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Atopic eczema (AE) is a chronic inflammatory skin disease with strong itching as the prominent symptom. The pathology of itch is still in discussion, but acetylcholine (ACH) seems to be a relevant pruritogenic mediator in AE. Since efficient benefit on pruritus and excoriations has been demonstrated with tricyclic agents, we investigated how the topical treatment with doxepin (5%, Boehringer Standard, Mannheim, Germany), a tricyclic compound with anticholinergic properties, may influence ACH induced itch and cutaneous sensations (erythema, wheal, axonreflex flare).
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Fatigue, pain, and emotional upset remain the most common problems affecting humanity and for which we still know so very little. Chronic fatigue syndrome is most likely a number of as yet unproven various undifferentiated illnesses that are exceedingly difficult to distinguish from depression. There probably is a subset of patients with CFS who do have true immune dysfunction and persistent viral infection, and this particular group of patients should be further investigated. This group is the minority of patients who present with chronic fatigue. Although chronic fatigue syndrome may be the result of an organic illness in psychologically susceptible individuals, it remains most important to assess underlying psychologic factors that then need to be addressed. These factors may very likely have a profound effect on immune function, but more research is needed in this area. The diagnostic evaluation of patients with chronic fatigue syndrome should initially focus on causes for fatigue other than Epstein-Barr viral infection. Significant underlying medical conditions should be ruled out, and extensive inquiry into symptoms suggestive of depression and anxiety should be aggressively pursued. Treatment should include psychiatric support and counseling, good nutrition, adequate rest, and a gradual increase in activity. Anti-inflammatory agents and serotonin-replenishing antidepressants are helpful when muscle pain and tenderness are a major part of the patient's symptoms. Psychoactive drugs are useful when indicated. Low doses of antidepressants such as doxepin (10-25 mg at night) are generally well tolerated and have shown efficacy in numerous patients, although there are no reports of controlled trials.
The extensive research currently ongoing and previously reported regarding the use of clomipramine as a potential antineoplastic agent aimed at targeting the mitochondria of gliomas is promising.
The authors conducted a computerized search of MEDLINE for articles. The review includes studies in which serum levels of drugs were obtained from nursing infants.
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The presence of therapeutic drugs and their metabolites in the hair of psychiatric patients was investigated using gas chromatography (GC)-mass spectroscopy (MS)-electron ionization (EI) and GC-MS-chemical ionization (CI). In hair samples tested from 35 subjects, carbamazepine, amitriptyline, doxepin, trihexyphenidyl, chlorpromazine, chlorprothixene, trifluoperazine, clozapine and haloperidol were detected, with maximal concentrations of 22.5, 57.7, 183.3, 15.6, 68.2, 30.0, 36.8, 59.2 and 20.1 ng/mg of hair sample, respectively. Chlorpromazine and clozapine concentrations in the hair were found to be dependent on the dosage used and their correlation coefficients were 0.8047 (P<0.001, n=16) and 0.7097 (P<0.001, n=16), respectively. Segmental analysis demonstrated that there was a correlation between the history of subject's drug exposure and the distribution of drug along the hair shaft. Our results also show that drug analysis in hair may provide useful information about drug treatment and the history of usage, and that drugs can be detected in normally kept hair for at least 16 months after intake.
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In a parallel-group double-blind study, 142 outpatients with "mixed anxiety/depression" were treated with amoxapine or doxepin for 4 weeks in mean maximum daily dosages of 260 mg and 130 mg, respectively. Patients in both groups improved significantly during treatment as shown by changes in the Hamilton, Zung, Patient Self-Evaluation, and Clinical Global Impressions scales. From 24 to 31 of the 71 subjects receiving amoxapine and 16 to 24 of the 71 receiving doxepin were rated as "unquestionably improved" at the end of the treatment period on these scales. The time to achieve this degree of response was significantly shorter with amoxapine on both the CGI (p = .018) and Hamilton (p = .005) scales. Side effects were roughly comparable with two exceptions: doxepin-treated patients experienced more daytime drowsiness (p less than or equal to .05) and amoxapine-treated patients experienced more constipation (p less than or equal to .01).
Depression is a frequent disorder in the elderly that is often treated with antidepressants. It is generally accepted that, since all antidepressants are equally effective and the elderly are differentially more susceptible to side effects, those antidepressants with the least side effects should be preferentially used. The actual use of antidepressants in 1986 and 1989 was reviewed. We found that (1) contrary to expectation, antidepressants were prescribed in 1986 in quantities that were directly proportional to their side effects, ie, the greater the side effects, the more they were used, and (2) there was a distinct shift to a more thoughtful pattern in 1989. After reviewing the side effect profiles of antidepressants, it is recommended that amitriptyline and doxepin be avoided and that the initial choice be restricted to desipramine, nortriptyline, fluoxetine, and possibly bupropion. This simple change would reduce the relatively high rate of falls and fractures from antidepressant-induced hypotension and of delirium in the elderly. It would also promote increased compliance and greater efficacy, since larger doses will be tolerated.
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No case of significant toxicity occurred in the children who experienced unintentional TCA ingestions in this study population. None of the children in the study had toxicity at doses <5 mg/kg. Further study is necessary to develop clinical guidelines for the appropriate referral of unintentional ingestions of TCA involving children.
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The relative potential of various antidepressants to induce seizures while being used at therapeutic doses was studied by examining their action on spike activity in perfused guinea pig hippocampal slices. Within the range of concentration studied, imipramine, amitriptyline, nortriptyline, maprotiline, and desipramine tended to increase spike activity in a descending order of effect. Doxepin and nomifensine increased spike activity at lower concentrations, but reduced it at higher concentrations. Protriptyline and trimipramine reduced spike activity with increasing concentrations, whereas mianserin and viloxazine had little effect at any concentration. These findings are discussed in light of previous clinical and laboratory reports, and the clinical implications of these findings are presented. Finally, results with the antidepressants are compared with those previously observed with neuroleptics. On the basis of this comparison and a review of clinical reports, the assumption that neuroleptics have greater epileptogenic potential than antidepressants is questioned.
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HERG (human ether-à-go-go-related gene) encodes channels responsible for the cardiac rapid delayed rectifier potassium current, I(Kr). This study investigated the effects on HERG channels of doxepin, a tricyclic antidepressant linked to QT interval prolongation and cardiac arrhythmia. Whole-cell patch-clamp recordings were made at 37 degrees C of recombinant HERG channel current (I(HERG)), and of native I(Kr) 'tails' from rabbit ventricular myocytes. Doxepin inhibited I(HERG) with an IC(50) value of 6.5+/-1.4 microM and native I(Kr) with an IC(50) of 4.4+/-0.6 microM. The inhibitory effect on I(HERG) developed rapidly upon membrane depolarization, but with no significant dependence on voltage and with little alteration to the voltage-dependent kinetics of I(HERG). Neither the S631A nor N588K inactivation-attenuating mutations (of residues located in the channel pore and external S5-Pore linker, respectively) significantly reduced the potency of inhibition. The S6 point mutation Y652A increased the IC(50) for I(HERG) blockade by approximately 4.2-fold; the F656A mutant also attenuated doxepin's action at some concentrations. HERG channel blockade is likely to underpin reported cases of QT interval prolongation with doxepin. Notably, this study also establishes doxepin as an effective inhibitor of mutant (N588K) HERG channels responsible for variant 1 of the short QT syndrome.
The tricyclic antidepressant, doxepin, has been reported to be a potent local anesthetic in rat sciatic nerve blockade. We hypothesized that topical doxepin has significantly longer antinociception compared with control and intrathecally compared with bupivacaine. Solutions of 0.3 mL of doxepin at 50, 75, and 100 mM and control (only the vehicle solution) were applied as a patch to the shaved dorsal skin of rats. After a 2-h contact interval, the patch was removed, and the rats were tested by three sets of six pinpricks. Inhibition of withdrawal to pain and cutaneous trunci muscle reflex were graded. In the second investigation, 60 muL of doxepin at 10, 20, and 50 mM was injected through intrathecal catheters implanted in the lumbar region of rats, which were evaluated for motor function, proprioception, and nociception. Topical doxepin at concentrations of 75 mM and 100 mM was significantly more effective than control (P < 0.05). Complete recovery for the 100-mM concentration occurred at 60 h, although two of five rats demonstrated erythema and scarring. Intrathecally, 20 mM of doxepin was not significantly different for motor and proprioceptive function from 23 mM (0.75%) bupivacaine; however, neurotoxicity (defined as persistent neurological deficit) commenced at 50 mM.
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Significantly more patients were prescribed trazodone concurrently with bupropion and SSRI antidepressants than with TCAs. Trazodone was prescribed significantly more often for patients receiving an SSRI (p = 0.0001, chi 2 = 14.59) or bupropion (p = 0.0295, chi 2 = 4.74) than for patients receiving a TCA. There was no significant difference in trazodone use between the patients taking SSRIs or bupropion. The percent of patients that received an SSRI, bupropion, or a TCA in combination with trazodone was 27%, 23%, and 13%, respectively. Overall, 23.7% of patients received trazodone concomitantly with a primary antidepressant.
Binding of [3H]-pyrilamine to guinea-pig brain in vivo was studied and analyzed kinetically on the basis of a four-compartment model to establish the method of analysis for the in vivo binding. The pharmacological properties of the [3H]-pyrilamine binding in vivo were similar to those of the in vitro binding to brain homogenate. The distribution of histamine H1-receptors in dog brain, which was obtained by positron emission tomography (PET) with [11C]-pyrilamine or doxepin as a tracer, was in good correlation to that obtained by the in vitro binding method. We finally applied this in vivo binding method to a living healthy human to reveal the distribution of H1-receptor in the brain.
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Published trials support anticholinergic drugs as efficacious therapy for urinary urge incontinence, with predictable side effects. At present, these agents represent the pharmacological treatment of choice for this condition. The potential value of selected alternative drugs is underscored by the available data.
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A neural-network analysis has been applied to predict adverse or side effects of drugs using a database of antidepressant agents with known effects as well as input from a database with both patient parameters and drug information. A NeuralWork software package was implemented on a Macintosh Quadra 700 and trained on a database of ten drugs with known adverse effects. Another agent (not in the database) was used to test the ability of the network to predict the relative incidence of its side effects. Despite the small number of drugs used for training, the adverse effects of some drugs, such as doxepin, were predicted with 90-100% accuracy. These results indicate that neural-network analysis can be used to predict adverse drug effects for drugs within a given class and ultimately can be extended to include patient parameters to predict the mechanisms of action of drugs from relatively large databases.
Study of 16 antidepressants, (imipramine, amitryptyline, doxepin, dibenzepin, maprotilin, mianserin, nomifensin, trazodon, caroxazon, adepren, viloxazin, nialamid, asaphen, pyrazidol, inkasan, ftoracizin) in experiments on white mice have shown that the drugs tested may be arranged in the following way as regards the intensity of the mydriatic effect they produce: ftoracizin, amitryptyline, doxepin, imipramine, dibenzepin. Pyrazidol produces a very weak and short-lived mydriatic effect. Adepren, inkasan, caroxazon, adepren produce no mydriatic action.
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New therapeutic approaches in urticaria are presented with special respect to chronic and physical types including symptomatic dermographism, cholinergic urticaria, pressure and solar urticaria as well as vibratory angioedema. Clinical efficacies of several antihistamines (clemastine, astemizole, terfenadine, acrivastine, hydroxyzine, cimetidine), of ketotifen as a H1 receptor antagonist and mast cell stabilizer, of tricyclic antidepressant doxepin with H1 and H2 antagonist properties, of the calcium channel antagonist nifedipine, of topical corticosteroids and of the attenuated androgen danazol are presented. The data are specified by a detailed description of the design and particular conditions of the underlying study protocols.
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The aim of this review was to describe the sleep anomalies in depression, the effects of antidepressants on sleep, the usefulness of antidepressants in the treatment of primary insomnia and insomnia in other psychiatric disorders. Depression is associated with abnormalities in the sleep pattern that include disturbances of sleep continuity, diminished slow-wave sleep (SWS) and altered rapid eye movement (REM) sleep parameters. Although none of the reported changes in sleep are specific to depression, many of them, for example increased REM density and reduced amount of SWS in the first sleep cycle, are used as biological markers for research on depression and in the development of antidepressant drugs. An antidepressant should reverse abnormalities in the sleep pattern. However, many antidepressants can worsen sleep. Because of the activating effects of some drugs, for example imipramine, desipramine, fluoxetine, paroxetine, venlafaxine, reboxetine and bupropion, many patients who take them have to be co-prescribed with sleep-promoting agents to improve sleep. Even in maintenance treatment with activating antidepressants as many as 30-40% of patients may still suffer from insomnia. Antidepressants with sleep-promoting effects include sedative antidepressants, for example doxepin, mirtazapine, trazodone, trimipramine, and agomelatine which promotes sleep not through a sedative action but through resynchronization of the circadian rhythm. Sedative antidepressants are frequently used in the treatment of primary insomnia, although not many double-blind studies have been provided to support such an approach to insomnia treatment. One exception is doxepin, which has been approved for the treatment of insomnia characterized by difficulties in maintaining sleep.
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Twenty healthy subjects took amitriptyline, doxepin, and placebo for 2 wk each in a double-blind crossover trial, and another 20 subjects similarly took nortriptyline, chlorimipramine, and placebo. The antidepressants were given three times daily in doses generally used for neurotic patients. The presence of antidepressants in tissues was checked with the tyramine pressor test. On the seventh and fourteenth days of each period, psychomotor skills (choice reaction, coordination, and attention) were measured after the administration of drugs in combination with an alcoholic or placebo drink. Dose-response graphs for the tyramine pressor effect were shifted to the right during the antidepressant treatment, indicating a blockade of the membrane pump in peripheral sympathetic terminals. This antityramine effect of antidepressants did not correlate with their psychomotor effects. No drug alone importantly impaired psychomotor skills. Amitriptyline in combination with alcohol increased cumulative choice reaction times, and doxepin in combination with alcohol increased both cumulative choice reaction times and inaccuracy of reactions. Coordination was impaired after both of these combinations on the seventh day. It seems as if doxepin and amitriptyline but not nortiriptyline or chlorimipramine, in combination with 0.5 gm/kg of alcohol, may be especially dangerous in driving.
Fluoxetine, imipramine, doxepine and opipramol after liquid-liquid extraction were separated by TLC on silica gel 60 GF254 by ascending and horizontal technique using suitable mobile phases. The substances were identified by UV irradiation at 254 nm and by spraying of Amelinka's reagnet (up to the amount 0.25 microgram fluoxetine and 0.05 microgram imipramine, doxepine and opipramol).
Future studies should use objective and subjective assessment. Focusing on efficacy, clinicians should favor benzodiazepine receptor agonists and classical benzodiazepines over antidepressants (including low-dose doxepin) for primary insomnia treatment, but the additional consideration of different side effect profiles can lead to alternative treatment decisions.
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Both preclinical and clinical evidence support the usefulness of antidepressants in chronic pain treatment. Monoamine uptake inhibitors influence the neurotransmissions of noradrenaline (NA) and/or serotonin (5-HT); their effect on nociception is thought to take place predominantly within the spinal cord. Antidepressant drugs seem to differ in their properties as analgesics and as thymoleptics. The present work is aimed at correlating the special mechanism of action of antidepressants in diminishing nocicepetion with the pharmacological profile of these drugs in clinical pain treatment. From a preclinical, experimental point of view, it can be expected, that mixed type uptake blockers should be superior to selective NA or 5-HT uptake inhibitors. The analgesic profile of antidepressants was established by a metaanalysis of clinical trials on the effect of these drugs, given alone or in combination with other analgetics, in chronic pain syndromes. 57 Clinical trials were separated into 5 groups according to their scientific quality:  placebo-controlled double-blind studies with high power;  placebo-controlled double-blind studies with low power; [3-4] open controlled studies or studies with historical controls;  case reports. A study was positive if the tested antidepressant was more effective than placebo or the compared drug or seemed beneficial with respect to the interval of its previous absence. The most effective antidepressants in chronic pain treatment only included unselective monoamine reuptake inhibitors in the following rank order: amitriptyline > clomipramine > or = desipramine > or = imipramine > or = doxepin. A statement about the appropriate dosage of these drugs in chronic pain treatment, however, must wait for properly conducted dose finding studies which include the measurement of plasma concentrations.
Medication was not tolerated by five patients. Twenty-six of 32 patients have experienced virtual total remission of symptoms (81%) and six patients had significant relief (19%). DOXCAM treatment resulted in a significant percent decrease in pain (65% versus 21%). Daytime frequency decreased from 17.6+/-5.7 to 11.3+/-3.6 voids while nocturia did not improve significantly. Twenty-three of the 26 patients who became symptom free and four of the six patients who showed significant improvement had a return of symptoms after cessation of therapy.
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Depressive symptoms may increase in a subgroup of obese individuals shortly after beginning a weight-reducing diet. Therefore an additional antidepressive medication should have a positive effect on the course and results of therapy. This hypothesis was tested in three different institutional settings, with identical therapeutic programs. In this study there were 23 obese women. Therapeutic strategies were concerned with an increase of self-control over eating behavior, the improvement of social skills, and the establishment of new problem-solving abilities. Doxepin was used as the anti-depressant in a double blind procedure. Our results seem to support the hypothesis of this study: depressive symptoms markedly increased soon after the beginning of weight-reduction; additional antidepressive medication helped to improve the symptoms and in the long term had a positive effect on the rate of weight loss.
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Six tricyclic antidepressants were tested for their ability to inhibit the binding of the histamine H1-receptor antagonist [3H]pyrilamine to membrane fractions from whole rat brain. Calculated inhibition constants (Ki) for the antidepressants were in the range of 2.6 x 10(-11) to 2.3 x 10(-7) M and correlated very well with their equilibrium dissociation constants derived from biological assays of the H1-receptor. Increasing the concentration of receptors present in the binding assay resulted in an overestimation of the calculated Ki's for doxepin, amitriptyline, and nortriptyline, but not for the lower affinity compounds of the series, imipramine, protriptyline, and desipramine. These results indicate: (1) the importance of receptor concentration in determining the potency of compounds which competitively inhibit, with very high affinity, the binding of a radioactively labeled ligand; (2) the need to correlate binding data with biological data.
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The anti-ulcer and antisecretory properties of 3-(dibenz[b,e] oxepin - 11(6H)-ylidene)-N,N- dimethylpropylamine hydrochloride (doxepin) were investigated in a series of acute experiments in rats with gastric and duodenal ulcer. Acute gastric ulceration induced by immobilisation and stress (waterbath), and by non-steroidal anti-inflammatory agents, was reduced by doxepin to the same extent as by pirenzepine and cimetidine. Doxepin and cimetidine showed a weak but significant effect against serotonin-induced ulcers in the rat, but pirenzepine did not. Duodenal ulcer caused by increased acid production (pentagastrin plus carbachol induced) was suppressed by pirenzepine, doxepin and cimetidine. The inhibition of gastric secretion by doxepin was studied in anaesthetised rats and conscious dogs. In the Lai rat, doxepin decreased carbachol-induced secretion of hydrochloric acid more effectively than cimetidine. Doxepin was as ineffective as pirenzepine against histamine- or pentagastrin-induced secretion. In the dog with gastric fistula, doxepin inhibited the acid production induced by 2-desoxy-d-glucose more effectively, and for longer periods, than that induced by pentagastrin or histamine. In the dog with a Heidenhain pouch, doxepin reduced the acid secretion stimulated by pentagastrin and carbachol, and by histamine, less effectively and for a shorter time, than cimetidine. The antagonism of doxepin to the action of carbachol in the rat and that of 2-desoxy-d-glucose in the dog appears to be an important factor in its mode of action. To inhibit the secretion of saliva and to delay intestinal transport, a dose of doxepin 3-10 times greater than that required for anti-ulcerative and secretion-inhibitory effects was necessary.
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Despite some evidence that neuroleptic medication is overused or misused in long-term care facilities for the elderly, there has been virtually no attention paid to the pattern of use of antidepressants in these facilities. All patients in long-term care in a geriatric hospital and a home for the aged who were receiving antidepressants were identified; 10.5% of the patients in the hospital and 12.7% in the home for the aged were receiving an antidepressant. The rate of use of antidepressants on the different units ranged from 0% to 26.8%. The most commonly prescribed antidepressant was doxepin followed by nortriptyline. The mean dose of antidepressant was 34.8 mg. Although depression was the most common reason for the prescription of an antidepressant (69% of patients receiving one), other reasons included pain, agitation, aggression, and insomnia. Patients had been receiving antidepressants for up to 10 years, with a mean duration of 32 months. The majority of patients (60%) had a history of depression predating their institutional admission. Patients receiving antidepressants were compared to a group not receiving antidepressants, who were matched for age, sex, unit, and attending physician. Patients receiving antidepressants were more likely to have a history of stroke (33.8% versus 16.9%). There was no significant difference between the two groups regarding the prevalence of dementia, Parkinson's disease, thyroid disease, malignant tumor, congestive heart failure, or diabetes mellitus. Prospective studies are required to determine the efficacy of antidepressants in this population and to identify factors that can predict a positive response to treatment.
Carbon-11 labeled metabolites in human plasma were analyzed by high-performance liquid chromatography during positron emission tomography (PET) studies using the dopamine D2 ligand [11C]YM-09151-2 as well as the histamine H1 ligands [11C]doxepin and [11C]pyrilamine. For all the three tracers, blood clearance of the radioactivity was extremely rapid after an i.v. injection. The plasma protein-binding of [11C]YM-09151-2 and [11C]doxepin had protective effects upon the metabolic alteration of the ligands, whereas [11C]pyrilamine was free from the protein-binding and immediately degraded. The degradation of [11C]doxepin was more rapid in epileptic patients on medication than in normal subjects. These results indicate that analysis of metabolites in the plasma is necessary to determine the accurate arterial input function for quantitative PET measurement.