and their possible utilization for preclinical screening tests is discussed.

Animals↗