Porous poly(butyl methacrylate-co-ethylene dimethacrylate), poly(benzyl methacrylate-co-ethylene dimethacrylate), and poly(styrene-co-divinylbenzene) monoliths have been prepared on the top of standard sample plates used for matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry and the modified plates were used for laser desorption/ionization mass spectrometry (LDI-MS). The hydrophobic porous surface of these monoliths enables the transfer of sufficient energy to the analyte to induce desorption and ionization prior to TOFMS analysis. Both UV and thermally initiated polymerization using a mask or circular openings in a thin gasket have been used to define spot locations matching those of the MALDI plates. The desorption/ionization ability of the monolithic materials depends on the applied laser power, the solvent used for sample preparation, and the pore size of the monoliths. The monolithic matrices are very stable and can be used even after long storage times in a typical laboratory environment without observing any deterioration of their properties. The performance of the monolithic material is demonstrated with the mass analysis of several small molecules including drugs, explosives, and acid labile compounds. The macroporous spots also enable the archiving of samples.
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The present status of the relationship between blood plasma concentrations of tricyclic antidepressants and clinical outcome is reviewed. Plasma levels of imipramine, desmethylimipramine and nortriptyline are generally accepted as useful clinically but it is more difficult to establish a well-defined relationship between clomipramine and amitriptyline blood levels and clinical outcome. These assays are clinically relevant, particularly in cases of treatment failure, but also in the treatment of the elderly and of overdosage. The technical problems of the assay have practically been solved with the development of new analytic methods.
The present study aimed to evaluate the action of NOP receptor antagonists in helpless mice.
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The relative contribution of cytochrome P450 3A (CYP3A) to the oral clearance of amitriptyline in humans has been assessed using a combination of in vitro approaches together with a clinical pharmacokinetic interaction study using the CYP3A-selective inhibitor ketoconazole. Lymphoblast-expressed CYPs were used to study amitriptyline N-demethylation and E-10 hydroxylation in vitro. The relative activity factor (RAF) approach was used to predict the relative contribution of each CYP isoform to the net hepatic intrinsic clearance (sum of N-demethylation and E-10 hydroxylation). Assuming no extrahepatic metabolism, the model-predicted contribution of CYP3A to net intrinsic clearance should equal the fractional decrement in apparent oral clearance of amitriptyline upon complete inhibition of the enzyme. This hypothesis was tested in a clinical study of amitriptyline (50 mg, p.o.) with ketoconazole (three 200 mg doses spaced 12 hours apart) in 8 healthy volunteers. The RAF approach predicted CYP2C19 to be the dominant contributor (34%), with a mean 21% contribution of CYP3A (range: 8%-42% in a panel of 12 human livers). The mean apparent oral clearance of amitriptyline in 8 human volunteers was decreased from 2791 ml/min in the control condition to 2069 ml/min with ketoconazole. The average 21% decrement (range: 2%-40%) was identical to the mean value predicted in vitro using the RAF approach. The central nervous system (CNS) sedative effects of amitriptyline were slightly greater when ketoconazole was coadministered, but the differences were not statistically significant. In conclusion, CYP3A plays a relatively minor role in amitriptyline clearance in vivo, which is consistent with in vitro predictions using the RAF approach.
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We report a case of an 8-year-old girl who presented to the emergency department with depressed mental status and seizure-like movements. An extensive workup was pursued to evaluate the cause of her mental status, which only revealed a positive urine toxicology screen for TCA. Quantified serum levels of amitriptyline were 121 ng/mL (therapeutic range, 50-300 ng/mL) and nortriptyline were 79 ng/mL (therapeutic range 70-170 ng/mL), 18 hours after onset of symptoms. Subsequent history obtained after her mental status returned to normal revealed that she had ingested amitriptyline at a dose of 0.8 mg/kg.
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Major depression is thought to be underdiagnosed and undertreated in primary medical care facilities. The authors conducted a clinical trial that included a three-phase assessment so only ambulatory medical patients judged eligible for treatment of this disorder in medical settings were recruited. In addition to administering the Center for Epidemiologic Studies-Depression scale and the Diagnostic Interview Schedule's (DIS) Depression section, the psychiatrists evaluated the DIS-positive patients. This third assessment determined that clinical characteristics of DIS-positive patients were such that 70% of the patients could be treated for major depression in a primary care setting, 13% should probably be referred to a mental health facility, and 17% were experiencing conditions other than major depression.
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The isolated anococcygeus muscle of the rat was used to study the effect of temperature on noradrenaline-induced contraction. The preparation was suspended in an organ bath containing Krebs bicarbonate solution for isometric tension recording. A decrease of the bath temperature from 37 degrees C to 20 degrees C (cooling) produced an increase in tissue sensitivity to noradrenaline, as reflected in a 5.37-fold leftward shift in the concentration-response curve, and increased the maximum contractile response to this agonist (14.3%). Cooling had no effect on tissue sensitivity to a selective alpha 1-adrenoceptor agonist, methoxamine, but increased (12.4%) the maximum contraction to a similar extent to that to noradrenaline. 6-Hydroxydopamine pretreatment or nortriptyline (1 mumol/l) induced a leftward shift of the noradrenaline concentration-response curve at 37 degrees C, and profoundly inhibited the potentiating effect of cooling on tissue sensitivity to the catecholamine; the effect of cooling on the maximum response was unaffected. The affinity of noradrenaline or methoxamine for alpha 1-adrenoceptors at 37 degrees C, determined from its dissociation constant (KA), was not significantly different from that at 20 degrees C. KA values were determined by use of irreversible antagonism with phenoxybenzamine. On the other hand, diltiazem at concentration of 3 mumol/l, which almost completely abolished the calcium ion-induced contraction of the potassium ion-depolarized muscle, caused only slight inhibition in the concentration-response curve for noradrenaline. The contractile responses to Ca2+ of the K+-depolarized muscle and of the tissue incubated in Ca2+ -free (EGTA 0.1 mmol/l) Krebs solution containing diltiazem and noradrenaline were both depressed by cooling.(ABSTRACT TRUNCATED AT 250 WORDS)
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Amitriptyline (AT), one of the tricyclic antidepressants, is still widely used for the treatment of the depression and control of anxiety states and panic disorders in the developing countries.
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The uptake of lidocaine, methyllidocaine, bupivacaine, etidocaine was studied in rat lung slices at different pH-values. The accumulation of the quaternary analogue, methyllidocaine, was not changed in the pH interval 7.0--8.0. The uptake of the three other substances was about 3--4 times lower at pH 7.0 than at pH 8.0. The rank order of distribution at a fixed cation/base ratio was bupivacaine greater than etidocaine greater than lidocaine. Interactions between lidocaine and other substances were studied in lung slices and in isolated perfused lungs. Bupivacaine and nortriptyline counteracted the accumulation of 14C-lidocaine in lung slices in a dose-dependent manner. Nortriptyline was more effective than bupivacaine. In isolated perfused lung, bolus injections of nortriptyline and lidocaine rapidly displaced 14C-lidocaine from the tissue. In this study we suggest that the base form of local anaesthetics accumulate in the lung tissue, while the cationic form binds to accessible binding sites in the cell membranes.
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Results suggest that elderly bereaved depressed individuals demonstrated ADL difficulty that responds positively to psychopharmacologic intervention.
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Plasma concentrations of nortriptyline have been assayed in four subjects after intravenous infusion of 57 mg nortriptyline hydrochloride. The data were evaluated according to a two compartment open model. The calculated best-fitting curves were in good agreement with the experimental data, better than could be expected from a simpler model. This justifies the assumption that the kinetics of nortriptyline in man may be described by this model with an appropriate input function. The data permitted estimation of all the parameters of the model. The meaning of the parameters is discussed, particularly in relation to individual variation.
The BENESCO-model was used to estimate the long-term health and economic benefits of smoking cessation for a cohort of smokers making a one-time quit attempt. The cohort represented the population of Dutch smokers with respect to gender, age, and prevalence of the smoking-related diseases included in the model: COPD, lung cancer, CHD, stroke, and asthma exacerbations. The model compared the cumulative incidence of smoking-related diseases, (quality-adjusted) life years, intervention costs, and direct medical costs between the cohort treated with varenicline and the same cohort either untreated (unaided cessation) or treated with bupropion, nortriptyline or NRT. The time horizon was lifetime. Future costs were discounted at 4%, health outcomes at 1.5%.
1. Various clinical and experimental reports indicate that tricyclic antidepressant drugs are specially useful in the treatment of chronic and acute pain conditions. The present work was aimed to study the mechanisms implicated in the antinociceptive response induced by these antidepressants on different experimental models of pain in mice, and particularly the role played by noradrenergic, serotonergic and opioidergic influences. 2. Electrical stimulation of the tail and formalin tests were used to evaluate pain perception in mice acutely treated with different antidepressants (imipramine, desipramine, amitriptyline, nortriptyline, clomipramine and desmethylclomipramine). Antinociceptive responses were more potent in formalin test than in tail electrical stimulation test. 3. These antinociceptive effects were inhibited by naloxone (2 mg/Kg, i.p.), alpha-methyl-p-tyrosine (200 mg/Kg) and p-chlorophenylalanine (600 mg/Kg). Naloxone elicited the same effectivity to inhibit antinociceptive responses induced by tricyclic antidepressants in both tail electrical stimulation and formalin tests. alpha-methyl-p-tyrosine and p-chlorophenylalanine were more effective on antinociceptive responses induced on formalin than in tail electrical stimulation test. 4. These results suggest that tricyclic antidepressants produce antinociception partly via the participation of the endogenous opioid system and partly by further activating noradrenergic and serotonergic pathways. Moreover, the analgesic responses and the mechanisms implicated were dependent of the analgesimeter test used.
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We conclude that nortriptyline led to an increased short-term cessation rate compared with placebo. In addition, there were significant, but relatively small, reductions in withdrawal symptoms. Nortriptyline may represent a new therapeutic approach to smoking cessation.