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1. To determine kinetic parameters (Vmax, K(m)) for cytochrome P450 (CYP) mediated metabolic pathways, nonlinear least squares regression is commonly used to fit a model equation (e.g., Michaelis Menten [MM]) to sets of data points (reaction velocity vs substrate concentration). This method can also be utilized to determine the parameters for more complex mechanisms involving allosteric or multi-enzyme systems. Akaike's Information Criterion (AIC), or an estimation of improvement of fit as successive parameters are introduced in the model (F-test), can be used to determine whether application of more complex models is helpful. To evaluate these approaches, we have examined the complex enzyme kinetics of amitriptyline (AMI) N-demethylation in vitro by human liver microsomes. 2. For a 15-point nortriptyline (NT) formation rate vs substrate (AMI) concentration curve, a two enzyme model, consisting of one enzyme with MM kinetics (Vmax = 1.2 nmol min-1 mg-1, K(m) = 24 microM) together with a sigmoidal component (described by an equation equivalent to the Hill equation for cooperative substrate binding; Vmax = 2.1 nmol min-1 mg-1, K' = 70 microM; Hill exponent n = 2.34), was favoured according to AIC and the F-test. 3. Data generated by incubating AMI under the same conditions but in the presence of 10 microM ketoconazole (KET), a CYP3A3/4 inhibitor, were consistent with a single enzyme model with substrate inhibition (Vmax = 0.74 nmol min-1 mg-1, K(m) = 186 microM, K1 = 0.0028 microM-1). 4. Sulphaphenazole (SPA), a CYP2C9 inhibitor, decreased the rate of NT formation in a concentration dependent manner, whereas a polyclonal rat liver CYP2C11 antibody, inhibitory for S-mephenytoin 4'-hydroxylation in humans, had no important effect on this reaction. 5. Incubation of AMI with 50 microM SPA resulted in a curve consistent with a two enzyme model, one with MM kinetics (Vmax = 0.72 nmol min-1 mg-1, K(m) = 54 microM) the other with 'Hill-kinetics' (Vmax = 2.1 nmol min-1 mg-1, K' = 195 microM; n = 2.38). 6. A fourth data-set was generated by incubating AMI with 10 microM KET and 50 microM SPA. The proposed model of best fit describes two activities, one obeying MM-kinetics (Vmax = 0.048 nmol min-1 mg-1, K(m) = 7 microM) and the other obeying MM kinetics but with substrate inhibition (Vmax = 0.8 nmol min-1 mg-1, K(m) = 443 microM, K1 = 0.0041 microM-1). 7. The combination of kinetic modelling tools and biological data has permitted the discrimination of at least three CYP enzymes involved in AMI N-demethylation. Two are identified as CYP3A3/4 and CYP2C9, although further work in several more livers is required to confirm the participation of the latter.
Significant depressive disorders are present in approximately 30-40% of patients with Parkinson's disease (PD). Depressive symptoms are correlated with poor health-related quality-of-life (HRQoL) scores, and are the major determinant of HRQoL. Studies that have evaluated pharmacotherapy for depressive symptoms in PD have shown that there is substantial variability in outcomes. Recently, two double-blind, placebo-controlled studies showed the superiority of nortriptyline and desipramine versus placebo and selective serotonin reuptake inhibitors. The antidepressant effects of dopamine agonists have been explored mainly in open and non-controlled studies. In a 14-week randomized trial comparing pramipexole with sertraline in depressed patients without motor complications, the Hamilton Depression Rating Scale score decreased in both groups; however, in the pramipexole group, the proportion of patients who recovered was significantly higher. Recently, in the first 12-week double-blind placebo-controlled clinical trial in PD patients without motor fluctuations on stable levodopa treatment, pramipexole reduced depressive symptoms as measured by Beck Depression Inventory score, with a significant difference in efficacy in favour of pramipexole. These data suggest that pramipexole might represent an alternative to antidepressant drugs to treat depressive symptoms in PD without adding the risk of antidepressant adverse events, and avoid polypharmacy.
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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.
The anterior cingulate cortex has been implicated in depression. Results are best interpreted by considering anatomic and cytoarchitectonic subdivisions. Evidence suggests depression is characterized by hypoactivity in the dorsal anterior cingulate, whereas hyperactivity in the rostral anterior cingulate is associated with good response to treatment. The authors tested the hypothesis that activity in the rostral anterior cingulate during the depressed state has prognostic value for the degree of eventual response to treatment. Whereas prior studies used hemodynamic imaging, this investigation used EEG.
Myofascial pain syndrome (MPS) treatment is challenging with a high recurrence rate and still lacks a clear treatment frame. Therefore research on new, more efficient and long lasting effect treatment modalities is necessary. This study looked at the effects of intravenous laser therapy (IVL) and percutaneous low level laser (PLLL) in the management of shoulder MPS.
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14 patients who had a moderate or severe depressive episode according to ICD-10 and who had not sufficiently responded (< or = 25% reduction of the Hamilton depression scale) to 3-week monotherapy with amitriptyline (n = 9) or imipramine (n = 5) with daily doses between 125 and 200 mg/day, received 20 mg/day paroxetine additionally under steady state conditions.
New data on the pharmacology of tricyclic antidepressants (TCAs), their affinities for human cloned CNS receptors and their cytochrome P450 enzyme inhibition profiles, allow improved deductions concerning their effects and interactions and indicate which of the TCAs are the most useful. The relative toxicity of TCAs continues to be more precisely defined, as do TCA interactions with selective serotonin reuptake inhibitors (SSRIs). TCA interactions with monoamine oxidase inhibitors (MAOIs) have been, historically, an uncertain and difficult question, but are now well understood, although this is not reflected in the literature. The data indicate that nortriptyline and desipramine have the most pharmacologically desirable characteristics as noradrenaline reuptake inhibitors (NRIs), and as drugs with few interactions that are also safe when coadministered with either MAOIs or SSRIs. Clomipramine is the only available antidepressant drug that has good evidence of clinically relevant serotonin and noradrenaline reuptake inhibition (SNRI). These data assist drug selection for monotherapy and combination therapy and predict reliably how and why pharmacodynamic and pharmacokinetic interactions occur. In comparison, two newer drugs proposed to have SNRI properties, duloxetine and venlafaxine, may have insufficient NRI potency to be effective SNRIs. Combinations such as sertraline and nortriptyline may therefore offer advantages over drugs like venlafaxine that have fixed ratios of SRI/NRI effects that are not ideal. However, no TCA/SSRI combination is sufficiently safe to be universally applicable without expert knowledge. Standard texts (e.g. the British National Formulary) and treatment guidelines would benefit by taking account of these new data and understandings.
A total of 194 studies were found that were eligible for inclusion in our analysis. Of these, 177 focused on the treatment of MDD and 17 on the treatment of dysthymic disorder. We found that antidepressant therapy was significantly more effective than placebo in dysthymic disorder (risk ratio = 1.75; 95% CI, 1.49-2.04; P < .0001), while placebo response rates in dysthymic disorder trials were significantly lower compared to MDD trials (29.9% vs 37.9%, respectively; P = .042). Meta-regression suggested a statistically significant difference in the risk ratio of responding to antidepressants versus placebo when comparing studies either on dysthymic disorder or on MDD, suggesting a greater risk ratio for response in favor of antidepressant therapy versus placebo in patients with dysthymic disorder versus MDD (coefficient of -0.113; P = .007).
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A 54-year-old woman developed the characteristic features of TTS 44 hours following nortriptyline overdose. The admission ECG showed increased QRS duration rapidly reversible after sodium bicarbonate infusion. There was a minimal increase in troponin I level. The ECG performed at the time of chest pain revealed deeply negative T waves in leads I, II, III, aVF, V1 to V6 and remained abnormal at 5 weeks follow-up. In contrast, a complete recovery of left ventricular function was observed within one week.
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Recent studies show that there may be a relationship between plasma levels of tricyclic antidepressants and clinical response. A number of commercial laboratories have introduced methods for measuring these drugs in plasma for clinical practice, and each recommends a particular method by which plasma samples should be drawn, processed, and stored. In this pilot study we compare results from 4 laboratories, using identical plasma samples containing amitriptyline and nortriptyline, in order to assess interlaboratory reliability. While there is generally good agreement between our results and those of the commercial facilities, some large interlaboratory discrepancies are evident. Caution is advised when utilizing plasma tricyclic levels to monitor patient progress, and we suggest using a laboratory which is well established in this area.
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A simultaneous determination of 20 antidepressant drugs (imipramine, amitriptyline, desipramine, trimipramine, nortriptyline, clomipramine, amoxapine, lofepramine, dosulepin, maprotiline, mianserin, setiptiline, trazodone, fluvoxamine, paroxetine, milnacipran, sulpiride, tandspirone, methylphenidate and melitracen) in human plasma was developed using LC/MS with sonic spray ionization (SSI) method. These drugs showed good separation and sensitivity by LC-MS using an Inertsil C-8 column with methanol:10mM ammonium acetate (pH 5.0):acetonitrile (70:20:10) as mobile phase at 0.10 mL/min at 35 degrees C. Solid-phase extraction of these drugs added to the human plasma was performed with an Oasis HLB cartridge column. Recovery and limit of detection of these drugs were between 69 and 102% and between 0.03 and 0.63 microg/mL, respectively. The present procedure offers an easier and more convenient screening method for antidepressants, and will be useful for forensic toxicology investigations.
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Genotyping for CYP2D6 has the potential to predict differences in metabolism of nortriptyline. This information could optimize pharmacotherapy. We determined the costs and effects of routine genotyping for old aged Dutch depressed inpatients.