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These findings are in part different from those obtained with local anesthetics and suggest that interference with G protein-coupled signaling might explain, in part, the analgesic properties of some antidepressants. However, use of antidepressants in high concentrations may be associated with cellular toxicity.
Conjugation of racemic E-10-hydroxynortriptyline (E-10-OH-NT) with glucuronic acid was studied in the liver microsomal fraction of rats and humans. The diastereomeric glucuronides of E-10-OH-NT were resolved and quantitated by HPLC. Only the (+)-enantiomer was glucuronidated in liver microsomes from humans. Rat liver microsomes catalyzed the formation of both glucuronides. Phenobarbital pretreatment of rats increased the glucuronidation of both enantiomers about five-fold. The formation rate of (+)-E-10-OH-NT glucuronide varied from 5.5 to 33.2 pmol/mg x min, in microsomes from 13 humans. High activity was found in individuals previously treated with pentobarbital. Inhibition experiments with human liver microsomes showed that amitriptyline is a potent competitive inhibitor of (+)-E-10-OH-NT glucuronidation. p-Nitrophenol, paracetamol and 2-hydroxydesipramine also inhibited this reaction.
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Both milnacipran and duloxetine were potent inhibitors of serotonin and norepinephrine uptake. Unlike duloxetine and venlafaxine, milnacipran appears serotonin transporter selective in binding (ratio = 2.61) and norepinephrine transporter selective in uptake (ratio =.45).
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In this randomized, single-blind clinical trial we compared the efficacy of parenteral vitamin B(12) and nortriptyline, for symptomatic improvement of pain, paresthesia, burning, freezing, stabbing and electrical sensation. Changes in nerve conduction parameters of amplitude, duration and latency were also compared.
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This was a 2 (medical management vs psychological intervention) x 3 (bupropion vs nortriptyline vs placebo) randomized trial. Participants were 220 cigarette smokers. Outcome measures were biologically verified abstinence from cigarettes at weeks 12, 24, 36, and 52.
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Hollow fibre liquid-phase microextraction (LPME) and desorption electrospray ionization mass spectrometry (DESI-MS) were evaluated for the identification and quantification of basic drugs in human urine samples. The selective extraction capabilities of three-phase LPME provided a significant reduction in the matrix effects otherwise observed in direct DESI-MS analysis of urine samples. Aqueous LPME extracts (in 10 mM HCl) were deposited on porous Teflon, dried at room temperature, and the dried spots were then analyzed directly with DESI-MS in full scan mode. Pethidine, diphenhydramine, nortriptyline, and methadone were used as model compounds for identification, and their limits of identification were determined to be 100, 25, 100, and 30 ng/mL, respectively. In a reliability test with 19 spiked urine samples, 100% of the positive samples containing the model drugs in concentrations at or above the limit of identification were identified. Diphenhydramine was used as a model compound for quantitative analysis with diphenhydramine-d(5) as an internal standard. The calibration curve was linear in the range 50-2000 ng/mL (R(2) = 0.992) with a limit of quantification at approximately 140 ng/mL. The intra- and inter-day relative standard deviations were <9.5%. In a reliability test with six spiked urine samples, deviations between the measured and the true values for diphenhydramine were in the range 0.2-22.9%.
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Using data from a therapeutic drug monitoring database, kinetic interactions between the neuroleptics zuclopenthixol and perphenazine and tricyclic antidepressives were studied. Out of 290 patients monitored for amitriptyline and 611 patients monitored for nortriptyline, 77 patients were comedicated with perphenazine and 50 patients with zuclopenthixol. Comedication with perphenazine increased the median steady-state serum concentration to daily dose ratio (C/D) of nortriptyline by 30-45%, whereas the median C/D of amitriptyline was unaffected. On the contrary, median C/D values of nortriptyline and amitriptyline were not significantly influenced by comedication with zuclopenthixol. Thus, in accordance with previous studies, perphenazine increases the concentration of tricyclic antidepressives to a moderate extent. Zuclopenthixol, on the other hand, does not exert any impact under routine therapeutic drug monitoring, even though the drug is known to partly depend on metabolism by the isozyme cytochrome P450 2D6.
Depression is a serious complication of stroke. Although tricyclic antidepressants have well-established efficacy in the treatment of functional depression, they are not often used to treat depression following stroke. Studies have identified two types of depression in patients following stroke: major depression and minor depression. Longitudinal studies indicate that untreated major depression may last about 1 year, whereas untreated minor depression may last more than 2 years. Patients with depression who are not treated with antidepressant medication have been found to do more poorly on several measures of physical and cognitive rehabilitation than depressed patients who are treated. Two double-blind drug treatment studies of depression following stroke have been done. Although adverse side effects were reported in both studies, serious side effects were no more common in the active drug group than in the placebo group. Both studies, however, reported significantly better outcome, measured by depression scores or activities of daily living, in patients treated with nortriptyline or trazodone than in placebo-treated controls. Thus, although the use of antidepressant medication requires caution, the recognition and treatment of depression in patients who have had a stroke may result in a significant enhancement of both physical and cognitive recovery as well as emotional state.
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Five academic medical centers and their outpatient psychiatry clinics.
In a double-blind parallel group study, thirty-two patients suffering from a primary affective disorder received either dothiepin or amitriptyline. Serum concentrations of total dothiepin plus northiaden or amitriptyline and nortriptyline were estimated. A similar therapeutic response was seen with both drugs but there was no correlation with serum concentrations of amitriptyline or nortriptyline, whereas serum dothiepin correlated positively with clinical response.
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We investigated eighteen unmedicated patients with major depressive disorder and eighteen matched healthy controls. Electrocardiogram and respiratory signals were obtained during a twenty minute resting period. Time- and frequency based parameters of HRV, respiratory sinus arrhythmia (RSA), approximate entropy of heart rate (ApEn(RR)) and respiratory rate (ApEn(Resp)) were calculated. Additionally, cross-ApEn between RR-intervals and respiration time series was determined, reflecting coupling of both signals.
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In this paper, we report baseline measures of red cell folate that were collected during a randomized trial of 107 patients with major depression. Red cell folate levels were examined for association with percentage improvement in depressive symptoms during treatment with fluoxetine or nortriptyline. The influences of possible confounding factors were assessed.
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Effective treatment of severe asthma is a major unmet need because patients' symptoms are not controlled on maximum treatment with inhaled therapy. Asthma symptoms can be poorly controlled because of poor adherence to controller therapy, and this might be addressed by using combination inhalers that contain a corticosteroid and long-acting β(2)-agonist as reliever therapy in addition to maintenance treatment. New bronchodilators with a longer duration of action are in development, and recent studies have demonstrated the benefit of a long-acting anticholinergic bronchodilator in addition to β(2)-agonists in patients with severe asthma. Anti-IgE therapy is beneficial in selected patients with severe asthma. Several new blockers of specific mediators, including prostaglandin D(2), IL-5, IL-9, and IL-13, are also in clinical trials and might benefit patients with subtypes of severe asthma. Several broad-spectrum anti-inflammatory therapies that target neutrophilic inflammation are in clinical development for the treatment of severe asthma, but adverse effects after oral administration might necessitate inhaled delivery. Macrolides might benefit some patients with infection by atypical bacteria, but recent results are not encouraging, although there could be an effect in patients with predominant neutrophilic asthma. Corticosteroid resistance is a major problem in patients with severe asthma, and several molecular mechanisms have been described that might lead to novel therapeutic approaches, including drugs that could reverse this resistance, such as theophylline and nortriptyline. In selected patients with severe asthma, bronchial thermoplasty might be beneficial, but thus far, clinical studies have not been encouraging. Finally, several subtypes of severe asthma are now recognized, and in the future, it will be necessary to find biomarkers that predict responses to specific forms of therapy.
The affinity and selectivity of milnacipran, duloxetine, venlafaxine, citalopram, amitriptyline, and nortriptyline were determined for the human serotonin, norepinephrine, and dopamine transporters.
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To assess the effectiveness of antidepressants in the treatment of tinnitus and to ascertain whether any benefit is due to a direct tinnitus effect or a secondary effect due to treatment of concomitant depressive states.
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The safety of tricyclic antidepressants in cardiac transplant recipients has not been established. The author used nortriptyline to treat major depressive episodes in eight cardiac transplant recipients. Nortriptyline therapy was associated with increased QRS interval and heart rate but did not significantly affect other hemodynamic or ECG variables or cyclosporine dose requirements. It appears that nortriptyline may be used safely in depressed cardiac transplant patients.
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Three separate cases of child administration of prescription drugs are described. Following liquid-liquid extraction, high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to identify and quantify methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenyl-1-pyrrolidine (EDDP), tramadol, amitriptyline, and nortriptyline in children's hair. The children's age ranged from 14 months to 7 years; in all three cases, the drug in question was detected in more than one section of hair. Methadone was detected in the concentration range of 0.65-0.99 and 0.04-0.4 ng/mg; tramadol was detected in the concentration range of 1.5-2.2 ng/mg; amitriptyline and nortriptyline were detected in the concentration range of 0.18-1.06 and 0.38-2.0 ng/mg, respectively. In each case, the children's parents admitted to or were found guilty of drug administration to the child. These cases demonstrate the added value of hair testing and emphasize the importance of using hair samples to complement conventional analyses.
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Major depressive disorder is one of the most common mental disorders in children and adolescents. However, whether to use pharmacological interventions in this population and which drug should be preferred are still matters of controversy. Consequently, we aimed to compare and rank antidepressants and placebo for major depressive disorder in young people.
A systematic search revealed 82 children and adolescents treated naturalistically with NT. All patients with available EKGs and serum NT levels were included in the series with the exception of those receiving concomitant antipsychotic agents. Forty-three percent of subjects were receiving medications in addition to NT.
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Carriers of the 5-HTTLPR high-activity L-variant had higher prolonged cessation rates with bupropion than placebo [odds ratio (OR) = 1.44, 95% confidence interval (CI) = 1.01-2.05, P = 0.04]. Combining the three variants resulted in increased prolonged cessation rates for both bupropion and nortriptyline among carriers of four to five high-activity variants (bupropion: OR = 2.00, 95% CI =1.21-3.29, P = 0.01; nortriptyline: OR = 1.91, 95% CI = 1.02-3.56, P = 0.04). Similar results were found for point prevalence abstinence.
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Twenty-nine patients completed the study. Three patients withdrew and two were lost to follow-up. Among those who completed, 22 (75.9%; 64.7% of the intention-to-treat population) had greater than 50% headache reduction. The mean frequency of migraine days decreased from 10.2 to 6.2 per month. Use of rescue medications decreased from 2.3 to 1.2 days/week. Adverse events were reported by nine (31%) patients.
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Studies were carried out to evaluate the antidepressant action of Mianserin as related to noradrenergic and serotonergic systems. The actions of known tricyclic anti-depressants were comparatively investigated together with Mianserin (Organon). Self-stimulation behavior induced by stimulation of the posterior hypothalamus and substantia nigra was unaffected by Mianserin and imipramine, was suppressed with chlorpromazine and markedly enhanced by methamphetamine. The enhancement due to methamphetamine was suppressed by both Mianserin and chlorpromazine, and was potentiated by imipramine. Mianserin, imipramine and amitriptyline enhanced the rolling movements induced by methamphetamine in rats in which the nigro-striatal dopaminergic system was destroyed by the injection of 6-hydroxydopamine. The excitation induced by ldopa administration, of isocarboxazid treated mouse was enhanced by Mianserin in doses over 25 mg/kg and by imipramine or amitriptyline. The excitation of MK-486 treated mouse, induced by L-5HTP was suppressed by Mianserin, nortriptyline augmented the excitation. The head twitches induced by 5HTP were reduced to 1/10 in onset frequency by Mianserin, 1 mg/kg, p.o. The suppressive potency of amitriptyline in this model was less than 1/5 of that of Mianserin. The potentiation of the flexor reflex of hind limbs of the spinal rat induced by the pretreatment with isocarboxazid and l-dopa, 20 hours after the reserpinization, was markedly suppressed by Mianserin and amitriptyline, but unaffected by imipramine nor chlorimipramine. The potentiation of the extensor reflex of hind limbs of the spinal rat, induced 20 hours after the reserpinization by pretreatment with isocarboxazid and 5-HTP was suppressed by Mianserin, even in a low dose of 0.5 mg/kg, and by amitriptyline in a dose of 10 mg/kg. As far as monoaminergic mechanisms are concerned, the mode of antidepresant action of Mianserin is probably different from that of tricyclic antidepressants.
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Part I. Expert 4: The object of this study was to investigate the applicability of commercially available expert system shells to interpretation in forensic toxicology. Amitriptyline toxicology was selected as a pilot trial. Blood and tissue concentrations of amitriptyline and nortriptyline in fatal and nonfatal amitriptyline cases from the literature and from the Registry of Human Toxicology databank were entered into the expert system shell Expert 4 (Rivers, Elsevier). The statistical evaluation routines of the shell were used to search for patterns in the data. Successive changes in the data base were made to test for the influence of the data base on the conclusions. Finally the data base was refined, based on the evaluations, to strengthen the probabilities of the conclusions. The refined database was coupled with the Expert 4 inference engine to infer unknown parameters in the cases. The results of the expert system analysis were compared to known values and published expert opinions. The ratio of amitriptyline/nortriptyline and tissue levels of nortriptyline were found to be the most significant measures for interpretation of effect and time since ingestion. Part II. Computer Induction of Rules: Blood and tissue concentrations of amitriptyline and nortriptyline in fatal and nonfatal amitriptyline cases from the literature and from the Registry of Human Toxicology databank were entered into the expert system shell BEAGLE, (Forsyth, Machine Learning Research, Ltd.). The automatic rule induction routines of the shell were used to search for patterns in the data. The program expressed these patterns as numerical predictions or Boolean logic rules. The results were compared to those obtained with the Expert 4 (Rivers, Elsevier) using the same case knowledge base.(ABSTRACT TRUNCATED AT 250 WORDS)
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A total of 104 patients with acute stroke enrolled between 1991 and 1997 entered a double-blind randomized study comparing nortriptyline, fluoxetine, and placebo over 12 weeks of treatment. The majority of patients were recruited from a rehabilitation hospital in Des Moines, Iowa, but other enrollment sites were also used. Both depressed and nondepressed patients were enrolled to determine whether improved recovery could be mediated by mechanisms unrelated to depression. Nortriptyline in doses of 25 mg/day gradually increased to 100 mg/day or fluoxetine in doses of 10 mg/day gradually increased to 40 mg/day or identical placebo were given over 12 weeks. Response to treatment of depression for individual patients was defined as a greater-than-50% reduction in scores on the Hamilton Rating Scale for Depression and no longer fulfilling diagnostic criteria for major or minor depression. Improved recovery for a treatment group was defined as a significantly higher mean score from baseline to end of the treatment trial, compared with patients treated with placebo, on measures of impairment in activities of daily living and levels of cognitive and social functioning.
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Natural health products (NHPs), including melatonin, are widely used products. Despite the widespread assumption that all NHPs are safe, they contain pharmacologically active substances and can therefore have adverse effects and/or interact with pharmaceuticals.
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Included were 41 randomized trials involving 6019 patients: 80% of the patients had nociceptive pain (osteoarthritis, rheumatoid arthritis or back pain); 12%, neuropathic pain (postherpetic neuralgia, diabetic neuropathy or phantom limb pain); 7%, fibromyalgia; and 1%, mixed pain. The methodological quality of 87% of the studies was high. The opioids studied were classified as weak (tramadol, propoxyphene, codeine) or strong (morphine, oxycodone). Average duration of treatment was 5 (range 1-16) weeks. Dropout rates averaged 33% in the opioid groups and 38% in the placebo groups. Opioids were more effective than placebo for both pain and functional outcomes in patients with nociceptive or neuropathic pain or fibromyalgia. Strong, but not weak, opioids were significantly superior to naproxen and nortriptyline, and only for pain relief. Among the side effects of opioids, only constipation and nausea were clinically and statistically significant.